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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
Pediatric TB – more work needed, especially with HIV-coinfection
Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.
“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.
Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
TB and CLHIV
Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.
Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
Pediatric TB diagnosis
Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.
However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.
In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.
“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
Pediatric TB treatment
Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.
Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.
In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.
Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.
“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.
Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.
Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.
Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.
“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.
Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.
Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.
“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.
Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
TB and CLHIV
Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.
Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
Pediatric TB diagnosis
Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.
However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.
In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.
“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
Pediatric TB treatment
Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.
Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.
In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.
Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.
“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.
Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.
Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.
Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.
“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.
Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.
Despite recent advances in the diagnosis, treatment, and prevention of pediatric tuberculosis in children living with HIV (CLHIV) and HIV-exposed uninfected children (HEU), several unmet needs remain, including studies evaluating the feasibility of shortened TB treatment regimens.
“Children living with HIV contribute disproportionately to pediatric TB mortality rates, accounting for 16% of child TB deaths, and many cases are underdiagnosed and underreported,” said Nicole Salazar-Austin, MD, of Johns Hopkins University in Baltimore. She provided an update on pediatric TB prevention and treatment during an educational symposium at this year’s virtual Conference on Retroviruses & Opportunistic Infections.
Dr. Salazar-Austin summarized current diagnostics for pediatric TB and reviewed options for the prevention and treatment of TB in CLHIV and HEU.
TB and CLHIV
Presently, TB is the most common opportunistic infection among CLHIV, and those with severe immune suppression have a fivefold greater risk of TB disease. While antiretroviral therapy (ART) is highly protective against TB disease in CLHIV, only about 50% of eligible children receive ART.
Dr. Salazar-Austin explained that many individuals with TB/HIV coinfection are unaware of their coinfection and not receiving treatment. Despite recommendations, TB preventive therapy is poorly implemented in CLHIV, especially in high-burden settings.
Pediatric TB diagnosis
Smear microscopy, culture, and Xpert MTB/RIF Ultra are the main diagnostic modalities for pediatric TB. The Xpert MTB/RIF test is an automated PCR-based assay that simultaneously and rapidly detects Mycobacterium tuberculosis complex and resistance to rifampin. The test is currently recommended by the World Health Organization as the initial diagnostic method for presumptive TB cases in both adults and children.
However, under optimal conditions, only 40% of TB cases will be detected. This is in part due to limited implementation of sputum collection procedures, but recent evidence has shown that collection of multiple specimens improves sensitivity for both culture and Xpert MTB/RIF Ultra across all specimen types, Dr. Salazar-Austin explained.
In 2020, the WHO endorsed the use of stool samples for the diagnosis of pediatric pulmonary TB. Stool Xpert is an emerging alternative, noninvasive method for ruling in pediatric TB disease, and has shown sensitivity and specificity similar to that of Xpert MTB/RIF Ultra.
“TB diagnostics have limited sensitivity in children, and efforts are ongoing to maximize current diagnostics, but new diagnostics are needed,” said Dr. Salazar-Austin.
Pediatric TB treatment
Despite the high frequency of TB as an opportunistic infection in CLHIV, current data on co-treatment strategies are limited.
Dolutegravir-based regimens are the preferred first-line regimen for CLHIV. In June 2020, the Food and Drug Administration approved the dispersible dolutegravir tablet, and it is expected to become widely available in 2021.
In children with TB/HIV coinfection who receive dolutegravir and rifampicin, dolutegravir is typically dosed twice daily because of a known drug interaction, based on data from the ODYSSEY study. The WHO recommendations for treatment of pediatric TB/HIV coinfection were recently updated to reflect twice-daily dosing of dolutegravir.
Despite these new recommendations, data are currently limited, and observational pharmacokinetic studies evaluating twice daily dolutegravir with TB treatment in young children are needed.
“More work is needed to evaluate the drug-drug interactions and proper dosing of rifamycins with dolutegravir for the treatment and prevention of TB in CLHIV,” Dr. Salazar-Austin said.
Based on data from TBTC Study 31/ACTG A5349, high-dose rifapentine (a rifamycin) with moxifloxacin (a fluoroquinolone) was noninferior to rifapentine alone in newly diagnosed, culture positive, drug-susceptible TB in children 12 years and older.
Whether rifapentine and moxifloxacin (RPT-Mox) can be used in children under 12 years remains unknown, but future studies may help answer this question, Dr. Salazar-Austin noted. The FDA has restricted the use of fluoroquinolones in children because of a possible effect on cartilage development, she explained.
Furthermore, recent data from the SHINE trial suggested that shortened treatment regimens may hold promise for children with TB.
“While shortened TB treatment regimens hold promise, much work needs to be done in children to implement RPT-Mox, but the results from SHINE can be implemented rapidly,” Dr. Salazar-Austin said.
Dr. Salazar-Austin disclosed no conflicts of interest. The presentation was funded by NICHD, UNITAID, Fogarty Institute, and the IMPAACT network.
FROM CROI 2021
Are long-acting injectables the future of TB treatment?
Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.
“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.
He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
Current TB preventive therapies
Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.
While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
LAI drugs
LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.
The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.
Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.
“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.
Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.
Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.
Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
Considerations for development and implementation
“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.
Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.
Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.
“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).
“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.
“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.
While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.
Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.
Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.
“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.
He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
Current TB preventive therapies
Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.
While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
LAI drugs
LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.
The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.
Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.
“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.
Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.
Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.
Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
Considerations for development and implementation
“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.
Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.
Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.
“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).
“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.
“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.
While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.
Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.
Long-acting injectable (LAI) drug formulations represent a promising new strategy for the prevention and treatment of tuberculosis in women and children, according to an online presentation at the Conference on Retroviruses & Opportunistic Infections, held virtually.
“As a delivery strategy, LAIs hold the potential to unlock a vast chemical space of lipophilic compounds with very potent anti-TB activity that would otherwise not be developed due to poor predicted oral bioavailability,” explained presenter Eric Nuermberger, MD.
He summarized current preventive treatment options for TB and reviewed the potential impact of LAI formulations on TB therapy. In addition, he identified key challenges for future LAI development and proposed a new development path for clinical implementation.
Current TB preventive therapies
Despite widespread availability, the uptake of TB preventive therapy is poor and currently lags behind global targets. One key barrier to widespread uptake is the long duration of treatment, which may hinder patient adherence to therapy.
While shorter preventive regimens, such as 1 month of daily isoniazid plus rifapentine, show similar efficacy and higher completion rates, further shortening of therapy and reducing clinic visits are the most direct methods to increase adherence and treatment completion rates, Dr. Nuermberger said.
LAI drugs
LAI drug formulations allow for slow release of suitable drugs from a depot injected subcutaneously or intramuscularly.
The goal of LAI formulations is to free patients from the daily burden of oral administration. Other potential benefits include better adherence and efficacy, drug exposure, and the potential to overcome intrinsic poor oral bioavailability by bypassing the GI tract entirely.
Potential indications for LAIs include treatment of latent tuberculosis infection (LTBI), and as continuous therapy in people living with HIV in high-burden settings. There is also potential for treating younger children, such as household contacts, who have difficulty taking oral medications.
“We’ve already seen LAIs revolutionize other areas, such as psychiatry and contraception, and we appear to have another revolution in HIV prevention and treatment,” Dr. Nuermberger explained.
Not all existing TB drugs are suitable for LAI formulations, but drugs such as rifapentine, rifabutin, delamanid, and bedaquiline, show more promise than isoniazid or rifampin because of their physiochemical composition. Of all, bedaquiline may offer the best profile for LAI formulation, Dr. Nuermberger said.
Early proof-of-concept in vivo studies have shown potential use of LAI bedaquiline for TB prevention in both drug-sensitive and drug-resistant TB contacts. Translational PK modeling and simulation predicted that a 1-g intramuscular injection of LAI bedaquiline could maintain therapeutic plasma concentrations in humans for greater than 1 month.
Dr. Nuermberger noted that novel diarylquinoline-based therapies, currently in phase 1 studies, may be even better candidates for LAI-based TB preventive therapy. Early data suggests these compounds may be 10-20 times more potent and have a lower CV risk profile than that of bedaquiline.
Considerations for development and implementation
“Despite the promising potential of long-acting injectables for TB, we are still in the very early stages,” said Dr. Nuermberger.
Ensuring and optimizing acceptance of LAI formulations, especially in at-risk populations, will be very important, he explained. Early involvement of children and pregnant women in studies of who may benefit most from LAI drugs will also be essential.
Other important considerations include cost-effectiveness, particularly in at-risk and vulnerable populations. Furthermore, new dedicated research and development programs are needed to continue to develop more drug candidates suitable for LAI.
“Long-acting formulations hold enormous promise to be transformative for combating TB, through simplification of delivery and overcoming issues of adherence that can compromise success of current interventions,” said Andrew Owen, PhD, of the University of Liverpool (England).
“The ability to deliver an entire course of drug in a single visit promises to ensure missed doses don’t compromise outcomes or place unnecessary selective pressure in favor of drug resistance,” Dr. Owen said.
“Recent studies showing the value of one-month oral treatment regimens for LTBI make long-acting formulations seem more realistic and drugs such as long-acting bedaquiline put a one-shot regimen within reach,” Charles W. Flexner, MD, of Johns Hopkins University, Baltimore, said in an interview.
While no LAIs have been approved for TB, Dr. Nuermberger was optimistic that the recent success of LAI formulations for HIV treatment and prevention will catalyze further efforts in the TB landscape.
Dr. Nuermberger disclosed research support from Janssen Pharmaceuticals, TB Alliance, and the Gates Medical Research Institute. The presentation was sponsored by Janssen Pharmaceuticals, Johns Hopkins CFAR, NIH, Unitaid, and the TB Alliance.
FROM CROI 2021
DOACs offered after heart valve surgery despite absence of data
Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.
In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.
There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
DOACs discouraged in patients with mechanical or bioprosthetic valves
In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.
In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.
There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
Registry shows trends in prescribing
In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.
Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.
In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).
The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).
“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.
The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.
“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
Expert: One percent is ‘very small number’
David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.
“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.
“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.
“The trials that established the benefits of DOACs were all in nonvalvular atrial fibrillation, but this did not mean non–aortic stenosis; it meant non–mitral valvular. There have been articles written about how that has been misinterpreted,” said Dr. Cohen, director of clinical and outcomes research at the Cardiovascular Research Foundation and director of academic affairs at St. Francis Hospital, Roslyn, N.Y.
For his part, Dr. Kalra reported that he does not consider DOACs in patients who have undergone a surgical mechanical valve replacement. For bioprosthetic valves, he “prefers” warfarin over DOACs.
Overall, the evidence from the registry led Dr. Kalra to suggest that physicians should continue to “exercise caution” in using DOACs instead of warfarin after any surgical valve replacement “until randomized clinical trials provide sufficient evidence” to make a judgment about relative efficacy and safety.
Results of the study were published online as a research letter in Jama Network Open after Dr. Kalra’s presentation. Dr. Kalra and Dr. Cohen report no potential conflicts of interest.
Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.
In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.
There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
DOACs discouraged in patients with mechanical or bioprosthetic valves
In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.
In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.
There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
Registry shows trends in prescribing
In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.
Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.
In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).
The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).
“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.
The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.
“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
Expert: One percent is ‘very small number’
David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.
“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.
“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.
“The trials that established the benefits of DOACs were all in nonvalvular atrial fibrillation, but this did not mean non–aortic stenosis; it meant non–mitral valvular. There have been articles written about how that has been misinterpreted,” said Dr. Cohen, director of clinical and outcomes research at the Cardiovascular Research Foundation and director of academic affairs at St. Francis Hospital, Roslyn, N.Y.
For his part, Dr. Kalra reported that he does not consider DOACs in patients who have undergone a surgical mechanical valve replacement. For bioprosthetic valves, he “prefers” warfarin over DOACs.
Overall, the evidence from the registry led Dr. Kalra to suggest that physicians should continue to “exercise caution” in using DOACs instead of warfarin after any surgical valve replacement “until randomized clinical trials provide sufficient evidence” to make a judgment about relative efficacy and safety.
Results of the study were published online as a research letter in Jama Network Open after Dr. Kalra’s presentation. Dr. Kalra and Dr. Cohen report no potential conflicts of interest.
Direct oral anticoagulants (DOACs) are used in about 1% of patients undergoing surgical mechanical aortic and mitral valve replacement, but in up to 6% of surgical bioprosthetic valve replacements, according to registry data presented at CRT 2021.
In an analysis of the Society of Thoracic Surgery (STS) registry during 2014-2017, DOAC use increased steadily among those undergoing surgical bioprosthetic valve replacement, reaching a number that is potentially clinically significant, according to Ankur Kalra, MD, an interventional cardiologist at Akron General Hospital who has an academic appointment at the Cleveland Clinic.
There was no increase in the use of DOACs observed among patients undergoing mechanical valve replacement, “but even if the number is 1%, they should probably not be used at all until we accrue more data,” Dr. Kalra said.
DOACs discouraged in patients with mechanical or bioprosthetic valves
In Food and Drug Administration labeling, DOACs are contraindicated or not recommended. This can be traced to the randomized RE-ALIGN trial, which was stopped prematurely due to evidence of harm from a DOAC, according to Dr. Kalra.
In RE-ALIGN, which enrolled patients undergoing mechanical aortic or mitral valve replacement, dabigatran was associated not only with more bleeding events than warfarin, but also more thromboembolic events.
There are no randomized data comparing the factor Xa inhibitors rivaroxaban or apixaban to warfarin in heart valve surgery, but Dr. Kalra noted cautionary language is found in the labeling of both, “perhaps due to the RE-ALIGN data.”
Registry shows trends in prescribing
In the STS registry data, 193 (1.1%) of the 18,142 patients undergoing mechanical aortic valve surgery, 139 (1.0%) of the 13,942 patients undergoing mechanical mitral valve surgery, 5,625 (4.7%) of the 116,203 patients undergoing aortic bioprosthetic aortic valve surgery, and 2,180 (5.9%) of the 39,243 patients undergoing bioprosthetic mitral valve surgery were on a DOAC at discharge.
Among those receiving a mechanical value and placed on a DOAC, about two-thirds were on a factor Xa inhibitor rather than dabigatran. For those receiving a bioprosthetic value, the proportion was greater than 80%. Dr. Kalra speculated that the RE-ALIGN trial might be the reason factor Xa inhibitors were favored.
In both types of valves, whether mechanical or bioprosthetic, more comorbidities predicted a greater likelihood of receiving a DOAC rather than warfarin. For those receiving mechanical values, the comorbidities with a significant association with greater DOAC use included hypertension (P = .003), dyslipidemia (P = .02), arrhythmia (P < .001), and peripheral arterial disease (P < 0.001).
The same factors were significant for predicting increased likelihood of a DOAC following bioprosthetic valve replacement, but there were additional factors, including atrial fibrillation independent of other types of arrhythmias (P < .001), a factor not significant for mechanical valves, as well as diabetes (P < .001), cerebrovascular disease (P < .001), dialysis (P < .001), and endocarditis (P < .001).
“This is probably intuitive, but patients who were on a factor Xa inhibitor before their valve replacement were also more likely to be discharged on a factor Xa inhibitor,” Dr. Kalra said at the virtual meeting, sponsored by MedStar Heart & Vascular Institute.
The year-to-year increase in DOAC use among those undergoing bioprosthetic valve replacement over the study period, which was a significant trend, was not observed among those undergoing mechanical valve replacement. Rather, the 1% proportion remained stable over the study period.
“We wanted to look at outcomes, but we found that the STS database, which only includes data out to 30 days, is not structured for this type of analysis,” Dr. Kalra said. He was also concerned about the limitations of a comparison in which 1% of the sample was being compared to 99%.
Expert: One percent is ‘very small number’
David J. Cohen, MD, commented on the 1% figure, which was so low that a moderator questioned whether it could be due mostly to coding errors.
“This is a very, very small number so at some level it is reassuring that it is so low in the mechanical valves,” Dr. Cohen said. However, he was more circumspect about the larger number in bioprosthetic valves.
“I have always thought it was a bit strange there was a warning against using them in bioprosthetic valves, especially in the aortic position,” he said.
“The trials that established the benefits of DOACs were all in nonvalvular atrial fibrillation, but this did not mean non–aortic stenosis; it meant non–mitral valvular. There have been articles written about how that has been misinterpreted,” said Dr. Cohen, director of clinical and outcomes research at the Cardiovascular Research Foundation and director of academic affairs at St. Francis Hospital, Roslyn, N.Y.
For his part, Dr. Kalra reported that he does not consider DOACs in patients who have undergone a surgical mechanical valve replacement. For bioprosthetic valves, he “prefers” warfarin over DOACs.
Overall, the evidence from the registry led Dr. Kalra to suggest that physicians should continue to “exercise caution” in using DOACs instead of warfarin after any surgical valve replacement “until randomized clinical trials provide sufficient evidence” to make a judgment about relative efficacy and safety.
Results of the study were published online as a research letter in Jama Network Open after Dr. Kalra’s presentation. Dr. Kalra and Dr. Cohen report no potential conflicts of interest.
FROM CRT 2021
Five-day course of oral antiviral appears to stop SARS-CoV-2 in its tracks
A single pill of the investigational drug molnupiravir taken twice a day for 5 days eliminated SARS-CoV-2 from the nasopharynx of 49 participants.
That led Carlos del Rio, MD, distinguished professor of medicine at Emory University, Atlanta, to suggest a future in which a drug like molnupiravir could be taken in the first few days of symptoms to prevent severe disease, similar to Tamiflu for influenza.
“I think it’s critically important,” he said of the data. Emory University was involved in the trial of molnupiravir but Dr. del Rio was not part of that team. “This drug offers the first antiviral oral drug that then could be used in an outpatient setting.”
Still, Dr. del Rio said it’s too soon to call this particular drug the breakthrough clinicians need to keep people out of the ICU. “It has the potential to be practice changing; it’s not practice changing at the moment.”
Wendy Painter, MD, of Ridgeback Biotherapeutics, who presented the data at the Conference on Retroviruses and Opportunistic Infections, agreed. While the data are promising, “We will need to see if people get better from actual illness” to assess the real value of the drug in clinical care.
“That’s a phase 3 objective we’ll need to prove,” she said in an interview.
Phase 2/3 efficacy and safety studies of the drug are now underway in hospitalized and nonhospitalized patients.
In a brief prerecorded presentation of the data, Dr. Painter laid out what researchers know so far: Preclinical studies suggest that molnupiravir is effective against a number of viruses, including coronaviruses and specifically SARS-CoV-2. It prevents a virus from replicating by inducing viral error catastrophe (Proc Natl Acad Sci U S A. 2002 Oct 15;99[21]:13374-6) – essentially overloading the virus with replication and mutation until the virus burns itself out and can’t produce replicable copies.
In this phase 2a, randomized, double-blind, controlled trial, researchers recruited 202 adults who were treated at an outpatient clinic with fever or other symptoms of a respiratory virus and confirmed SARS-CoV-2 infection by day 4. Participants were randomly assigned to three different groups: 200 mg of molnupiravir, 400 mg, or 800 mg. The 200-mg arm was matched 1:1 with a placebo-controlled group, and the other two groups had three participants in the active group for every one control.
Participants took the pills twice daily for 5 days, and then were followed for a total of 28 days to monitor for complications or adverse events. At days 3, 5, 7, 14, and 28, researchers also took nasopharyngeal swabs for polymerase chain reaction tests, to sequence the virus, and to grow cultures of SARS-CoV-2 to see if the virus that’s present is actually capable of infecting others.
Notably, the pills do not have to be refrigerated at any point in the process, alleviating the cold-chain challenges that have plagued vaccines.
“There’s an urgent need for an easily produced, transported, stored, and administered antiviral drug against SARS-CoV-2,” Dr. Painter said.
Of the 202 people recruited, 182 had swabs that could be evaluated, of which 78 showed infection at baseline. The results are based on labs of those 78 participants.
By day 3, 28% of patients in the placebo arm had SARS-CoV-2 in their nasopharynx, compared with 20.4% of patients receiving any dose of molnupiravir. But by day 5, none of the participants receiving the active drug had evidence of SARS-CoV-2 in their nasopharynx. In comparison, 24% of people in the placebo arm still had detectable virus.
Halfway through the treatment course, differences in the presence of infectious virus were already evident. By day 3 of the 5-day course, 36.4% of participants in the 200-mg group had detectable virus in the nasopharynx, compared with 21% in the 400-mg group and just 12.5% in the 800-mg group. And although the reduction in SARS-CoV-2 was noticeable in the 200-mg and the 400-mg arms, it was only statistically significant in the 800-mg arm.
In contrast, by the end of the 5 days in the placebo groups, infectious virus varied from 18.2% in the 200-mg placebo group to 30% in the 800-mg group. This points out the variability of the disease course of SARS-CoV-2.
“You just don’t know” which infections will lead to serious disease, Dr. Painter said in an interview. “And don’t you wish we did?”
Seven participants discontinued treatment, though only four experienced adverse events. Three of those discontinued the trial because of adverse events. The study is still blinded, so it’s unclear what those events were, but Dr. Painter said that they were not thought to be related to the study drug.
The bottom line, said Dr. Painter, was that people treated with molnupiravir had starkly different outcomes in lab measures during the study.
“An average of 10 days after symptom onset, 24% of placebo patients remained culture positive” for SARS-CoV-2 – meaning there wasn’t just virus in the nasopharynx, but it was capable of replicating, Dr. Painter said. “In contrast, no infectious virus could be recovered at study day 5 in any molnupiravir-treated patients.”
A version of this article first appeared on Medscape.com.
A single pill of the investigational drug molnupiravir taken twice a day for 5 days eliminated SARS-CoV-2 from the nasopharynx of 49 participants.
That led Carlos del Rio, MD, distinguished professor of medicine at Emory University, Atlanta, to suggest a future in which a drug like molnupiravir could be taken in the first few days of symptoms to prevent severe disease, similar to Tamiflu for influenza.
“I think it’s critically important,” he said of the data. Emory University was involved in the trial of molnupiravir but Dr. del Rio was not part of that team. “This drug offers the first antiviral oral drug that then could be used in an outpatient setting.”
Still, Dr. del Rio said it’s too soon to call this particular drug the breakthrough clinicians need to keep people out of the ICU. “It has the potential to be practice changing; it’s not practice changing at the moment.”
Wendy Painter, MD, of Ridgeback Biotherapeutics, who presented the data at the Conference on Retroviruses and Opportunistic Infections, agreed. While the data are promising, “We will need to see if people get better from actual illness” to assess the real value of the drug in clinical care.
“That’s a phase 3 objective we’ll need to prove,” she said in an interview.
Phase 2/3 efficacy and safety studies of the drug are now underway in hospitalized and nonhospitalized patients.
In a brief prerecorded presentation of the data, Dr. Painter laid out what researchers know so far: Preclinical studies suggest that molnupiravir is effective against a number of viruses, including coronaviruses and specifically SARS-CoV-2. It prevents a virus from replicating by inducing viral error catastrophe (Proc Natl Acad Sci U S A. 2002 Oct 15;99[21]:13374-6) – essentially overloading the virus with replication and mutation until the virus burns itself out and can’t produce replicable copies.
In this phase 2a, randomized, double-blind, controlled trial, researchers recruited 202 adults who were treated at an outpatient clinic with fever or other symptoms of a respiratory virus and confirmed SARS-CoV-2 infection by day 4. Participants were randomly assigned to three different groups: 200 mg of molnupiravir, 400 mg, or 800 mg. The 200-mg arm was matched 1:1 with a placebo-controlled group, and the other two groups had three participants in the active group for every one control.
Participants took the pills twice daily for 5 days, and then were followed for a total of 28 days to monitor for complications or adverse events. At days 3, 5, 7, 14, and 28, researchers also took nasopharyngeal swabs for polymerase chain reaction tests, to sequence the virus, and to grow cultures of SARS-CoV-2 to see if the virus that’s present is actually capable of infecting others.
Notably, the pills do not have to be refrigerated at any point in the process, alleviating the cold-chain challenges that have plagued vaccines.
“There’s an urgent need for an easily produced, transported, stored, and administered antiviral drug against SARS-CoV-2,” Dr. Painter said.
Of the 202 people recruited, 182 had swabs that could be evaluated, of which 78 showed infection at baseline. The results are based on labs of those 78 participants.
By day 3, 28% of patients in the placebo arm had SARS-CoV-2 in their nasopharynx, compared with 20.4% of patients receiving any dose of molnupiravir. But by day 5, none of the participants receiving the active drug had evidence of SARS-CoV-2 in their nasopharynx. In comparison, 24% of people in the placebo arm still had detectable virus.
Halfway through the treatment course, differences in the presence of infectious virus were already evident. By day 3 of the 5-day course, 36.4% of participants in the 200-mg group had detectable virus in the nasopharynx, compared with 21% in the 400-mg group and just 12.5% in the 800-mg group. And although the reduction in SARS-CoV-2 was noticeable in the 200-mg and the 400-mg arms, it was only statistically significant in the 800-mg arm.
In contrast, by the end of the 5 days in the placebo groups, infectious virus varied from 18.2% in the 200-mg placebo group to 30% in the 800-mg group. This points out the variability of the disease course of SARS-CoV-2.
“You just don’t know” which infections will lead to serious disease, Dr. Painter said in an interview. “And don’t you wish we did?”
Seven participants discontinued treatment, though only four experienced adverse events. Three of those discontinued the trial because of adverse events. The study is still blinded, so it’s unclear what those events were, but Dr. Painter said that they were not thought to be related to the study drug.
The bottom line, said Dr. Painter, was that people treated with molnupiravir had starkly different outcomes in lab measures during the study.
“An average of 10 days after symptom onset, 24% of placebo patients remained culture positive” for SARS-CoV-2 – meaning there wasn’t just virus in the nasopharynx, but it was capable of replicating, Dr. Painter said. “In contrast, no infectious virus could be recovered at study day 5 in any molnupiravir-treated patients.”
A version of this article first appeared on Medscape.com.
A single pill of the investigational drug molnupiravir taken twice a day for 5 days eliminated SARS-CoV-2 from the nasopharynx of 49 participants.
That led Carlos del Rio, MD, distinguished professor of medicine at Emory University, Atlanta, to suggest a future in which a drug like molnupiravir could be taken in the first few days of symptoms to prevent severe disease, similar to Tamiflu for influenza.
“I think it’s critically important,” he said of the data. Emory University was involved in the trial of molnupiravir but Dr. del Rio was not part of that team. “This drug offers the first antiviral oral drug that then could be used in an outpatient setting.”
Still, Dr. del Rio said it’s too soon to call this particular drug the breakthrough clinicians need to keep people out of the ICU. “It has the potential to be practice changing; it’s not practice changing at the moment.”
Wendy Painter, MD, of Ridgeback Biotherapeutics, who presented the data at the Conference on Retroviruses and Opportunistic Infections, agreed. While the data are promising, “We will need to see if people get better from actual illness” to assess the real value of the drug in clinical care.
“That’s a phase 3 objective we’ll need to prove,” she said in an interview.
Phase 2/3 efficacy and safety studies of the drug are now underway in hospitalized and nonhospitalized patients.
In a brief prerecorded presentation of the data, Dr. Painter laid out what researchers know so far: Preclinical studies suggest that molnupiravir is effective against a number of viruses, including coronaviruses and specifically SARS-CoV-2. It prevents a virus from replicating by inducing viral error catastrophe (Proc Natl Acad Sci U S A. 2002 Oct 15;99[21]:13374-6) – essentially overloading the virus with replication and mutation until the virus burns itself out and can’t produce replicable copies.
In this phase 2a, randomized, double-blind, controlled trial, researchers recruited 202 adults who were treated at an outpatient clinic with fever or other symptoms of a respiratory virus and confirmed SARS-CoV-2 infection by day 4. Participants were randomly assigned to three different groups: 200 mg of molnupiravir, 400 mg, or 800 mg. The 200-mg arm was matched 1:1 with a placebo-controlled group, and the other two groups had three participants in the active group for every one control.
Participants took the pills twice daily for 5 days, and then were followed for a total of 28 days to monitor for complications or adverse events. At days 3, 5, 7, 14, and 28, researchers also took nasopharyngeal swabs for polymerase chain reaction tests, to sequence the virus, and to grow cultures of SARS-CoV-2 to see if the virus that’s present is actually capable of infecting others.
Notably, the pills do not have to be refrigerated at any point in the process, alleviating the cold-chain challenges that have plagued vaccines.
“There’s an urgent need for an easily produced, transported, stored, and administered antiviral drug against SARS-CoV-2,” Dr. Painter said.
Of the 202 people recruited, 182 had swabs that could be evaluated, of which 78 showed infection at baseline. The results are based on labs of those 78 participants.
By day 3, 28% of patients in the placebo arm had SARS-CoV-2 in their nasopharynx, compared with 20.4% of patients receiving any dose of molnupiravir. But by day 5, none of the participants receiving the active drug had evidence of SARS-CoV-2 in their nasopharynx. In comparison, 24% of people in the placebo arm still had detectable virus.
Halfway through the treatment course, differences in the presence of infectious virus were already evident. By day 3 of the 5-day course, 36.4% of participants in the 200-mg group had detectable virus in the nasopharynx, compared with 21% in the 400-mg group and just 12.5% in the 800-mg group. And although the reduction in SARS-CoV-2 was noticeable in the 200-mg and the 400-mg arms, it was only statistically significant in the 800-mg arm.
In contrast, by the end of the 5 days in the placebo groups, infectious virus varied from 18.2% in the 200-mg placebo group to 30% in the 800-mg group. This points out the variability of the disease course of SARS-CoV-2.
“You just don’t know” which infections will lead to serious disease, Dr. Painter said in an interview. “And don’t you wish we did?”
Seven participants discontinued treatment, though only four experienced adverse events. Three of those discontinued the trial because of adverse events. The study is still blinded, so it’s unclear what those events were, but Dr. Painter said that they were not thought to be related to the study drug.
The bottom line, said Dr. Painter, was that people treated with molnupiravir had starkly different outcomes in lab measures during the study.
“An average of 10 days after symptom onset, 24% of placebo patients remained culture positive” for SARS-CoV-2 – meaning there wasn’t just virus in the nasopharynx, but it was capable of replicating, Dr. Painter said. “In contrast, no infectious virus could be recovered at study day 5 in any molnupiravir-treated patients.”
A version of this article first appeared on Medscape.com.
Infections – especially urinary and kidney – are higher in MS
Each year, roughly 1 in 60 adult patients with multiple sclerosis (MS) aged 65 years and under is hospitalized with urinary or kidney infections, a new study suggests. That’s more than quadruple the rate in a control cohort. Other types of infections affected patients with MS at a higher rate too.
While we expected there to be increased relative risk of urinary or kidney and respiratory infections, we also found higher relative risk of viral, fungal, skin, and opportunistic infections,” said study lead author Riley Bove, MD, an assistant professor at the Weill Institute for Neurosciences at the University of California, San Francisco, who presented the findings at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. She answered follow-up questions in an interview.
The researchers analyzed U.S. commercial insurer claim data from 2010 to 2019. They matched patients with MS (aged 18-64 years who had 2 or more diagnoses of MS at least 30 days apart and met other criteria) to controls who had diagnoses for any other condition at least 30 days apart and met other criteria.
A total of 87,755 patients were included in the study (mean age, 47.3 years; 75.7% female). In outpatient claims, urinary and kidney infections were the most common infections by far in patients with MS. They were also much more common than in the control cohort (14.23% vs. 7.82%; relative risk, 1.82; 95% confidence interval, 1.77-1.87; P < .0001). Other results for outpatient claims – patients with MS versus controls – were: pneumonia/influenza (3.20% vs. 2.76%; RR, 1.16; 95% CI, 1.10-1.23; P < .0001), other respiratory/throat (30.31% vs. 30.05%; RR, 1.01; 95% CI, 0.99-1.02; P = .24), viral (6.83% vs. 5.74%; RR, 1.19; 95% CI, 1.15-1.23; P < .0001), skin (5.99% vs. 4.73%; RR, 1.26; 95% CI, 1.22-1.32; P < .0001), fungal (6.30% vs. 4.88%; RR, 1.29; 95% CI, 1.24-1.34; P < .0001), and opportunistic infections (1.02% vs. 0.68%; RR, 1.50; 95% CI, 1.35-1.66; P < .0001).
In regard to inpatient hospitalizations, the results for patients with MS versus controls were: urinary/kidney infections (1.60% vs. 0.36%; RR, 4.49; 95% CI, 3.98-5.08; P < .0001), pneumonia/influenza (0.77% vs. 0.35%; RR, 2.22; 95% CI, 1.94-2.54; P < .0001), other respiratory/throat (0.43% vs. 0.18%; RR, 2.37; 95% CI, 1.97-2.85; P < .0001), viral (0.23% vs. 0.09%; RR, 2.5; 95% CI, 1.99-3.36; P < .0001), skin (0.57% vs. 0.29%; RR, 1.95; 95% CI, 1.68-2.27; P < .0001), fungal (0.32% vs. 0.09%; RR, 3.69; 95% CI, 2.86-4.77; P < .0001), and opportunistic infections (0.07% vs. 0.04%; RR, 1.94; 95% CI, 1.26-2.97; P = .0024).
A common and treatable condition
“Bladder dysfunction may be present in over 80% of persons in MS and can be a significant source of decreased function and quality of life in addition to increased health care costs and morbidity,” neurologist Barbara Giesser, MD, of the University of California, Los Angeles, said in an interview. “It is common among persons with MS to have bladders that do not empty urine completely. This can predispose them to bladder and kidney infections. Also, some patients may try to self-manage bladder symptoms by restricting fluids, and this can predispose them to infection as well.”
Dr. Giesser, who was asked to comment on the present research, advised neurologists to bring up urinary disorders themselves instead of waiting for patients to mention them. “Patients are often embarrassed to start a discussion about genitourinary dysfunction with their neurologists but will be very appreciative of the opportunity for it to be investigated and treated,” she said. “Neurologists should make sure that this area of neurologic function is addressed in the routine management of their patients with MS because bladder dysfunction, morbidity, and complications associated with it are treatable and preventable.”
For her part, Dr. Bove recommended “early and effective identification of risk, appropriate referral to first-line interventions such as pelvic floor physical therapy and patient education, and early referral to urologists skilled in treating neurogenic bladder. Further, it is important to monitor side effects of medications to ensure there are no unrecognized immune deficits.”
She also cautioned that “common symptoms of [urinary tract infections] in people with MS include symptoms that are also prevalent in neurogenic bladder: urgency, incontinence, and frequency. It is possible that having baseline lower urinary tract symptoms could mask the recognition of a urinary infection, resulting in delayed recognition and treatment of the infections.”
EMD Serono funded the study. Dr. Bove is funded by the National MS Society’s Harry Weaver Award. She has received research support from Biogen and Roche Genentech and consulting/advisory board fees from Alexion, Biogen, EMD Serono, Roche Genentech, Sanofi Genzyme, and Novartis. Dr. Giesser reported no disclosures.
Each year, roughly 1 in 60 adult patients with multiple sclerosis (MS) aged 65 years and under is hospitalized with urinary or kidney infections, a new study suggests. That’s more than quadruple the rate in a control cohort. Other types of infections affected patients with MS at a higher rate too.
While we expected there to be increased relative risk of urinary or kidney and respiratory infections, we also found higher relative risk of viral, fungal, skin, and opportunistic infections,” said study lead author Riley Bove, MD, an assistant professor at the Weill Institute for Neurosciences at the University of California, San Francisco, who presented the findings at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. She answered follow-up questions in an interview.
The researchers analyzed U.S. commercial insurer claim data from 2010 to 2019. They matched patients with MS (aged 18-64 years who had 2 or more diagnoses of MS at least 30 days apart and met other criteria) to controls who had diagnoses for any other condition at least 30 days apart and met other criteria.
A total of 87,755 patients were included in the study (mean age, 47.3 years; 75.7% female). In outpatient claims, urinary and kidney infections were the most common infections by far in patients with MS. They were also much more common than in the control cohort (14.23% vs. 7.82%; relative risk, 1.82; 95% confidence interval, 1.77-1.87; P < .0001). Other results for outpatient claims – patients with MS versus controls – were: pneumonia/influenza (3.20% vs. 2.76%; RR, 1.16; 95% CI, 1.10-1.23; P < .0001), other respiratory/throat (30.31% vs. 30.05%; RR, 1.01; 95% CI, 0.99-1.02; P = .24), viral (6.83% vs. 5.74%; RR, 1.19; 95% CI, 1.15-1.23; P < .0001), skin (5.99% vs. 4.73%; RR, 1.26; 95% CI, 1.22-1.32; P < .0001), fungal (6.30% vs. 4.88%; RR, 1.29; 95% CI, 1.24-1.34; P < .0001), and opportunistic infections (1.02% vs. 0.68%; RR, 1.50; 95% CI, 1.35-1.66; P < .0001).
In regard to inpatient hospitalizations, the results for patients with MS versus controls were: urinary/kidney infections (1.60% vs. 0.36%; RR, 4.49; 95% CI, 3.98-5.08; P < .0001), pneumonia/influenza (0.77% vs. 0.35%; RR, 2.22; 95% CI, 1.94-2.54; P < .0001), other respiratory/throat (0.43% vs. 0.18%; RR, 2.37; 95% CI, 1.97-2.85; P < .0001), viral (0.23% vs. 0.09%; RR, 2.5; 95% CI, 1.99-3.36; P < .0001), skin (0.57% vs. 0.29%; RR, 1.95; 95% CI, 1.68-2.27; P < .0001), fungal (0.32% vs. 0.09%; RR, 3.69; 95% CI, 2.86-4.77; P < .0001), and opportunistic infections (0.07% vs. 0.04%; RR, 1.94; 95% CI, 1.26-2.97; P = .0024).
A common and treatable condition
“Bladder dysfunction may be present in over 80% of persons in MS and can be a significant source of decreased function and quality of life in addition to increased health care costs and morbidity,” neurologist Barbara Giesser, MD, of the University of California, Los Angeles, said in an interview. “It is common among persons with MS to have bladders that do not empty urine completely. This can predispose them to bladder and kidney infections. Also, some patients may try to self-manage bladder symptoms by restricting fluids, and this can predispose them to infection as well.”
Dr. Giesser, who was asked to comment on the present research, advised neurologists to bring up urinary disorders themselves instead of waiting for patients to mention them. “Patients are often embarrassed to start a discussion about genitourinary dysfunction with their neurologists but will be very appreciative of the opportunity for it to be investigated and treated,” she said. “Neurologists should make sure that this area of neurologic function is addressed in the routine management of their patients with MS because bladder dysfunction, morbidity, and complications associated with it are treatable and preventable.”
For her part, Dr. Bove recommended “early and effective identification of risk, appropriate referral to first-line interventions such as pelvic floor physical therapy and patient education, and early referral to urologists skilled in treating neurogenic bladder. Further, it is important to monitor side effects of medications to ensure there are no unrecognized immune deficits.”
She also cautioned that “common symptoms of [urinary tract infections] in people with MS include symptoms that are also prevalent in neurogenic bladder: urgency, incontinence, and frequency. It is possible that having baseline lower urinary tract symptoms could mask the recognition of a urinary infection, resulting in delayed recognition and treatment of the infections.”
EMD Serono funded the study. Dr. Bove is funded by the National MS Society’s Harry Weaver Award. She has received research support from Biogen and Roche Genentech and consulting/advisory board fees from Alexion, Biogen, EMD Serono, Roche Genentech, Sanofi Genzyme, and Novartis. Dr. Giesser reported no disclosures.
Each year, roughly 1 in 60 adult patients with multiple sclerosis (MS) aged 65 years and under is hospitalized with urinary or kidney infections, a new study suggests. That’s more than quadruple the rate in a control cohort. Other types of infections affected patients with MS at a higher rate too.
While we expected there to be increased relative risk of urinary or kidney and respiratory infections, we also found higher relative risk of viral, fungal, skin, and opportunistic infections,” said study lead author Riley Bove, MD, an assistant professor at the Weill Institute for Neurosciences at the University of California, San Francisco, who presented the findings at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. She answered follow-up questions in an interview.
The researchers analyzed U.S. commercial insurer claim data from 2010 to 2019. They matched patients with MS (aged 18-64 years who had 2 or more diagnoses of MS at least 30 days apart and met other criteria) to controls who had diagnoses for any other condition at least 30 days apart and met other criteria.
A total of 87,755 patients were included in the study (mean age, 47.3 years; 75.7% female). In outpatient claims, urinary and kidney infections were the most common infections by far in patients with MS. They were also much more common than in the control cohort (14.23% vs. 7.82%; relative risk, 1.82; 95% confidence interval, 1.77-1.87; P < .0001). Other results for outpatient claims – patients with MS versus controls – were: pneumonia/influenza (3.20% vs. 2.76%; RR, 1.16; 95% CI, 1.10-1.23; P < .0001), other respiratory/throat (30.31% vs. 30.05%; RR, 1.01; 95% CI, 0.99-1.02; P = .24), viral (6.83% vs. 5.74%; RR, 1.19; 95% CI, 1.15-1.23; P < .0001), skin (5.99% vs. 4.73%; RR, 1.26; 95% CI, 1.22-1.32; P < .0001), fungal (6.30% vs. 4.88%; RR, 1.29; 95% CI, 1.24-1.34; P < .0001), and opportunistic infections (1.02% vs. 0.68%; RR, 1.50; 95% CI, 1.35-1.66; P < .0001).
In regard to inpatient hospitalizations, the results for patients with MS versus controls were: urinary/kidney infections (1.60% vs. 0.36%; RR, 4.49; 95% CI, 3.98-5.08; P < .0001), pneumonia/influenza (0.77% vs. 0.35%; RR, 2.22; 95% CI, 1.94-2.54; P < .0001), other respiratory/throat (0.43% vs. 0.18%; RR, 2.37; 95% CI, 1.97-2.85; P < .0001), viral (0.23% vs. 0.09%; RR, 2.5; 95% CI, 1.99-3.36; P < .0001), skin (0.57% vs. 0.29%; RR, 1.95; 95% CI, 1.68-2.27; P < .0001), fungal (0.32% vs. 0.09%; RR, 3.69; 95% CI, 2.86-4.77; P < .0001), and opportunistic infections (0.07% vs. 0.04%; RR, 1.94; 95% CI, 1.26-2.97; P = .0024).
A common and treatable condition
“Bladder dysfunction may be present in over 80% of persons in MS and can be a significant source of decreased function and quality of life in addition to increased health care costs and morbidity,” neurologist Barbara Giesser, MD, of the University of California, Los Angeles, said in an interview. “It is common among persons with MS to have bladders that do not empty urine completely. This can predispose them to bladder and kidney infections. Also, some patients may try to self-manage bladder symptoms by restricting fluids, and this can predispose them to infection as well.”
Dr. Giesser, who was asked to comment on the present research, advised neurologists to bring up urinary disorders themselves instead of waiting for patients to mention them. “Patients are often embarrassed to start a discussion about genitourinary dysfunction with their neurologists but will be very appreciative of the opportunity for it to be investigated and treated,” she said. “Neurologists should make sure that this area of neurologic function is addressed in the routine management of their patients with MS because bladder dysfunction, morbidity, and complications associated with it are treatable and preventable.”
For her part, Dr. Bove recommended “early and effective identification of risk, appropriate referral to first-line interventions such as pelvic floor physical therapy and patient education, and early referral to urologists skilled in treating neurogenic bladder. Further, it is important to monitor side effects of medications to ensure there are no unrecognized immune deficits.”
She also cautioned that “common symptoms of [urinary tract infections] in people with MS include symptoms that are also prevalent in neurogenic bladder: urgency, incontinence, and frequency. It is possible that having baseline lower urinary tract symptoms could mask the recognition of a urinary infection, resulting in delayed recognition and treatment of the infections.”
EMD Serono funded the study. Dr. Bove is funded by the National MS Society’s Harry Weaver Award. She has received research support from Biogen and Roche Genentech and consulting/advisory board fees from Alexion, Biogen, EMD Serono, Roche Genentech, Sanofi Genzyme, and Novartis. Dr. Giesser reported no disclosures.
FROM ACTRIMS FORUM 2021
Bleeding disorder diagnoses delayed by years in girls and women
Diagnosis of bleeding disorders in girls and women can lag behind diagnosis in boys and men by more than a decade, meaning needless delays in treatment and poor quality of life for many with hemophilia or related conditions.
“There is increasing awareness about issues faced by women and girls with inherited bleeding disorders, but disparities still exist both in both access to diagnosis and treatment,” said Roseline D’Oiron, MD, from Hôpital Bicêtre in Paris.
“Diagnosis, when it is made, is often made late, particularly in women. Indeed, a recent study from the European Hemophilia Consortium including more than 700 women with bleeding disorders showed that the median age at diagnosis was 16 years old,” she said during the annual congress of the European Association for Haemophilia and Allied Disorders.
She said that delayed diagnosis of bleeding disorders in women and girls may be caused by a lack of knowledge by patients, families, and general practitioners about family history of bleeding disorders, abnormal bleeding events, and heavy menstrual bleeding. In addition, despite the frequency and severity of heavy bleeding events, patients, their families, and caregivers may underestimate the effect on the patient’s quality of life.
Disparities documented
Dr. D’Oiron pointed to several studies showing clear sex-based disparities in time to diagnosis. For example, a study published in Haemophilia showed that in 22 girls with hemophilia A or hemophilia B, the diagnosis of severe hemophilia was delayed by a median of 6.5 months compared with the diagnosis in boys, and a diagnosis of moderate hemophilia in girls was delayed by a median of 39 months.
In a second, single-center study comparing 44 women and girls with mild hemophilia (factor VIII or factor XI levels from 5 to 50 IU/dL) with 77 men and boys with mild hemophilia, the mean age at diagnosis was 31.63 years versus 19.18 years, respectively – a delay of 12.45 years.
A third study comparing 442 girls/women and 442 boys/men with mild hemophilia in France showed a difference of 6.07 years in diagnosis: the median age for girls/women at diagnosis was 16.91 years versus10.84 years for boys/men.
Why it matters
Dr. D’Oiron described the case of a patient named Clare, who first experienced, at age 8, 12 hours of bleeding following a dental procedure. At age 12.5, she began having heavy menstrual bleeding, causing her to miss school for a few days each month, to be feel tired, and have poor-quality sleep.
Despite repeated bleeding episodes, severe anemia, and iron deficiency, her hemophilia was not suspected until after her 16th birthday, and a definitive diagnosis of hemophilia in both Clare and her mother was finally made when Clare was past 17, when a nonsense variant factor in F8, the gene encoding for factor VIII, was detected.
“For Clare, it took more the 8 years after the first bleeding symptoms, and nearly 4 years after presenting with heavy menstrual bleeding to recognize that she had a bleeding problem,” she said.
In total, Clare had about 450 days of heavy menstrual bleeding, causing her to miss an estimated 140 days of school because of the delayed diagnosis and treatment.
“In my view, this is the main argument why it is urgent for these patients to achieve diagnosis early: this is to reduce the duration [of] a very poor quality of life,” Dr. D’Oiron said.
Barriers to diagnosis
Patients and families have reported difficulty distinguishing normal bleeding from abnormal symptoms, and girls may be reluctant to discuss their symptoms with their family or peers. In addition, primary care practitioners may not recognize the severity of the symptoms and therefore may not refer patients to hematologists for further workup.
These findings emphasize the need for improved tools to help patients differentiate between normal and abnormal bleeding, using symptom recognition–based language tools that can lead to early testing and application of accurate diagnostic tools, she said.
Standardization of definitions can help to improve screening and diagnosis, Dr. D’Oiron said, pointing to a recent study in Blood Advances proposing definitions for future research in von Willebrand disease.
For example, the authors of that study proposed a definition of heavy menstrual bleeding to include any of the following:
- Bleeding lasting 8 or more days
- Bleeding that consistently soaks through one or more sanitary protections every 2 hours on multiple days
- Requires use of more than one sanitary protection item at a time
- Requires changing sanitary protection during the night
- Is associated with repeat passing of blood clots
- Has a Pictorial Blood Assessment Chart score greater than 100.
Problem and solutions
Answering the question posed in the title of her talk, Dr. D’Oiron said: “Yes, we do have a problem with the diagnosis of bleeding disorders in women and girls, but we also have solutions.”
The solutions include family and patient outreach efforts; communication to improve awareness; inclusion of general practitioners in the circle of care; and early screening, diagnosis, and treatment.
A bleeding disorders specialist who was not involved in the study said that Dr. D’Oiron’s report closely reflects what she sees in the clinic.
“I do pediatrics, and usually what happens is that I see a teenager with heavy menstrual bleeding and we take her history, and we find out that Mom and multiple female family members have had horrible menstrual bleeding, possibly many of whom have had hysterectomies for it, and then diagnosing the parents and other family members after diagnosing the girl that we’re seeing” said Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee.
“It is unfortunately a very real thing,” she added.
Reasons for the delay likely include lack of awareness of bleeding disorders.
“If you present to a hematologist, we think about bleeding disorders, but if you present to a primary care physician, they don’t always have that on their radar,” she said.
Additionally, a girl from a family with a history of heavy menstrual bleeding may just assume that what she is experiencing is “normal,” despite the serious affect it has on her quality of life, Dr. Flood said.
Dr. D’Oiron’s research is supported by her institution, the French Hemophilia Association, FranceCoag and Mhemon, the European Hemophilia Consortium, and the World Federation of Hemophilia. She reported advisory board or invited speaker activities for multiple companies. Dr. Flood reported having no conflicts of interest to disclose.
Diagnosis of bleeding disorders in girls and women can lag behind diagnosis in boys and men by more than a decade, meaning needless delays in treatment and poor quality of life for many with hemophilia or related conditions.
“There is increasing awareness about issues faced by women and girls with inherited bleeding disorders, but disparities still exist both in both access to diagnosis and treatment,” said Roseline D’Oiron, MD, from Hôpital Bicêtre in Paris.
“Diagnosis, when it is made, is often made late, particularly in women. Indeed, a recent study from the European Hemophilia Consortium including more than 700 women with bleeding disorders showed that the median age at diagnosis was 16 years old,” she said during the annual congress of the European Association for Haemophilia and Allied Disorders.
She said that delayed diagnosis of bleeding disorders in women and girls may be caused by a lack of knowledge by patients, families, and general practitioners about family history of bleeding disorders, abnormal bleeding events, and heavy menstrual bleeding. In addition, despite the frequency and severity of heavy bleeding events, patients, their families, and caregivers may underestimate the effect on the patient’s quality of life.
Disparities documented
Dr. D’Oiron pointed to several studies showing clear sex-based disparities in time to diagnosis. For example, a study published in Haemophilia showed that in 22 girls with hemophilia A or hemophilia B, the diagnosis of severe hemophilia was delayed by a median of 6.5 months compared with the diagnosis in boys, and a diagnosis of moderate hemophilia in girls was delayed by a median of 39 months.
In a second, single-center study comparing 44 women and girls with mild hemophilia (factor VIII or factor XI levels from 5 to 50 IU/dL) with 77 men and boys with mild hemophilia, the mean age at diagnosis was 31.63 years versus 19.18 years, respectively – a delay of 12.45 years.
A third study comparing 442 girls/women and 442 boys/men with mild hemophilia in France showed a difference of 6.07 years in diagnosis: the median age for girls/women at diagnosis was 16.91 years versus10.84 years for boys/men.
Why it matters
Dr. D’Oiron described the case of a patient named Clare, who first experienced, at age 8, 12 hours of bleeding following a dental procedure. At age 12.5, she began having heavy menstrual bleeding, causing her to miss school for a few days each month, to be feel tired, and have poor-quality sleep.
Despite repeated bleeding episodes, severe anemia, and iron deficiency, her hemophilia was not suspected until after her 16th birthday, and a definitive diagnosis of hemophilia in both Clare and her mother was finally made when Clare was past 17, when a nonsense variant factor in F8, the gene encoding for factor VIII, was detected.
“For Clare, it took more the 8 years after the first bleeding symptoms, and nearly 4 years after presenting with heavy menstrual bleeding to recognize that she had a bleeding problem,” she said.
In total, Clare had about 450 days of heavy menstrual bleeding, causing her to miss an estimated 140 days of school because of the delayed diagnosis and treatment.
“In my view, this is the main argument why it is urgent for these patients to achieve diagnosis early: this is to reduce the duration [of] a very poor quality of life,” Dr. D’Oiron said.
Barriers to diagnosis
Patients and families have reported difficulty distinguishing normal bleeding from abnormal symptoms, and girls may be reluctant to discuss their symptoms with their family or peers. In addition, primary care practitioners may not recognize the severity of the symptoms and therefore may not refer patients to hematologists for further workup.
These findings emphasize the need for improved tools to help patients differentiate between normal and abnormal bleeding, using symptom recognition–based language tools that can lead to early testing and application of accurate diagnostic tools, she said.
Standardization of definitions can help to improve screening and diagnosis, Dr. D’Oiron said, pointing to a recent study in Blood Advances proposing definitions for future research in von Willebrand disease.
For example, the authors of that study proposed a definition of heavy menstrual bleeding to include any of the following:
- Bleeding lasting 8 or more days
- Bleeding that consistently soaks through one or more sanitary protections every 2 hours on multiple days
- Requires use of more than one sanitary protection item at a time
- Requires changing sanitary protection during the night
- Is associated with repeat passing of blood clots
- Has a Pictorial Blood Assessment Chart score greater than 100.
Problem and solutions
Answering the question posed in the title of her talk, Dr. D’Oiron said: “Yes, we do have a problem with the diagnosis of bleeding disorders in women and girls, but we also have solutions.”
The solutions include family and patient outreach efforts; communication to improve awareness; inclusion of general practitioners in the circle of care; and early screening, diagnosis, and treatment.
A bleeding disorders specialist who was not involved in the study said that Dr. D’Oiron’s report closely reflects what she sees in the clinic.
“I do pediatrics, and usually what happens is that I see a teenager with heavy menstrual bleeding and we take her history, and we find out that Mom and multiple female family members have had horrible menstrual bleeding, possibly many of whom have had hysterectomies for it, and then diagnosing the parents and other family members after diagnosing the girl that we’re seeing” said Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee.
“It is unfortunately a very real thing,” she added.
Reasons for the delay likely include lack of awareness of bleeding disorders.
“If you present to a hematologist, we think about bleeding disorders, but if you present to a primary care physician, they don’t always have that on their radar,” she said.
Additionally, a girl from a family with a history of heavy menstrual bleeding may just assume that what she is experiencing is “normal,” despite the serious affect it has on her quality of life, Dr. Flood said.
Dr. D’Oiron’s research is supported by her institution, the French Hemophilia Association, FranceCoag and Mhemon, the European Hemophilia Consortium, and the World Federation of Hemophilia. She reported advisory board or invited speaker activities for multiple companies. Dr. Flood reported having no conflicts of interest to disclose.
Diagnosis of bleeding disorders in girls and women can lag behind diagnosis in boys and men by more than a decade, meaning needless delays in treatment and poor quality of life for many with hemophilia or related conditions.
“There is increasing awareness about issues faced by women and girls with inherited bleeding disorders, but disparities still exist both in both access to diagnosis and treatment,” said Roseline D’Oiron, MD, from Hôpital Bicêtre in Paris.
“Diagnosis, when it is made, is often made late, particularly in women. Indeed, a recent study from the European Hemophilia Consortium including more than 700 women with bleeding disorders showed that the median age at diagnosis was 16 years old,” she said during the annual congress of the European Association for Haemophilia and Allied Disorders.
She said that delayed diagnosis of bleeding disorders in women and girls may be caused by a lack of knowledge by patients, families, and general practitioners about family history of bleeding disorders, abnormal bleeding events, and heavy menstrual bleeding. In addition, despite the frequency and severity of heavy bleeding events, patients, their families, and caregivers may underestimate the effect on the patient’s quality of life.
Disparities documented
Dr. D’Oiron pointed to several studies showing clear sex-based disparities in time to diagnosis. For example, a study published in Haemophilia showed that in 22 girls with hemophilia A or hemophilia B, the diagnosis of severe hemophilia was delayed by a median of 6.5 months compared with the diagnosis in boys, and a diagnosis of moderate hemophilia in girls was delayed by a median of 39 months.
In a second, single-center study comparing 44 women and girls with mild hemophilia (factor VIII or factor XI levels from 5 to 50 IU/dL) with 77 men and boys with mild hemophilia, the mean age at diagnosis was 31.63 years versus 19.18 years, respectively – a delay of 12.45 years.
A third study comparing 442 girls/women and 442 boys/men with mild hemophilia in France showed a difference of 6.07 years in diagnosis: the median age for girls/women at diagnosis was 16.91 years versus10.84 years for boys/men.
Why it matters
Dr. D’Oiron described the case of a patient named Clare, who first experienced, at age 8, 12 hours of bleeding following a dental procedure. At age 12.5, she began having heavy menstrual bleeding, causing her to miss school for a few days each month, to be feel tired, and have poor-quality sleep.
Despite repeated bleeding episodes, severe anemia, and iron deficiency, her hemophilia was not suspected until after her 16th birthday, and a definitive diagnosis of hemophilia in both Clare and her mother was finally made when Clare was past 17, when a nonsense variant factor in F8, the gene encoding for factor VIII, was detected.
“For Clare, it took more the 8 years after the first bleeding symptoms, and nearly 4 years after presenting with heavy menstrual bleeding to recognize that she had a bleeding problem,” she said.
In total, Clare had about 450 days of heavy menstrual bleeding, causing her to miss an estimated 140 days of school because of the delayed diagnosis and treatment.
“In my view, this is the main argument why it is urgent for these patients to achieve diagnosis early: this is to reduce the duration [of] a very poor quality of life,” Dr. D’Oiron said.
Barriers to diagnosis
Patients and families have reported difficulty distinguishing normal bleeding from abnormal symptoms, and girls may be reluctant to discuss their symptoms with their family or peers. In addition, primary care practitioners may not recognize the severity of the symptoms and therefore may not refer patients to hematologists for further workup.
These findings emphasize the need for improved tools to help patients differentiate between normal and abnormal bleeding, using symptom recognition–based language tools that can lead to early testing and application of accurate diagnostic tools, she said.
Standardization of definitions can help to improve screening and diagnosis, Dr. D’Oiron said, pointing to a recent study in Blood Advances proposing definitions for future research in von Willebrand disease.
For example, the authors of that study proposed a definition of heavy menstrual bleeding to include any of the following:
- Bleeding lasting 8 or more days
- Bleeding that consistently soaks through one or more sanitary protections every 2 hours on multiple days
- Requires use of more than one sanitary protection item at a time
- Requires changing sanitary protection during the night
- Is associated with repeat passing of blood clots
- Has a Pictorial Blood Assessment Chart score greater than 100.
Problem and solutions
Answering the question posed in the title of her talk, Dr. D’Oiron said: “Yes, we do have a problem with the diagnosis of bleeding disorders in women and girls, but we also have solutions.”
The solutions include family and patient outreach efforts; communication to improve awareness; inclusion of general practitioners in the circle of care; and early screening, diagnosis, and treatment.
A bleeding disorders specialist who was not involved in the study said that Dr. D’Oiron’s report closely reflects what she sees in the clinic.
“I do pediatrics, and usually what happens is that I see a teenager with heavy menstrual bleeding and we take her history, and we find out that Mom and multiple female family members have had horrible menstrual bleeding, possibly many of whom have had hysterectomies for it, and then diagnosing the parents and other family members after diagnosing the girl that we’re seeing” said Veronica H. Flood, MD, from the Medical College of Wisconsin, Milwaukee.
“It is unfortunately a very real thing,” she added.
Reasons for the delay likely include lack of awareness of bleeding disorders.
“If you present to a hematologist, we think about bleeding disorders, but if you present to a primary care physician, they don’t always have that on their radar,” she said.
Additionally, a girl from a family with a history of heavy menstrual bleeding may just assume that what she is experiencing is “normal,” despite the serious affect it has on her quality of life, Dr. Flood said.
Dr. D’Oiron’s research is supported by her institution, the French Hemophilia Association, FranceCoag and Mhemon, the European Hemophilia Consortium, and the World Federation of Hemophilia. She reported advisory board or invited speaker activities for multiple companies. Dr. Flood reported having no conflicts of interest to disclose.
FROM EAHAD 2021
Asthma-COPD overlap linked to occupational pollutants
The development and worsening of overlapping asthma and chronic obstructive pulmonary disease (COPD) can be affected by pollutants found in rural and urban environments, according to a recent presentation at the annual meeting of the American Academy of Allergy, Asthma, and Immunology, held virtually this year.
“ features,” Jill A. Poole, MD, division chief of allergy and immunology at the University of Nebraska Medical Center, Omaha, said in her presentation.
The Global Initiative for Asthma (GINA) first outlined a syndrome in 2015 described as “persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD” and called asthma-COPD overlap syndrome. In 2017, a joint American Thoracic Society/National Heart, Lung, and Blood Institute workshop outlined knowledge gaps about asthma-COPD overlap, noting it “does not represent a single discrete disease entity.”
“This is not a single disease and should be thought of as being heterogeneous and used as a descriptive label for patients commonly seen in clinical practice,” Dr. Poole said. “Both asthma and COPD definitions are not mutually exclusive because each disease includes several phenotypes with different underlining mechanisms.” An example of how asthma-COPD overlap might present is through a patient with allergic asthma who has a history of smoking who develops airflow obstruction that isn’t fully reversible, or a patient with COPD “with high reversible airflow, obstruction, type 2 inflammation, and perhaps the presence of peripheral blood eosinophils or sputum eosinophils.”
A patient’s interaction with urban, rural, and occupational environments may additionally impact their disease, Dr. Poole explained. “The environmental factors of an urban versus rural environment may not be necessarily mutually exclusive,” she said. “It’s also important to recognize occupational exposures that can be both seen in an urban or rural environment [can] contribute to asthma-COPD overlap.”
In a study of 6,040 men and women with asthma living in Canada, 630 (10.4%) had asthma-COPD overlap, with increased air pollution raising the likelihood of developing asthma-COPD overlap (odds ratio, 2.78; 95% confidence interval, 1.62-4.78). These people experienced later onset asthma, increased emergency department visits before a diagnosis of COPD, and increased mortality. Another study in Canada of women from Ontario in the Breast Cancer Screening Study found 1,705 of 4,051 women with asthma also had COPD. While air pollution did not increase the risk of developing asthma-COPD overlap, there was an association between body mass index, low level of education, living in a rural area, and smoking status.
Among farmers in rural areas, “it has been recognized that there is something called the asthma-like syndrome that’s been reported in adult farming communities,” Dr. Poole said, which includes “some degree of airflow obstruction and reversibility” that can be worsened by smoking and could be an overlap of asthma and COPD. Farmers can also experience asthma exacerbations while working, and “livestock farmers appear more at risk of developing [chronic bronchitis and/or COPD] than do the crop farmers,” she noted.
Occupational environments outside of agriculture exposure can cause incident asthma, with high-molecular-weight antigens such as flour cereal, animal dander, latex, psyllium, crab processing products, and enzymes as well as low-molecular-weight antigens such as isocyanates, woods, antibiotics, glues, epoxies colophony products, and dyes presenting a risk. In food processing, main allergen sources can include raw and processed animal and plant products, additives and preservatives, contaminants from microbes or insects, inhaled dust particles or aerosols, which can be “IgE mediated, mixed IgE-mediated and non-lgE mediated.”
While some studies have been conducted on the prevalence of work-related asthma and asthma-COPD overlap, “in general, the prevalence and clinical features have been scarcely investigated,” Dr. Poole said. One survey of 23,137 patients found 52.9% of adults with work-related asthma also had COPD, compared with 25.6% of participants whose asthma was not work related.
To prevent asthma-COPD overlap, Dr. Poole recommended tobacco cessation, reducing indoor biomass fuel use, medical surveillance programs such as preplacement questionnaires, and considering “reducing exposure to the respiratory sensitizers with ideally monitoring the levels to keep the levels below the permissible limits.”
Dr. Poole noted there is currently no unique treatment for asthma-COPD overlap, but it is “important to fully characterize and phenotype your individual patients, looking for eosinophilia or seeing if they have more neutrophil features and whether or not the allergy features are prevalent and can be treated,” she said. “[A]wareness is really required such that counseling is encouraged for prevention and or interventional strategies as we move forward.”
For patients with features of both asthma and COPD where there is a high likelihood of asthma, treat the disease as if it were asthma, Dr. Poole said, but clinicians should follow GINA GOLD COPD treatment recommendations, adding on long-acting beta-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) when needed, but avoiding LABAs and/or LAMAs without use of inhaled corticosteroids, and avoiding oral corticosteroids entirely. Clinicians should be reviewing the treatments of patients with asthma and COPD features “every 2-3 months to see how their response is to it, and what additional therapies could be used,” she said.
Dr. Poole reports receiving grant support from National Institute of Environmental Health Sciences, National Institute for Occupational Safety and Health, and the Central States Center for Agricultural Safety and Health at the University of Nebraska Medical Center.
The development and worsening of overlapping asthma and chronic obstructive pulmonary disease (COPD) can be affected by pollutants found in rural and urban environments, according to a recent presentation at the annual meeting of the American Academy of Allergy, Asthma, and Immunology, held virtually this year.
“ features,” Jill A. Poole, MD, division chief of allergy and immunology at the University of Nebraska Medical Center, Omaha, said in her presentation.
The Global Initiative for Asthma (GINA) first outlined a syndrome in 2015 described as “persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD” and called asthma-COPD overlap syndrome. In 2017, a joint American Thoracic Society/National Heart, Lung, and Blood Institute workshop outlined knowledge gaps about asthma-COPD overlap, noting it “does not represent a single discrete disease entity.”
“This is not a single disease and should be thought of as being heterogeneous and used as a descriptive label for patients commonly seen in clinical practice,” Dr. Poole said. “Both asthma and COPD definitions are not mutually exclusive because each disease includes several phenotypes with different underlining mechanisms.” An example of how asthma-COPD overlap might present is through a patient with allergic asthma who has a history of smoking who develops airflow obstruction that isn’t fully reversible, or a patient with COPD “with high reversible airflow, obstruction, type 2 inflammation, and perhaps the presence of peripheral blood eosinophils or sputum eosinophils.”
A patient’s interaction with urban, rural, and occupational environments may additionally impact their disease, Dr. Poole explained. “The environmental factors of an urban versus rural environment may not be necessarily mutually exclusive,” she said. “It’s also important to recognize occupational exposures that can be both seen in an urban or rural environment [can] contribute to asthma-COPD overlap.”
In a study of 6,040 men and women with asthma living in Canada, 630 (10.4%) had asthma-COPD overlap, with increased air pollution raising the likelihood of developing asthma-COPD overlap (odds ratio, 2.78; 95% confidence interval, 1.62-4.78). These people experienced later onset asthma, increased emergency department visits before a diagnosis of COPD, and increased mortality. Another study in Canada of women from Ontario in the Breast Cancer Screening Study found 1,705 of 4,051 women with asthma also had COPD. While air pollution did not increase the risk of developing asthma-COPD overlap, there was an association between body mass index, low level of education, living in a rural area, and smoking status.
Among farmers in rural areas, “it has been recognized that there is something called the asthma-like syndrome that’s been reported in adult farming communities,” Dr. Poole said, which includes “some degree of airflow obstruction and reversibility” that can be worsened by smoking and could be an overlap of asthma and COPD. Farmers can also experience asthma exacerbations while working, and “livestock farmers appear more at risk of developing [chronic bronchitis and/or COPD] than do the crop farmers,” she noted.
Occupational environments outside of agriculture exposure can cause incident asthma, with high-molecular-weight antigens such as flour cereal, animal dander, latex, psyllium, crab processing products, and enzymes as well as low-molecular-weight antigens such as isocyanates, woods, antibiotics, glues, epoxies colophony products, and dyes presenting a risk. In food processing, main allergen sources can include raw and processed animal and plant products, additives and preservatives, contaminants from microbes or insects, inhaled dust particles or aerosols, which can be “IgE mediated, mixed IgE-mediated and non-lgE mediated.”
While some studies have been conducted on the prevalence of work-related asthma and asthma-COPD overlap, “in general, the prevalence and clinical features have been scarcely investigated,” Dr. Poole said. One survey of 23,137 patients found 52.9% of adults with work-related asthma also had COPD, compared with 25.6% of participants whose asthma was not work related.
To prevent asthma-COPD overlap, Dr. Poole recommended tobacco cessation, reducing indoor biomass fuel use, medical surveillance programs such as preplacement questionnaires, and considering “reducing exposure to the respiratory sensitizers with ideally monitoring the levels to keep the levels below the permissible limits.”
Dr. Poole noted there is currently no unique treatment for asthma-COPD overlap, but it is “important to fully characterize and phenotype your individual patients, looking for eosinophilia or seeing if they have more neutrophil features and whether or not the allergy features are prevalent and can be treated,” she said. “[A]wareness is really required such that counseling is encouraged for prevention and or interventional strategies as we move forward.”
For patients with features of both asthma and COPD where there is a high likelihood of asthma, treat the disease as if it were asthma, Dr. Poole said, but clinicians should follow GINA GOLD COPD treatment recommendations, adding on long-acting beta-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) when needed, but avoiding LABAs and/or LAMAs without use of inhaled corticosteroids, and avoiding oral corticosteroids entirely. Clinicians should be reviewing the treatments of patients with asthma and COPD features “every 2-3 months to see how their response is to it, and what additional therapies could be used,” she said.
Dr. Poole reports receiving grant support from National Institute of Environmental Health Sciences, National Institute for Occupational Safety and Health, and the Central States Center for Agricultural Safety and Health at the University of Nebraska Medical Center.
The development and worsening of overlapping asthma and chronic obstructive pulmonary disease (COPD) can be affected by pollutants found in rural and urban environments, according to a recent presentation at the annual meeting of the American Academy of Allergy, Asthma, and Immunology, held virtually this year.
“ features,” Jill A. Poole, MD, division chief of allergy and immunology at the University of Nebraska Medical Center, Omaha, said in her presentation.
The Global Initiative for Asthma (GINA) first outlined a syndrome in 2015 described as “persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD” and called asthma-COPD overlap syndrome. In 2017, a joint American Thoracic Society/National Heart, Lung, and Blood Institute workshop outlined knowledge gaps about asthma-COPD overlap, noting it “does not represent a single discrete disease entity.”
“This is not a single disease and should be thought of as being heterogeneous and used as a descriptive label for patients commonly seen in clinical practice,” Dr. Poole said. “Both asthma and COPD definitions are not mutually exclusive because each disease includes several phenotypes with different underlining mechanisms.” An example of how asthma-COPD overlap might present is through a patient with allergic asthma who has a history of smoking who develops airflow obstruction that isn’t fully reversible, or a patient with COPD “with high reversible airflow, obstruction, type 2 inflammation, and perhaps the presence of peripheral blood eosinophils or sputum eosinophils.”
A patient’s interaction with urban, rural, and occupational environments may additionally impact their disease, Dr. Poole explained. “The environmental factors of an urban versus rural environment may not be necessarily mutually exclusive,” she said. “It’s also important to recognize occupational exposures that can be both seen in an urban or rural environment [can] contribute to asthma-COPD overlap.”
In a study of 6,040 men and women with asthma living in Canada, 630 (10.4%) had asthma-COPD overlap, with increased air pollution raising the likelihood of developing asthma-COPD overlap (odds ratio, 2.78; 95% confidence interval, 1.62-4.78). These people experienced later onset asthma, increased emergency department visits before a diagnosis of COPD, and increased mortality. Another study in Canada of women from Ontario in the Breast Cancer Screening Study found 1,705 of 4,051 women with asthma also had COPD. While air pollution did not increase the risk of developing asthma-COPD overlap, there was an association between body mass index, low level of education, living in a rural area, and smoking status.
Among farmers in rural areas, “it has been recognized that there is something called the asthma-like syndrome that’s been reported in adult farming communities,” Dr. Poole said, which includes “some degree of airflow obstruction and reversibility” that can be worsened by smoking and could be an overlap of asthma and COPD. Farmers can also experience asthma exacerbations while working, and “livestock farmers appear more at risk of developing [chronic bronchitis and/or COPD] than do the crop farmers,” she noted.
Occupational environments outside of agriculture exposure can cause incident asthma, with high-molecular-weight antigens such as flour cereal, animal dander, latex, psyllium, crab processing products, and enzymes as well as low-molecular-weight antigens such as isocyanates, woods, antibiotics, glues, epoxies colophony products, and dyes presenting a risk. In food processing, main allergen sources can include raw and processed animal and plant products, additives and preservatives, contaminants from microbes or insects, inhaled dust particles or aerosols, which can be “IgE mediated, mixed IgE-mediated and non-lgE mediated.”
While some studies have been conducted on the prevalence of work-related asthma and asthma-COPD overlap, “in general, the prevalence and clinical features have been scarcely investigated,” Dr. Poole said. One survey of 23,137 patients found 52.9% of adults with work-related asthma also had COPD, compared with 25.6% of participants whose asthma was not work related.
To prevent asthma-COPD overlap, Dr. Poole recommended tobacco cessation, reducing indoor biomass fuel use, medical surveillance programs such as preplacement questionnaires, and considering “reducing exposure to the respiratory sensitizers with ideally monitoring the levels to keep the levels below the permissible limits.”
Dr. Poole noted there is currently no unique treatment for asthma-COPD overlap, but it is “important to fully characterize and phenotype your individual patients, looking for eosinophilia or seeing if they have more neutrophil features and whether or not the allergy features are prevalent and can be treated,” she said. “[A]wareness is really required such that counseling is encouraged for prevention and or interventional strategies as we move forward.”
For patients with features of both asthma and COPD where there is a high likelihood of asthma, treat the disease as if it were asthma, Dr. Poole said, but clinicians should follow GINA GOLD COPD treatment recommendations, adding on long-acting beta-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) when needed, but avoiding LABAs and/or LAMAs without use of inhaled corticosteroids, and avoiding oral corticosteroids entirely. Clinicians should be reviewing the treatments of patients with asthma and COPD features “every 2-3 months to see how their response is to it, and what additional therapies could be used,” she said.
Dr. Poole reports receiving grant support from National Institute of Environmental Health Sciences, National Institute for Occupational Safety and Health, and the Central States Center for Agricultural Safety and Health at the University of Nebraska Medical Center.
FROM AAAAI 2021
Fear, stigma can stymie the care of criminal justice-involved outpatients
One of the greatest challenges psychotherapists face when working with justice-involved outpatients is a lack of familiarity with the criminal legal system, according to Debra A. Pinals, MD.
“It’s certainly nothing we learned about in medical school or in our mental health training, per se,” said Dr. Pinals, director of the program in psychiatry, law, and ethics at the University of Michigan, Ann Arbor, during an annual psychopharmacology update held by the Nevada Psychiatric Association.
“Another challenge is a lack of comfort with some patient personality styles, particularly those with antisocial personality styles,” she said. “We may have countertransference issues that emerge in our work with this population. That can lead to concerns about our own safety, which may at times be reasonable but often because of stereotypes often becomes of mythical proportion. The population is a high-demand population with limited resources, usually tapping public mental health services. That becomes a challenge as well. And there can be burnout when the challenges of our patient population exceed our capacity.”
Despite such obstacles, Dr. Pinals described the outpatient treatment of individuals involved in the criminal justice system as exciting, interesting, and intellectually challenging. But she acknowledged the role that stigma and fear can play.
“Though there are some unique challenges, the benefits of working with criminal justice–involved persons with serious mental illness are often not discussed,” Dr. Pinals said. “There is a tendency to overvalue the risk they may present without really looking at the specific nuances that would be involved in conducting true risk assessments and understanding that not all of these patients will be as risky as we might believe due to stigma and fear.”
Separate from how patients with criminal histories may be perceived in clinical settings. There is much to learn about the role of mental illness in crime. In a 2014 study, researchers reviewed the records of criminal arrests in 143 people with mental illness and tried to discern whether the crime itself was completely independent or completely directly connected to the symptoms of mental illness the individual was experiencing. They found that 65% were completely independent of mental illness symptoms while 8% were directly related to mental illness symptoms.
“This means that as clinicians working with outpatients, we have to understand the whole person, and what might be going on in their lives that leads them down this criminal pathway,” said Dr. Pinals, who is also a clinical professor of psychiatry at the medical school.
According to the risk-need-responsivity (RNR) paradigm, eight criminogenic risk factors are associated with recurrent involvement in the criminal legal system (Crime & Delinquency. 2006;52:7-27). The big four include history of antisocial behavior, antisocial personality pattern, antisocial cognition, and antisocial attitudes. “These are the factors that certain cognitive-behavioral therapy approaches try to address, in an effort to reduce those antisocial cognitive tendencies,” Dr. Pinals said. The other four risk factors include family or marital discord, poor school and/or work performance, few leisure or recreation activities, and substance misuse.
“You’ll notice that mental illness is not listed,” she said. “ although it might be considered a responsivity factor within this RNR paradigm. This means it’s important to address it because it may help people better respond to criminal justice supervision and thereby have an indirect effect in reducing criminal recidivism. For example, if somebody has a social anxiety disorder or agoraphobia and therefore can’t make their probation appointment, probation won’t be able to help them adhere to the terms of their probation conditions. So, we do have to treat the illnesses underlying responsivity to how the criminal justice system operates.”
To optimally serve this population, Dr. Pinals recommends that psychotherapists become familiar with the Sequential Intercept Model, which was first published in 2006. “It takes the premise that individuals move through the criminal legal system in logical steps, and if we could identify those with mental health or substance use conditions and redirect them out of the criminal legal system and into treatment, we could reduce the overall penetration of those individuals from the criminal legal system,” she said. “We know that individuals with mental illness are overrepresented in the criminal legal system.”
By understanding what happens when a patient is arrested, mental health professionals can foster communication that could facilitate treatment for their patients.
“It’s important that we remember that these are people who are going through a challenging time,” Dr. Pinals said. “Maybe we don’t like what they did. Maybe we don’t like that they were accused of committing some kind of crime. However, it is important to realize that they are patients, and we want them to achieve the best outcome, whatever setting they’re in, that continuity of care and communication across systems might be beneficial. It might reduce their chance of returning to the criminal system and having other people victimized.”
Mental health services vary across jails and prisons, she continued, but they are generally required to be commensurate with community standards.
“Of course, that’s often fraught with complexity and may not be available in particular jurisdictions” she said. Prisons, unlike local county jails, tend to have more levels of outpatient care, including inpatient, outpatient, and residential services. “Persons with mental illness can be moved in and out of these levels of care as needed,” Dr. Pinals said. “However, persons with mental illness can be at more risk for disciplinary infractions, especially if they’re not able to follow directions or if they’re psychotic or manic.”
Reentry creates certain risks to be mindful of, including social isolation, recurrent symptoms, problems acquiring medications and housing, suicide, violence, and a return to substance use. A reentry approach she recommended is the APIC model, which stands for Assess, Plan, Identify, and Coordinate. “That means individuals approaching release should be screened and assessed for their needs with a plan to meet the needs, identify critical periods and needed policies, and coordinate across systems,” Dr. Pinals said. “So, if you get a call as an outpatient provider from the reentry coordinator at a local jail trying to help you coordinate a patient’s reentry, that’s something to pay attention to.”
When first meeting with patients after a criminal justice experience, Dr. Pinals recommends asking them to discuss their arrest and criminal justice experience, and to address any emerging psychiatric or clinical issues, including trauma and adjustment associated with the arrests, incarceration, and legal processes. “The risks of rearrest are higher for those who have already touched the criminal justice system, so we want to help minimize that risk of rearrest,” she said.
Some clinics won’t allow patients with a criminal record to return, “which means you have to help potentially find alternative places for them to be seen,” she noted. “You may want to consult a specialist if you have doubts about your capacity to work with the patient. You also want to support staff who might have concerns about how to continue to treat this patient and you want to advocate for the patient’s needs and help them return to a stable treatment setting.”
Dr. Pinals concluded her presentation by underscoring the importance of delivering treatment services that are trauma informed. “There are high levels of trauma for those receiving care in psychiatric settings and among those who have spent time in jails and prisons,” she said. “We want to be sensitive to the fact that any of our patients who were involved in the criminal legal system might have a strong trauma history. Help instill a sense of safety and community, and hold hope for positive change.”
She reported consulting to jurisdictions and attorneys pertaining to behavioral health and justice, and forensic psychiatry. She reported having no relevant commercial financial disclosures.
One of the greatest challenges psychotherapists face when working with justice-involved outpatients is a lack of familiarity with the criminal legal system, according to Debra A. Pinals, MD.
“It’s certainly nothing we learned about in medical school or in our mental health training, per se,” said Dr. Pinals, director of the program in psychiatry, law, and ethics at the University of Michigan, Ann Arbor, during an annual psychopharmacology update held by the Nevada Psychiatric Association.
“Another challenge is a lack of comfort with some patient personality styles, particularly those with antisocial personality styles,” she said. “We may have countertransference issues that emerge in our work with this population. That can lead to concerns about our own safety, which may at times be reasonable but often because of stereotypes often becomes of mythical proportion. The population is a high-demand population with limited resources, usually tapping public mental health services. That becomes a challenge as well. And there can be burnout when the challenges of our patient population exceed our capacity.”
Despite such obstacles, Dr. Pinals described the outpatient treatment of individuals involved in the criminal justice system as exciting, interesting, and intellectually challenging. But she acknowledged the role that stigma and fear can play.
“Though there are some unique challenges, the benefits of working with criminal justice–involved persons with serious mental illness are often not discussed,” Dr. Pinals said. “There is a tendency to overvalue the risk they may present without really looking at the specific nuances that would be involved in conducting true risk assessments and understanding that not all of these patients will be as risky as we might believe due to stigma and fear.”
Separate from how patients with criminal histories may be perceived in clinical settings. There is much to learn about the role of mental illness in crime. In a 2014 study, researchers reviewed the records of criminal arrests in 143 people with mental illness and tried to discern whether the crime itself was completely independent or completely directly connected to the symptoms of mental illness the individual was experiencing. They found that 65% were completely independent of mental illness symptoms while 8% were directly related to mental illness symptoms.
“This means that as clinicians working with outpatients, we have to understand the whole person, and what might be going on in their lives that leads them down this criminal pathway,” said Dr. Pinals, who is also a clinical professor of psychiatry at the medical school.
According to the risk-need-responsivity (RNR) paradigm, eight criminogenic risk factors are associated with recurrent involvement in the criminal legal system (Crime & Delinquency. 2006;52:7-27). The big four include history of antisocial behavior, antisocial personality pattern, antisocial cognition, and antisocial attitudes. “These are the factors that certain cognitive-behavioral therapy approaches try to address, in an effort to reduce those antisocial cognitive tendencies,” Dr. Pinals said. The other four risk factors include family or marital discord, poor school and/or work performance, few leisure or recreation activities, and substance misuse.
“You’ll notice that mental illness is not listed,” she said. “ although it might be considered a responsivity factor within this RNR paradigm. This means it’s important to address it because it may help people better respond to criminal justice supervision and thereby have an indirect effect in reducing criminal recidivism. For example, if somebody has a social anxiety disorder or agoraphobia and therefore can’t make their probation appointment, probation won’t be able to help them adhere to the terms of their probation conditions. So, we do have to treat the illnesses underlying responsivity to how the criminal justice system operates.”
To optimally serve this population, Dr. Pinals recommends that psychotherapists become familiar with the Sequential Intercept Model, which was first published in 2006. “It takes the premise that individuals move through the criminal legal system in logical steps, and if we could identify those with mental health or substance use conditions and redirect them out of the criminal legal system and into treatment, we could reduce the overall penetration of those individuals from the criminal legal system,” she said. “We know that individuals with mental illness are overrepresented in the criminal legal system.”
By understanding what happens when a patient is arrested, mental health professionals can foster communication that could facilitate treatment for their patients.
“It’s important that we remember that these are people who are going through a challenging time,” Dr. Pinals said. “Maybe we don’t like what they did. Maybe we don’t like that they were accused of committing some kind of crime. However, it is important to realize that they are patients, and we want them to achieve the best outcome, whatever setting they’re in, that continuity of care and communication across systems might be beneficial. It might reduce their chance of returning to the criminal system and having other people victimized.”
Mental health services vary across jails and prisons, she continued, but they are generally required to be commensurate with community standards.
“Of course, that’s often fraught with complexity and may not be available in particular jurisdictions” she said. Prisons, unlike local county jails, tend to have more levels of outpatient care, including inpatient, outpatient, and residential services. “Persons with mental illness can be moved in and out of these levels of care as needed,” Dr. Pinals said. “However, persons with mental illness can be at more risk for disciplinary infractions, especially if they’re not able to follow directions or if they’re psychotic or manic.”
Reentry creates certain risks to be mindful of, including social isolation, recurrent symptoms, problems acquiring medications and housing, suicide, violence, and a return to substance use. A reentry approach she recommended is the APIC model, which stands for Assess, Plan, Identify, and Coordinate. “That means individuals approaching release should be screened and assessed for their needs with a plan to meet the needs, identify critical periods and needed policies, and coordinate across systems,” Dr. Pinals said. “So, if you get a call as an outpatient provider from the reentry coordinator at a local jail trying to help you coordinate a patient’s reentry, that’s something to pay attention to.”
When first meeting with patients after a criminal justice experience, Dr. Pinals recommends asking them to discuss their arrest and criminal justice experience, and to address any emerging psychiatric or clinical issues, including trauma and adjustment associated with the arrests, incarceration, and legal processes. “The risks of rearrest are higher for those who have already touched the criminal justice system, so we want to help minimize that risk of rearrest,” she said.
Some clinics won’t allow patients with a criminal record to return, “which means you have to help potentially find alternative places for them to be seen,” she noted. “You may want to consult a specialist if you have doubts about your capacity to work with the patient. You also want to support staff who might have concerns about how to continue to treat this patient and you want to advocate for the patient’s needs and help them return to a stable treatment setting.”
Dr. Pinals concluded her presentation by underscoring the importance of delivering treatment services that are trauma informed. “There are high levels of trauma for those receiving care in psychiatric settings and among those who have spent time in jails and prisons,” she said. “We want to be sensitive to the fact that any of our patients who were involved in the criminal legal system might have a strong trauma history. Help instill a sense of safety and community, and hold hope for positive change.”
She reported consulting to jurisdictions and attorneys pertaining to behavioral health and justice, and forensic psychiatry. She reported having no relevant commercial financial disclosures.
One of the greatest challenges psychotherapists face when working with justice-involved outpatients is a lack of familiarity with the criminal legal system, according to Debra A. Pinals, MD.
“It’s certainly nothing we learned about in medical school or in our mental health training, per se,” said Dr. Pinals, director of the program in psychiatry, law, and ethics at the University of Michigan, Ann Arbor, during an annual psychopharmacology update held by the Nevada Psychiatric Association.
“Another challenge is a lack of comfort with some patient personality styles, particularly those with antisocial personality styles,” she said. “We may have countertransference issues that emerge in our work with this population. That can lead to concerns about our own safety, which may at times be reasonable but often because of stereotypes often becomes of mythical proportion. The population is a high-demand population with limited resources, usually tapping public mental health services. That becomes a challenge as well. And there can be burnout when the challenges of our patient population exceed our capacity.”
Despite such obstacles, Dr. Pinals described the outpatient treatment of individuals involved in the criminal justice system as exciting, interesting, and intellectually challenging. But she acknowledged the role that stigma and fear can play.
“Though there are some unique challenges, the benefits of working with criminal justice–involved persons with serious mental illness are often not discussed,” Dr. Pinals said. “There is a tendency to overvalue the risk they may present without really looking at the specific nuances that would be involved in conducting true risk assessments and understanding that not all of these patients will be as risky as we might believe due to stigma and fear.”
Separate from how patients with criminal histories may be perceived in clinical settings. There is much to learn about the role of mental illness in crime. In a 2014 study, researchers reviewed the records of criminal arrests in 143 people with mental illness and tried to discern whether the crime itself was completely independent or completely directly connected to the symptoms of mental illness the individual was experiencing. They found that 65% were completely independent of mental illness symptoms while 8% were directly related to mental illness symptoms.
“This means that as clinicians working with outpatients, we have to understand the whole person, and what might be going on in their lives that leads them down this criminal pathway,” said Dr. Pinals, who is also a clinical professor of psychiatry at the medical school.
According to the risk-need-responsivity (RNR) paradigm, eight criminogenic risk factors are associated with recurrent involvement in the criminal legal system (Crime & Delinquency. 2006;52:7-27). The big four include history of antisocial behavior, antisocial personality pattern, antisocial cognition, and antisocial attitudes. “These are the factors that certain cognitive-behavioral therapy approaches try to address, in an effort to reduce those antisocial cognitive tendencies,” Dr. Pinals said. The other four risk factors include family or marital discord, poor school and/or work performance, few leisure or recreation activities, and substance misuse.
“You’ll notice that mental illness is not listed,” she said. “ although it might be considered a responsivity factor within this RNR paradigm. This means it’s important to address it because it may help people better respond to criminal justice supervision and thereby have an indirect effect in reducing criminal recidivism. For example, if somebody has a social anxiety disorder or agoraphobia and therefore can’t make their probation appointment, probation won’t be able to help them adhere to the terms of their probation conditions. So, we do have to treat the illnesses underlying responsivity to how the criminal justice system operates.”
To optimally serve this population, Dr. Pinals recommends that psychotherapists become familiar with the Sequential Intercept Model, which was first published in 2006. “It takes the premise that individuals move through the criminal legal system in logical steps, and if we could identify those with mental health or substance use conditions and redirect them out of the criminal legal system and into treatment, we could reduce the overall penetration of those individuals from the criminal legal system,” she said. “We know that individuals with mental illness are overrepresented in the criminal legal system.”
By understanding what happens when a patient is arrested, mental health professionals can foster communication that could facilitate treatment for their patients.
“It’s important that we remember that these are people who are going through a challenging time,” Dr. Pinals said. “Maybe we don’t like what they did. Maybe we don’t like that they were accused of committing some kind of crime. However, it is important to realize that they are patients, and we want them to achieve the best outcome, whatever setting they’re in, that continuity of care and communication across systems might be beneficial. It might reduce their chance of returning to the criminal system and having other people victimized.”
Mental health services vary across jails and prisons, she continued, but they are generally required to be commensurate with community standards.
“Of course, that’s often fraught with complexity and may not be available in particular jurisdictions” she said. Prisons, unlike local county jails, tend to have more levels of outpatient care, including inpatient, outpatient, and residential services. “Persons with mental illness can be moved in and out of these levels of care as needed,” Dr. Pinals said. “However, persons with mental illness can be at more risk for disciplinary infractions, especially if they’re not able to follow directions or if they’re psychotic or manic.”
Reentry creates certain risks to be mindful of, including social isolation, recurrent symptoms, problems acquiring medications and housing, suicide, violence, and a return to substance use. A reentry approach she recommended is the APIC model, which stands for Assess, Plan, Identify, and Coordinate. “That means individuals approaching release should be screened and assessed for their needs with a plan to meet the needs, identify critical periods and needed policies, and coordinate across systems,” Dr. Pinals said. “So, if you get a call as an outpatient provider from the reentry coordinator at a local jail trying to help you coordinate a patient’s reentry, that’s something to pay attention to.”
When first meeting with patients after a criminal justice experience, Dr. Pinals recommends asking them to discuss their arrest and criminal justice experience, and to address any emerging psychiatric or clinical issues, including trauma and adjustment associated with the arrests, incarceration, and legal processes. “The risks of rearrest are higher for those who have already touched the criminal justice system, so we want to help minimize that risk of rearrest,” she said.
Some clinics won’t allow patients with a criminal record to return, “which means you have to help potentially find alternative places for them to be seen,” she noted. “You may want to consult a specialist if you have doubts about your capacity to work with the patient. You also want to support staff who might have concerns about how to continue to treat this patient and you want to advocate for the patient’s needs and help them return to a stable treatment setting.”
Dr. Pinals concluded her presentation by underscoring the importance of delivering treatment services that are trauma informed. “There are high levels of trauma for those receiving care in psychiatric settings and among those who have spent time in jails and prisons,” she said. “We want to be sensitive to the fact that any of our patients who were involved in the criminal legal system might have a strong trauma history. Help instill a sense of safety and community, and hold hope for positive change.”
She reported consulting to jurisdictions and attorneys pertaining to behavioral health and justice, and forensic psychiatry. She reported having no relevant commercial financial disclosures.
FROM NPA 2021
Atopic dermatitis, sleep difficulties often intertwined
According to Phyllis C. Zee, MD, PhD, proinflammatory cytokines influence neural processes that affect sleep and circadian rhythm. “It’s almost like when you’re most vulnerable, when you’re sleeping, the immune system is kind of poised for attack,” Dr. Zee, chief of the division of sleep medicine at Northwestern University, Chicago, said at the Revolutionizing Atopic Dermatitis symposium. “This is normal, and perhaps in some of these inflammatory disorders, it’s gone a little haywire.”
Circulation of interleukins and cytokines are high in the morning, become lower in the afternoon, and then get higher again in the evening hours and into the night during sleep, she continued. “Whereas if you look at something like blood flow, it increases on a diurnal basis,” she said. “It’s higher during the day and a little bit lower during the mid-day, and a little bit higher during the evening. That parallels changes in the sebum production of the skin and the transepidermal water loss, which has been implicated in some of the symptoms of AD. What’s curious about this is that the transdermal/epidermal water loss is really highest during the sleep period. Some of this is sleep gated, but some of this is circadian gated as well. There’s a bidirectional relationship between sleep and immunity.”
Disturbance of sleep can have multiple consequences. It can activate the hypothalamic-pituitary-adrenal axis through autonomic activation, increase brain metabolic activity, trigger mood disturbances and cognitive impairment, and cause daytime sleepiness and health consequences that affect cardiometabolic and immunologic health.
One study conducted by Anna B. Fishbein, MD, Dr. Zee, and colleagues at Northwestern examined the effects of sleep duration and sleep disruption and movements in 38 children with and without moderate to severe AD. It found that children with AD get about 1 hour less of sleep per night overall, compared with age-matched healthy controls. “It’s not so much difficulty falling asleep, but more difficulty staying asleep as determined by wake after sleep onset,” said Dr. Zee, who is also a professor of neurology at Northwestern.
A study of 34,613 adults who participated in the 2012 National Health and Nutrition Examination Survey found that eczema increased the odds of fatigue (odds ratio, 2.97), daytime sleepiness (OR, 2.66), and regular insomnia (OR, 2.36).
“Very importantly, it predicted poor health,” said Dr. Zee, who was one of the study’s coauthors. “This gives us an opportunity to think about how we can improve sleep to improve outcomes.”
Dr. Zee advises dermatologists and primary care clinicians to ask patients with AD about their sleep health by using a screening tool such as the self-reported STOP questionnaire, which consists of the following questions: “Do you snore loudly?” “Do you often feel tired, fatigued, or sleepy during daytime?” “Has anyone observed you stop breathing during your sleep?” “Do you have or are you being treated for high blood pressure?”
Other clinical indicators of a sleep disorder, such as obstructive sleep apnea (OSA), include having a neck circumference of 17 inches or greater in men and 16 inches or greater in women. “You want to also do a brief upper-airway examination, the Mallampati classification where you say to the patient, ‘open your mouth, don’t stick your mouth out too much,’ and you look at how crowded the upper airway is,” Dr. Zee said . “Someone with a Mallampati score of 3 has a very high risk of having sleep apnea.”
She also recommends asking patients with AD if they have difficulty falling asleep or staying asleep 3 or more nights per week, and about the frequency and duration of awakenings. “Maybe they have insomnia as a disorder,” she said. “If they have trouble falling asleep, maybe they have a circadian rhythm disorder. You want to ask about snoring, choking, and stop breathing episodes, because those are symptoms of sleep apnea. You want to ask about itch, uncomfortable sensations in the limbs during sleep or while trying to get to sleep, because that may be something like restless legs syndrome. Sleep disorder assessment is important because it impair daytime function, cognition, attention, and disruptive behavior, especially in children.”
For the management of insomnia, try behavioral approaches first. “You don’t want to try medications from the get-go,” Dr. Zee advised. Techniques include sleep hygiene and stimulus control therapy, “to make the bedroom a safe place to sleep. Lower the temperature a little bit and get rid of the allergens as much as possible. Relaxation and cognitive-behavioral therapy can also help. If you get a lot of light during the day, structure your physical activity, and watch what and when you eat.”
An OSA diagnosis requires evaluation of objective information from a sleep study. Common treatments of mild to moderate OSA include nasal continuous positive airway pressure and oral appliances.
Dr. Zee disclosed that she had received research funding from the National Institutes of Health, Jazz Pharmaceuticals, Harmony and Apnimed. She also serves on the scientific advisory board of Eisai, Jazz, CVS-Caremark, Takeda, and Sanofi-Aventis, and holds stock in Teva.
According to Phyllis C. Zee, MD, PhD, proinflammatory cytokines influence neural processes that affect sleep and circadian rhythm. “It’s almost like when you’re most vulnerable, when you’re sleeping, the immune system is kind of poised for attack,” Dr. Zee, chief of the division of sleep medicine at Northwestern University, Chicago, said at the Revolutionizing Atopic Dermatitis symposium. “This is normal, and perhaps in some of these inflammatory disorders, it’s gone a little haywire.”
Circulation of interleukins and cytokines are high in the morning, become lower in the afternoon, and then get higher again in the evening hours and into the night during sleep, she continued. “Whereas if you look at something like blood flow, it increases on a diurnal basis,” she said. “It’s higher during the day and a little bit lower during the mid-day, and a little bit higher during the evening. That parallels changes in the sebum production of the skin and the transepidermal water loss, which has been implicated in some of the symptoms of AD. What’s curious about this is that the transdermal/epidermal water loss is really highest during the sleep period. Some of this is sleep gated, but some of this is circadian gated as well. There’s a bidirectional relationship between sleep and immunity.”
Disturbance of sleep can have multiple consequences. It can activate the hypothalamic-pituitary-adrenal axis through autonomic activation, increase brain metabolic activity, trigger mood disturbances and cognitive impairment, and cause daytime sleepiness and health consequences that affect cardiometabolic and immunologic health.
One study conducted by Anna B. Fishbein, MD, Dr. Zee, and colleagues at Northwestern examined the effects of sleep duration and sleep disruption and movements in 38 children with and without moderate to severe AD. It found that children with AD get about 1 hour less of sleep per night overall, compared with age-matched healthy controls. “It’s not so much difficulty falling asleep, but more difficulty staying asleep as determined by wake after sleep onset,” said Dr. Zee, who is also a professor of neurology at Northwestern.
A study of 34,613 adults who participated in the 2012 National Health and Nutrition Examination Survey found that eczema increased the odds of fatigue (odds ratio, 2.97), daytime sleepiness (OR, 2.66), and regular insomnia (OR, 2.36).
“Very importantly, it predicted poor health,” said Dr. Zee, who was one of the study’s coauthors. “This gives us an opportunity to think about how we can improve sleep to improve outcomes.”
Dr. Zee advises dermatologists and primary care clinicians to ask patients with AD about their sleep health by using a screening tool such as the self-reported STOP questionnaire, which consists of the following questions: “Do you snore loudly?” “Do you often feel tired, fatigued, or sleepy during daytime?” “Has anyone observed you stop breathing during your sleep?” “Do you have or are you being treated for high blood pressure?”
Other clinical indicators of a sleep disorder, such as obstructive sleep apnea (OSA), include having a neck circumference of 17 inches or greater in men and 16 inches or greater in women. “You want to also do a brief upper-airway examination, the Mallampati classification where you say to the patient, ‘open your mouth, don’t stick your mouth out too much,’ and you look at how crowded the upper airway is,” Dr. Zee said . “Someone with a Mallampati score of 3 has a very high risk of having sleep apnea.”
She also recommends asking patients with AD if they have difficulty falling asleep or staying asleep 3 or more nights per week, and about the frequency and duration of awakenings. “Maybe they have insomnia as a disorder,” she said. “If they have trouble falling asleep, maybe they have a circadian rhythm disorder. You want to ask about snoring, choking, and stop breathing episodes, because those are symptoms of sleep apnea. You want to ask about itch, uncomfortable sensations in the limbs during sleep or while trying to get to sleep, because that may be something like restless legs syndrome. Sleep disorder assessment is important because it impair daytime function, cognition, attention, and disruptive behavior, especially in children.”
For the management of insomnia, try behavioral approaches first. “You don’t want to try medications from the get-go,” Dr. Zee advised. Techniques include sleep hygiene and stimulus control therapy, “to make the bedroom a safe place to sleep. Lower the temperature a little bit and get rid of the allergens as much as possible. Relaxation and cognitive-behavioral therapy can also help. If you get a lot of light during the day, structure your physical activity, and watch what and when you eat.”
An OSA diagnosis requires evaluation of objective information from a sleep study. Common treatments of mild to moderate OSA include nasal continuous positive airway pressure and oral appliances.
Dr. Zee disclosed that she had received research funding from the National Institutes of Health, Jazz Pharmaceuticals, Harmony and Apnimed. She also serves on the scientific advisory board of Eisai, Jazz, CVS-Caremark, Takeda, and Sanofi-Aventis, and holds stock in Teva.
According to Phyllis C. Zee, MD, PhD, proinflammatory cytokines influence neural processes that affect sleep and circadian rhythm. “It’s almost like when you’re most vulnerable, when you’re sleeping, the immune system is kind of poised for attack,” Dr. Zee, chief of the division of sleep medicine at Northwestern University, Chicago, said at the Revolutionizing Atopic Dermatitis symposium. “This is normal, and perhaps in some of these inflammatory disorders, it’s gone a little haywire.”
Circulation of interleukins and cytokines are high in the morning, become lower in the afternoon, and then get higher again in the evening hours and into the night during sleep, she continued. “Whereas if you look at something like blood flow, it increases on a diurnal basis,” she said. “It’s higher during the day and a little bit lower during the mid-day, and a little bit higher during the evening. That parallels changes in the sebum production of the skin and the transepidermal water loss, which has been implicated in some of the symptoms of AD. What’s curious about this is that the transdermal/epidermal water loss is really highest during the sleep period. Some of this is sleep gated, but some of this is circadian gated as well. There’s a bidirectional relationship between sleep and immunity.”
Disturbance of sleep can have multiple consequences. It can activate the hypothalamic-pituitary-adrenal axis through autonomic activation, increase brain metabolic activity, trigger mood disturbances and cognitive impairment, and cause daytime sleepiness and health consequences that affect cardiometabolic and immunologic health.
One study conducted by Anna B. Fishbein, MD, Dr. Zee, and colleagues at Northwestern examined the effects of sleep duration and sleep disruption and movements in 38 children with and without moderate to severe AD. It found that children with AD get about 1 hour less of sleep per night overall, compared with age-matched healthy controls. “It’s not so much difficulty falling asleep, but more difficulty staying asleep as determined by wake after sleep onset,” said Dr. Zee, who is also a professor of neurology at Northwestern.
A study of 34,613 adults who participated in the 2012 National Health and Nutrition Examination Survey found that eczema increased the odds of fatigue (odds ratio, 2.97), daytime sleepiness (OR, 2.66), and regular insomnia (OR, 2.36).
“Very importantly, it predicted poor health,” said Dr. Zee, who was one of the study’s coauthors. “This gives us an opportunity to think about how we can improve sleep to improve outcomes.”
Dr. Zee advises dermatologists and primary care clinicians to ask patients with AD about their sleep health by using a screening tool such as the self-reported STOP questionnaire, which consists of the following questions: “Do you snore loudly?” “Do you often feel tired, fatigued, or sleepy during daytime?” “Has anyone observed you stop breathing during your sleep?” “Do you have or are you being treated for high blood pressure?”
Other clinical indicators of a sleep disorder, such as obstructive sleep apnea (OSA), include having a neck circumference of 17 inches or greater in men and 16 inches or greater in women. “You want to also do a brief upper-airway examination, the Mallampati classification where you say to the patient, ‘open your mouth, don’t stick your mouth out too much,’ and you look at how crowded the upper airway is,” Dr. Zee said . “Someone with a Mallampati score of 3 has a very high risk of having sleep apnea.”
She also recommends asking patients with AD if they have difficulty falling asleep or staying asleep 3 or more nights per week, and about the frequency and duration of awakenings. “Maybe they have insomnia as a disorder,” she said. “If they have trouble falling asleep, maybe they have a circadian rhythm disorder. You want to ask about snoring, choking, and stop breathing episodes, because those are symptoms of sleep apnea. You want to ask about itch, uncomfortable sensations in the limbs during sleep or while trying to get to sleep, because that may be something like restless legs syndrome. Sleep disorder assessment is important because it impair daytime function, cognition, attention, and disruptive behavior, especially in children.”
For the management of insomnia, try behavioral approaches first. “You don’t want to try medications from the get-go,” Dr. Zee advised. Techniques include sleep hygiene and stimulus control therapy, “to make the bedroom a safe place to sleep. Lower the temperature a little bit and get rid of the allergens as much as possible. Relaxation and cognitive-behavioral therapy can also help. If you get a lot of light during the day, structure your physical activity, and watch what and when you eat.”
An OSA diagnosis requires evaluation of objective information from a sleep study. Common treatments of mild to moderate OSA include nasal continuous positive airway pressure and oral appliances.
Dr. Zee disclosed that she had received research funding from the National Institutes of Health, Jazz Pharmaceuticals, Harmony and Apnimed. She also serves on the scientific advisory board of Eisai, Jazz, CVS-Caremark, Takeda, and Sanofi-Aventis, and holds stock in Teva.
FROM REVOLUTIONIZING AD 2020
Can smoke exposure inform CRC surveillance in IBD?
Cigarette smoking may be associated with a higher probability of developing colorectal neoplasia (CRN) among patients with inflammatory bowel disease (IBD), a finding that if confirmed could help to refine colorectal cancer surveillance guidelines. IBD patients undergo surveillance at specific time points of their disease with the aim to detect and potentially treat early CRN.
But these procedures are costly and burdensome to patients, and some previous studies have revealed a relatively low utility for patients, according to Kimberley van der Sloot, MD, a PhD candidate at the University Medical Center Groningen (the Netherlands). She presented the research at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. The study was also published in Clinical Gastroenterology and Hepatology.
“We aimed to explore the role of cigarette exposure in colorectal neoplasia risk in patients with IBD, and we aimed to improve the CRN risk stratification model that we are currently using for these surveillance guidelines,” Dr. van der Sloot said during her talk.
Commenters during the Q&A period noted that the population database used in the study did not include measures of inflammation, which is a known risk for CRN. One review found that smoking worsens inflammation in Crohn’s disease but improves it in ulcerative colitis.
“It certainly raises the issue that we’ve always said, which is that people should quit smoking for other health reasons, but it doesn’t necessarily answer the question definitively,” said David Rubin, MD, who moderated the session and is professor of medicine at the University of Chicago and chair of the congress’s organizing committee. He added that the association between smoking and CRN risk may nevertheless inform future management surveillance guidelines if it is confirmed.
The researchers analyzed data from the 1000IBD cohort, which is prospectively following IBD patients in the Netherlands. The study included 1,386 patients who had at least one colorectal biopsy. Compared to a general population CRN incidence of 2.4%, Crohn’s disease patients who were never smokers had an incidence of 4.7% versus 10.3% among former or current smokers. In ulcerative colitis, the incidence was 12.5% among never smokers and 17.9% among former or current smokers.
In Crohn’s disease, previous or current smokers had about a twofold increased risk (hazard ratio, 2.04; P = .044). Compared to never smokers, former smokers trended toward an increased risk (HR, 2.16; P = .051), and active smokers had a significantly increased risk (HR, 2.20; P = .044). Passive smoke exposure was also associated with greater risk, both in childhood (HR, 4.79; P = .003) and current (HR, 1.87; P = .024).
In ulcerative colitis, the only statistically significant association between smoke exposure and CRN risk was among former smokers (HR, 1.73; P = .032).
The researchers also looked at patients with a disease duration longer than 8 years and stratified patients according to low risk (left-side ulcerative colitis, <50% of colon affected in Crohn’s disease; n = 425), medium risk (postinflammatory polyposis present or extensive colitis; n = 467), and high risk (concordant primary sclerosing cholangitis or having a first-degree relative with colorectal cancer; n = 143). In Crohn’s disease, current smoking was associated with greater CRN incidence (P = .046), and former smoking trended in that direction but was nonsignificant (P = .068). Former smoking also trended toward a risk in ulcerative colitis (P = .068), but there was no sign of an association for current smoking (P = .883).
In Crohn’s disease, after adjustment for risk stratification, greater CRN risk was associated with passive smoke exposure both during childhood (P = .001) and at present (P = .003).
“We believe this is the first study to describe the important role of cigarette smoking in development of colorectal neoplasia in IBD patients in a large, prospective, cohort, and I think [it] has shown the importance of lifestyle and smoking particularly in IBD. This is one more example. Alongside that, we’ve shown that adding this risk factor can improve the current risk stratification that is used for surveillance guidelines, and might be of benefit in the development of future guidelines,” said Dr. van der Sloot.
Dr. van der Sloot and Dr. Rubin had no relevant financial disclosures.
This article was updated Mar. 11, 2021.
Cigarette smoking may be associated with a higher probability of developing colorectal neoplasia (CRN) among patients with inflammatory bowel disease (IBD), a finding that if confirmed could help to refine colorectal cancer surveillance guidelines. IBD patients undergo surveillance at specific time points of their disease with the aim to detect and potentially treat early CRN.
But these procedures are costly and burdensome to patients, and some previous studies have revealed a relatively low utility for patients, according to Kimberley van der Sloot, MD, a PhD candidate at the University Medical Center Groningen (the Netherlands). She presented the research at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. The study was also published in Clinical Gastroenterology and Hepatology.
“We aimed to explore the role of cigarette exposure in colorectal neoplasia risk in patients with IBD, and we aimed to improve the CRN risk stratification model that we are currently using for these surveillance guidelines,” Dr. van der Sloot said during her talk.
Commenters during the Q&A period noted that the population database used in the study did not include measures of inflammation, which is a known risk for CRN. One review found that smoking worsens inflammation in Crohn’s disease but improves it in ulcerative colitis.
“It certainly raises the issue that we’ve always said, which is that people should quit smoking for other health reasons, but it doesn’t necessarily answer the question definitively,” said David Rubin, MD, who moderated the session and is professor of medicine at the University of Chicago and chair of the congress’s organizing committee. He added that the association between smoking and CRN risk may nevertheless inform future management surveillance guidelines if it is confirmed.
The researchers analyzed data from the 1000IBD cohort, which is prospectively following IBD patients in the Netherlands. The study included 1,386 patients who had at least one colorectal biopsy. Compared to a general population CRN incidence of 2.4%, Crohn’s disease patients who were never smokers had an incidence of 4.7% versus 10.3% among former or current smokers. In ulcerative colitis, the incidence was 12.5% among never smokers and 17.9% among former or current smokers.
In Crohn’s disease, previous or current smokers had about a twofold increased risk (hazard ratio, 2.04; P = .044). Compared to never smokers, former smokers trended toward an increased risk (HR, 2.16; P = .051), and active smokers had a significantly increased risk (HR, 2.20; P = .044). Passive smoke exposure was also associated with greater risk, both in childhood (HR, 4.79; P = .003) and current (HR, 1.87; P = .024).
In ulcerative colitis, the only statistically significant association between smoke exposure and CRN risk was among former smokers (HR, 1.73; P = .032).
The researchers also looked at patients with a disease duration longer than 8 years and stratified patients according to low risk (left-side ulcerative colitis, <50% of colon affected in Crohn’s disease; n = 425), medium risk (postinflammatory polyposis present or extensive colitis; n = 467), and high risk (concordant primary sclerosing cholangitis or having a first-degree relative with colorectal cancer; n = 143). In Crohn’s disease, current smoking was associated with greater CRN incidence (P = .046), and former smoking trended in that direction but was nonsignificant (P = .068). Former smoking also trended toward a risk in ulcerative colitis (P = .068), but there was no sign of an association for current smoking (P = .883).
In Crohn’s disease, after adjustment for risk stratification, greater CRN risk was associated with passive smoke exposure both during childhood (P = .001) and at present (P = .003).
“We believe this is the first study to describe the important role of cigarette smoking in development of colorectal neoplasia in IBD patients in a large, prospective, cohort, and I think [it] has shown the importance of lifestyle and smoking particularly in IBD. This is one more example. Alongside that, we’ve shown that adding this risk factor can improve the current risk stratification that is used for surveillance guidelines, and might be of benefit in the development of future guidelines,” said Dr. van der Sloot.
Dr. van der Sloot and Dr. Rubin had no relevant financial disclosures.
This article was updated Mar. 11, 2021.
Cigarette smoking may be associated with a higher probability of developing colorectal neoplasia (CRN) among patients with inflammatory bowel disease (IBD), a finding that if confirmed could help to refine colorectal cancer surveillance guidelines. IBD patients undergo surveillance at specific time points of their disease with the aim to detect and potentially treat early CRN.
But these procedures are costly and burdensome to patients, and some previous studies have revealed a relatively low utility for patients, according to Kimberley van der Sloot, MD, a PhD candidate at the University Medical Center Groningen (the Netherlands). She presented the research at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. The study was also published in Clinical Gastroenterology and Hepatology.
“We aimed to explore the role of cigarette exposure in colorectal neoplasia risk in patients with IBD, and we aimed to improve the CRN risk stratification model that we are currently using for these surveillance guidelines,” Dr. van der Sloot said during her talk.
Commenters during the Q&A period noted that the population database used in the study did not include measures of inflammation, which is a known risk for CRN. One review found that smoking worsens inflammation in Crohn’s disease but improves it in ulcerative colitis.
“It certainly raises the issue that we’ve always said, which is that people should quit smoking for other health reasons, but it doesn’t necessarily answer the question definitively,” said David Rubin, MD, who moderated the session and is professor of medicine at the University of Chicago and chair of the congress’s organizing committee. He added that the association between smoking and CRN risk may nevertheless inform future management surveillance guidelines if it is confirmed.
The researchers analyzed data from the 1000IBD cohort, which is prospectively following IBD patients in the Netherlands. The study included 1,386 patients who had at least one colorectal biopsy. Compared to a general population CRN incidence of 2.4%, Crohn’s disease patients who were never smokers had an incidence of 4.7% versus 10.3% among former or current smokers. In ulcerative colitis, the incidence was 12.5% among never smokers and 17.9% among former or current smokers.
In Crohn’s disease, previous or current smokers had about a twofold increased risk (hazard ratio, 2.04; P = .044). Compared to never smokers, former smokers trended toward an increased risk (HR, 2.16; P = .051), and active smokers had a significantly increased risk (HR, 2.20; P = .044). Passive smoke exposure was also associated with greater risk, both in childhood (HR, 4.79; P = .003) and current (HR, 1.87; P = .024).
In ulcerative colitis, the only statistically significant association between smoke exposure and CRN risk was among former smokers (HR, 1.73; P = .032).
The researchers also looked at patients with a disease duration longer than 8 years and stratified patients according to low risk (left-side ulcerative colitis, <50% of colon affected in Crohn’s disease; n = 425), medium risk (postinflammatory polyposis present or extensive colitis; n = 467), and high risk (concordant primary sclerosing cholangitis or having a first-degree relative with colorectal cancer; n = 143). In Crohn’s disease, current smoking was associated with greater CRN incidence (P = .046), and former smoking trended in that direction but was nonsignificant (P = .068). Former smoking also trended toward a risk in ulcerative colitis (P = .068), but there was no sign of an association for current smoking (P = .883).
In Crohn’s disease, after adjustment for risk stratification, greater CRN risk was associated with passive smoke exposure both during childhood (P = .001) and at present (P = .003).
“We believe this is the first study to describe the important role of cigarette smoking in development of colorectal neoplasia in IBD patients in a large, prospective, cohort, and I think [it] has shown the importance of lifestyle and smoking particularly in IBD. This is one more example. Alongside that, we’ve shown that adding this risk factor can improve the current risk stratification that is used for surveillance guidelines, and might be of benefit in the development of future guidelines,” said Dr. van der Sloot.
Dr. van der Sloot and Dr. Rubin had no relevant financial disclosures.
This article was updated Mar. 11, 2021.
FROM THE CROHN’S AND COLITIS CONGRESS