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SAN DIEGO – Use of noninvasive ventilation during an exercise session in hypercapnic patients with very severe chronic obstructive pulmonary disease (COPD) led to a clinically relevant increase in endurance time, a randomized trial showed.

At an international conference of the American Thoracic Society, lead study author Tessa Schneeberger noted that nocturnal noninvasive ventilation (NIV) in hypercapnic COPD patients has been shown to improve quality of life and survival (Lancet Resp Med. 2014;2[9]:698-705). Another study found that NIV with unchanged nocturnal settings during a 6-minute walk test in hypercapnic COPD patients can increase oxygenation, decrease dyspnea, and increase walking distance (Eur Respir J. 2007;29:930-6).

For the current study, Ms. Schneeberger, a physiotherapist at the Institute for Pulmonary Rehabilitation Research, Schoenau am Koenigssee, Germany, and her associates set out to investigate short-term effects of using NIV during exercise in hypercapnic patients with very severe COPD, as part of a 3-week inpatient physical rehabilitation program. The researchers limited their analysis to 20 Global Initiative for Chronic Obstructive Lung Disease stage IV patients aged 40-80 years with a carbon dioxide partial pressure (PCO₂) of greater than 50 mm Hg at rest and/or during exercise and who were non-naive to NIV, and excluded patients with concomitant conditions that make cycling impossible, those with acute exacerbations, and those with exercise-limiting cardiovascular diseases.

The day after an initial incremental cycle ergometer test, patients performed two constant work rate tests (CWRT) at 60% of the peak work rate, with and without NIV, in randomized order and with a resting time of 1 hour between tests. The inspiratory positive airway pressure (IPAP) was individually adjusted from each patient’s nocturnal settings to provide sufficient pressure to relieve the work on breathing muscles and to decrease transcutaneous PCO₂ (TcPCO₂) levels during NIV. The primary outcome was cycle endurance time. Other outcomes of interest were TcPCO₂, oxygen saturation (SpO₂) and perceived dyspnea/leg fatigue via the 10-point Borg scale during CWRTs.

The mean age of the study participants was 60 years, their mean body mass index was 23 kg/m², their mean forced expiratory volume in1 second was 19% predicted, their mean PaCO₂ was 51 mm Hg, their mean PaO₂ was 54.5 mm Hg, their mean distance on the 6-minute walk test was 243 meters, and their mean peak work rate was 42 watts.

NIV via full face mask and assisted pressure control ventilation mode was performed with mean IPAP/expiratory PAP levels of 27/6 cm H₂O.

During CWRTs patients cycled with NIV for 663 seconds and without NIV for 476 seconds, a significant difference (P = .013) and one that was clinically relevant. At isotime (the time of CWRT with shortest duration), TcPCO₂ was significantly lower with NIV (a mean of –6.1 mm Hg), while SpO₂ was significantly higher with NIV (a mean of 3.6%). In addition, after CWRT, NIV patients perceived less dyspnea (P = .008) with comparable leg fatigue (P = .79).

“We found that NIV during cycling exercise in hypercapnic patients with very severe COPD can lead to an acutely significant increase in exercise duration, with lower TcPCO₂ and a reduced sensation of dyspnea,” Ms. Schneeberger concluded. “It can be performed with high-pressure assisted-controlled ventilation comparable as that used nocturnally to effectively reduce TcPCO₂ in people with COPD.”

She emphasized that this approach requires appropriate equipment and special staff expertise for setup titration. “We will continue this research to look into the underlying physiological mechanisms to define nonresponders and responders, and also to look how at this might improve outcomes of an exercise training program.”

Ms. Schneeberger reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Schneeberger T et al. ATS 2018, Abstract A2453.


 

SAN DIEGO – Use of noninvasive ventilation during an exercise session in hypercapnic patients with very severe chronic obstructive pulmonary disease (COPD) led to a clinically relevant increase in endurance time, a randomized trial showed.

At an international conference of the American Thoracic Society, lead study author Tessa Schneeberger noted that nocturnal noninvasive ventilation (NIV) in hypercapnic COPD patients has been shown to improve quality of life and survival (Lancet Resp Med. 2014;2[9]:698-705). Another study found that NIV with unchanged nocturnal settings during a 6-minute walk test in hypercapnic COPD patients can increase oxygenation, decrease dyspnea, and increase walking distance (Eur Respir J. 2007;29:930-6).

For the current study, Ms. Schneeberger, a physiotherapist at the Institute for Pulmonary Rehabilitation Research, Schoenau am Koenigssee, Germany, and her associates set out to investigate short-term effects of using NIV during exercise in hypercapnic patients with very severe COPD, as part of a 3-week inpatient physical rehabilitation program. The researchers limited their analysis to 20 Global Initiative for Chronic Obstructive Lung Disease stage IV patients aged 40-80 years with a carbon dioxide partial pressure (PCO₂) of greater than 50 mm Hg at rest and/or during exercise and who were non-naive to NIV, and excluded patients with concomitant conditions that make cycling impossible, those with acute exacerbations, and those with exercise-limiting cardiovascular diseases.

The day after an initial incremental cycle ergometer test, patients performed two constant work rate tests (CWRT) at 60% of the peak work rate, with and without NIV, in randomized order and with a resting time of 1 hour between tests. The inspiratory positive airway pressure (IPAP) was individually adjusted from each patient’s nocturnal settings to provide sufficient pressure to relieve the work on breathing muscles and to decrease transcutaneous PCO₂ (TcPCO₂) levels during NIV. The primary outcome was cycle endurance time. Other outcomes of interest were TcPCO₂, oxygen saturation (SpO₂) and perceived dyspnea/leg fatigue via the 10-point Borg scale during CWRTs.

The mean age of the study participants was 60 years, their mean body mass index was 23 kg/m², their mean forced expiratory volume in1 second was 19% predicted, their mean PaCO₂ was 51 mm Hg, their mean PaO₂ was 54.5 mm Hg, their mean distance on the 6-minute walk test was 243 meters, and their mean peak work rate was 42 watts.

NIV via full face mask and assisted pressure control ventilation mode was performed with mean IPAP/expiratory PAP levels of 27/6 cm H₂O.

During CWRTs patients cycled with NIV for 663 seconds and without NIV for 476 seconds, a significant difference (P = .013) and one that was clinically relevant. At isotime (the time of CWRT with shortest duration), TcPCO₂ was significantly lower with NIV (a mean of –6.1 mm Hg), while SpO₂ was significantly higher with NIV (a mean of 3.6%). In addition, after CWRT, NIV patients perceived less dyspnea (P = .008) with comparable leg fatigue (P = .79).

“We found that NIV during cycling exercise in hypercapnic patients with very severe COPD can lead to an acutely significant increase in exercise duration, with lower TcPCO₂ and a reduced sensation of dyspnea,” Ms. Schneeberger concluded. “It can be performed with high-pressure assisted-controlled ventilation comparable as that used nocturnally to effectively reduce TcPCO₂ in people with COPD.”

She emphasized that this approach requires appropriate equipment and special staff expertise for setup titration. “We will continue this research to look into the underlying physiological mechanisms to define nonresponders and responders, and also to look how at this might improve outcomes of an exercise training program.”

Ms. Schneeberger reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Schneeberger T et al. ATS 2018, Abstract A2453.


 

SAN DIEGO – Use of noninvasive ventilation during an exercise session in hypercapnic patients with very severe chronic obstructive pulmonary disease (COPD) led to a clinically relevant increase in endurance time, a randomized trial showed.

At an international conference of the American Thoracic Society, lead study author Tessa Schneeberger noted that nocturnal noninvasive ventilation (NIV) in hypercapnic COPD patients has been shown to improve quality of life and survival (Lancet Resp Med. 2014;2[9]:698-705). Another study found that NIV with unchanged nocturnal settings during a 6-minute walk test in hypercapnic COPD patients can increase oxygenation, decrease dyspnea, and increase walking distance (Eur Respir J. 2007;29:930-6).

For the current study, Ms. Schneeberger, a physiotherapist at the Institute for Pulmonary Rehabilitation Research, Schoenau am Koenigssee, Germany, and her associates set out to investigate short-term effects of using NIV during exercise in hypercapnic patients with very severe COPD, as part of a 3-week inpatient physical rehabilitation program. The researchers limited their analysis to 20 Global Initiative for Chronic Obstructive Lung Disease stage IV patients aged 40-80 years with a carbon dioxide partial pressure (PCO₂) of greater than 50 mm Hg at rest and/or during exercise and who were non-naive to NIV, and excluded patients with concomitant conditions that make cycling impossible, those with acute exacerbations, and those with exercise-limiting cardiovascular diseases.

The day after an initial incremental cycle ergometer test, patients performed two constant work rate tests (CWRT) at 60% of the peak work rate, with and without NIV, in randomized order and with a resting time of 1 hour between tests. The inspiratory positive airway pressure (IPAP) was individually adjusted from each patient’s nocturnal settings to provide sufficient pressure to relieve the work on breathing muscles and to decrease transcutaneous PCO₂ (TcPCO₂) levels during NIV. The primary outcome was cycle endurance time. Other outcomes of interest were TcPCO₂, oxygen saturation (SpO₂) and perceived dyspnea/leg fatigue via the 10-point Borg scale during CWRTs.

The mean age of the study participants was 60 years, their mean body mass index was 23 kg/m², their mean forced expiratory volume in1 second was 19% predicted, their mean PaCO₂ was 51 mm Hg, their mean PaO₂ was 54.5 mm Hg, their mean distance on the 6-minute walk test was 243 meters, and their mean peak work rate was 42 watts.

NIV via full face mask and assisted pressure control ventilation mode was performed with mean IPAP/expiratory PAP levels of 27/6 cm H₂O.

During CWRTs patients cycled with NIV for 663 seconds and without NIV for 476 seconds, a significant difference (P = .013) and one that was clinically relevant. At isotime (the time of CWRT with shortest duration), TcPCO₂ was significantly lower with NIV (a mean of –6.1 mm Hg), while SpO₂ was significantly higher with NIV (a mean of 3.6%). In addition, after CWRT, NIV patients perceived less dyspnea (P = .008) with comparable leg fatigue (P = .79).

“We found that NIV during cycling exercise in hypercapnic patients with very severe COPD can lead to an acutely significant increase in exercise duration, with lower TcPCO₂ and a reduced sensation of dyspnea,” Ms. Schneeberger concluded. “It can be performed with high-pressure assisted-controlled ventilation comparable as that used nocturnally to effectively reduce TcPCO₂ in people with COPD.”

She emphasized that this approach requires appropriate equipment and special staff expertise for setup titration. “We will continue this research to look into the underlying physiological mechanisms to define nonresponders and responders, and also to look how at this might improve outcomes of an exercise training program.”

Ms. Schneeberger reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Schneeberger T et al. ATS 2018, Abstract A2453.


 

SAN DIEGO – A massive effort to better understand and treat patients with pulmonary hypertension and right heart dysfunction is underway.

The endeavor, funded by the National Heart, Lung, and Blood Institute and the Pulmonary Hypertension Association and known as Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics (PVDOMICS), began recruiting participants in 2017, with a goal of 1,500 by 2019. The aim is to perform comprehensive phenotyping and endophenotyping across the World Health Organization–classified pulmonary hypertension (PH) clinical groups 1 through 5 in order to deconstruct the traditional classification and define new meaningful subclassifications of patients with pulmonary vascular disease.

Purestock/thinkstockphotos

At an international conference of the American Thoracic Society, one of the study’s investigators, Robert P. Frantz, MD, discussed the role of echocardiography and MRI in the overall PVDOMICS program, which he characterized as a work in progress. “Imaging is critically important as we try to integrate severity of pulmonary vascular disease along with how well the ventricle functions as way to try and understand why some patients have a failing RV at a given pulmonary resistance and others don’t,” said Dr. Frantz, who directs the Mayo Pulmonary Hypertension Clinic in Rochester, Minn. The goals are to be able to integrate cardiac morphology and function with contemporaneous hemodynamics, he said. This will allow for validation of noninvasive hemodynamics versus right heart catheterization across all the phenotypes.

“In addition, we’ll have imaging parameters as predictors of hemodynamics at rest and with exercise, particularly in conditions like heart failure with preserved ejection fraction or concerns about left atrial stiffness,” he said. “In these cases, our ability on the basis of echocardiography or MRI to guess what the wedge pressure is at rest or exercise, or to think about other more recently described phenotypes like left atrial stiffness in patients who have left atrial ablation procedures, will be enabled by looking at parameters such as left atrial strain.”

Ultimately, he continued, a key goal of PVDOMICS is to be able to correlate the “-omics” with markers of RV compensation in an effort to understand what the determinants of RV compensation are across the varying types of pulmonary vascular disease.

“If we could do that, we might be able to develop new targets for therapy,” said Dr. Frantz. To illustrate how this might work, he cited findings from researchers who set out to identify and characterize homogeneous phenotypes by a cluster analysis in scleroderma patients with pulmonary hypertension, who were identified from two prospective cohorts in the United States and France (PLoS One 2018 May 15;13[5]:e0197112).

The researchers identified four different clusters of scleroderma patients: those with mild to moderate PAH with no or minimal interstitial lung disease and low-diffusing capacity for carbon monoxide; those with precapillary PH with severe ILD and worse survival; those with severe PAH, who trended toward worse survival, and those similar to the first cluster but with higher DLCO.

Dr. Frantz then shared preliminary findings of echocardiographic parameters by primary WHO group in PVDOMICS, on behalf of his PVDOMICS collaborators. They found, for example, that the mean right ventricular systolic pressure in group 3 was 45 mm Hg, as opposed to group 1, which was 64 mm Hg. “In general we had some patients in group 3 with less severe elevation of PA pressures,” he said.

Other parameters that can be compared across WHO groups include ventricular fractional area change, tricuspid annular plane systolic excursion, and RV free wall strain. “That strain of the right ventricle is one of the most important ways of looking at how the right ventricle works,” Dr. Frantz explained. “With this, we can integrate the concept of severity of RV dysfunction with severity of pulmonary vascular disease. This is where the rubber hits the road. It’s going to be very complicated and time consuming, but I think critically important. Ultimately, we can make proteomic heat maps that track these correlates, and ultimately identify pathways that may be driving RV compensation in pulmonary vascular disease.”

Dr. Frantz reported having no relevant financial disclosures.

dbrunk@mdedge.com

SAN DIEGO – A massive effort to better understand and treat patients with pulmonary hypertension and right heart dysfunction is underway.

The endeavor, funded by the National Heart, Lung, and Blood Institute and the Pulmonary Hypertension Association and known as Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics (PVDOMICS), began recruiting participants in 2017, with a goal of 1,500 by 2019. The aim is to perform comprehensive phenotyping and endophenotyping across the World Health Organization–classified pulmonary hypertension (PH) clinical groups 1 through 5 in order to deconstruct the traditional classification and define new meaningful subclassifications of patients with pulmonary vascular disease.

Purestock/thinkstockphotos

At an international conference of the American Thoracic Society, one of the study’s investigators, Robert P. Frantz, MD, discussed the role of echocardiography and MRI in the overall PVDOMICS program, which he characterized as a work in progress. “Imaging is critically important as we try to integrate severity of pulmonary vascular disease along with how well the ventricle functions as way to try and understand why some patients have a failing RV at a given pulmonary resistance and others don’t,” said Dr. Frantz, who directs the Mayo Pulmonary Hypertension Clinic in Rochester, Minn. The goals are to be able to integrate cardiac morphology and function with contemporaneous hemodynamics, he said. This will allow for validation of noninvasive hemodynamics versus right heart catheterization across all the phenotypes.

“In addition, we’ll have imaging parameters as predictors of hemodynamics at rest and with exercise, particularly in conditions like heart failure with preserved ejection fraction or concerns about left atrial stiffness,” he said. “In these cases, our ability on the basis of echocardiography or MRI to guess what the wedge pressure is at rest or exercise, or to think about other more recently described phenotypes like left atrial stiffness in patients who have left atrial ablation procedures, will be enabled by looking at parameters such as left atrial strain.”

Ultimately, he continued, a key goal of PVDOMICS is to be able to correlate the “-omics” with markers of RV compensation in an effort to understand what the determinants of RV compensation are across the varying types of pulmonary vascular disease.

“If we could do that, we might be able to develop new targets for therapy,” said Dr. Frantz. To illustrate how this might work, he cited findings from researchers who set out to identify and characterize homogeneous phenotypes by a cluster analysis in scleroderma patients with pulmonary hypertension, who were identified from two prospective cohorts in the United States and France (PLoS One 2018 May 15;13[5]:e0197112).

The researchers identified four different clusters of scleroderma patients: those with mild to moderate PAH with no or minimal interstitial lung disease and low-diffusing capacity for carbon monoxide; those with precapillary PH with severe ILD and worse survival; those with severe PAH, who trended toward worse survival, and those similar to the first cluster but with higher DLCO.

Dr. Frantz then shared preliminary findings of echocardiographic parameters by primary WHO group in PVDOMICS, on behalf of his PVDOMICS collaborators. They found, for example, that the mean right ventricular systolic pressure in group 3 was 45 mm Hg, as opposed to group 1, which was 64 mm Hg. “In general we had some patients in group 3 with less severe elevation of PA pressures,” he said.

Other parameters that can be compared across WHO groups include ventricular fractional area change, tricuspid annular plane systolic excursion, and RV free wall strain. “That strain of the right ventricle is one of the most important ways of looking at how the right ventricle works,” Dr. Frantz explained. “With this, we can integrate the concept of severity of RV dysfunction with severity of pulmonary vascular disease. This is where the rubber hits the road. It’s going to be very complicated and time consuming, but I think critically important. Ultimately, we can make proteomic heat maps that track these correlates, and ultimately identify pathways that may be driving RV compensation in pulmonary vascular disease.”

Dr. Frantz reported having no relevant financial disclosures.

dbrunk@mdedge.com

SAN DIEGO – A massive effort to better understand and treat patients with pulmonary hypertension and right heart dysfunction is underway.

The endeavor, funded by the National Heart, Lung, and Blood Institute and the Pulmonary Hypertension Association and known as Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics (PVDOMICS), began recruiting participants in 2017, with a goal of 1,500 by 2019. The aim is to perform comprehensive phenotyping and endophenotyping across the World Health Organization–classified pulmonary hypertension (PH) clinical groups 1 through 5 in order to deconstruct the traditional classification and define new meaningful subclassifications of patients with pulmonary vascular disease.

Purestock/thinkstockphotos

At an international conference of the American Thoracic Society, one of the study’s investigators, Robert P. Frantz, MD, discussed the role of echocardiography and MRI in the overall PVDOMICS program, which he characterized as a work in progress. “Imaging is critically important as we try to integrate severity of pulmonary vascular disease along with how well the ventricle functions as way to try and understand why some patients have a failing RV at a given pulmonary resistance and others don’t,” said Dr. Frantz, who directs the Mayo Pulmonary Hypertension Clinic in Rochester, Minn. The goals are to be able to integrate cardiac morphology and function with contemporaneous hemodynamics, he said. This will allow for validation of noninvasive hemodynamics versus right heart catheterization across all the phenotypes.

“In addition, we’ll have imaging parameters as predictors of hemodynamics at rest and with exercise, particularly in conditions like heart failure with preserved ejection fraction or concerns about left atrial stiffness,” he said. “In these cases, our ability on the basis of echocardiography or MRI to guess what the wedge pressure is at rest or exercise, or to think about other more recently described phenotypes like left atrial stiffness in patients who have left atrial ablation procedures, will be enabled by looking at parameters such as left atrial strain.”

Ultimately, he continued, a key goal of PVDOMICS is to be able to correlate the “-omics” with markers of RV compensation in an effort to understand what the determinants of RV compensation are across the varying types of pulmonary vascular disease.

“If we could do that, we might be able to develop new targets for therapy,” said Dr. Frantz. To illustrate how this might work, he cited findings from researchers who set out to identify and characterize homogeneous phenotypes by a cluster analysis in scleroderma patients with pulmonary hypertension, who were identified from two prospective cohorts in the United States and France (PLoS One 2018 May 15;13[5]:e0197112).

The researchers identified four different clusters of scleroderma patients: those with mild to moderate PAH with no or minimal interstitial lung disease and low-diffusing capacity for carbon monoxide; those with precapillary PH with severe ILD and worse survival; those with severe PAH, who trended toward worse survival, and those similar to the first cluster but with higher DLCO.

Dr. Frantz then shared preliminary findings of echocardiographic parameters by primary WHO group in PVDOMICS, on behalf of his PVDOMICS collaborators. They found, for example, that the mean right ventricular systolic pressure in group 3 was 45 mm Hg, as opposed to group 1, which was 64 mm Hg. “In general we had some patients in group 3 with less severe elevation of PA pressures,” he said.

Other parameters that can be compared across WHO groups include ventricular fractional area change, tricuspid annular plane systolic excursion, and RV free wall strain. “That strain of the right ventricle is one of the most important ways of looking at how the right ventricle works,” Dr. Frantz explained. “With this, we can integrate the concept of severity of RV dysfunction with severity of pulmonary vascular disease. This is where the rubber hits the road. It’s going to be very complicated and time consuming, but I think critically important. Ultimately, we can make proteomic heat maps that track these correlates, and ultimately identify pathways that may be driving RV compensation in pulmonary vascular disease.”

Dr. Frantz reported having no relevant financial disclosures.

dbrunk@mdedge.com

All fourteen members of the Advisory Committee on Immunization Practices voted to approve the anthrax vaccine recommendations for 2018-2019 at their meeting.

The recommendations to the committee sought to optimize the use of Anthrax Vaccine Adsorbed (AVA) in post-exposure prophylaxis (PEP) in the event of a wide-area release of Bacillus anthracis spores. In this event, a mass vaccination effort would be undertaken, requiring expedited administration of AVA. ACIP now recommends that the intramuscular administration may be used over the traditional subcutaneous approach if there are any operational or logistical challenges that delay effective vaccination. Another recommendation from ACIP would allow two full doses or three half doses of AVA to be used to expand vaccine coverage for PEP in the event there is an inadequate vaccine supply. The committee also recommended that AbxPEP, an antimicrobial, be stopped 42 days after the first dose of AVA or 2 weeks after the last dose.

Carolina K. Smith, MD/Fotolia.com

William A. Bower, MD, of the division of high-consequence pathogens and pathology at the Centers for Disease Control and Prevention, and the anthrax work group looked at three nonhuman primate studies and eight human immunogenicity and adverse event studies during the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). All of the animal studies were used to predict human survival by vaccinating the nonhuman primates with AVA, then challenging them with B. anthracis. Using animal studies to predict human survival is common practice under the “animal rule.”

When Dr. Bower and the work group assessed the studies comparing intramuscular administration with subcutaneous administration of AVA, they rated the overall evidence as GRADE 2. However, they rated the adverse events data as GRADE 1.

Dr. Bower and his colleagues also reviewed dose-sparing studies to identify the feasibility of allowing two full doses or three half doses of AVA to be used to expand vaccine coverage for PEP in the event there is an inadequate vaccine supply. For these studies, the anthrax work group gave a GRADE score of 2.

The overall evidence score for microbial duration for PEP was judged to be GRADE 2.

“These forthcoming recommendations will be used by the CDC to inform state and local health departments to better prepare for an emergency response to a wide-area release of Bacillus anthracis spores,” said Dr. Bower.

The committee’s recommendations must be approved by the CDC’s director before they are considered official recommendations.

Dr. Bower did not report any relevant financial conflicts of interest.

ilacy@mdedge.com

All fourteen members of the Advisory Committee on Immunization Practices voted to approve the anthrax vaccine recommendations for 2018-2019 at their meeting.

The recommendations to the committee sought to optimize the use of Anthrax Vaccine Adsorbed (AVA) in post-exposure prophylaxis (PEP) in the event of a wide-area release of Bacillus anthracis spores. In this event, a mass vaccination effort would be undertaken, requiring expedited administration of AVA. ACIP now recommends that the intramuscular administration may be used over the traditional subcutaneous approach if there are any operational or logistical challenges that delay effective vaccination. Another recommendation from ACIP would allow two full doses or three half doses of AVA to be used to expand vaccine coverage for PEP in the event there is an inadequate vaccine supply. The committee also recommended that AbxPEP, an antimicrobial, be stopped 42 days after the first dose of AVA or 2 weeks after the last dose.

Carolina K. Smith, MD/Fotolia.com

William A. Bower, MD, of the division of high-consequence pathogens and pathology at the Centers for Disease Control and Prevention, and the anthrax work group looked at three nonhuman primate studies and eight human immunogenicity and adverse event studies during the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). All of the animal studies were used to predict human survival by vaccinating the nonhuman primates with AVA, then challenging them with B. anthracis. Using animal studies to predict human survival is common practice under the “animal rule.”

When Dr. Bower and the work group assessed the studies comparing intramuscular administration with subcutaneous administration of AVA, they rated the overall evidence as GRADE 2. However, they rated the adverse events data as GRADE 1.

Dr. Bower and his colleagues also reviewed dose-sparing studies to identify the feasibility of allowing two full doses or three half doses of AVA to be used to expand vaccine coverage for PEP in the event there is an inadequate vaccine supply. For these studies, the anthrax work group gave a GRADE score of 2.

The overall evidence score for microbial duration for PEP was judged to be GRADE 2.

“These forthcoming recommendations will be used by the CDC to inform state and local health departments to better prepare for an emergency response to a wide-area release of Bacillus anthracis spores,” said Dr. Bower.

The committee’s recommendations must be approved by the CDC’s director before they are considered official recommendations.

Dr. Bower did not report any relevant financial conflicts of interest.

ilacy@mdedge.com

All fourteen members of the Advisory Committee on Immunization Practices voted to approve the anthrax vaccine recommendations for 2018-2019 at their meeting.

The recommendations to the committee sought to optimize the use of Anthrax Vaccine Adsorbed (AVA) in post-exposure prophylaxis (PEP) in the event of a wide-area release of Bacillus anthracis spores. In this event, a mass vaccination effort would be undertaken, requiring expedited administration of AVA. ACIP now recommends that the intramuscular administration may be used over the traditional subcutaneous approach if there are any operational or logistical challenges that delay effective vaccination. Another recommendation from ACIP would allow two full doses or three half doses of AVA to be used to expand vaccine coverage for PEP in the event there is an inadequate vaccine supply. The committee also recommended that AbxPEP, an antimicrobial, be stopped 42 days after the first dose of AVA or 2 weeks after the last dose.

Carolina K. Smith, MD/Fotolia.com

William A. Bower, MD, of the division of high-consequence pathogens and pathology at the Centers for Disease Control and Prevention, and the anthrax work group looked at three nonhuman primate studies and eight human immunogenicity and adverse event studies during the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). All of the animal studies were used to predict human survival by vaccinating the nonhuman primates with AVA, then challenging them with B. anthracis. Using animal studies to predict human survival is common practice under the “animal rule.”

When Dr. Bower and the work group assessed the studies comparing intramuscular administration with subcutaneous administration of AVA, they rated the overall evidence as GRADE 2. However, they rated the adverse events data as GRADE 1.

Dr. Bower and his colleagues also reviewed dose-sparing studies to identify the feasibility of allowing two full doses or three half doses of AVA to be used to expand vaccine coverage for PEP in the event there is an inadequate vaccine supply. For these studies, the anthrax work group gave a GRADE score of 2.

The overall evidence score for microbial duration for PEP was judged to be GRADE 2.

“These forthcoming recommendations will be used by the CDC to inform state and local health departments to better prepare for an emergency response to a wide-area release of Bacillus anthracis spores,” said Dr. Bower.

The committee’s recommendations must be approved by the CDC’s director before they are considered official recommendations.

Dr. Bower did not report any relevant financial conflicts of interest.

ilacy@mdedge.com

Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.

The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.

By week 12, FEV1 it had already increased by 0.32 L, they said.

“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”

Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
 

Liberty Asthma Quest

This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.

Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.

Both doses outperformed placebo in all endpoints.

Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.

The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.

By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.

Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.

The benefit was already noticeable by the 2-week evaluation, the investigators noted.

Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).

Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
 

Liberty Asthma Venture

In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.

These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.

Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.

By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.

Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”

In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.

Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.

Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.

The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.

Antidrug antibodies developed in five patients in each group, without clinical effect.

Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.

msullivan@mdedge.com

SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.

Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.

The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.

By week 12, FEV1 it had already increased by 0.32 L, they said.

“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”

Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
 

Liberty Asthma Quest

This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.

Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.

Both doses outperformed placebo in all endpoints.

Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.

The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.

By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.

Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.

The benefit was already noticeable by the 2-week evaluation, the investigators noted.

Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).

Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
 

Liberty Asthma Venture

In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.

These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.

Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.

By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.

Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”

In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.

Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.

Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.

The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.

Antidrug antibodies developed in five patients in each group, without clinical effect.

Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.

msullivan@mdedge.com

SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.

Among patients with moderate to severe asthma, dupilumab reduced exacerbations by almost 50%, while also allowing glucocorticoid-treated patients to cut their use of that medication by 70%, with no increased risk of exacerbation.

The pair of placebo-controlled studies – Liberty Asthma Quest and Liberty Asthma Venture – also showed treatment-associated stability in forced expiratory volume (FEV1) evidence of lung remodeling among those who took the antibody, Mario Castro, MD, of Washington University, St. Louis, and his colleagues reported in the New England Journal of Medicine.

By week 12, FEV1 it had already increased by 0.32 L, they said.

“An analysis of the postbronchodilator FEV1 slope showed a loss of lung function in patients who received placebo and no loss in those who received dupilumab, findings that suggest a potential effect of dupilumab on airway remodeling,” wrote Dr. Castro and his colleagues. “The slope analysis showed that patients who received placebo lost, on average, approximately 40 mL annually, which is consistent with data from other cohorts of patients with asthma.”

Dupilumab is an anti–interleukin-4 alpha antibody that blocks both IL-4 and IL-13. The Quest trial examined efficacy and safety of two doses (200 mg and 300 mg every 2 weeks), compared with placebo in patients with uncontrolled asthma. Venture examined efficacy and safety of 300 mg or placebo as add-on therapy for patients with severe asthma who were taking glucocorticoids.
 

Liberty Asthma Quest

This 52-week study randomized 1,902 patients with severe, uncontrolled asthma to placebo or dupilumab 200 mg or 300 mg every other week. The primary endpoints were annual rate of severe asthma exacerbations and the change in FEV1 by week 12. The study also looked at these endpoints in patients whose baseline eosinophil count was greater than 300 per cubic millimeter.

Patients were a mean of 48 years old with a mean baseline FEV1 of about 1.75 L (about 58% of the predicted normal value). They had a mean of two exacerbations per year and an average eosinophil count of about 350 per cubic millimeter.

Both doses outperformed placebo in all endpoints.

Among those taking 200 mg, the annual relapse rate was 0.46 versus 0.87 among those taking placebo – a significant 47.7% risk reduction. Among those taking 300 mg, the exacerbation rate was 0.52 versus 0.97; this translated to a significant 46% risk reduction.

The response rate was even greater among those with an eosinophil count greater than 300 per cubic millimeter: 0.37 for 200 mg and 0.40 for 300 mg versus the placebo rates of 1.08 and 1.24. This translated to risk reductions of 65.8% and 67.4%, respectively.

By week 12, FEV1 had significantly increased by 0.32 L in the 200-mg group and by 0.34 L in the 300-mg group, compared with nonsignificant increases among those taking placebo.

Again, patients with the high eosinophil counts experienced the greatest benefits, with FEV1 increasing by a mean of 0.43 L at 12 weeks in the 200-mg group and by 0.47 L in the 300-mg group, significantly better than either placebo comparator.

The benefit was already noticeable by the 2-week evaluation, the investigators noted.

Dupilumab appeared safe; injection-site reactions were the most common adverse event, occurring in 15% of the low-dose group and 18% of the high-dose group. However, 52 patients taking the drug experienced eosinophilia, compared with four of those taking placebo (4.1% vs. 0.6%).

Four of those taking the study drug experienced clinical symptoms associated with eosinophilia, including worsening eosinophilia and chronic eosinophilic pneumonia.
 

Liberty Asthma Venture

In this study, the effect of dupilumab on glucocorticoid use among 210 patients with severe asthma was examined. Patients were randomized to add-on dupilumab 300 mg every 2 weeks for 24 weeks. Glucocorticoids were tapered downward from weeks 4 to 20. The primary endpoints were percent reduction in glucocorticoid dose at week 24, and the percentage of patients who experienced a reduction of at least 50% in glucocorticoid dose.

These patients were a mean of 51 years old, with a mean of two severe asthma exacerbations in the past year. Their mean daily oral glucocorticoid dose at randomization was about 11 mg per day. Their mean prebronchodilator FEV1 was about 1.6 liters – about 52% of predicted value.

Oral glucocorticoid use decreased by a mean of 70.1% in the active group, compared with 41.9% in the placebo group, a statistically significant difference, Klaus F. Rabe, MD, of Christian Albrechts University, Kiel, Germany, and his coauthors wrote in the New England Journal of Medicine. The median change was even better: A 100% reduction in the active group and 50% reduction in the placebo group.

By week 24, 80% of those taking dupilumab had decreased their glucocorticoid intake by at least 50%, compared with 50% of the placebo group reaching this goal. The glucocorticoid dose was less than 5 mg/day in 69% of the dupilumab group, compared with 33% of the placebo group.

Like Quest, Venture showed a treatment advantage among patients with high baseline eosinophil count. “The magnitude of the effect was largest in patients with a higher eosinophil count at baseline,” the investigators wrote. “… The odds ratios [a 50% glucocorticoid reduction] for dupilumab versus placebo were 6.59 among patients with 300 or more cells per cubic millimeter at baseline and 2.91 among those with less than 300 cells per cubic millimeter at baseline.”

In a fully adjusted model at week 24, 48% of the patients in the dupilumab group were able to stop oral glucocorticoids entirely, compared with 25% of the placebo group.

Dupilumab was also associated with a significant 59% reduction in severe annual asthma exacerbations. FEV1 among the active group was 0.22 L better than that in the placebo group at week 24.

Again, patients with a higher baseline blood eosinophil count experienced greater treatment benefit; among these, the rate of severe asthma exacerbations was 71% lower than the rate in the placebo group, and FEV1 was 0.32 L higher.

The most frequent adverse events were viral infections (9% of the patients in the dupilumab group vs. 18% of those in the placebo group), bronchitis (7% vs. 6%), sinusitis (7% vs. 4%), influenza (3% vs. 6%), and eosinophilia (14% vs. 1%). Injection-site reactions occurred in 9% of those taking dupilumab and 4% of those taking placebo.

Antidrug antibodies developed in five patients in each group, without clinical effect.

Both trials were funded by Sanofi and Regeneron. Dr. Castro has received grant support from Sanofi. Dr. Rabe has received consulting and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, Sanofi, and Teva Pharmaceutical Industries.

msullivan@mdedge.com

SOURCES: Castro M et al. N Engl J Med. 2018;378:2486-96; KF Rabe et al. N Engl J Med. 2018;378:2475-85.

Ibrutinib in combination with rituximab as a treatment for Waldenström macroglobulinemia (WM) is under priority review by the Food and Drug Administration.

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is already approved as a single agent for WM. The addition of rituximab to the indication is based on positive results from the phase 3 INNOVATE study. In particular, the trial showed a superior progression-free survival rate at 30 months for the ibrutinib-rituximab combination at 82%, compared with placebo plus rituximab at 28% (N Engl J Med. 2018;378:2399-410).

The study’s lead investigator, Meletios A. Dimopoulos, MD, called the combination a “new standard of care” for WM at the recent annual meeting of the American Society of Clinical Oncology.

Ibrutinib, marketed as Imbruvica, is jointly developed and commercialized by Pharmacyclics and Janssen Biotech.

mschneider@mdedge.com

Ibrutinib in combination with rituximab as a treatment for Waldenström macroglobulinemia (WM) is under priority review by the Food and Drug Administration.

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is already approved as a single agent for WM. The addition of rituximab to the indication is based on positive results from the phase 3 INNOVATE study. In particular, the trial showed a superior progression-free survival rate at 30 months for the ibrutinib-rituximab combination at 82%, compared with placebo plus rituximab at 28% (N Engl J Med. 2018;378:2399-410).

The study’s lead investigator, Meletios A. Dimopoulos, MD, called the combination a “new standard of care” for WM at the recent annual meeting of the American Society of Clinical Oncology.

Ibrutinib, marketed as Imbruvica, is jointly developed and commercialized by Pharmacyclics and Janssen Biotech.

mschneider@mdedge.com

Ibrutinib in combination with rituximab as a treatment for Waldenström macroglobulinemia (WM) is under priority review by the Food and Drug Administration.

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is already approved as a single agent for WM. The addition of rituximab to the indication is based on positive results from the phase 3 INNOVATE study. In particular, the trial showed a superior progression-free survival rate at 30 months for the ibrutinib-rituximab combination at 82%, compared with placebo plus rituximab at 28% (N Engl J Med. 2018;378:2399-410).

The study’s lead investigator, Meletios A. Dimopoulos, MD, called the combination a “new standard of care” for WM at the recent annual meeting of the American Society of Clinical Oncology.

Ibrutinib, marketed as Imbruvica, is jointly developed and commercialized by Pharmacyclics and Janssen Biotech.

mschneider@mdedge.com

The FDA has approved Epidiolex (cannabidiol [CBD]) oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients age 2 and older. Epidiolex is the first FDA-approved drug that contains a derivative of marijuana. It also is the first drug approved by the FDA for the treatment of Dravet syndrome.

The approval was based on three randomized, double-blind, placebo-controlled clinical trials that included 516 patients with Lennox-Gastaut syndrome or Dravet syndrome. Epidiolex taken with other epilepsy medications reduced the frequency of seizures, compared with placebo. The most common side effects included lethargy, elevated liver enzymes, decreased appetite, diarrhea, rash, weakness, sleep disorder, and infection.

“Because of the adequate and well-controlled clinical studies that supported this approval, prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes,” said FDA Commissioner Scott Gottlieb, MD. “We will continue to support rigorous scientific research on the potential medical uses of marijuana-derived products…. But at the same time, we are prepared to take action when we see the illegal marketing of CBD-containing products with serious, unproven medical claims.”

The FDA has approved Epidiolex (cannabidiol [CBD]) oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients age 2 and older. Epidiolex is the first FDA-approved drug that contains a derivative of marijuana. It also is the first drug approved by the FDA for the treatment of Dravet syndrome.

The approval was based on three randomized, double-blind, placebo-controlled clinical trials that included 516 patients with Lennox-Gastaut syndrome or Dravet syndrome. Epidiolex taken with other epilepsy medications reduced the frequency of seizures, compared with placebo. The most common side effects included lethargy, elevated liver enzymes, decreased appetite, diarrhea, rash, weakness, sleep disorder, and infection.

“Because of the adequate and well-controlled clinical studies that supported this approval, prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes,” said FDA Commissioner Scott Gottlieb, MD. “We will continue to support rigorous scientific research on the potential medical uses of marijuana-derived products…. But at the same time, we are prepared to take action when we see the illegal marketing of CBD-containing products with serious, unproven medical claims.”

The FDA has approved Epidiolex (cannabidiol [CBD]) oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients age 2 and older. Epidiolex is the first FDA-approved drug that contains a derivative of marijuana. It also is the first drug approved by the FDA for the treatment of Dravet syndrome.

The approval was based on three randomized, double-blind, placebo-controlled clinical trials that included 516 patients with Lennox-Gastaut syndrome or Dravet syndrome. Epidiolex taken with other epilepsy medications reduced the frequency of seizures, compared with placebo. The most common side effects included lethargy, elevated liver enzymes, decreased appetite, diarrhea, rash, weakness, sleep disorder, and infection.

“Because of the adequate and well-controlled clinical studies that supported this approval, prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes,” said FDA Commissioner Scott Gottlieb, MD. “We will continue to support rigorous scientific research on the potential medical uses of marijuana-derived products…. But at the same time, we are prepared to take action when we see the illegal marketing of CBD-containing products with serious, unproven medical claims.”

A cost-effective community program at Pennsylvania State University helped most participants change their behavior and significantly improve their HbA_1c and blood pressure, according to a report in Preventing Chronic Disease.

The researchers for the extension program, Dining with Diabetes, collected data on 2,738 adults with type 2 diabetes or prediabetes and adult family members without diabetes. The program consisted of 4 weekly 2-hour classes and a follow-up class conducted 3 months later. The classes included hands-on food preparation, food tastings, and physical activity.

At the follow-up class, participants who completed the program had significant improvements in diabetes-related biomarkers. A greater percentage said they were confident they could keep their diabetes under control, compared with the number at baseline (67% v 58%). At baseline, most participants were adhering to medications; the researchers found no significant change in adherence.

Participants also increased the number of days per week on which they exercised for ≥ 20 minutes (from 2.9 to 3.4 days), and slightly increased the number of days on which they ate a variety of fruits and vegetables.

Nearly half of participants with baseline and follow-up measurements had a drop in HbA_1c. At follow-up, 21% had a reduction large enough to lower their diabetes status. The changes translated to a 5.9% decrease in HbA_1c for 27% of those who had uncontrolled diabetes at baseline. More than half (59%) had a drop in blood pressure, including 60% of those with uncontrolled diabetes.

The program, which was free to participants, cost Penn State Extension $407 per person. The researchers estimate that extending the program to half of the 1.3 million people with diabetes in Pennsylvania would save the state approximately $195 million at 1 year.

A cost-effective community program at Pennsylvania State University helped most participants change their behavior and significantly improve their HbA_1c and blood pressure, according to a report in Preventing Chronic Disease.

The researchers for the extension program, Dining with Diabetes, collected data on 2,738 adults with type 2 diabetes or prediabetes and adult family members without diabetes. The program consisted of 4 weekly 2-hour classes and a follow-up class conducted 3 months later. The classes included hands-on food preparation, food tastings, and physical activity.

At the follow-up class, participants who completed the program had significant improvements in diabetes-related biomarkers. A greater percentage said they were confident they could keep their diabetes under control, compared with the number at baseline (67% v 58%). At baseline, most participants were adhering to medications; the researchers found no significant change in adherence.

Participants also increased the number of days per week on which they exercised for ≥ 20 minutes (from 2.9 to 3.4 days), and slightly increased the number of days on which they ate a variety of fruits and vegetables.

Nearly half of participants with baseline and follow-up measurements had a drop in HbA_1c. At follow-up, 21% had a reduction large enough to lower their diabetes status. The changes translated to a 5.9% decrease in HbA_1c for 27% of those who had uncontrolled diabetes at baseline. More than half (59%) had a drop in blood pressure, including 60% of those with uncontrolled diabetes.

The program, which was free to participants, cost Penn State Extension $407 per person. The researchers estimate that extending the program to half of the 1.3 million people with diabetes in Pennsylvania would save the state approximately $195 million at 1 year.

A cost-effective community program at Pennsylvania State University helped most participants change their behavior and significantly improve their HbA_1c and blood pressure, according to a report in Preventing Chronic Disease.

The researchers for the extension program, Dining with Diabetes, collected data on 2,738 adults with type 2 diabetes or prediabetes and adult family members without diabetes. The program consisted of 4 weekly 2-hour classes and a follow-up class conducted 3 months later. The classes included hands-on food preparation, food tastings, and physical activity.

At the follow-up class, participants who completed the program had significant improvements in diabetes-related biomarkers. A greater percentage said they were confident they could keep their diabetes under control, compared with the number at baseline (67% v 58%). At baseline, most participants were adhering to medications; the researchers found no significant change in adherence.

Participants also increased the number of days per week on which they exercised for ≥ 20 minutes (from 2.9 to 3.4 days), and slightly increased the number of days on which they ate a variety of fruits and vegetables.

Nearly half of participants with baseline and follow-up measurements had a drop in HbA_1c. At follow-up, 21% had a reduction large enough to lower their diabetes status. The changes translated to a 5.9% decrease in HbA_1c for 27% of those who had uncontrolled diabetes at baseline. More than half (59%) had a drop in blood pressure, including 60% of those with uncontrolled diabetes.

The program, which was free to participants, cost Penn State Extension $407 per person. The researchers estimate that extending the program to half of the 1.3 million people with diabetes in Pennsylvania would save the state approximately $195 million at 1 year.

Many things can reactivate chronic hepatitis B virus (HBV) infection—withdrawal of antiviral therapy, pregnancy, and chemotherapy, to name a few. So when a patient with stable chronic HBV virus presented with significant hepatitis flare, clinicians from Beth Israel Deaconess Medical Center in Boston, Massachusetts, had a long list to check.

They first ruled out drug-associated hepatotoxicity and screened the patient for common causes of acute hepatitis. Beyond the HBV, the patient did not have other significant medical conditions, had not had close contact with anyone ill, and was not pregnant. Tests were negative for cytomegalovirus, Epstein-Barr syndrome, HIV, hepatitis A, C, and D. The patient tested negative for both antihepatitis E virus (HEV) IgM and IgG in a visit about 9 months before.

However, she reported regularly consuming pork, including a recent barbecue meal. Thus, the clinicians focused on HEV serology, which confirmed that she had an acute HEV infection.

Pigs act as a “natural reservoir” for HEV; contaminated meats and direct contact with animals are the most common causes of HEV human infection in industrialized countries. Recent data reveal the prevalence of HEV antibodies in the US is about 6%, illustrating that it is not as uncommon as it was thought to be. Although there was no direct evidence to confirm the source of her infection, it seemed likely due to the pork consumption.

The patient was started on tenofovir but stopped it 4 months later because she felt well. After a subsequent flare, “repeated counseling” persuaded the patient to start on entecavir, with successful viral suppression.

Hepatitis E superinfection on chronic HBV can contribute to significant morbidity and mortality, the clinicians say, particularly in patients with cirrhosis. Concurrent infection with another viral hepatitis should be considered in both immunodeficient and immunocompetent patients with chronic HBV reactivation.

Source:

Aslam A, Susheela A, Iriana S, Chan SS, Lau D. BMJ Case Rep. 2018;2018. pii: bcr-2017-223616.
doi: 10.1136/bcr-2017-223616.

Many things can reactivate chronic hepatitis B virus (HBV) infection—withdrawal of antiviral therapy, pregnancy, and chemotherapy, to name a few. So when a patient with stable chronic HBV virus presented with significant hepatitis flare, clinicians from Beth Israel Deaconess Medical Center in Boston, Massachusetts, had a long list to check.

They first ruled out drug-associated hepatotoxicity and screened the patient for common causes of acute hepatitis. Beyond the HBV, the patient did not have other significant medical conditions, had not had close contact with anyone ill, and was not pregnant. Tests were negative for cytomegalovirus, Epstein-Barr syndrome, HIV, hepatitis A, C, and D. The patient tested negative for both antihepatitis E virus (HEV) IgM and IgG in a visit about 9 months before.

However, she reported regularly consuming pork, including a recent barbecue meal. Thus, the clinicians focused on HEV serology, which confirmed that she had an acute HEV infection.

Pigs act as a “natural reservoir” for HEV; contaminated meats and direct contact with animals are the most common causes of HEV human infection in industrialized countries. Recent data reveal the prevalence of HEV antibodies in the US is about 6%, illustrating that it is not as uncommon as it was thought to be. Although there was no direct evidence to confirm the source of her infection, it seemed likely due to the pork consumption.

The patient was started on tenofovir but stopped it 4 months later because she felt well. After a subsequent flare, “repeated counseling” persuaded the patient to start on entecavir, with successful viral suppression.

Hepatitis E superinfection on chronic HBV can contribute to significant morbidity and mortality, the clinicians say, particularly in patients with cirrhosis. Concurrent infection with another viral hepatitis should be considered in both immunodeficient and immunocompetent patients with chronic HBV reactivation.

Source:

Aslam A, Susheela A, Iriana S, Chan SS, Lau D. BMJ Case Rep. 2018;2018. pii: bcr-2017-223616.
doi: 10.1136/bcr-2017-223616.

Many things can reactivate chronic hepatitis B virus (HBV) infection—withdrawal of antiviral therapy, pregnancy, and chemotherapy, to name a few. So when a patient with stable chronic HBV virus presented with significant hepatitis flare, clinicians from Beth Israel Deaconess Medical Center in Boston, Massachusetts, had a long list to check.

They first ruled out drug-associated hepatotoxicity and screened the patient for common causes of acute hepatitis. Beyond the HBV, the patient did not have other significant medical conditions, had not had close contact with anyone ill, and was not pregnant. Tests were negative for cytomegalovirus, Epstein-Barr syndrome, HIV, hepatitis A, C, and D. The patient tested negative for both antihepatitis E virus (HEV) IgM and IgG in a visit about 9 months before.

However, she reported regularly consuming pork, including a recent barbecue meal. Thus, the clinicians focused on HEV serology, which confirmed that she had an acute HEV infection.

Pigs act as a “natural reservoir” for HEV; contaminated meats and direct contact with animals are the most common causes of HEV human infection in industrialized countries. Recent data reveal the prevalence of HEV antibodies in the US is about 6%, illustrating that it is not as uncommon as it was thought to be. Although there was no direct evidence to confirm the source of her infection, it seemed likely due to the pork consumption.

The patient was started on tenofovir but stopped it 4 months later because she felt well. After a subsequent flare, “repeated counseling” persuaded the patient to start on entecavir, with successful viral suppression.

Hepatitis E superinfection on chronic HBV can contribute to significant morbidity and mortality, the clinicians say, particularly in patients with cirrhosis. Concurrent infection with another viral hepatitis should be considered in both immunodeficient and immunocompetent patients with chronic HBV reactivation.

Source:

Aslam A, Susheela A, Iriana S, Chan SS, Lau D. BMJ Case Rep. 2018;2018. pii: bcr-2017-223616.
doi: 10.1136/bcr-2017-223616.

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761