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WHO unveils global roadmap to defeat meningitis by 2030
The World Health Organization and its partners recently released an ambitious plan, Defeating meningitis by 2030: A global road map. The goal is to reduce deaths and disabilities from bacterial meningitis, which kills about 250,000 people annually of the 1.2 million estimated to be infected.
This type of infection around the brain and spinal cord also causes long-term disabilities – deafness, learning problems, seizures, loss of limbs – in about one-quarter of survivors.
The leading causes of bacterial meningitis are Neisseria meningitidis (meningococcus), Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae, and group B streptococcus. As with malaria, about half of the cases are in children under age 5 years. The most severely affected area for both infections is sub-Saharan Africa.
The main goal of the roadmap is to reduce vaccine-preventable cases of bacterial meningitis by 50% and deaths by 70% by 2030. WHO’s partners included the Centers for Disease Control and Prevention, the London School of Hygiene and Tropical Medicine, Médecins Sans Frontières (Doctors Without Borders), the Meningitis Research Foundation, PATH, UNICEF, and numerous global consultants.
For primary prevention and epidemic control, a major goal is to achieve higher vaccine coverage. Another goal is developing and deploying rapid diagnostic tests to guide treatment and prevention activities and measure the impact of vaccination. The lack of laboratory capacity to confirm the bacteria is a significant challenge. Also, patients often receive antibiotics before appropriate tests are conducted, and lumbar punctures are frequently not done.
The commitment to this project emerged in 2017. It was followed by a baseline analysis in 2018 and a draft roadmap the following year. Consultations with experts and with more than 600 patient groups in more than 90 countries followed.
Prevention through greater vaccine uptake was the top priority. Vaccination is considered the first line of defense against antibiotic resistance among the targeted bacteria.
Another goal is to quantify the decrease in antibiotic use for invasive infections or prophylaxis and the subsequent reduction in antimicrobial resistance in relation to increased vaccination.
Surveillance is weak in many regions, limiting the ability to detect epidemics and to respond appropriately. Similarly, there are limited data on the burden of sequelae, such as deafness, on meningitis survivors.
There is an inadequate supply of affordable vaccines to respond to epidemics. Currently, routine vaccination against Neisseria meningitidis is occurring in 18 of 26 countries in the meningitis belt. Epidemics of meningococcus occur every few years in the driest time of the year and abate with the rains. Epidemics of pneumococcal meningitis are much rarer but follow a similar pattern; they have also been associated with crowding and alcohol use.
Care for those affected by meningitis is another focus, as is affirming the right to prevention and care. There’s a need for earlier recognition of the complications of meningitis and an increase in efforts to treat those complications.
WHO’s final goal in its roadmap is to boost awareness of meningitis and make it a priority for policymakers. Similarly, there is a need to educate communities about the disease, including how to access vaccines. If someone becomes ill, they need to be aware of the symptoms, the need for early treatment, and what aftercare is available.
Marie-Pierre Préziosi, MD, the core secretariat of WHO’s Technical Taskforce, told this news organization that while the roadmap looks aspirational, “it is feasible … you have strategic goals – each has milestones with time limits and who will do it.”
Regarding vaccinations, Dr. Préziosi said that “the strategy was a victim of its success. The mass campaign knocked down transmission completely.” Some countries are now waiting for multivalent vaccines. She said that vaccine hesitancy is not a significant problem in Africa “because the disease is so feared.”
Major obstacles to implementing the roadmap include the complacency of public health leaders and the COVID-19 lockdowns, which decreased vaccination coverage rates. “The second thing is also sufficient funding to do the research and innovation so that we get the affordable tools that we need globally,” Dr. Préziosi said.
Marilyn Felkner, DrPH, School of Human Ecology, University of Texas at Austin, said in an interview, “It’s very cliché, but we have often said that communicable diseases do not respect political boundaries. So to expect a country to be able to control that by themselves is a false hope.”
Regarding the roadmap, Dr. Felkner said, “I think that organizing ideas and having them in writing is always a good first step. And it can help people move forward if they’re feeling overwhelmed ... Having a written plan can certainly provide that fundamental basis. So, the important thing is not to say, ‘Oh, we have this great plan done; hope somebody picks up the plan.’ There’s got to be some momentum behind it, and hopefully some funding.”
Dr. Préziosi and Dr. Felkner have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The World Health Organization and its partners recently released an ambitious plan, Defeating meningitis by 2030: A global road map. The goal is to reduce deaths and disabilities from bacterial meningitis, which kills about 250,000 people annually of the 1.2 million estimated to be infected.
This type of infection around the brain and spinal cord also causes long-term disabilities – deafness, learning problems, seizures, loss of limbs – in about one-quarter of survivors.
The leading causes of bacterial meningitis are Neisseria meningitidis (meningococcus), Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae, and group B streptococcus. As with malaria, about half of the cases are in children under age 5 years. The most severely affected area for both infections is sub-Saharan Africa.
The main goal of the roadmap is to reduce vaccine-preventable cases of bacterial meningitis by 50% and deaths by 70% by 2030. WHO’s partners included the Centers for Disease Control and Prevention, the London School of Hygiene and Tropical Medicine, Médecins Sans Frontières (Doctors Without Borders), the Meningitis Research Foundation, PATH, UNICEF, and numerous global consultants.
For primary prevention and epidemic control, a major goal is to achieve higher vaccine coverage. Another goal is developing and deploying rapid diagnostic tests to guide treatment and prevention activities and measure the impact of vaccination. The lack of laboratory capacity to confirm the bacteria is a significant challenge. Also, patients often receive antibiotics before appropriate tests are conducted, and lumbar punctures are frequently not done.
The commitment to this project emerged in 2017. It was followed by a baseline analysis in 2018 and a draft roadmap the following year. Consultations with experts and with more than 600 patient groups in more than 90 countries followed.
Prevention through greater vaccine uptake was the top priority. Vaccination is considered the first line of defense against antibiotic resistance among the targeted bacteria.
Another goal is to quantify the decrease in antibiotic use for invasive infections or prophylaxis and the subsequent reduction in antimicrobial resistance in relation to increased vaccination.
Surveillance is weak in many regions, limiting the ability to detect epidemics and to respond appropriately. Similarly, there are limited data on the burden of sequelae, such as deafness, on meningitis survivors.
There is an inadequate supply of affordable vaccines to respond to epidemics. Currently, routine vaccination against Neisseria meningitidis is occurring in 18 of 26 countries in the meningitis belt. Epidemics of meningococcus occur every few years in the driest time of the year and abate with the rains. Epidemics of pneumococcal meningitis are much rarer but follow a similar pattern; they have also been associated with crowding and alcohol use.
Care for those affected by meningitis is another focus, as is affirming the right to prevention and care. There’s a need for earlier recognition of the complications of meningitis and an increase in efforts to treat those complications.
WHO’s final goal in its roadmap is to boost awareness of meningitis and make it a priority for policymakers. Similarly, there is a need to educate communities about the disease, including how to access vaccines. If someone becomes ill, they need to be aware of the symptoms, the need for early treatment, and what aftercare is available.
Marie-Pierre Préziosi, MD, the core secretariat of WHO’s Technical Taskforce, told this news organization that while the roadmap looks aspirational, “it is feasible … you have strategic goals – each has milestones with time limits and who will do it.”
Regarding vaccinations, Dr. Préziosi said that “the strategy was a victim of its success. The mass campaign knocked down transmission completely.” Some countries are now waiting for multivalent vaccines. She said that vaccine hesitancy is not a significant problem in Africa “because the disease is so feared.”
Major obstacles to implementing the roadmap include the complacency of public health leaders and the COVID-19 lockdowns, which decreased vaccination coverage rates. “The second thing is also sufficient funding to do the research and innovation so that we get the affordable tools that we need globally,” Dr. Préziosi said.
Marilyn Felkner, DrPH, School of Human Ecology, University of Texas at Austin, said in an interview, “It’s very cliché, but we have often said that communicable diseases do not respect political boundaries. So to expect a country to be able to control that by themselves is a false hope.”
Regarding the roadmap, Dr. Felkner said, “I think that organizing ideas and having them in writing is always a good first step. And it can help people move forward if they’re feeling overwhelmed ... Having a written plan can certainly provide that fundamental basis. So, the important thing is not to say, ‘Oh, we have this great plan done; hope somebody picks up the plan.’ There’s got to be some momentum behind it, and hopefully some funding.”
Dr. Préziosi and Dr. Felkner have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The World Health Organization and its partners recently released an ambitious plan, Defeating meningitis by 2030: A global road map. The goal is to reduce deaths and disabilities from bacterial meningitis, which kills about 250,000 people annually of the 1.2 million estimated to be infected.
This type of infection around the brain and spinal cord also causes long-term disabilities – deafness, learning problems, seizures, loss of limbs – in about one-quarter of survivors.
The leading causes of bacterial meningitis are Neisseria meningitidis (meningococcus), Streptococcus pneumoniae (pneumococcus), Haemophilus influenzae, and group B streptococcus. As with malaria, about half of the cases are in children under age 5 years. The most severely affected area for both infections is sub-Saharan Africa.
The main goal of the roadmap is to reduce vaccine-preventable cases of bacterial meningitis by 50% and deaths by 70% by 2030. WHO’s partners included the Centers for Disease Control and Prevention, the London School of Hygiene and Tropical Medicine, Médecins Sans Frontières (Doctors Without Borders), the Meningitis Research Foundation, PATH, UNICEF, and numerous global consultants.
For primary prevention and epidemic control, a major goal is to achieve higher vaccine coverage. Another goal is developing and deploying rapid diagnostic tests to guide treatment and prevention activities and measure the impact of vaccination. The lack of laboratory capacity to confirm the bacteria is a significant challenge. Also, patients often receive antibiotics before appropriate tests are conducted, and lumbar punctures are frequently not done.
The commitment to this project emerged in 2017. It was followed by a baseline analysis in 2018 and a draft roadmap the following year. Consultations with experts and with more than 600 patient groups in more than 90 countries followed.
Prevention through greater vaccine uptake was the top priority. Vaccination is considered the first line of defense against antibiotic resistance among the targeted bacteria.
Another goal is to quantify the decrease in antibiotic use for invasive infections or prophylaxis and the subsequent reduction in antimicrobial resistance in relation to increased vaccination.
Surveillance is weak in many regions, limiting the ability to detect epidemics and to respond appropriately. Similarly, there are limited data on the burden of sequelae, such as deafness, on meningitis survivors.
There is an inadequate supply of affordable vaccines to respond to epidemics. Currently, routine vaccination against Neisseria meningitidis is occurring in 18 of 26 countries in the meningitis belt. Epidemics of meningococcus occur every few years in the driest time of the year and abate with the rains. Epidemics of pneumococcal meningitis are much rarer but follow a similar pattern; they have also been associated with crowding and alcohol use.
Care for those affected by meningitis is another focus, as is affirming the right to prevention and care. There’s a need for earlier recognition of the complications of meningitis and an increase in efforts to treat those complications.
WHO’s final goal in its roadmap is to boost awareness of meningitis and make it a priority for policymakers. Similarly, there is a need to educate communities about the disease, including how to access vaccines. If someone becomes ill, they need to be aware of the symptoms, the need for early treatment, and what aftercare is available.
Marie-Pierre Préziosi, MD, the core secretariat of WHO’s Technical Taskforce, told this news organization that while the roadmap looks aspirational, “it is feasible … you have strategic goals – each has milestones with time limits and who will do it.”
Regarding vaccinations, Dr. Préziosi said that “the strategy was a victim of its success. The mass campaign knocked down transmission completely.” Some countries are now waiting for multivalent vaccines. She said that vaccine hesitancy is not a significant problem in Africa “because the disease is so feared.”
Major obstacles to implementing the roadmap include the complacency of public health leaders and the COVID-19 lockdowns, which decreased vaccination coverage rates. “The second thing is also sufficient funding to do the research and innovation so that we get the affordable tools that we need globally,” Dr. Préziosi said.
Marilyn Felkner, DrPH, School of Human Ecology, University of Texas at Austin, said in an interview, “It’s very cliché, but we have often said that communicable diseases do not respect political boundaries. So to expect a country to be able to control that by themselves is a false hope.”
Regarding the roadmap, Dr. Felkner said, “I think that organizing ideas and having them in writing is always a good first step. And it can help people move forward if they’re feeling overwhelmed ... Having a written plan can certainly provide that fundamental basis. So, the important thing is not to say, ‘Oh, we have this great plan done; hope somebody picks up the plan.’ There’s got to be some momentum behind it, and hopefully some funding.”
Dr. Préziosi and Dr. Felkner have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Fecal microbiota transplants may improve resistance to melanoma immunotherapy
In the fall of 2020, Hassane M. Zarour, MD, and colleagues began to pore over raw data from their
Preclinical mouse studies have demonstrated that the gut microbiota could influence the response of tumors to anti–PD-1 immunotherapy, but FMT had not been previously evaluated in human patients with malignant melanoma whose disease persisted or progressed after medical therapy. Only 30%-40% of melanoma patients respond to anti–PD-1 immunotherapy, so the researchers’ sense of anticipation was palpable. “It’s a high-risk, high-reward study, so you never know,” Dr. Zarour, a dermatologist and immunologist who is coleader of the melanoma program at the University of Pittsburgh Medical Center’s Hillman Cancer Center, said in an interview.
For the study, which was funded by the National Institutes of Health and published in Science, Dr. Zarour and a team of colleagues, including Diwakar Davar, MD, a medical oncologist/hematologist at UPMC and Giorgio Trinchieri, MD, head of the cancer immunology section at the National Cancer Institute, enrolled 16 patients with advanced melanoma whose disease had persisted or progressed with anti-PD-1 drugs; donors were 7 patients with advanced melanoma who had responded to pembrolizumab, 4 with a complete response and 3 with a partial response, with a median progression-free survival of 56 months.
After donors and patients underwent serial stool sampling and studies to stamp out the potential for transmitting infectious agents, the researchers administered the donor-derived FMT to patients via colonoscopy every 14 days for 3 weeks, followed by pembrolizumab. To their delight, 6 of the 15 evaluable recipients responded to treatment, with a reduction in tumor or long-term disease stabilization. Moreover, responders also showed increased abundance of taxa that were previously associated with response to immunotherapy, increased activation of CD8+ T cells, and decreased frequency of interleukin-8–expressing myeloid cells.
“This opens new doors for the future,” Dr. Zarour said. “It’s very encouraging, but I don’t want to overstate the data. It’s a small, nonrandomized trial, but one has to keep in mind that people were skeptical about this work; they didn’t think FMT would work. Now we see many people coming into the field to investigate the role of the microbiome as a therapeutic tool, which is great.”
Teri Greiling, MD, characterized the finding as a key development in understanding the microbiome’s potential to influence the course of melanoma and other diseases. “What’s emerging over the last decade of research is that our immune system has a close, back-and-forth relationship with our microbiota,” said Dr. Greiling, associate professor of dermatology at Oregon Health & Science University, Portland. “From day 1 of birth, we’re colonized by microbes that train our immune system how to function. In response, your immune system keeps those microbes in check and shapes which ones are allowed to colonize, and which ones are a target for attack. Thus, inflammatory responses are generated. Similarly, the goal of immunotherapy is to activate the immune system to fight cancer. This study shows that the immune system continues to need the colonizing microbes in our body to function optimally.”
Immunotherapy with checkpoint inhibitors was not an option for malignant melanoma patients until 2011, she noted, so the potential for FMT to further improve outcomes is welcome news for patients and their families. “We went from a less than 5% chance of survival with metastatic melanoma to now, with the right combination of checkpoint inhibitors, we’re up over 50%, which is amazing in a decade,” Dr. Greiling said. “Still, we’re losing half of our patients. If [FMT provides] a 30% improvement over that, that would be great, but it’s hard to extrapolate from such small numbers.”
Positive results in an Israeli study
Results from a similar, smaller phase 1 trial of 2 FMT donors and 10 recipients with metastatic melanoma who had progressed on anti-PD-1 therapy, from the Ella Lemelbaum Institute for Immuno-Oncology at Sheba Medical Center in Tel HaShomer, Israel, yielded similar results. The FMT protocol in this study included colonoscopy and oral stool capsules, followed by the reintroduction of anti–PD-1 therapy with nivolumab. The two FMT donors had previously been treated with anti–PD-1 monotherapy for metastatic melanoma and had achieved a clinical response for at least 1 year. Of the 10 FMT recipients, 1 had a complete response and 2 had a partial response.
“We expected changes in the immune system but did not expect that 3 out of the 10 patients in our study would be turned from nonresponders to responders,” the study’s lead author, Erez N. Baruch, MD, PhD, told this news organization. “Since this was a first-in-human study, we were aiming to assess safety and not clinical responses. [We found] that microbiota modulation can change the immune infiltration within melanoma tumors and by this affect response to immunotherapy.”
Dr. Baruch, an internal medicine resident in the physician-scientist track program at the University of Texas, Houston, said that the findings create a potential new therapeutic paradigm, or a new “playing ground” for drug development that can support existing immunotherapies. “It is important for dermatologists to understand that disruptions of the gut microbiota, mainly by antibiotics, may be harmful to melanoma patients,” he said. “Antibiotics in cancer patients should be used judiciously but of course should not be avoided when there’s an indication.”
As for next steps, Dr. Zarour and colleagues are recruiting more patients to boost their sample size and conducting sequential analysis of the microbiome of study participants “to better determine what the good and bad bugs are,” he said. “There are so many variables, including diet and geography. We need more data.” The hope is to develop a “microbiome signature” to identify patients likely to respond to FMT, and maybe one day, a probiotic capsule that patients take to optimize their response to immunotherapy.
“We don’t want to say that the microbiome is responsible for everything, but it’s responsible for some of the response and some of the resistance to treatment,” Dr. Zarour said. “So, we want to identify what candidate nonresponders are more likely to respond to FMT and be able to stick the right stool in the donor. This goes to better education of the microbiome signature. We are working hard on that.”
Dr. Baruch added that performing FMT for melanoma patients requires tight collaborations between oncologists, dermatologists, GI, and infectious disease experts. “These usually can be done in the setting of large cancer centers and will probably not be available in any hospital,” he said. “This is why understanding the mechanisms and developing an FMT-like drug is important. We are focusing on studying the mechanisms behind the clinical effect in order to develop a drug with an FMT-like effect without the safety and logistic issues related to FMTs.”
Tamia A. Harris-Tryon, MD, PhD, whose lab at the University of Texas Southwestern Medical Center at Dallas is studying how diet and the microbiota impact skin immunity, underscored the importance of evaluating the characteristics of the diet of patients as trials of FMT in melanoma patients carry on. “We know that the diet impacts the repertoire of microbes that colonize the gut,” said Dr. Harris-Tryon, assistant professor in the department of dermatology at the medical center. “The diet of the recipient likely has an impact” on the success of donor FMT.
She also noted that other skin conditions have been linked to a disrupted gut microbiome, such as psoriasis. “Given the safety of FMT in both of these studies, trials of FMT in psoriasis and other systemic skin conditions should be considered,” she said.
According to Dr. Zarour, mounting data from separate studies show that some gut microbiota play a role in adverse events experienced by melanoma patients on immunotherapy. “That is very important, especially with combination therapy,” he said. “There are also microbes involved in resistance to treatment, so the idea would be to identify these microbes.”
Studies raise more questions
In the opinion of Dr. Greiling, results from these two studies raise more questions than they answer. “The big question ... is why and how does FMT work, and how can we make the response better?” she said. “Is there one particular gene product from one microbe that is the key magic ingredient, and we can harness this as a drug? More likely it’s a complex interplay between multiple bacterial species needed to direct the immune response. Is there a group of microbes that is the same from person to person, or is it more complex?”
Then there are pending regulatory concerns. “We know that FMT works for [Clostridioides] difficile colitis but it’s not officially [Food and Drug Administration] approved,” Dr. Greiling said. “The FDA is really struggling with how to approve or regulate using bacteria as a drug. Where is that crossover? That inhibits things moving forward, for good reason. You want to balance safety with live microbes.”
The UPMC clinical trial was supported by Merck. Dr. Zarour disclosed that he is supported by grants from the National Cancer Institute and the James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research at UPMC. The Israeli study was funded by the Ella Lemelbaum Institute for Immuno-Oncology. Dr. Baruch was supported by the Allen Berg Fund for Excellence in Immuno-Oncology Research. Dr. Greiling and Dr. Harris-Tryon reported having no relevant financial disclosures.
In the fall of 2020, Hassane M. Zarour, MD, and colleagues began to pore over raw data from their
Preclinical mouse studies have demonstrated that the gut microbiota could influence the response of tumors to anti–PD-1 immunotherapy, but FMT had not been previously evaluated in human patients with malignant melanoma whose disease persisted or progressed after medical therapy. Only 30%-40% of melanoma patients respond to anti–PD-1 immunotherapy, so the researchers’ sense of anticipation was palpable. “It’s a high-risk, high-reward study, so you never know,” Dr. Zarour, a dermatologist and immunologist who is coleader of the melanoma program at the University of Pittsburgh Medical Center’s Hillman Cancer Center, said in an interview.
For the study, which was funded by the National Institutes of Health and published in Science, Dr. Zarour and a team of colleagues, including Diwakar Davar, MD, a medical oncologist/hematologist at UPMC and Giorgio Trinchieri, MD, head of the cancer immunology section at the National Cancer Institute, enrolled 16 patients with advanced melanoma whose disease had persisted or progressed with anti-PD-1 drugs; donors were 7 patients with advanced melanoma who had responded to pembrolizumab, 4 with a complete response and 3 with a partial response, with a median progression-free survival of 56 months.
After donors and patients underwent serial stool sampling and studies to stamp out the potential for transmitting infectious agents, the researchers administered the donor-derived FMT to patients via colonoscopy every 14 days for 3 weeks, followed by pembrolizumab. To their delight, 6 of the 15 evaluable recipients responded to treatment, with a reduction in tumor or long-term disease stabilization. Moreover, responders also showed increased abundance of taxa that were previously associated with response to immunotherapy, increased activation of CD8+ T cells, and decreased frequency of interleukin-8–expressing myeloid cells.
“This opens new doors for the future,” Dr. Zarour said. “It’s very encouraging, but I don’t want to overstate the data. It’s a small, nonrandomized trial, but one has to keep in mind that people were skeptical about this work; they didn’t think FMT would work. Now we see many people coming into the field to investigate the role of the microbiome as a therapeutic tool, which is great.”
Teri Greiling, MD, characterized the finding as a key development in understanding the microbiome’s potential to influence the course of melanoma and other diseases. “What’s emerging over the last decade of research is that our immune system has a close, back-and-forth relationship with our microbiota,” said Dr. Greiling, associate professor of dermatology at Oregon Health & Science University, Portland. “From day 1 of birth, we’re colonized by microbes that train our immune system how to function. In response, your immune system keeps those microbes in check and shapes which ones are allowed to colonize, and which ones are a target for attack. Thus, inflammatory responses are generated. Similarly, the goal of immunotherapy is to activate the immune system to fight cancer. This study shows that the immune system continues to need the colonizing microbes in our body to function optimally.”
Immunotherapy with checkpoint inhibitors was not an option for malignant melanoma patients until 2011, she noted, so the potential for FMT to further improve outcomes is welcome news for patients and their families. “We went from a less than 5% chance of survival with metastatic melanoma to now, with the right combination of checkpoint inhibitors, we’re up over 50%, which is amazing in a decade,” Dr. Greiling said. “Still, we’re losing half of our patients. If [FMT provides] a 30% improvement over that, that would be great, but it’s hard to extrapolate from such small numbers.”
Positive results in an Israeli study
Results from a similar, smaller phase 1 trial of 2 FMT donors and 10 recipients with metastatic melanoma who had progressed on anti-PD-1 therapy, from the Ella Lemelbaum Institute for Immuno-Oncology at Sheba Medical Center in Tel HaShomer, Israel, yielded similar results. The FMT protocol in this study included colonoscopy and oral stool capsules, followed by the reintroduction of anti–PD-1 therapy with nivolumab. The two FMT donors had previously been treated with anti–PD-1 monotherapy for metastatic melanoma and had achieved a clinical response for at least 1 year. Of the 10 FMT recipients, 1 had a complete response and 2 had a partial response.
“We expected changes in the immune system but did not expect that 3 out of the 10 patients in our study would be turned from nonresponders to responders,” the study’s lead author, Erez N. Baruch, MD, PhD, told this news organization. “Since this was a first-in-human study, we were aiming to assess safety and not clinical responses. [We found] that microbiota modulation can change the immune infiltration within melanoma tumors and by this affect response to immunotherapy.”
Dr. Baruch, an internal medicine resident in the physician-scientist track program at the University of Texas, Houston, said that the findings create a potential new therapeutic paradigm, or a new “playing ground” for drug development that can support existing immunotherapies. “It is important for dermatologists to understand that disruptions of the gut microbiota, mainly by antibiotics, may be harmful to melanoma patients,” he said. “Antibiotics in cancer patients should be used judiciously but of course should not be avoided when there’s an indication.”
As for next steps, Dr. Zarour and colleagues are recruiting more patients to boost their sample size and conducting sequential analysis of the microbiome of study participants “to better determine what the good and bad bugs are,” he said. “There are so many variables, including diet and geography. We need more data.” The hope is to develop a “microbiome signature” to identify patients likely to respond to FMT, and maybe one day, a probiotic capsule that patients take to optimize their response to immunotherapy.
“We don’t want to say that the microbiome is responsible for everything, but it’s responsible for some of the response and some of the resistance to treatment,” Dr. Zarour said. “So, we want to identify what candidate nonresponders are more likely to respond to FMT and be able to stick the right stool in the donor. This goes to better education of the microbiome signature. We are working hard on that.”
Dr. Baruch added that performing FMT for melanoma patients requires tight collaborations between oncologists, dermatologists, GI, and infectious disease experts. “These usually can be done in the setting of large cancer centers and will probably not be available in any hospital,” he said. “This is why understanding the mechanisms and developing an FMT-like drug is important. We are focusing on studying the mechanisms behind the clinical effect in order to develop a drug with an FMT-like effect without the safety and logistic issues related to FMTs.”
Tamia A. Harris-Tryon, MD, PhD, whose lab at the University of Texas Southwestern Medical Center at Dallas is studying how diet and the microbiota impact skin immunity, underscored the importance of evaluating the characteristics of the diet of patients as trials of FMT in melanoma patients carry on. “We know that the diet impacts the repertoire of microbes that colonize the gut,” said Dr. Harris-Tryon, assistant professor in the department of dermatology at the medical center. “The diet of the recipient likely has an impact” on the success of donor FMT.
She also noted that other skin conditions have been linked to a disrupted gut microbiome, such as psoriasis. “Given the safety of FMT in both of these studies, trials of FMT in psoriasis and other systemic skin conditions should be considered,” she said.
According to Dr. Zarour, mounting data from separate studies show that some gut microbiota play a role in adverse events experienced by melanoma patients on immunotherapy. “That is very important, especially with combination therapy,” he said. “There are also microbes involved in resistance to treatment, so the idea would be to identify these microbes.”
Studies raise more questions
In the opinion of Dr. Greiling, results from these two studies raise more questions than they answer. “The big question ... is why and how does FMT work, and how can we make the response better?” she said. “Is there one particular gene product from one microbe that is the key magic ingredient, and we can harness this as a drug? More likely it’s a complex interplay between multiple bacterial species needed to direct the immune response. Is there a group of microbes that is the same from person to person, or is it more complex?”
Then there are pending regulatory concerns. “We know that FMT works for [Clostridioides] difficile colitis but it’s not officially [Food and Drug Administration] approved,” Dr. Greiling said. “The FDA is really struggling with how to approve or regulate using bacteria as a drug. Where is that crossover? That inhibits things moving forward, for good reason. You want to balance safety with live microbes.”
The UPMC clinical trial was supported by Merck. Dr. Zarour disclosed that he is supported by grants from the National Cancer Institute and the James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research at UPMC. The Israeli study was funded by the Ella Lemelbaum Institute for Immuno-Oncology. Dr. Baruch was supported by the Allen Berg Fund for Excellence in Immuno-Oncology Research. Dr. Greiling and Dr. Harris-Tryon reported having no relevant financial disclosures.
In the fall of 2020, Hassane M. Zarour, MD, and colleagues began to pore over raw data from their
Preclinical mouse studies have demonstrated that the gut microbiota could influence the response of tumors to anti–PD-1 immunotherapy, but FMT had not been previously evaluated in human patients with malignant melanoma whose disease persisted or progressed after medical therapy. Only 30%-40% of melanoma patients respond to anti–PD-1 immunotherapy, so the researchers’ sense of anticipation was palpable. “It’s a high-risk, high-reward study, so you never know,” Dr. Zarour, a dermatologist and immunologist who is coleader of the melanoma program at the University of Pittsburgh Medical Center’s Hillman Cancer Center, said in an interview.
For the study, which was funded by the National Institutes of Health and published in Science, Dr. Zarour and a team of colleagues, including Diwakar Davar, MD, a medical oncologist/hematologist at UPMC and Giorgio Trinchieri, MD, head of the cancer immunology section at the National Cancer Institute, enrolled 16 patients with advanced melanoma whose disease had persisted or progressed with anti-PD-1 drugs; donors were 7 patients with advanced melanoma who had responded to pembrolizumab, 4 with a complete response and 3 with a partial response, with a median progression-free survival of 56 months.
After donors and patients underwent serial stool sampling and studies to stamp out the potential for transmitting infectious agents, the researchers administered the donor-derived FMT to patients via colonoscopy every 14 days for 3 weeks, followed by pembrolizumab. To their delight, 6 of the 15 evaluable recipients responded to treatment, with a reduction in tumor or long-term disease stabilization. Moreover, responders also showed increased abundance of taxa that were previously associated with response to immunotherapy, increased activation of CD8+ T cells, and decreased frequency of interleukin-8–expressing myeloid cells.
“This opens new doors for the future,” Dr. Zarour said. “It’s very encouraging, but I don’t want to overstate the data. It’s a small, nonrandomized trial, but one has to keep in mind that people were skeptical about this work; they didn’t think FMT would work. Now we see many people coming into the field to investigate the role of the microbiome as a therapeutic tool, which is great.”
Teri Greiling, MD, characterized the finding as a key development in understanding the microbiome’s potential to influence the course of melanoma and other diseases. “What’s emerging over the last decade of research is that our immune system has a close, back-and-forth relationship with our microbiota,” said Dr. Greiling, associate professor of dermatology at Oregon Health & Science University, Portland. “From day 1 of birth, we’re colonized by microbes that train our immune system how to function. In response, your immune system keeps those microbes in check and shapes which ones are allowed to colonize, and which ones are a target for attack. Thus, inflammatory responses are generated. Similarly, the goal of immunotherapy is to activate the immune system to fight cancer. This study shows that the immune system continues to need the colonizing microbes in our body to function optimally.”
Immunotherapy with checkpoint inhibitors was not an option for malignant melanoma patients until 2011, she noted, so the potential for FMT to further improve outcomes is welcome news for patients and their families. “We went from a less than 5% chance of survival with metastatic melanoma to now, with the right combination of checkpoint inhibitors, we’re up over 50%, which is amazing in a decade,” Dr. Greiling said. “Still, we’re losing half of our patients. If [FMT provides] a 30% improvement over that, that would be great, but it’s hard to extrapolate from such small numbers.”
Positive results in an Israeli study
Results from a similar, smaller phase 1 trial of 2 FMT donors and 10 recipients with metastatic melanoma who had progressed on anti-PD-1 therapy, from the Ella Lemelbaum Institute for Immuno-Oncology at Sheba Medical Center in Tel HaShomer, Israel, yielded similar results. The FMT protocol in this study included colonoscopy and oral stool capsules, followed by the reintroduction of anti–PD-1 therapy with nivolumab. The two FMT donors had previously been treated with anti–PD-1 monotherapy for metastatic melanoma and had achieved a clinical response for at least 1 year. Of the 10 FMT recipients, 1 had a complete response and 2 had a partial response.
“We expected changes in the immune system but did not expect that 3 out of the 10 patients in our study would be turned from nonresponders to responders,” the study’s lead author, Erez N. Baruch, MD, PhD, told this news organization. “Since this was a first-in-human study, we were aiming to assess safety and not clinical responses. [We found] that microbiota modulation can change the immune infiltration within melanoma tumors and by this affect response to immunotherapy.”
Dr. Baruch, an internal medicine resident in the physician-scientist track program at the University of Texas, Houston, said that the findings create a potential new therapeutic paradigm, or a new “playing ground” for drug development that can support existing immunotherapies. “It is important for dermatologists to understand that disruptions of the gut microbiota, mainly by antibiotics, may be harmful to melanoma patients,” he said. “Antibiotics in cancer patients should be used judiciously but of course should not be avoided when there’s an indication.”
As for next steps, Dr. Zarour and colleagues are recruiting more patients to boost their sample size and conducting sequential analysis of the microbiome of study participants “to better determine what the good and bad bugs are,” he said. “There are so many variables, including diet and geography. We need more data.” The hope is to develop a “microbiome signature” to identify patients likely to respond to FMT, and maybe one day, a probiotic capsule that patients take to optimize their response to immunotherapy.
“We don’t want to say that the microbiome is responsible for everything, but it’s responsible for some of the response and some of the resistance to treatment,” Dr. Zarour said. “So, we want to identify what candidate nonresponders are more likely to respond to FMT and be able to stick the right stool in the donor. This goes to better education of the microbiome signature. We are working hard on that.”
Dr. Baruch added that performing FMT for melanoma patients requires tight collaborations between oncologists, dermatologists, GI, and infectious disease experts. “These usually can be done in the setting of large cancer centers and will probably not be available in any hospital,” he said. “This is why understanding the mechanisms and developing an FMT-like drug is important. We are focusing on studying the mechanisms behind the clinical effect in order to develop a drug with an FMT-like effect without the safety and logistic issues related to FMTs.”
Tamia A. Harris-Tryon, MD, PhD, whose lab at the University of Texas Southwestern Medical Center at Dallas is studying how diet and the microbiota impact skin immunity, underscored the importance of evaluating the characteristics of the diet of patients as trials of FMT in melanoma patients carry on. “We know that the diet impacts the repertoire of microbes that colonize the gut,” said Dr. Harris-Tryon, assistant professor in the department of dermatology at the medical center. “The diet of the recipient likely has an impact” on the success of donor FMT.
She also noted that other skin conditions have been linked to a disrupted gut microbiome, such as psoriasis. “Given the safety of FMT in both of these studies, trials of FMT in psoriasis and other systemic skin conditions should be considered,” she said.
According to Dr. Zarour, mounting data from separate studies show that some gut microbiota play a role in adverse events experienced by melanoma patients on immunotherapy. “That is very important, especially with combination therapy,” he said. “There are also microbes involved in resistance to treatment, so the idea would be to identify these microbes.”
Studies raise more questions
In the opinion of Dr. Greiling, results from these two studies raise more questions than they answer. “The big question ... is why and how does FMT work, and how can we make the response better?” she said. “Is there one particular gene product from one microbe that is the key magic ingredient, and we can harness this as a drug? More likely it’s a complex interplay between multiple bacterial species needed to direct the immune response. Is there a group of microbes that is the same from person to person, or is it more complex?”
Then there are pending regulatory concerns. “We know that FMT works for [Clostridioides] difficile colitis but it’s not officially [Food and Drug Administration] approved,” Dr. Greiling said. “The FDA is really struggling with how to approve or regulate using bacteria as a drug. Where is that crossover? That inhibits things moving forward, for good reason. You want to balance safety with live microbes.”
The UPMC clinical trial was supported by Merck. Dr. Zarour disclosed that he is supported by grants from the National Cancer Institute and the James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research at UPMC. The Israeli study was funded by the Ella Lemelbaum Institute for Immuno-Oncology. Dr. Baruch was supported by the Allen Berg Fund for Excellence in Immuno-Oncology Research. Dr. Greiling and Dr. Harris-Tryon reported having no relevant financial disclosures.
COPD: Higher mortality with low baseline CO diffusing capacity
Patients with a baseline DLCO (diffusing capacity for carbon monoxide) of < 60% of predicted have more severe disease clinical expression with higher mortality risk, according to a long-term observational study of Global Initiative for Obstructive Lung Disease (GOLD) I chronic obstructive pulmonary disease (COPD) patients. Clarifying mechanisms of low DLCO may help clinicians direct interventions toward ameliorating the low capacity, Juan Pablo de Torres, MD, and colleagues wrote in the journal CHEST®.
Defining increased risk
“Can a DLCO threshold help define an increased risk of death and a different clinical presentation in GOLD I patients?” the researchers questioned. For evaluation of COPD, the GOLD does not currently promote the use of DLCO, and the clinical and prognostic utility of a low DLCO has not been studied, the authors noted.
Several COPD studies, however, have shown associations between low DLCO values and reduced exercise capacity, increased symptoms, risk of severe exacerbations, and mortality. The patients included in these studies, however, have generally had moderate to severe airflow limitation, and have not had postbronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 0.70 and an FEV1 ≥ 80%, defined by GOLD as COPD spirometric stage I. These mild obstruction GOLD I patients, in large epidemiological studies, do have increased risk of death. But it is often assumed, Dr. de Torres and colleagues noted, that “mild” suggests a good prognosis. They propose that a simple DLCO measurement could help identify those GOLD I patients with “worse overall COPD compromise and an increased risk of death.” Importantly, GOLD I represents the largest percentage of patients with airflow limitation that epidemiological studies have identified.
The researchers enrolled 360 GOLD stage I COPD patients, recording their age, sex, pack-years’ history, body mass index, dyspnea, lung function measurements, exercise capacity, BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, and history of exacerbations, and followed them for a mean of 109 months. They identified a cutoff DLCO value for all-cause mortality, compared the clinical and physiological characteristics of patients above and below the threshold, and explored the predictive power of that cutoff value.
All-cause mortality difference
The mean age in the overall population studied was 63 years (31% were women), with 43% active smokers, and pack-years history of 45. Overall mortality was 11% during the follow-up period. The predominantly male population was mildly overweight, had few comorbidities, normal FEV1 values, mild dyspnea, normal 6-minute walk distance, and very few exacerbations.
Analysis showed a DLCO cutoff value of < 60% was associated with a significant all-cause mortality differential (DLCO ≥ 60%: 9% vs. DLCO < 60%: 23%, P = .01). At a same FEV1% predicted and Charlson score, patients with DLCO < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-minute walk distance, and higher BODE index. Adjusted Cox multiple regression analysis confirmed that a DLCO < 60% was associated with an all-cause mortality hazard ratio [HR] of 3.37, (95% confidence interval, 1.35-8.39; P = .009).
Multiorgan loss of tissue
The researchers found that patients with baseline DLCO < 60% were more likely to be women (46% versus 28%), and to have a lower BMI (25 vs. 27), higher pack-year history (54 vs. 43), the same spirometric values but lower IC/TLC ratio (.37 vs. .40), a lower walk distance (443 vs. 485 meters), higher dyspnea (MRC score 1.1 vs. .7), similar exacerbation rate, higher BODE index (.5 vs. .2) and higher mortality than patients with higher DLCO % predicted values. This group, Dr. de Torres and colleagues suggest, represents a multiorgan loss of tissue, a phenotype associated with worse clinical outcomes and prognosis.
“Low DLCO in these patients,” Dr. de Torres said in an interview, “could mainly be secondary to coexistent emphysema, which is the most common cause of low DLCO in this population. Also possible, but less likely, is coexistent pulmonary hypertension.” He noted further that “This study opens the door to research specifically testing if such is the case, and if it is, for clinicians to use available therapies to prevent adverse outcomes.”
Comorbidity burden
Patients with GOLD I COPD die more often of cardiovascular disease instead of underlying lung disease, according to Richard H. Zou, MD, and Jessica Bon, MD, of the University of Pittsburgh, in an accompanying editorial in the journal CHEST.
Increased mortality rates, they suggest, may be related to higher comorbidity burden, particularly comorbidities associated with cardiovascular-related health. Subclinical cardiovascular disease is a common comorbidity in COPD, and concomitant endothelial dysfunction has been associated with both cardiovascular disease and early emphysema in smokers. They may have disproportionately reduced DLCO levels because of parenchymal destruction.
“This study suggests that DLCO can be used to identify patients with GOLD I COPD at increased death risk and that individuals with mild airflow obstruction with DLCO <60% predicted are a clinical phenotype distinct from those with higher DLCO levels,” Dr. Zhou and Dr. Bon concluded.
The researchers and the editorialists declared that they had no disclosures. One of the three cohorts assessed in the current study (CHAIN cohort in Spain) received funding from AstraZeneca.
Patients with a baseline DLCO (diffusing capacity for carbon monoxide) of < 60% of predicted have more severe disease clinical expression with higher mortality risk, according to a long-term observational study of Global Initiative for Obstructive Lung Disease (GOLD) I chronic obstructive pulmonary disease (COPD) patients. Clarifying mechanisms of low DLCO may help clinicians direct interventions toward ameliorating the low capacity, Juan Pablo de Torres, MD, and colleagues wrote in the journal CHEST®.
Defining increased risk
“Can a DLCO threshold help define an increased risk of death and a different clinical presentation in GOLD I patients?” the researchers questioned. For evaluation of COPD, the GOLD does not currently promote the use of DLCO, and the clinical and prognostic utility of a low DLCO has not been studied, the authors noted.
Several COPD studies, however, have shown associations between low DLCO values and reduced exercise capacity, increased symptoms, risk of severe exacerbations, and mortality. The patients included in these studies, however, have generally had moderate to severe airflow limitation, and have not had postbronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 0.70 and an FEV1 ≥ 80%, defined by GOLD as COPD spirometric stage I. These mild obstruction GOLD I patients, in large epidemiological studies, do have increased risk of death. But it is often assumed, Dr. de Torres and colleagues noted, that “mild” suggests a good prognosis. They propose that a simple DLCO measurement could help identify those GOLD I patients with “worse overall COPD compromise and an increased risk of death.” Importantly, GOLD I represents the largest percentage of patients with airflow limitation that epidemiological studies have identified.
The researchers enrolled 360 GOLD stage I COPD patients, recording their age, sex, pack-years’ history, body mass index, dyspnea, lung function measurements, exercise capacity, BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, and history of exacerbations, and followed them for a mean of 109 months. They identified a cutoff DLCO value for all-cause mortality, compared the clinical and physiological characteristics of patients above and below the threshold, and explored the predictive power of that cutoff value.
All-cause mortality difference
The mean age in the overall population studied was 63 years (31% were women), with 43% active smokers, and pack-years history of 45. Overall mortality was 11% during the follow-up period. The predominantly male population was mildly overweight, had few comorbidities, normal FEV1 values, mild dyspnea, normal 6-minute walk distance, and very few exacerbations.
Analysis showed a DLCO cutoff value of < 60% was associated with a significant all-cause mortality differential (DLCO ≥ 60%: 9% vs. DLCO < 60%: 23%, P = .01). At a same FEV1% predicted and Charlson score, patients with DLCO < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-minute walk distance, and higher BODE index. Adjusted Cox multiple regression analysis confirmed that a DLCO < 60% was associated with an all-cause mortality hazard ratio [HR] of 3.37, (95% confidence interval, 1.35-8.39; P = .009).
Multiorgan loss of tissue
The researchers found that patients with baseline DLCO < 60% were more likely to be women (46% versus 28%), and to have a lower BMI (25 vs. 27), higher pack-year history (54 vs. 43), the same spirometric values but lower IC/TLC ratio (.37 vs. .40), a lower walk distance (443 vs. 485 meters), higher dyspnea (MRC score 1.1 vs. .7), similar exacerbation rate, higher BODE index (.5 vs. .2) and higher mortality than patients with higher DLCO % predicted values. This group, Dr. de Torres and colleagues suggest, represents a multiorgan loss of tissue, a phenotype associated with worse clinical outcomes and prognosis.
“Low DLCO in these patients,” Dr. de Torres said in an interview, “could mainly be secondary to coexistent emphysema, which is the most common cause of low DLCO in this population. Also possible, but less likely, is coexistent pulmonary hypertension.” He noted further that “This study opens the door to research specifically testing if such is the case, and if it is, for clinicians to use available therapies to prevent adverse outcomes.”
Comorbidity burden
Patients with GOLD I COPD die more often of cardiovascular disease instead of underlying lung disease, according to Richard H. Zou, MD, and Jessica Bon, MD, of the University of Pittsburgh, in an accompanying editorial in the journal CHEST.
Increased mortality rates, they suggest, may be related to higher comorbidity burden, particularly comorbidities associated with cardiovascular-related health. Subclinical cardiovascular disease is a common comorbidity in COPD, and concomitant endothelial dysfunction has been associated with both cardiovascular disease and early emphysema in smokers. They may have disproportionately reduced DLCO levels because of parenchymal destruction.
“This study suggests that DLCO can be used to identify patients with GOLD I COPD at increased death risk and that individuals with mild airflow obstruction with DLCO <60% predicted are a clinical phenotype distinct from those with higher DLCO levels,” Dr. Zhou and Dr. Bon concluded.
The researchers and the editorialists declared that they had no disclosures. One of the three cohorts assessed in the current study (CHAIN cohort in Spain) received funding from AstraZeneca.
Patients with a baseline DLCO (diffusing capacity for carbon monoxide) of < 60% of predicted have more severe disease clinical expression with higher mortality risk, according to a long-term observational study of Global Initiative for Obstructive Lung Disease (GOLD) I chronic obstructive pulmonary disease (COPD) patients. Clarifying mechanisms of low DLCO may help clinicians direct interventions toward ameliorating the low capacity, Juan Pablo de Torres, MD, and colleagues wrote in the journal CHEST®.
Defining increased risk
“Can a DLCO threshold help define an increased risk of death and a different clinical presentation in GOLD I patients?” the researchers questioned. For evaluation of COPD, the GOLD does not currently promote the use of DLCO, and the clinical and prognostic utility of a low DLCO has not been studied, the authors noted.
Several COPD studies, however, have shown associations between low DLCO values and reduced exercise capacity, increased symptoms, risk of severe exacerbations, and mortality. The patients included in these studies, however, have generally had moderate to severe airflow limitation, and have not had postbronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 0.70 and an FEV1 ≥ 80%, defined by GOLD as COPD spirometric stage I. These mild obstruction GOLD I patients, in large epidemiological studies, do have increased risk of death. But it is often assumed, Dr. de Torres and colleagues noted, that “mild” suggests a good prognosis. They propose that a simple DLCO measurement could help identify those GOLD I patients with “worse overall COPD compromise and an increased risk of death.” Importantly, GOLD I represents the largest percentage of patients with airflow limitation that epidemiological studies have identified.
The researchers enrolled 360 GOLD stage I COPD patients, recording their age, sex, pack-years’ history, body mass index, dyspnea, lung function measurements, exercise capacity, BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, and history of exacerbations, and followed them for a mean of 109 months. They identified a cutoff DLCO value for all-cause mortality, compared the clinical and physiological characteristics of patients above and below the threshold, and explored the predictive power of that cutoff value.
All-cause mortality difference
The mean age in the overall population studied was 63 years (31% were women), with 43% active smokers, and pack-years history of 45. Overall mortality was 11% during the follow-up period. The predominantly male population was mildly overweight, had few comorbidities, normal FEV1 values, mild dyspnea, normal 6-minute walk distance, and very few exacerbations.
Analysis showed a DLCO cutoff value of < 60% was associated with a significant all-cause mortality differential (DLCO ≥ 60%: 9% vs. DLCO < 60%: 23%, P = .01). At a same FEV1% predicted and Charlson score, patients with DLCO < 60% had lower BMI, more dyspnea, lower inspiratory capacity (IC)/total lung capacity (TLC) ratio, lower 6-minute walk distance, and higher BODE index. Adjusted Cox multiple regression analysis confirmed that a DLCO < 60% was associated with an all-cause mortality hazard ratio [HR] of 3.37, (95% confidence interval, 1.35-8.39; P = .009).
Multiorgan loss of tissue
The researchers found that patients with baseline DLCO < 60% were more likely to be women (46% versus 28%), and to have a lower BMI (25 vs. 27), higher pack-year history (54 vs. 43), the same spirometric values but lower IC/TLC ratio (.37 vs. .40), a lower walk distance (443 vs. 485 meters), higher dyspnea (MRC score 1.1 vs. .7), similar exacerbation rate, higher BODE index (.5 vs. .2) and higher mortality than patients with higher DLCO % predicted values. This group, Dr. de Torres and colleagues suggest, represents a multiorgan loss of tissue, a phenotype associated with worse clinical outcomes and prognosis.
“Low DLCO in these patients,” Dr. de Torres said in an interview, “could mainly be secondary to coexistent emphysema, which is the most common cause of low DLCO in this population. Also possible, but less likely, is coexistent pulmonary hypertension.” He noted further that “This study opens the door to research specifically testing if such is the case, and if it is, for clinicians to use available therapies to prevent adverse outcomes.”
Comorbidity burden
Patients with GOLD I COPD die more often of cardiovascular disease instead of underlying lung disease, according to Richard H. Zou, MD, and Jessica Bon, MD, of the University of Pittsburgh, in an accompanying editorial in the journal CHEST.
Increased mortality rates, they suggest, may be related to higher comorbidity burden, particularly comorbidities associated with cardiovascular-related health. Subclinical cardiovascular disease is a common comorbidity in COPD, and concomitant endothelial dysfunction has been associated with both cardiovascular disease and early emphysema in smokers. They may have disproportionately reduced DLCO levels because of parenchymal destruction.
“This study suggests that DLCO can be used to identify patients with GOLD I COPD at increased death risk and that individuals with mild airflow obstruction with DLCO <60% predicted are a clinical phenotype distinct from those with higher DLCO levels,” Dr. Zhou and Dr. Bon concluded.
The researchers and the editorialists declared that they had no disclosures. One of the three cohorts assessed in the current study (CHAIN cohort in Spain) received funding from AstraZeneca.
FROM THE JOURNAL CHEST®
Wearable sensors pick up infection before symptoms occur
A simple wristband containing biometric monitoring sensors is able to pick up early infection from both influenza and the common cold before symptoms develop. Moreover, it can predict the severity of the illness once it becomes symptomatic, new research shows.
“Prior to the development of symptoms, people are still infectious and can potentially infect others,” senior author Jessilyn Dunn, PhD, Duke University, Durham, N.C., told this news organization.
“That’s why it’s so important to be able to detect infection even when a person doesn’t feel symptomatic, as this would help prevent the spread of pathogens that occur before somebody knows they are sick – and which is why it is important from a public health perspective,” she added.
The study was published online Sept. 29, 2021, in JAMA Network Open.
Two challenge studies
The study involved 31 participants who were inoculated with the H1N1 influenza virus and 18 others who were inoculated with rhinovirus. The rhinovirus challenge study was conducted in 2015, and the H1N1 challenge study was carried out in 2018. Both groups of patients were inoculated via intranasal drops of either the diluted H1N1 virus or the diluted rhinovirus strain type 16.
Participants in both challenge studies wore the E4 wristband (Empatica). Those in the influenza study wore the wristband 1 day before and 11 days after being inoculated, and those in the rhinovirus study wore the wristband for 4 days before and 5 days after inoculation. The E4 wristband measures heart rate, skin temperature, electrodermal activity, and movement.
Symptoms were typical of each infection and were classified as both observable events, such as runny nose, cough, and wheezy chest, or unobservable events, such as muscle soreness and fatigue. Infection status was classified as asymptomatic or noninfectious (AON), mild, or moderate.
The biosensors contained within the wristband were able to detect the presence or absence of H1N1 infection with an accuracy of 79% within 12 hours after participants had been inoculated and an accuracy of 92% within 24 hours of being inoculated, the authors report. Thus, “we could assess whether or not a participant was infected with H1N1 between 24 and 36 hours before symptom onset,” the investigators noted.
The median time for symptom onset following the rhinovirus challenge was 36 hours after inoculation. The biosensors predicted the presence or absence of rhinovirus infection with an accuracy of 88%, the authors wrote. And when both viral challenges were combined, models predicting infection had an accuracy of 76% at 24 hours after participants being inoculated.
Prediction of severity
Twelve hours after participants had been inoculated, the technology was also able to predict the development of either AON or moderate H1N1 infection with 83% accuracy. For rhinovirus, the predictive accuracy of distinguishing AON versus moderate infection was slightly higher at 92% whereas for both viruses combined, the technology predicted the future development of AON versus moderate infection with an 84% accuracy rate.
As the authors pointed out, the ability to identify individuals during the early critical stage of viral infection could have wide-ranging effects. “In the midst of the global SARS-CoV-2 pandemic, the need for novel approaches like this has never been more apparent,” they suggested.
And in point of fact, in a not-yet peer-reviewed study using a real-time smartwatch-based alerting system again designed to detect aberrant physiologic and activity signals associated with early infection, Stanford (Calif.) University investigators found that alerts were generated for presymptomatic and asymptomatic COVID-19 infections in 78% of cases in over 3200 participants tested at a median of 3 days prior to symptom onset.
The authors also noted that their system is scalable to millions of users, thus offering a personal health monitoring system that can operate in real time.
In a comment, Steven Steinhubl, MD, a research scientist and formerly the director of digital medicine at Scripps Research’s Translational Institute, La Jolla, Calif., told this news organization that he personally has a lot of faith in this type of technology.
“Unfortunately, COVID-19 has changed our perspective about respiratory infections but if you think of the bad flu seasons we’ve had in the past, people do die from influenza, so I think there is a lot of value [in this technology], although the degree of value depends on the severity of the infection,” he said.
For example, if people actually ever go back into work together, early recognition that an employee might have influenza or another highly contagious infection could alert them to the necessity to stay home and self-isolate.
“We have a bit to go before we get there,” Dr. Steinhubl acknowledged, “but you could have a really big impact on the spread of any infectious disease that would be better for everybody.”
Dr. Dunn has disclosed no relevant financial relationships. Dr. Steinhubl is chief medical officer at physIQ, a company involved in the development of personalized analytics.
A version of this article first appeared on Medscape.com.
A simple wristband containing biometric monitoring sensors is able to pick up early infection from both influenza and the common cold before symptoms develop. Moreover, it can predict the severity of the illness once it becomes symptomatic, new research shows.
“Prior to the development of symptoms, people are still infectious and can potentially infect others,” senior author Jessilyn Dunn, PhD, Duke University, Durham, N.C., told this news organization.
“That’s why it’s so important to be able to detect infection even when a person doesn’t feel symptomatic, as this would help prevent the spread of pathogens that occur before somebody knows they are sick – and which is why it is important from a public health perspective,” she added.
The study was published online Sept. 29, 2021, in JAMA Network Open.
Two challenge studies
The study involved 31 participants who were inoculated with the H1N1 influenza virus and 18 others who were inoculated with rhinovirus. The rhinovirus challenge study was conducted in 2015, and the H1N1 challenge study was carried out in 2018. Both groups of patients were inoculated via intranasal drops of either the diluted H1N1 virus or the diluted rhinovirus strain type 16.
Participants in both challenge studies wore the E4 wristband (Empatica). Those in the influenza study wore the wristband 1 day before and 11 days after being inoculated, and those in the rhinovirus study wore the wristband for 4 days before and 5 days after inoculation. The E4 wristband measures heart rate, skin temperature, electrodermal activity, and movement.
Symptoms were typical of each infection and were classified as both observable events, such as runny nose, cough, and wheezy chest, or unobservable events, such as muscle soreness and fatigue. Infection status was classified as asymptomatic or noninfectious (AON), mild, or moderate.
The biosensors contained within the wristband were able to detect the presence or absence of H1N1 infection with an accuracy of 79% within 12 hours after participants had been inoculated and an accuracy of 92% within 24 hours of being inoculated, the authors report. Thus, “we could assess whether or not a participant was infected with H1N1 between 24 and 36 hours before symptom onset,” the investigators noted.
The median time for symptom onset following the rhinovirus challenge was 36 hours after inoculation. The biosensors predicted the presence or absence of rhinovirus infection with an accuracy of 88%, the authors wrote. And when both viral challenges were combined, models predicting infection had an accuracy of 76% at 24 hours after participants being inoculated.
Prediction of severity
Twelve hours after participants had been inoculated, the technology was also able to predict the development of either AON or moderate H1N1 infection with 83% accuracy. For rhinovirus, the predictive accuracy of distinguishing AON versus moderate infection was slightly higher at 92% whereas for both viruses combined, the technology predicted the future development of AON versus moderate infection with an 84% accuracy rate.
As the authors pointed out, the ability to identify individuals during the early critical stage of viral infection could have wide-ranging effects. “In the midst of the global SARS-CoV-2 pandemic, the need for novel approaches like this has never been more apparent,” they suggested.
And in point of fact, in a not-yet peer-reviewed study using a real-time smartwatch-based alerting system again designed to detect aberrant physiologic and activity signals associated with early infection, Stanford (Calif.) University investigators found that alerts were generated for presymptomatic and asymptomatic COVID-19 infections in 78% of cases in over 3200 participants tested at a median of 3 days prior to symptom onset.
The authors also noted that their system is scalable to millions of users, thus offering a personal health monitoring system that can operate in real time.
In a comment, Steven Steinhubl, MD, a research scientist and formerly the director of digital medicine at Scripps Research’s Translational Institute, La Jolla, Calif., told this news organization that he personally has a lot of faith in this type of technology.
“Unfortunately, COVID-19 has changed our perspective about respiratory infections but if you think of the bad flu seasons we’ve had in the past, people do die from influenza, so I think there is a lot of value [in this technology], although the degree of value depends on the severity of the infection,” he said.
For example, if people actually ever go back into work together, early recognition that an employee might have influenza or another highly contagious infection could alert them to the necessity to stay home and self-isolate.
“We have a bit to go before we get there,” Dr. Steinhubl acknowledged, “but you could have a really big impact on the spread of any infectious disease that would be better for everybody.”
Dr. Dunn has disclosed no relevant financial relationships. Dr. Steinhubl is chief medical officer at physIQ, a company involved in the development of personalized analytics.
A version of this article first appeared on Medscape.com.
A simple wristband containing biometric monitoring sensors is able to pick up early infection from both influenza and the common cold before symptoms develop. Moreover, it can predict the severity of the illness once it becomes symptomatic, new research shows.
“Prior to the development of symptoms, people are still infectious and can potentially infect others,” senior author Jessilyn Dunn, PhD, Duke University, Durham, N.C., told this news organization.
“That’s why it’s so important to be able to detect infection even when a person doesn’t feel symptomatic, as this would help prevent the spread of pathogens that occur before somebody knows they are sick – and which is why it is important from a public health perspective,” she added.
The study was published online Sept. 29, 2021, in JAMA Network Open.
Two challenge studies
The study involved 31 participants who were inoculated with the H1N1 influenza virus and 18 others who were inoculated with rhinovirus. The rhinovirus challenge study was conducted in 2015, and the H1N1 challenge study was carried out in 2018. Both groups of patients were inoculated via intranasal drops of either the diluted H1N1 virus or the diluted rhinovirus strain type 16.
Participants in both challenge studies wore the E4 wristband (Empatica). Those in the influenza study wore the wristband 1 day before and 11 days after being inoculated, and those in the rhinovirus study wore the wristband for 4 days before and 5 days after inoculation. The E4 wristband measures heart rate, skin temperature, electrodermal activity, and movement.
Symptoms were typical of each infection and were classified as both observable events, such as runny nose, cough, and wheezy chest, or unobservable events, such as muscle soreness and fatigue. Infection status was classified as asymptomatic or noninfectious (AON), mild, or moderate.
The biosensors contained within the wristband were able to detect the presence or absence of H1N1 infection with an accuracy of 79% within 12 hours after participants had been inoculated and an accuracy of 92% within 24 hours of being inoculated, the authors report. Thus, “we could assess whether or not a participant was infected with H1N1 between 24 and 36 hours before symptom onset,” the investigators noted.
The median time for symptom onset following the rhinovirus challenge was 36 hours after inoculation. The biosensors predicted the presence or absence of rhinovirus infection with an accuracy of 88%, the authors wrote. And when both viral challenges were combined, models predicting infection had an accuracy of 76% at 24 hours after participants being inoculated.
Prediction of severity
Twelve hours after participants had been inoculated, the technology was also able to predict the development of either AON or moderate H1N1 infection with 83% accuracy. For rhinovirus, the predictive accuracy of distinguishing AON versus moderate infection was slightly higher at 92% whereas for both viruses combined, the technology predicted the future development of AON versus moderate infection with an 84% accuracy rate.
As the authors pointed out, the ability to identify individuals during the early critical stage of viral infection could have wide-ranging effects. “In the midst of the global SARS-CoV-2 pandemic, the need for novel approaches like this has never been more apparent,” they suggested.
And in point of fact, in a not-yet peer-reviewed study using a real-time smartwatch-based alerting system again designed to detect aberrant physiologic and activity signals associated with early infection, Stanford (Calif.) University investigators found that alerts were generated for presymptomatic and asymptomatic COVID-19 infections in 78% of cases in over 3200 participants tested at a median of 3 days prior to symptom onset.
The authors also noted that their system is scalable to millions of users, thus offering a personal health monitoring system that can operate in real time.
In a comment, Steven Steinhubl, MD, a research scientist and formerly the director of digital medicine at Scripps Research’s Translational Institute, La Jolla, Calif., told this news organization that he personally has a lot of faith in this type of technology.
“Unfortunately, COVID-19 has changed our perspective about respiratory infections but if you think of the bad flu seasons we’ve had in the past, people do die from influenza, so I think there is a lot of value [in this technology], although the degree of value depends on the severity of the infection,” he said.
For example, if people actually ever go back into work together, early recognition that an employee might have influenza or another highly contagious infection could alert them to the necessity to stay home and self-isolate.
“We have a bit to go before we get there,” Dr. Steinhubl acknowledged, “but you could have a really big impact on the spread of any infectious disease that would be better for everybody.”
Dr. Dunn has disclosed no relevant financial relationships. Dr. Steinhubl is chief medical officer at physIQ, a company involved in the development of personalized analytics.
A version of this article first appeared on Medscape.com.
New approval in early breast cancer: First advance in 20 years
Abemaciclib had already been approved for use in the treatment of HR+, HER2– advanced or metastatic breast cancer.
Now it is also approved for use in HR+, HER2– early breast cancer for patients who have high-risk, node-positive disease and whose tumors have a Ki-67 score of 20% or higher, as determined by a U.S. Food and Drug Administration–approved test.
The FDA also approved the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay for use as a companion diagnostic test.
This is the first CDK4/6 inhibitor to be approved for use in this patient population.
Approximately 70% of all breast cancers are of the HR+, HER2– subtype.
The approval is based on some of the results from the monarchE study, which was presented last year at the annual meeting of the European Society of Medical Oncology and was simultaneously published in the Journal of Clinical Oncology.
The results showed that the addition of abemaciclib to endocrine therapy (tamoxifen or aromatase inhibitors) significantly improved invasive disease-free survival (IDFS), which was defined on the basis of the length of time before breast cancer comes back, any new cancer develops, or death.
The 2-year IDFS rates were 92.2% with the combination vs. 88.7% for endocrine therapy alone for the overall patient population.
“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust, London, said at the meeting, as reported at the time by this news organization.
Reacting to the findings, Giuseppe Curigliano, MD, PhD, head of the division of early drug development at the European Institute of Oncology, Milan, said, “This is a very important trial and the findings will change practice.”
He predicted that once the drug is approved for use in high-risk HR+, HER2– early breast cancer, “the new standard of care for these patients will be to add 2 years of abemaciclib to endocrine therapy.”
In a press release about the new approval from the manufacturer (Lilly), another investigator on the monarchE study, Sara M. Tolaney, MD, MPH, Harvard Medical School and the Dana-Farber Cancer Institute, Boston, agreed that the results are practice changing. She said that the combination of abemaciclib and endocrine therapy is a potential new standard of care for this patient population. “We are encouraged by the marked reduction in the risk of recurrence even beyond the 2-year treatment period in these patients, and I’m grateful to be able to offer this as a treatment option to my patients,” she said.
On Twitter, she commented that restricting the indication to patients who show Ki67 ≥20% is “interesting,” inasmuch as benefits were seen in patients with both low and high Ki67.
Hal Burstein, MD, from Dana-Farber, also found this detail “interesting, as Ki67 testing remains a very controversial topic and difficult to standardize.”
Replying, Pedro Exman, MD, from the Hospital Alemão Oswaldo Cruz, in São Paulo, said: “Does it make sense to approve only in a subset of patients based in a positive subgroup analysis of a positive ITT study that was not even described in the JCO publication?”
Other experts said they were eagerly awaiting further results, particularly on overall survival, from the monarchE trial. New data are due to be presented on Oct. 14 at an ESMO virtual plenary session.
Commenting late last year about these results, George W. Sledge Jr, MD, professor of medicine at Stanford University Medical Center, Palo Alto, Calif., said that the median follow-up time “is still quite short for a study of ER+ adjuvant therapy, where the majority of recurrences and deaths occur after 5 years in many studies.”
Consequently, “we still have a long way to go to understand the ultimate effects of CDK4/6 inhibition on early-stage ER+ breast cancer, particularly on late recurrences,” he told this news organization at the time.
Agreed, said C. Kent Osborne, MD, codirector of the San Antonio Breast Cancer Symposium and founding director of the Duncan Cancer Center at Baylor College of Medicine, Houston, Tex. The results are “very encouraging, especially in the subgroup of tumors with high proliferation” (identified by the K1-67 score).
However, Dr. Osborne also urged caution in the interpretation of the results, “given the still rather short follow-up, given that that ER+ disease is known for its persistent recurrence rate, even past 10 years.”
He also noted that “this class of inhibitors is likely cytostatic, rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells.” Questions therefore remain over whether the survival curves for combination therapy will come together with those for endocrine therapy alone once patients stop taking the drug.
Study details
The monarchE trial involved patients with HR+, HER2–, high-risk early breast cancer who had undergone surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes or one to three nodes and either tumors of size ≥5 cm, histologic grade 3, or central Ki-67 ≥20% were eligible; 5,637 patients were randomly assigned in a 1:1 ratio to receive standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years).
A preplanned interim analysis was carried out after 323 IDFS events were observed in the intent-to-treat population. The results, as published last year in the Journal of Clinical Oncology, show that abemaciclib plus ET yielded superior IDFS in comparison with ET alone (P = .01; hazard ratio, 0.75; 95% confidence interval, 0.60-0.93), with 2-year IDFS rates of 92.2% vs. 88.7%.
In the press release announcing the approval of the new indication, the manufacturer notes that the approval was based on the results from a subgroup of 2,003 patients whose tumors had a Ki-67 score of ≥20% and who were also at high risk for recurrence (≥four positive axillary lymph nodes [ALN], or one-three positive ALN with grade 3 disease and/or tumor size ≥5 cm).
There was a statistically significant improvement in IDFS for this prespecified subgroup of patients (HR, 0.643; 95% CI, 0.475-0.872; P = .0042).
With additional follow-up, conducted post hoc, the results showed a 37% decrease in the risk for breast cancer recurrence or death, compared with ET alone (HR, 0.626; 95% CI, 0.49-0.80) and an absolute benefit in IDFS event rate of 7.1% at 3 years. IDFS was 86.1% for abemaciclib plus ET vs. 79.0% for ET alone.
Adverse reactions from monarchE were consistent with the known safety profile for abemaciclib, the company noted. Safety and tolerability were evaluated in 5,591 patients. The most common adverse reactions reported (≥10%) with abemaciclib plus ET vs. ET alone were diarrhea (84% vs. 9%), infections (51% vs. 39%), neutropenia (46% vs. 6%), fatigue (41% vs. 18%), leukopenia (38% vs. 7%), nausea (30% vs. 9%), anemia (24% vs. 4%), headache (20% vs. 15%), vomiting (18% vs. 4.6%), stomatitis (14% vs. 5%), lymphopenia (14% vs. 3%), thrombocytopenia (13% vs. 2%), decreased appetite (12% vs. 2.4%), increased ALT (12% vs. 6%), increased AST (12% vs. 5%), dizziness (11% vs. 7%), rash (11% vs. 4.5%), and alopecia (11% vs. 2.7 %).
A version of this article first appeared on Medscape.com.
Abemaciclib had already been approved for use in the treatment of HR+, HER2– advanced or metastatic breast cancer.
Now it is also approved for use in HR+, HER2– early breast cancer for patients who have high-risk, node-positive disease and whose tumors have a Ki-67 score of 20% or higher, as determined by a U.S. Food and Drug Administration–approved test.
The FDA also approved the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay for use as a companion diagnostic test.
This is the first CDK4/6 inhibitor to be approved for use in this patient population.
Approximately 70% of all breast cancers are of the HR+, HER2– subtype.
The approval is based on some of the results from the monarchE study, which was presented last year at the annual meeting of the European Society of Medical Oncology and was simultaneously published in the Journal of Clinical Oncology.
The results showed that the addition of abemaciclib to endocrine therapy (tamoxifen or aromatase inhibitors) significantly improved invasive disease-free survival (IDFS), which was defined on the basis of the length of time before breast cancer comes back, any new cancer develops, or death.
The 2-year IDFS rates were 92.2% with the combination vs. 88.7% for endocrine therapy alone for the overall patient population.
“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust, London, said at the meeting, as reported at the time by this news organization.
Reacting to the findings, Giuseppe Curigliano, MD, PhD, head of the division of early drug development at the European Institute of Oncology, Milan, said, “This is a very important trial and the findings will change practice.”
He predicted that once the drug is approved for use in high-risk HR+, HER2– early breast cancer, “the new standard of care for these patients will be to add 2 years of abemaciclib to endocrine therapy.”
In a press release about the new approval from the manufacturer (Lilly), another investigator on the monarchE study, Sara M. Tolaney, MD, MPH, Harvard Medical School and the Dana-Farber Cancer Institute, Boston, agreed that the results are practice changing. She said that the combination of abemaciclib and endocrine therapy is a potential new standard of care for this patient population. “We are encouraged by the marked reduction in the risk of recurrence even beyond the 2-year treatment period in these patients, and I’m grateful to be able to offer this as a treatment option to my patients,” she said.
On Twitter, she commented that restricting the indication to patients who show Ki67 ≥20% is “interesting,” inasmuch as benefits were seen in patients with both low and high Ki67.
Hal Burstein, MD, from Dana-Farber, also found this detail “interesting, as Ki67 testing remains a very controversial topic and difficult to standardize.”
Replying, Pedro Exman, MD, from the Hospital Alemão Oswaldo Cruz, in São Paulo, said: “Does it make sense to approve only in a subset of patients based in a positive subgroup analysis of a positive ITT study that was not even described in the JCO publication?”
Other experts said they were eagerly awaiting further results, particularly on overall survival, from the monarchE trial. New data are due to be presented on Oct. 14 at an ESMO virtual plenary session.
Commenting late last year about these results, George W. Sledge Jr, MD, professor of medicine at Stanford University Medical Center, Palo Alto, Calif., said that the median follow-up time “is still quite short for a study of ER+ adjuvant therapy, where the majority of recurrences and deaths occur after 5 years in many studies.”
Consequently, “we still have a long way to go to understand the ultimate effects of CDK4/6 inhibition on early-stage ER+ breast cancer, particularly on late recurrences,” he told this news organization at the time.
Agreed, said C. Kent Osborne, MD, codirector of the San Antonio Breast Cancer Symposium and founding director of the Duncan Cancer Center at Baylor College of Medicine, Houston, Tex. The results are “very encouraging, especially in the subgroup of tumors with high proliferation” (identified by the K1-67 score).
However, Dr. Osborne also urged caution in the interpretation of the results, “given the still rather short follow-up, given that that ER+ disease is known for its persistent recurrence rate, even past 10 years.”
He also noted that “this class of inhibitors is likely cytostatic, rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells.” Questions therefore remain over whether the survival curves for combination therapy will come together with those for endocrine therapy alone once patients stop taking the drug.
Study details
The monarchE trial involved patients with HR+, HER2–, high-risk early breast cancer who had undergone surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes or one to three nodes and either tumors of size ≥5 cm, histologic grade 3, or central Ki-67 ≥20% were eligible; 5,637 patients were randomly assigned in a 1:1 ratio to receive standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years).
A preplanned interim analysis was carried out after 323 IDFS events were observed in the intent-to-treat population. The results, as published last year in the Journal of Clinical Oncology, show that abemaciclib plus ET yielded superior IDFS in comparison with ET alone (P = .01; hazard ratio, 0.75; 95% confidence interval, 0.60-0.93), with 2-year IDFS rates of 92.2% vs. 88.7%.
In the press release announcing the approval of the new indication, the manufacturer notes that the approval was based on the results from a subgroup of 2,003 patients whose tumors had a Ki-67 score of ≥20% and who were also at high risk for recurrence (≥four positive axillary lymph nodes [ALN], or one-three positive ALN with grade 3 disease and/or tumor size ≥5 cm).
There was a statistically significant improvement in IDFS for this prespecified subgroup of patients (HR, 0.643; 95% CI, 0.475-0.872; P = .0042).
With additional follow-up, conducted post hoc, the results showed a 37% decrease in the risk for breast cancer recurrence or death, compared with ET alone (HR, 0.626; 95% CI, 0.49-0.80) and an absolute benefit in IDFS event rate of 7.1% at 3 years. IDFS was 86.1% for abemaciclib plus ET vs. 79.0% for ET alone.
Adverse reactions from monarchE were consistent with the known safety profile for abemaciclib, the company noted. Safety and tolerability were evaluated in 5,591 patients. The most common adverse reactions reported (≥10%) with abemaciclib plus ET vs. ET alone were diarrhea (84% vs. 9%), infections (51% vs. 39%), neutropenia (46% vs. 6%), fatigue (41% vs. 18%), leukopenia (38% vs. 7%), nausea (30% vs. 9%), anemia (24% vs. 4%), headache (20% vs. 15%), vomiting (18% vs. 4.6%), stomatitis (14% vs. 5%), lymphopenia (14% vs. 3%), thrombocytopenia (13% vs. 2%), decreased appetite (12% vs. 2.4%), increased ALT (12% vs. 6%), increased AST (12% vs. 5%), dizziness (11% vs. 7%), rash (11% vs. 4.5%), and alopecia (11% vs. 2.7 %).
A version of this article first appeared on Medscape.com.
Abemaciclib had already been approved for use in the treatment of HR+, HER2– advanced or metastatic breast cancer.
Now it is also approved for use in HR+, HER2– early breast cancer for patients who have high-risk, node-positive disease and whose tumors have a Ki-67 score of 20% or higher, as determined by a U.S. Food and Drug Administration–approved test.
The FDA also approved the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay for use as a companion diagnostic test.
This is the first CDK4/6 inhibitor to be approved for use in this patient population.
Approximately 70% of all breast cancers are of the HR+, HER2– subtype.
The approval is based on some of the results from the monarchE study, which was presented last year at the annual meeting of the European Society of Medical Oncology and was simultaneously published in the Journal of Clinical Oncology.
The results showed that the addition of abemaciclib to endocrine therapy (tamoxifen or aromatase inhibitors) significantly improved invasive disease-free survival (IDFS), which was defined on the basis of the length of time before breast cancer comes back, any new cancer develops, or death.
The 2-year IDFS rates were 92.2% with the combination vs. 88.7% for endocrine therapy alone for the overall patient population.
“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust, London, said at the meeting, as reported at the time by this news organization.
Reacting to the findings, Giuseppe Curigliano, MD, PhD, head of the division of early drug development at the European Institute of Oncology, Milan, said, “This is a very important trial and the findings will change practice.”
He predicted that once the drug is approved for use in high-risk HR+, HER2– early breast cancer, “the new standard of care for these patients will be to add 2 years of abemaciclib to endocrine therapy.”
In a press release about the new approval from the manufacturer (Lilly), another investigator on the monarchE study, Sara M. Tolaney, MD, MPH, Harvard Medical School and the Dana-Farber Cancer Institute, Boston, agreed that the results are practice changing. She said that the combination of abemaciclib and endocrine therapy is a potential new standard of care for this patient population. “We are encouraged by the marked reduction in the risk of recurrence even beyond the 2-year treatment period in these patients, and I’m grateful to be able to offer this as a treatment option to my patients,” she said.
On Twitter, she commented that restricting the indication to patients who show Ki67 ≥20% is “interesting,” inasmuch as benefits were seen in patients with both low and high Ki67.
Hal Burstein, MD, from Dana-Farber, also found this detail “interesting, as Ki67 testing remains a very controversial topic and difficult to standardize.”
Replying, Pedro Exman, MD, from the Hospital Alemão Oswaldo Cruz, in São Paulo, said: “Does it make sense to approve only in a subset of patients based in a positive subgroup analysis of a positive ITT study that was not even described in the JCO publication?”
Other experts said they were eagerly awaiting further results, particularly on overall survival, from the monarchE trial. New data are due to be presented on Oct. 14 at an ESMO virtual plenary session.
Commenting late last year about these results, George W. Sledge Jr, MD, professor of medicine at Stanford University Medical Center, Palo Alto, Calif., said that the median follow-up time “is still quite short for a study of ER+ adjuvant therapy, where the majority of recurrences and deaths occur after 5 years in many studies.”
Consequently, “we still have a long way to go to understand the ultimate effects of CDK4/6 inhibition on early-stage ER+ breast cancer, particularly on late recurrences,” he told this news organization at the time.
Agreed, said C. Kent Osborne, MD, codirector of the San Antonio Breast Cancer Symposium and founding director of the Duncan Cancer Center at Baylor College of Medicine, Houston, Tex. The results are “very encouraging, especially in the subgroup of tumors with high proliferation” (identified by the K1-67 score).
However, Dr. Osborne also urged caution in the interpretation of the results, “given the still rather short follow-up, given that that ER+ disease is known for its persistent recurrence rate, even past 10 years.”
He also noted that “this class of inhibitors is likely cytostatic, rather than cytocidal, meaning that it blocks cell proliferation rather than killing the cells.” Questions therefore remain over whether the survival curves for combination therapy will come together with those for endocrine therapy alone once patients stop taking the drug.
Study details
The monarchE trial involved patients with HR+, HER2–, high-risk early breast cancer who had undergone surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes or one to three nodes and either tumors of size ≥5 cm, histologic grade 3, or central Ki-67 ≥20% were eligible; 5,637 patients were randomly assigned in a 1:1 ratio to receive standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years).
A preplanned interim analysis was carried out after 323 IDFS events were observed in the intent-to-treat population. The results, as published last year in the Journal of Clinical Oncology, show that abemaciclib plus ET yielded superior IDFS in comparison with ET alone (P = .01; hazard ratio, 0.75; 95% confidence interval, 0.60-0.93), with 2-year IDFS rates of 92.2% vs. 88.7%.
In the press release announcing the approval of the new indication, the manufacturer notes that the approval was based on the results from a subgroup of 2,003 patients whose tumors had a Ki-67 score of ≥20% and who were also at high risk for recurrence (≥four positive axillary lymph nodes [ALN], or one-three positive ALN with grade 3 disease and/or tumor size ≥5 cm).
There was a statistically significant improvement in IDFS for this prespecified subgroup of patients (HR, 0.643; 95% CI, 0.475-0.872; P = .0042).
With additional follow-up, conducted post hoc, the results showed a 37% decrease in the risk for breast cancer recurrence or death, compared with ET alone (HR, 0.626; 95% CI, 0.49-0.80) and an absolute benefit in IDFS event rate of 7.1% at 3 years. IDFS was 86.1% for abemaciclib plus ET vs. 79.0% for ET alone.
Adverse reactions from monarchE were consistent with the known safety profile for abemaciclib, the company noted. Safety and tolerability were evaluated in 5,591 patients. The most common adverse reactions reported (≥10%) with abemaciclib plus ET vs. ET alone were diarrhea (84% vs. 9%), infections (51% vs. 39%), neutropenia (46% vs. 6%), fatigue (41% vs. 18%), leukopenia (38% vs. 7%), nausea (30% vs. 9%), anemia (24% vs. 4%), headache (20% vs. 15%), vomiting (18% vs. 4.6%), stomatitis (14% vs. 5%), lymphopenia (14% vs. 3%), thrombocytopenia (13% vs. 2%), decreased appetite (12% vs. 2.4%), increased ALT (12% vs. 6%), increased AST (12% vs. 5%), dizziness (11% vs. 7%), rash (11% vs. 4.5%), and alopecia (11% vs. 2.7 %).
A version of this article first appeared on Medscape.com.
No short-term death risk in elderly after COVID-19 vaccines
and launched an investigation into the safety of the BNT162b2 vaccine (Comirnaty; Pfizer-BioNTech).
Now, the results of that investigation and of a subsequent larger study of nursing home residents in Norway have shown no increased risk for short-term mortality following COVID-19 vaccination in the overall population of elderly patients. The new research also showed clear evidence of a survival benefit compared with the unvaccinated population, Anette Hylen Ranhoff, MD, PhD, said at the annual meeting of the European Geriatric Medicine Society, held in a hybrid format in Athens, Greece, and online.
“We found no evidence of increased short-term mortality among vaccinated older individuals, and particularly not among the nursing home patients,” said Dr. Ranhoff, a senior researcher at the Norwegian Institute of Public Health and professor at University of Bergen, Norway. “But we think that this [lower] mortality risk was most likely a sort of ‘healthy-vaccinee’ effect, which means that people who were a bit more healthy were vaccinated, and not those who were the very, very most frail.”
“We have more or less the same data in France about events, with very high rates of vaccination,” said session moderator Athanase Benetos MD, PhD, professor and chairman of geriatric medicine at the University Hospital of Nancy in France, who was not involved in the study.
“In my department, a month after the end of the vaccination and at the same time while the pandemic in the city was going up, we had a 90% decrease in mortality from COVID in the nursing homes,” he told Dr. Ranhoff.
Potential risks
Frail elderly patients were not included in clinical trials of COVID-19 vaccines, and although previous studies have shown a low incidence of local or systemic reactions to vaccination among older people, “we think that quite mild adverse events following vaccination could trigger and destabilize a frail person,” Dr. Ranhoff said.
As reported Jan. 15, 2021, in BMJ, investigation by the Norwegian Medicines Agency (NOMA) into 13 of the 23 reported cases concluded that common adverse reactions associated with mRNA vaccines could have contributed to the deaths of some of the frail elderly patients
Steinar Madsen, MD, NOMA medical director, told BMJ “we are not alarmed or worried about this, because these are very rare occurrences and they occurred in very frail patients with very serious disease.”
Health authorities investigate
In response to the report and at the request of the Norwegian Public Health Institute and NOMA, Dr. Ranhoff and colleagues investigated the first 100 deaths among nursing-home residents who received the vaccine. The team consisted of three geriatricians and an infectious disease specialist who sees patients in nursing homes.
They looked at each patient’s clinical course before and after vaccination, their health trajectory and life expectancy at the time of vaccination, new symptoms following vaccination, and the time from vaccination to new symptoms and to death.
In addition, the investigators evaluated Clinical Frailty Scale (CFS) scores for each patient. CFS scores range from 1 (very fit) to 9 (terminally ill, with a life expectancy of less than 6 months who are otherwise evidently frail).
The initial investigation found that among 95 evaluable patients, the association between vaccination and death was “probable” in 10, “possible” in 26, and “unlikely” in 59.
The mean time from vaccination to symptoms was 1.4 days in the probable cases, 2.5 days in the possible cases, and 4.7 days in the unlikely cases.
The mean time from vaccination to death was 3.1, 8.3, and 8.2 days, respectively.
In all three categories, the patients had mean CFS scores ranging from 7.6 to 7.9, putting them in the “severely frail” category, defined as people who are completely dependent for personal care but seem stable and not at high risk for dying.
“We have quite many nursing home residents in Norway, 35,000; more than 80% have dementia, and the mean age is 85 years. We know that approximately 45 people die every day in these nursing homes, and their mean age of death is 87.5 years,” Dr. Ranhoff said.
Population-wide study
Dr. Ranhoff and colleagues also looked more broadly into the question of potential vaccine-related mortality in the total population of older people in Norway from the day of vaccination to follow-up at 3 weeks.
They conducted a matched cohort study to investigate the relationship between the mRNA SARS-CoV-2 vaccine and overall death among persons aged 65 and older in the general population, and across four groups: patients receiving home-based care, long-term nursing home patients, short-term nursing home patients, and those not receiving health services.
The researchers identified a total of 967,786 residents of Norway aged 65 and over at the start of the country’s vaccination campaign at the end of December, 2020, and they matched vaccinated individuals with unvaccinated persons based on demographic, geographic, and clinical risk group factors.
Dr. Ranhoff showed Kaplan-Meier survival curves for the total population and for each of the health-service states. In all cases there was a clear survival benefit for vaccinated vs. unvaccinated patients. She did not, however, provide specific numbers or hazard ratios for the differences between vaccinated and unvaccinated individuals in each of the comparisons.
The study was supported by the Norwegian Institute of Public Health. Dr. Ranhoff and Dr. Benetos reported no conflicts of interest.
and launched an investigation into the safety of the BNT162b2 vaccine (Comirnaty; Pfizer-BioNTech).
Now, the results of that investigation and of a subsequent larger study of nursing home residents in Norway have shown no increased risk for short-term mortality following COVID-19 vaccination in the overall population of elderly patients. The new research also showed clear evidence of a survival benefit compared with the unvaccinated population, Anette Hylen Ranhoff, MD, PhD, said at the annual meeting of the European Geriatric Medicine Society, held in a hybrid format in Athens, Greece, and online.
“We found no evidence of increased short-term mortality among vaccinated older individuals, and particularly not among the nursing home patients,” said Dr. Ranhoff, a senior researcher at the Norwegian Institute of Public Health and professor at University of Bergen, Norway. “But we think that this [lower] mortality risk was most likely a sort of ‘healthy-vaccinee’ effect, which means that people who were a bit more healthy were vaccinated, and not those who were the very, very most frail.”
“We have more or less the same data in France about events, with very high rates of vaccination,” said session moderator Athanase Benetos MD, PhD, professor and chairman of geriatric medicine at the University Hospital of Nancy in France, who was not involved in the study.
“In my department, a month after the end of the vaccination and at the same time while the pandemic in the city was going up, we had a 90% decrease in mortality from COVID in the nursing homes,” he told Dr. Ranhoff.
Potential risks
Frail elderly patients were not included in clinical trials of COVID-19 vaccines, and although previous studies have shown a low incidence of local or systemic reactions to vaccination among older people, “we think that quite mild adverse events following vaccination could trigger and destabilize a frail person,” Dr. Ranhoff said.
As reported Jan. 15, 2021, in BMJ, investigation by the Norwegian Medicines Agency (NOMA) into 13 of the 23 reported cases concluded that common adverse reactions associated with mRNA vaccines could have contributed to the deaths of some of the frail elderly patients
Steinar Madsen, MD, NOMA medical director, told BMJ “we are not alarmed or worried about this, because these are very rare occurrences and they occurred in very frail patients with very serious disease.”
Health authorities investigate
In response to the report and at the request of the Norwegian Public Health Institute and NOMA, Dr. Ranhoff and colleagues investigated the first 100 deaths among nursing-home residents who received the vaccine. The team consisted of three geriatricians and an infectious disease specialist who sees patients in nursing homes.
They looked at each patient’s clinical course before and after vaccination, their health trajectory and life expectancy at the time of vaccination, new symptoms following vaccination, and the time from vaccination to new symptoms and to death.
In addition, the investigators evaluated Clinical Frailty Scale (CFS) scores for each patient. CFS scores range from 1 (very fit) to 9 (terminally ill, with a life expectancy of less than 6 months who are otherwise evidently frail).
The initial investigation found that among 95 evaluable patients, the association between vaccination and death was “probable” in 10, “possible” in 26, and “unlikely” in 59.
The mean time from vaccination to symptoms was 1.4 days in the probable cases, 2.5 days in the possible cases, and 4.7 days in the unlikely cases.
The mean time from vaccination to death was 3.1, 8.3, and 8.2 days, respectively.
In all three categories, the patients had mean CFS scores ranging from 7.6 to 7.9, putting them in the “severely frail” category, defined as people who are completely dependent for personal care but seem stable and not at high risk for dying.
“We have quite many nursing home residents in Norway, 35,000; more than 80% have dementia, and the mean age is 85 years. We know that approximately 45 people die every day in these nursing homes, and their mean age of death is 87.5 years,” Dr. Ranhoff said.
Population-wide study
Dr. Ranhoff and colleagues also looked more broadly into the question of potential vaccine-related mortality in the total population of older people in Norway from the day of vaccination to follow-up at 3 weeks.
They conducted a matched cohort study to investigate the relationship between the mRNA SARS-CoV-2 vaccine and overall death among persons aged 65 and older in the general population, and across four groups: patients receiving home-based care, long-term nursing home patients, short-term nursing home patients, and those not receiving health services.
The researchers identified a total of 967,786 residents of Norway aged 65 and over at the start of the country’s vaccination campaign at the end of December, 2020, and they matched vaccinated individuals with unvaccinated persons based on demographic, geographic, and clinical risk group factors.
Dr. Ranhoff showed Kaplan-Meier survival curves for the total population and for each of the health-service states. In all cases there was a clear survival benefit for vaccinated vs. unvaccinated patients. She did not, however, provide specific numbers or hazard ratios for the differences between vaccinated and unvaccinated individuals in each of the comparisons.
The study was supported by the Norwegian Institute of Public Health. Dr. Ranhoff and Dr. Benetos reported no conflicts of interest.
and launched an investigation into the safety of the BNT162b2 vaccine (Comirnaty; Pfizer-BioNTech).
Now, the results of that investigation and of a subsequent larger study of nursing home residents in Norway have shown no increased risk for short-term mortality following COVID-19 vaccination in the overall population of elderly patients. The new research also showed clear evidence of a survival benefit compared with the unvaccinated population, Anette Hylen Ranhoff, MD, PhD, said at the annual meeting of the European Geriatric Medicine Society, held in a hybrid format in Athens, Greece, and online.
“We found no evidence of increased short-term mortality among vaccinated older individuals, and particularly not among the nursing home patients,” said Dr. Ranhoff, a senior researcher at the Norwegian Institute of Public Health and professor at University of Bergen, Norway. “But we think that this [lower] mortality risk was most likely a sort of ‘healthy-vaccinee’ effect, which means that people who were a bit more healthy were vaccinated, and not those who were the very, very most frail.”
“We have more or less the same data in France about events, with very high rates of vaccination,” said session moderator Athanase Benetos MD, PhD, professor and chairman of geriatric medicine at the University Hospital of Nancy in France, who was not involved in the study.
“In my department, a month after the end of the vaccination and at the same time while the pandemic in the city was going up, we had a 90% decrease in mortality from COVID in the nursing homes,” he told Dr. Ranhoff.
Potential risks
Frail elderly patients were not included in clinical trials of COVID-19 vaccines, and although previous studies have shown a low incidence of local or systemic reactions to vaccination among older people, “we think that quite mild adverse events following vaccination could trigger and destabilize a frail person,” Dr. Ranhoff said.
As reported Jan. 15, 2021, in BMJ, investigation by the Norwegian Medicines Agency (NOMA) into 13 of the 23 reported cases concluded that common adverse reactions associated with mRNA vaccines could have contributed to the deaths of some of the frail elderly patients
Steinar Madsen, MD, NOMA medical director, told BMJ “we are not alarmed or worried about this, because these are very rare occurrences and they occurred in very frail patients with very serious disease.”
Health authorities investigate
In response to the report and at the request of the Norwegian Public Health Institute and NOMA, Dr. Ranhoff and colleagues investigated the first 100 deaths among nursing-home residents who received the vaccine. The team consisted of three geriatricians and an infectious disease specialist who sees patients in nursing homes.
They looked at each patient’s clinical course before and after vaccination, their health trajectory and life expectancy at the time of vaccination, new symptoms following vaccination, and the time from vaccination to new symptoms and to death.
In addition, the investigators evaluated Clinical Frailty Scale (CFS) scores for each patient. CFS scores range from 1 (very fit) to 9 (terminally ill, with a life expectancy of less than 6 months who are otherwise evidently frail).
The initial investigation found that among 95 evaluable patients, the association between vaccination and death was “probable” in 10, “possible” in 26, and “unlikely” in 59.
The mean time from vaccination to symptoms was 1.4 days in the probable cases, 2.5 days in the possible cases, and 4.7 days in the unlikely cases.
The mean time from vaccination to death was 3.1, 8.3, and 8.2 days, respectively.
In all three categories, the patients had mean CFS scores ranging from 7.6 to 7.9, putting them in the “severely frail” category, defined as people who are completely dependent for personal care but seem stable and not at high risk for dying.
“We have quite many nursing home residents in Norway, 35,000; more than 80% have dementia, and the mean age is 85 years. We know that approximately 45 people die every day in these nursing homes, and their mean age of death is 87.5 years,” Dr. Ranhoff said.
Population-wide study
Dr. Ranhoff and colleagues also looked more broadly into the question of potential vaccine-related mortality in the total population of older people in Norway from the day of vaccination to follow-up at 3 weeks.
They conducted a matched cohort study to investigate the relationship between the mRNA SARS-CoV-2 vaccine and overall death among persons aged 65 and older in the general population, and across four groups: patients receiving home-based care, long-term nursing home patients, short-term nursing home patients, and those not receiving health services.
The researchers identified a total of 967,786 residents of Norway aged 65 and over at the start of the country’s vaccination campaign at the end of December, 2020, and they matched vaccinated individuals with unvaccinated persons based on demographic, geographic, and clinical risk group factors.
Dr. Ranhoff showed Kaplan-Meier survival curves for the total population and for each of the health-service states. In all cases there was a clear survival benefit for vaccinated vs. unvaccinated patients. She did not, however, provide specific numbers or hazard ratios for the differences between vaccinated and unvaccinated individuals in each of the comparisons.
The study was supported by the Norwegian Institute of Public Health. Dr. Ranhoff and Dr. Benetos reported no conflicts of interest.
FROM EUGMS 2021
Uncomplicated pediatric chest infection: Antibiotics don’t help
Unless pneumonia is suspected, clinicians should not prescribe antibiotics for most children with chest infections, according to findings of the ARTIC-PC randomized controlled trial, published in The Lancet.
“Prescribing for children with uncomplicated chest infections is still common in most countries,” said lead author Paul Little, MD, professor of primary care research at the University of Southampton, England, in an interview.
But there are barriers to stopping this practice, he said. “If you prescribe an antibiotic and the child gets better, even if the antibiotic was not doing that much, the parents then think that it was the antibiotic that was responsible for the recovery and so expect antibiotics the next time. So, physician prescribing of antibiotics in effect medicalizes illness and keeps the cycle of expectations, reconsultations, and prescriptions going.”
The study included 432 children aged 6 months to 12 years (median age, 3.2 years) who presented at 56 general practices in England with acute, uncomplicated lower respiratory tract infection (LRTI) of less than 21 days’ duration and in whom pneumonia was not suspected clinically. The children were randomly assigned to undergo 7 days of treatment with either amoxicillin 50 mg/kg or placebo. The primary outcome was duration of symptoms rated moderately bad or worse.
For up to 4 weeks, parents scored symptoms – including cough, phlegm, shortness of breath, wheeze, blocked or runny nose, disturbed sleep, feeling generally unwell, fever, and interference with normal activities – in a daily diary. The secondary outcome was symptom severity. Prespecified analyses were made for key clinical subgroups of patients for whom clinicians commonly prescribe (those with chest signs, fever, physician rating of unwell, sputum or chest rattle, and shortness of breath).
There was no significant difference in outcome between children treated with antibiotics and those treated with placebo. The median duration of moderately bad or worse symptoms was similar between the antibiotics group and the placebo group (5 vs. 6 days; hazard ratio, 1.13), as was the median time until symptoms were rated absent or as causing very little problem (7 vs. 8 days; HR, 1.09). There was a small significant difference between the groups in symptom severity score on days 2-4 after seeing the doctor (1.8 in the antibiotics group vs. 2.1 in the placebo group), “which was equivalent to less than one child in three rating symptoms a slight problem rather than very little problem,” the study authors report. “The treatment effects for all outcomes were similar for most subgroups ... but the effect of antibiotics was slightly, but not significantly, greater among those with fever or those who were unwell,” they add.
The investigators conclude that “similar to adults, antibiotics are unlikely to make a clinically important difference to the symptom burden for uncomplicated lower respiratory tract infections in children – both overall, and for the key clinical subgroups where antibiotic prescribing is most common.” They recommend that clinicians provide “safety-netting advice” to parents, such as explaining what illness course to expect and when a return visit would be necessary.
The findings provide “more evidence to do less,” wrote Rianne Oostenbrink, MD, PhD, from Erasmus MC-Sophia, in Rotterdam, the Netherlands, and Lina Jankauskaite, MD, PhD, from Lithuanian University of Health Sciences, Kaunas, in an accompanying comment.
“Overtesting and overtreatment of children are especially prominent in infectious diseases, when fever or other symptoms such as cough can be unspecific and can be of viral or bacterial origin,” they write.
The commenters note that despite antibiotics, most children did have moderately bad or worse symptoms on day 3, and symptoms had improved in about 75% of children in both groups at day 14. “A notable finding of this study is that only a few children had moderately bad or worse symptoms by day 14, and antibiotics did not alleviate the symptoms compared with placebo. Additionally, this trial aligns with other studies that have shown that reducing antibiotic treatment for LRTI is not associated with prolonged morbidity or higher incidence of complications.”
The study was funded by the UK National Institute for Health Research. Dr. Little, Dr. Jankauskaite, and Dr. Oostenbrink have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Unless pneumonia is suspected, clinicians should not prescribe antibiotics for most children with chest infections, according to findings of the ARTIC-PC randomized controlled trial, published in The Lancet.
“Prescribing for children with uncomplicated chest infections is still common in most countries,” said lead author Paul Little, MD, professor of primary care research at the University of Southampton, England, in an interview.
But there are barriers to stopping this practice, he said. “If you prescribe an antibiotic and the child gets better, even if the antibiotic was not doing that much, the parents then think that it was the antibiotic that was responsible for the recovery and so expect antibiotics the next time. So, physician prescribing of antibiotics in effect medicalizes illness and keeps the cycle of expectations, reconsultations, and prescriptions going.”
The study included 432 children aged 6 months to 12 years (median age, 3.2 years) who presented at 56 general practices in England with acute, uncomplicated lower respiratory tract infection (LRTI) of less than 21 days’ duration and in whom pneumonia was not suspected clinically. The children were randomly assigned to undergo 7 days of treatment with either amoxicillin 50 mg/kg or placebo. The primary outcome was duration of symptoms rated moderately bad or worse.
For up to 4 weeks, parents scored symptoms – including cough, phlegm, shortness of breath, wheeze, blocked or runny nose, disturbed sleep, feeling generally unwell, fever, and interference with normal activities – in a daily diary. The secondary outcome was symptom severity. Prespecified analyses were made for key clinical subgroups of patients for whom clinicians commonly prescribe (those with chest signs, fever, physician rating of unwell, sputum or chest rattle, and shortness of breath).
There was no significant difference in outcome between children treated with antibiotics and those treated with placebo. The median duration of moderately bad or worse symptoms was similar between the antibiotics group and the placebo group (5 vs. 6 days; hazard ratio, 1.13), as was the median time until symptoms were rated absent or as causing very little problem (7 vs. 8 days; HR, 1.09). There was a small significant difference between the groups in symptom severity score on days 2-4 after seeing the doctor (1.8 in the antibiotics group vs. 2.1 in the placebo group), “which was equivalent to less than one child in three rating symptoms a slight problem rather than very little problem,” the study authors report. “The treatment effects for all outcomes were similar for most subgroups ... but the effect of antibiotics was slightly, but not significantly, greater among those with fever or those who were unwell,” they add.
The investigators conclude that “similar to adults, antibiotics are unlikely to make a clinically important difference to the symptom burden for uncomplicated lower respiratory tract infections in children – both overall, and for the key clinical subgroups where antibiotic prescribing is most common.” They recommend that clinicians provide “safety-netting advice” to parents, such as explaining what illness course to expect and when a return visit would be necessary.
The findings provide “more evidence to do less,” wrote Rianne Oostenbrink, MD, PhD, from Erasmus MC-Sophia, in Rotterdam, the Netherlands, and Lina Jankauskaite, MD, PhD, from Lithuanian University of Health Sciences, Kaunas, in an accompanying comment.
“Overtesting and overtreatment of children are especially prominent in infectious diseases, when fever or other symptoms such as cough can be unspecific and can be of viral or bacterial origin,” they write.
The commenters note that despite antibiotics, most children did have moderately bad or worse symptoms on day 3, and symptoms had improved in about 75% of children in both groups at day 14. “A notable finding of this study is that only a few children had moderately bad or worse symptoms by day 14, and antibiotics did not alleviate the symptoms compared with placebo. Additionally, this trial aligns with other studies that have shown that reducing antibiotic treatment for LRTI is not associated with prolonged morbidity or higher incidence of complications.”
The study was funded by the UK National Institute for Health Research. Dr. Little, Dr. Jankauskaite, and Dr. Oostenbrink have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Unless pneumonia is suspected, clinicians should not prescribe antibiotics for most children with chest infections, according to findings of the ARTIC-PC randomized controlled trial, published in The Lancet.
“Prescribing for children with uncomplicated chest infections is still common in most countries,” said lead author Paul Little, MD, professor of primary care research at the University of Southampton, England, in an interview.
But there are barriers to stopping this practice, he said. “If you prescribe an antibiotic and the child gets better, even if the antibiotic was not doing that much, the parents then think that it was the antibiotic that was responsible for the recovery and so expect antibiotics the next time. So, physician prescribing of antibiotics in effect medicalizes illness and keeps the cycle of expectations, reconsultations, and prescriptions going.”
The study included 432 children aged 6 months to 12 years (median age, 3.2 years) who presented at 56 general practices in England with acute, uncomplicated lower respiratory tract infection (LRTI) of less than 21 days’ duration and in whom pneumonia was not suspected clinically. The children were randomly assigned to undergo 7 days of treatment with either amoxicillin 50 mg/kg or placebo. The primary outcome was duration of symptoms rated moderately bad or worse.
For up to 4 weeks, parents scored symptoms – including cough, phlegm, shortness of breath, wheeze, blocked or runny nose, disturbed sleep, feeling generally unwell, fever, and interference with normal activities – in a daily diary. The secondary outcome was symptom severity. Prespecified analyses were made for key clinical subgroups of patients for whom clinicians commonly prescribe (those with chest signs, fever, physician rating of unwell, sputum or chest rattle, and shortness of breath).
There was no significant difference in outcome between children treated with antibiotics and those treated with placebo. The median duration of moderately bad or worse symptoms was similar between the antibiotics group and the placebo group (5 vs. 6 days; hazard ratio, 1.13), as was the median time until symptoms were rated absent or as causing very little problem (7 vs. 8 days; HR, 1.09). There was a small significant difference between the groups in symptom severity score on days 2-4 after seeing the doctor (1.8 in the antibiotics group vs. 2.1 in the placebo group), “which was equivalent to less than one child in three rating symptoms a slight problem rather than very little problem,” the study authors report. “The treatment effects for all outcomes were similar for most subgroups ... but the effect of antibiotics was slightly, but not significantly, greater among those with fever or those who were unwell,” they add.
The investigators conclude that “similar to adults, antibiotics are unlikely to make a clinically important difference to the symptom burden for uncomplicated lower respiratory tract infections in children – both overall, and for the key clinical subgroups where antibiotic prescribing is most common.” They recommend that clinicians provide “safety-netting advice” to parents, such as explaining what illness course to expect and when a return visit would be necessary.
The findings provide “more evidence to do less,” wrote Rianne Oostenbrink, MD, PhD, from Erasmus MC-Sophia, in Rotterdam, the Netherlands, and Lina Jankauskaite, MD, PhD, from Lithuanian University of Health Sciences, Kaunas, in an accompanying comment.
“Overtesting and overtreatment of children are especially prominent in infectious diseases, when fever or other symptoms such as cough can be unspecific and can be of viral or bacterial origin,” they write.
The commenters note that despite antibiotics, most children did have moderately bad or worse symptoms on day 3, and symptoms had improved in about 75% of children in both groups at day 14. “A notable finding of this study is that only a few children had moderately bad or worse symptoms by day 14, and antibiotics did not alleviate the symptoms compared with placebo. Additionally, this trial aligns with other studies that have shown that reducing antibiotic treatment for LRTI is not associated with prolonged morbidity or higher incidence of complications.”
The study was funded by the UK National Institute for Health Research. Dr. Little, Dr. Jankauskaite, and Dr. Oostenbrink have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Oral PTH shows promise for osteoporosis in early phase 2 study
An investigational oral form of parathyroid hormone (PTH 1-34), EB 613 (Entera Bio) met its primary efficacy outcome in a phase 2 dosing study involving postmenopausal women with low bone mineral density (BMD).
The adverse effect profile of the drug was similar to that of the injectable PTH 1-34 teriparatide (Forteo), which is approved for osteoporosis.
Arthur C. Santora, MD, chief medical officer, Entera Bio, presented 6-month findings from the study during an oral session at the annual meeting of the American Society of Bone and Mineral Research. The 3-month findings from the study were reported as a poster.
If the drug demonstrates efficacy and safety in larger phase 3 trials, it could be the first oral bone-building (anabolic) therapy for osteoporosis.
Clifford J. Rosen, MD, PhD, who was not involved with the research, told this news organization: “I think this is an intriguing study.” The most likely patients for oral PTH, he added, “are those that have osteoporosis, previous fracture, or very low BMD, particularly those unlikely or unwilling to take bisphosphonates.”
However, “this is very early in the process before this drug could come to market,” cautioned Dr. Rosen, who is director of the Center for Clinical and Translational Research, Maine Medical Research Institute, Scarborough.
“Much more data on efficacy are required at 12 and 24 months for phase 2, and then a full phase 3 [clinical trial] with high-risk fracture patients,” he said.
The company is seeking input from the Food and Drug Administration to develop the protocol for a phase 3 trial. They expect to start this trial in 2022 at sites in the United States, Europe, and Israel, Dr. Santora said.
Primary outcome met
The study randomly assigned 161 postmenopausal women with osteoporosis or low BMD to receive placebo or the investigational oral PTH for 6 months.
Compared with women who received placebo, those who received the study drug experienced a significantly greater increase in the bone formation marker procollagen type I N-terminal propeptide (P1NP) from baseline to 3 months, thereby meeting the study’s primary outcome.
In secondary outcomes, women who received the 2.5-mg/d dose experienced a similar 6-month increase in BMD at the spine and greater increases in BMD at the total hip and femoral neck than those who received injectable teriparatide, Dr. Santora reported.
“The study’s key takeaway is that a once-daily oral PTH [tablet] has the potential to produce the same BMD effects as subcutaneous injections of PTH,” he said in an interview.
Additionally, “the drug was well tolerated when the dose was titrated by adding additional tablets, which suggests that the dose can be tailored to each patient,” he said.
Other study findings
Injectable teriparatide reduces the risk for vertebral fractures by up to 80%, Dr. Santora noted, but the fact that the drug must be administered by injection may deter some older patients from using it.
The company developed an oral form of biosynthetic human PTH with a proprietary drug delivery.
The researchers conducted the phase 2 study at four sites in Israel between June 2019 and May 2021. They enrolled women aged 50 years and older who had entered menopause at least 3 years earlier and who had osteoporosis or low BMD.
Forty-three women received placebo, and the others received oral PTH at doses of 0.5 mg/d (n = 25), 1.0 mg/d (n = 29), 1.5 mg/d (n = 28), 2.5 mg/d (n = 19), or at a dose that was titrated up to 2.5 mg/d starting at 1.5 mg/d for month 1, then 2 mg/d for month 2, and then 2.5 mg/d for months 3 to 6 (n = 17).
The mean age of the patients was 61 years, the mean body mass index was 25-27 kg/m2, and the mean T score at the spine of –2.2 to –2.45.
Among the women who received 2.5 mg/d of oral PTH for the full 6 months, serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) decreased 21% from baseline to 6 months, and serum levels of P1NP increased at month 1 and then decreased to baseline by month 6.
The women who received 2.5 mg/d of oral PTH for the full 6 months also demonstrated significantly greater increases in BMD at the lumbar spine (3.8%), total hip (1.4%), and femoral neck (2.4%), compared with women who received placebo.
The safety profile of oral PTH was consistent with that of subcutaneous PTH. Patients experienced headache, nausea, presyncope, and dizziness; there were no treatment-emergent hypercalcemia adverse events.
A few ‘unexpected findings’
Suzanne M. Jan De Beur, MD, outgoing ASBMR president, said, “Oral PTH appeared to increase BMD by [dual-energy x-ray absorptiometry] at the lumbar spine effectively and to a similar degree as teriparatide in previous studies.”
She identified two unexpected findings.
“There were increases in BMD by DXA at the femoral neck and total hip at 6 months that were [greater than those] seen in previous trials of teriparatide. Second, markers of bone resorption (CTX) decreased at 6 months, and this is in stark contrast to the increases observed with teriparatide treatment,” she noted in an interview.
Dr. Rosen also noted that “the decrease in CTX is very unusual for PTH and difficult to explain.” He added: “P1NP, a marker of bone formation, was not increased.”
Dr. Jan de Beur continued: “Teriparatide (PTH1-34) and abaloparatide are effective anabolic agents that we use to treat patients with high risk of osteoporotic fracture. Although effective, the burden of daily subcutaneous injection can be a barrier for older individuals, those with poor dexterity, and those that are averse to self-injection.
“Taken together, these results appear promising, that oral PTH may prove to be an effective anabolic agent for osteoporosis treatment,” she summarized.
She stressed that a larger phase 3 study is needed to demonstrate safety and efficacy.
The study was funded by Entera Bio. Dr. Santora is chief medical officer of Entera Bio.
A version of this article first appeared on Medscape.com .
An investigational oral form of parathyroid hormone (PTH 1-34), EB 613 (Entera Bio) met its primary efficacy outcome in a phase 2 dosing study involving postmenopausal women with low bone mineral density (BMD).
The adverse effect profile of the drug was similar to that of the injectable PTH 1-34 teriparatide (Forteo), which is approved for osteoporosis.
Arthur C. Santora, MD, chief medical officer, Entera Bio, presented 6-month findings from the study during an oral session at the annual meeting of the American Society of Bone and Mineral Research. The 3-month findings from the study were reported as a poster.
If the drug demonstrates efficacy and safety in larger phase 3 trials, it could be the first oral bone-building (anabolic) therapy for osteoporosis.
Clifford J. Rosen, MD, PhD, who was not involved with the research, told this news organization: “I think this is an intriguing study.” The most likely patients for oral PTH, he added, “are those that have osteoporosis, previous fracture, or very low BMD, particularly those unlikely or unwilling to take bisphosphonates.”
However, “this is very early in the process before this drug could come to market,” cautioned Dr. Rosen, who is director of the Center for Clinical and Translational Research, Maine Medical Research Institute, Scarborough.
“Much more data on efficacy are required at 12 and 24 months for phase 2, and then a full phase 3 [clinical trial] with high-risk fracture patients,” he said.
The company is seeking input from the Food and Drug Administration to develop the protocol for a phase 3 trial. They expect to start this trial in 2022 at sites in the United States, Europe, and Israel, Dr. Santora said.
Primary outcome met
The study randomly assigned 161 postmenopausal women with osteoporosis or low BMD to receive placebo or the investigational oral PTH for 6 months.
Compared with women who received placebo, those who received the study drug experienced a significantly greater increase in the bone formation marker procollagen type I N-terminal propeptide (P1NP) from baseline to 3 months, thereby meeting the study’s primary outcome.
In secondary outcomes, women who received the 2.5-mg/d dose experienced a similar 6-month increase in BMD at the spine and greater increases in BMD at the total hip and femoral neck than those who received injectable teriparatide, Dr. Santora reported.
“The study’s key takeaway is that a once-daily oral PTH [tablet] has the potential to produce the same BMD effects as subcutaneous injections of PTH,” he said in an interview.
Additionally, “the drug was well tolerated when the dose was titrated by adding additional tablets, which suggests that the dose can be tailored to each patient,” he said.
Other study findings
Injectable teriparatide reduces the risk for vertebral fractures by up to 80%, Dr. Santora noted, but the fact that the drug must be administered by injection may deter some older patients from using it.
The company developed an oral form of biosynthetic human PTH with a proprietary drug delivery.
The researchers conducted the phase 2 study at four sites in Israel between June 2019 and May 2021. They enrolled women aged 50 years and older who had entered menopause at least 3 years earlier and who had osteoporosis or low BMD.
Forty-three women received placebo, and the others received oral PTH at doses of 0.5 mg/d (n = 25), 1.0 mg/d (n = 29), 1.5 mg/d (n = 28), 2.5 mg/d (n = 19), or at a dose that was titrated up to 2.5 mg/d starting at 1.5 mg/d for month 1, then 2 mg/d for month 2, and then 2.5 mg/d for months 3 to 6 (n = 17).
The mean age of the patients was 61 years, the mean body mass index was 25-27 kg/m2, and the mean T score at the spine of –2.2 to –2.45.
Among the women who received 2.5 mg/d of oral PTH for the full 6 months, serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) decreased 21% from baseline to 6 months, and serum levels of P1NP increased at month 1 and then decreased to baseline by month 6.
The women who received 2.5 mg/d of oral PTH for the full 6 months also demonstrated significantly greater increases in BMD at the lumbar spine (3.8%), total hip (1.4%), and femoral neck (2.4%), compared with women who received placebo.
The safety profile of oral PTH was consistent with that of subcutaneous PTH. Patients experienced headache, nausea, presyncope, and dizziness; there were no treatment-emergent hypercalcemia adverse events.
A few ‘unexpected findings’
Suzanne M. Jan De Beur, MD, outgoing ASBMR president, said, “Oral PTH appeared to increase BMD by [dual-energy x-ray absorptiometry] at the lumbar spine effectively and to a similar degree as teriparatide in previous studies.”
She identified two unexpected findings.
“There were increases in BMD by DXA at the femoral neck and total hip at 6 months that were [greater than those] seen in previous trials of teriparatide. Second, markers of bone resorption (CTX) decreased at 6 months, and this is in stark contrast to the increases observed with teriparatide treatment,” she noted in an interview.
Dr. Rosen also noted that “the decrease in CTX is very unusual for PTH and difficult to explain.” He added: “P1NP, a marker of bone formation, was not increased.”
Dr. Jan de Beur continued: “Teriparatide (PTH1-34) and abaloparatide are effective anabolic agents that we use to treat patients with high risk of osteoporotic fracture. Although effective, the burden of daily subcutaneous injection can be a barrier for older individuals, those with poor dexterity, and those that are averse to self-injection.
“Taken together, these results appear promising, that oral PTH may prove to be an effective anabolic agent for osteoporosis treatment,” she summarized.
She stressed that a larger phase 3 study is needed to demonstrate safety and efficacy.
The study was funded by Entera Bio. Dr. Santora is chief medical officer of Entera Bio.
A version of this article first appeared on Medscape.com .
An investigational oral form of parathyroid hormone (PTH 1-34), EB 613 (Entera Bio) met its primary efficacy outcome in a phase 2 dosing study involving postmenopausal women with low bone mineral density (BMD).
The adverse effect profile of the drug was similar to that of the injectable PTH 1-34 teriparatide (Forteo), which is approved for osteoporosis.
Arthur C. Santora, MD, chief medical officer, Entera Bio, presented 6-month findings from the study during an oral session at the annual meeting of the American Society of Bone and Mineral Research. The 3-month findings from the study were reported as a poster.
If the drug demonstrates efficacy and safety in larger phase 3 trials, it could be the first oral bone-building (anabolic) therapy for osteoporosis.
Clifford J. Rosen, MD, PhD, who was not involved with the research, told this news organization: “I think this is an intriguing study.” The most likely patients for oral PTH, he added, “are those that have osteoporosis, previous fracture, or very low BMD, particularly those unlikely or unwilling to take bisphosphonates.”
However, “this is very early in the process before this drug could come to market,” cautioned Dr. Rosen, who is director of the Center for Clinical and Translational Research, Maine Medical Research Institute, Scarborough.
“Much more data on efficacy are required at 12 and 24 months for phase 2, and then a full phase 3 [clinical trial] with high-risk fracture patients,” he said.
The company is seeking input from the Food and Drug Administration to develop the protocol for a phase 3 trial. They expect to start this trial in 2022 at sites in the United States, Europe, and Israel, Dr. Santora said.
Primary outcome met
The study randomly assigned 161 postmenopausal women with osteoporosis or low BMD to receive placebo or the investigational oral PTH for 6 months.
Compared with women who received placebo, those who received the study drug experienced a significantly greater increase in the bone formation marker procollagen type I N-terminal propeptide (P1NP) from baseline to 3 months, thereby meeting the study’s primary outcome.
In secondary outcomes, women who received the 2.5-mg/d dose experienced a similar 6-month increase in BMD at the spine and greater increases in BMD at the total hip and femoral neck than those who received injectable teriparatide, Dr. Santora reported.
“The study’s key takeaway is that a once-daily oral PTH [tablet] has the potential to produce the same BMD effects as subcutaneous injections of PTH,” he said in an interview.
Additionally, “the drug was well tolerated when the dose was titrated by adding additional tablets, which suggests that the dose can be tailored to each patient,” he said.
Other study findings
Injectable teriparatide reduces the risk for vertebral fractures by up to 80%, Dr. Santora noted, but the fact that the drug must be administered by injection may deter some older patients from using it.
The company developed an oral form of biosynthetic human PTH with a proprietary drug delivery.
The researchers conducted the phase 2 study at four sites in Israel between June 2019 and May 2021. They enrolled women aged 50 years and older who had entered menopause at least 3 years earlier and who had osteoporosis or low BMD.
Forty-three women received placebo, and the others received oral PTH at doses of 0.5 mg/d (n = 25), 1.0 mg/d (n = 29), 1.5 mg/d (n = 28), 2.5 mg/d (n = 19), or at a dose that was titrated up to 2.5 mg/d starting at 1.5 mg/d for month 1, then 2 mg/d for month 2, and then 2.5 mg/d for months 3 to 6 (n = 17).
The mean age of the patients was 61 years, the mean body mass index was 25-27 kg/m2, and the mean T score at the spine of –2.2 to –2.45.
Among the women who received 2.5 mg/d of oral PTH for the full 6 months, serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) decreased 21% from baseline to 6 months, and serum levels of P1NP increased at month 1 and then decreased to baseline by month 6.
The women who received 2.5 mg/d of oral PTH for the full 6 months also demonstrated significantly greater increases in BMD at the lumbar spine (3.8%), total hip (1.4%), and femoral neck (2.4%), compared with women who received placebo.
The safety profile of oral PTH was consistent with that of subcutaneous PTH. Patients experienced headache, nausea, presyncope, and dizziness; there were no treatment-emergent hypercalcemia adverse events.
A few ‘unexpected findings’
Suzanne M. Jan De Beur, MD, outgoing ASBMR president, said, “Oral PTH appeared to increase BMD by [dual-energy x-ray absorptiometry] at the lumbar spine effectively and to a similar degree as teriparatide in previous studies.”
She identified two unexpected findings.
“There were increases in BMD by DXA at the femoral neck and total hip at 6 months that were [greater than those] seen in previous trials of teriparatide. Second, markers of bone resorption (CTX) decreased at 6 months, and this is in stark contrast to the increases observed with teriparatide treatment,” she noted in an interview.
Dr. Rosen also noted that “the decrease in CTX is very unusual for PTH and difficult to explain.” He added: “P1NP, a marker of bone formation, was not increased.”
Dr. Jan de Beur continued: “Teriparatide (PTH1-34) and abaloparatide are effective anabolic agents that we use to treat patients with high risk of osteoporotic fracture. Although effective, the burden of daily subcutaneous injection can be a barrier for older individuals, those with poor dexterity, and those that are averse to self-injection.
“Taken together, these results appear promising, that oral PTH may prove to be an effective anabolic agent for osteoporosis treatment,” she summarized.
She stressed that a larger phase 3 study is needed to demonstrate safety and efficacy.
The study was funded by Entera Bio. Dr. Santora is chief medical officer of Entera Bio.
A version of this article first appeared on Medscape.com .
CrossFit enters primary care with fitness-minded docs, data
with the launch of its newest service, CrossFit Precision Care.
Developed by family medicine physician Julie Foucher, MD, and other CrossFit-trained doctors, the new service aims to help CrossFit members build plans to protect and improve their health, according to a statement by the company.
CrossFit Precision Care plans to meet this goal through utilizing doctors who understand the CrossFit philosophy, individualized care, data-driven recommendations, proactive lifestyle changes, and continual health optimization. Informing these plans and changes are CrossFit Precision Care’s analysis through a few different methods.
CrossFit’s partner in the endeavor, Wild Health, will provide genomic testing to determine a patient’s genetic predispositions to help optimize the health plans. Blood testing reveals many things that may affect a person’s health, such as hormone status, lipid levels, thyroid function, and cardiovascular risks. An overall lifestyle review includes exercise routines, eating habits, social life, and other patterns or behaviors.
Connecting with doctors who understand CrossFit
Dr. Foucher is no stranger to CrossFit. She has competed in the CrossFit Games four times and discusses the sport regularly on Twitter and Instagram. Now, she works directly with CrossFit to help it provide users with individualized data-driven plans.
“I met Eric Roza last July,” Dr. Foucher says of CrossFit’s CEO. “We talked and saw a lot of potential for CrossFit and health care providers to work together, so we started brainstorming.”
When Dr. Foucher and Mr. Roza got to know Wild Health, specifically, two of its physician cofounders, it was a natural fit, she said. Dr. Foucher says that many who train in CrossFit or go to CrossFit-affiliated gyms feel a disconnect with their family doctors: “[CrossFit is] a pretty polarizing topic, but there are also a lot of doctors who know that people are having health improvements with these programs,” she said.
Through use of Wild Health’s precision services and algorithms, CrossFit Precision Care plans to connect its users with CrossFit-trained health care practitioners. This personalized approach allows health care practitioners to build closer relationships with users of the program, who may feel more comfortable working with doctors who understand their lifestyle. Wild Health’s precision medicine approach, with trackable data such as biomarker status and risk scores, gives doctors a more complete picture of a patient’s needs and history, according to a statement on the partnership.
A better use of data
“To me,” Dr. Foucher says of family medicine, “that was the best option coming out of residency. It was consistent with my morals.” She says much of the current health care system is algorithm based. If a patient is experiencing certain symptoms, treatment is recommended on the basis of whatever yields the best results from the data – but this doesn’t always factor in a patient’s full history and genetics. It can be difficult for doctors to build trusting and personal relationships with patients. “In our current system, there’s not a lot of time or great tools to do that,” she says.
With the approach Wild Health and CrossFit Precision Care both use, however, Dr. Foucher says she sees a huge opportunity for optimizing patient and health care practitioner relationships.
“I see huge potential here, and I really think that this should be the standard for primary care going forwards,” Dr. Foucher explains. “The nice thing about [this approach] is that it has a really quick learning curve and is relatively easy to implement with patients. Before Wild Health optimized it, the tech and data would take about 10 hours per patient to put together. But now, we can incorporate things that work with wearable tech and track results over time and allow the patient and doctor to use this platform to create relationships. And this is something that can scale to many more patients.”
According to its website, CrossFit Precision Care is currently launching an invite-only beta test version of the program in eight states ahead of an expected national release.
A version of this article first appeared on Medscape.com.
with the launch of its newest service, CrossFit Precision Care.
Developed by family medicine physician Julie Foucher, MD, and other CrossFit-trained doctors, the new service aims to help CrossFit members build plans to protect and improve their health, according to a statement by the company.
CrossFit Precision Care plans to meet this goal through utilizing doctors who understand the CrossFit philosophy, individualized care, data-driven recommendations, proactive lifestyle changes, and continual health optimization. Informing these plans and changes are CrossFit Precision Care’s analysis through a few different methods.
CrossFit’s partner in the endeavor, Wild Health, will provide genomic testing to determine a patient’s genetic predispositions to help optimize the health plans. Blood testing reveals many things that may affect a person’s health, such as hormone status, lipid levels, thyroid function, and cardiovascular risks. An overall lifestyle review includes exercise routines, eating habits, social life, and other patterns or behaviors.
Connecting with doctors who understand CrossFit
Dr. Foucher is no stranger to CrossFit. She has competed in the CrossFit Games four times and discusses the sport regularly on Twitter and Instagram. Now, she works directly with CrossFit to help it provide users with individualized data-driven plans.
“I met Eric Roza last July,” Dr. Foucher says of CrossFit’s CEO. “We talked and saw a lot of potential for CrossFit and health care providers to work together, so we started brainstorming.”
When Dr. Foucher and Mr. Roza got to know Wild Health, specifically, two of its physician cofounders, it was a natural fit, she said. Dr. Foucher says that many who train in CrossFit or go to CrossFit-affiliated gyms feel a disconnect with their family doctors: “[CrossFit is] a pretty polarizing topic, but there are also a lot of doctors who know that people are having health improvements with these programs,” she said.
Through use of Wild Health’s precision services and algorithms, CrossFit Precision Care plans to connect its users with CrossFit-trained health care practitioners. This personalized approach allows health care practitioners to build closer relationships with users of the program, who may feel more comfortable working with doctors who understand their lifestyle. Wild Health’s precision medicine approach, with trackable data such as biomarker status and risk scores, gives doctors a more complete picture of a patient’s needs and history, according to a statement on the partnership.
A better use of data
“To me,” Dr. Foucher says of family medicine, “that was the best option coming out of residency. It was consistent with my morals.” She says much of the current health care system is algorithm based. If a patient is experiencing certain symptoms, treatment is recommended on the basis of whatever yields the best results from the data – but this doesn’t always factor in a patient’s full history and genetics. It can be difficult for doctors to build trusting and personal relationships with patients. “In our current system, there’s not a lot of time or great tools to do that,” she says.
With the approach Wild Health and CrossFit Precision Care both use, however, Dr. Foucher says she sees a huge opportunity for optimizing patient and health care practitioner relationships.
“I see huge potential here, and I really think that this should be the standard for primary care going forwards,” Dr. Foucher explains. “The nice thing about [this approach] is that it has a really quick learning curve and is relatively easy to implement with patients. Before Wild Health optimized it, the tech and data would take about 10 hours per patient to put together. But now, we can incorporate things that work with wearable tech and track results over time and allow the patient and doctor to use this platform to create relationships. And this is something that can scale to many more patients.”
According to its website, CrossFit Precision Care is currently launching an invite-only beta test version of the program in eight states ahead of an expected national release.
A version of this article first appeared on Medscape.com.
with the launch of its newest service, CrossFit Precision Care.
Developed by family medicine physician Julie Foucher, MD, and other CrossFit-trained doctors, the new service aims to help CrossFit members build plans to protect and improve their health, according to a statement by the company.
CrossFit Precision Care plans to meet this goal through utilizing doctors who understand the CrossFit philosophy, individualized care, data-driven recommendations, proactive lifestyle changes, and continual health optimization. Informing these plans and changes are CrossFit Precision Care’s analysis through a few different methods.
CrossFit’s partner in the endeavor, Wild Health, will provide genomic testing to determine a patient’s genetic predispositions to help optimize the health plans. Blood testing reveals many things that may affect a person’s health, such as hormone status, lipid levels, thyroid function, and cardiovascular risks. An overall lifestyle review includes exercise routines, eating habits, social life, and other patterns or behaviors.
Connecting with doctors who understand CrossFit
Dr. Foucher is no stranger to CrossFit. She has competed in the CrossFit Games four times and discusses the sport regularly on Twitter and Instagram. Now, she works directly with CrossFit to help it provide users with individualized data-driven plans.
“I met Eric Roza last July,” Dr. Foucher says of CrossFit’s CEO. “We talked and saw a lot of potential for CrossFit and health care providers to work together, so we started brainstorming.”
When Dr. Foucher and Mr. Roza got to know Wild Health, specifically, two of its physician cofounders, it was a natural fit, she said. Dr. Foucher says that many who train in CrossFit or go to CrossFit-affiliated gyms feel a disconnect with their family doctors: “[CrossFit is] a pretty polarizing topic, but there are also a lot of doctors who know that people are having health improvements with these programs,” she said.
Through use of Wild Health’s precision services and algorithms, CrossFit Precision Care plans to connect its users with CrossFit-trained health care practitioners. This personalized approach allows health care practitioners to build closer relationships with users of the program, who may feel more comfortable working with doctors who understand their lifestyle. Wild Health’s precision medicine approach, with trackable data such as biomarker status and risk scores, gives doctors a more complete picture of a patient’s needs and history, according to a statement on the partnership.
A better use of data
“To me,” Dr. Foucher says of family medicine, “that was the best option coming out of residency. It was consistent with my morals.” She says much of the current health care system is algorithm based. If a patient is experiencing certain symptoms, treatment is recommended on the basis of whatever yields the best results from the data – but this doesn’t always factor in a patient’s full history and genetics. It can be difficult for doctors to build trusting and personal relationships with patients. “In our current system, there’s not a lot of time or great tools to do that,” she says.
With the approach Wild Health and CrossFit Precision Care both use, however, Dr. Foucher says she sees a huge opportunity for optimizing patient and health care practitioner relationships.
“I see huge potential here, and I really think that this should be the standard for primary care going forwards,” Dr. Foucher explains. “The nice thing about [this approach] is that it has a really quick learning curve and is relatively easy to implement with patients. Before Wild Health optimized it, the tech and data would take about 10 hours per patient to put together. But now, we can incorporate things that work with wearable tech and track results over time and allow the patient and doctor to use this platform to create relationships. And this is something that can scale to many more patients.”
According to its website, CrossFit Precision Care is currently launching an invite-only beta test version of the program in eight states ahead of an expected national release.
A version of this article first appeared on Medscape.com.
FDA OKs iPLEDGE change for gender-neutral language
The Food and Drug Administration has approved a modification to the isotretinoin risk-mitigation program to make it more inclusive for transgender patients.
Beginning on Dec. 13, 2021, Previously, there were three risk categories: females of reproductive potential, females not of reproductive potential, and males.
In recent years, dermatologists and others have advocated for the change, hoping to make the process more inclusive and less intrusive for their transgender patients.
Isotretinoin (Accutane, Absorica, Amnesteem, Claravis, others) has a high risk of severe birth defects, and has been linked with other health issues, making it crucial for those with the ability to become pregnant to take contraceptive precautions while on the medication. Under the iPLEDGE program, physicians, patients, and pharmacies prescribing, using, or dispensing the drug must all be registered, with requirements that include the use of two forms of an effective contraceptive and regular pregnancy testing for patients who can become pregnant.
The FDA had given notification in June 2018 that the REMS modification and labeling change would be required, replacing the gender-specific language with gender-neutral language, according to an FDA spokesperson. The change was based on feedback that the gender-specific language can be a barrier to access for some patients. The FDA approved the modification on Oct. 8.
Expert reactions
“This is an exciting and welcome change from the FDA on iPLEDGE that many dermatologists, myself included, have advocated for quite a few years,” Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, said in an interview.
In a report on the dermatologic care for lesbian, gay, bisexual, and transgender persons published in the Journal of the American Academy of Dermatology, Dr. Yeung and his colleagues noted that more than 10 million lesbian, gay, bisexual and transgender people live in the United States and that improving their health is a public health priority.
“For cisgender patients, nothing has changed – patients will continue to receive appropriate educational material related to isotretinoin based on their pregnancy potential,” Dr. Yeung said. “For transgender and gender diverse patients, this is a huge step forward.”
Under the previous system, doctors were asked to register patients using gender binary categories, “which were confusing when they did not reflect reality” for these patients, Dr. Yeung said. The new system, Dr. Yeung added, “will make my job easier. I no longer have to struggle between respecting the patient’s gender identity and providing medically necessary care for patients with severe acne.”
“The new terminology is not just respectful, it also is simpler and makes more sense,” agreed Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery at Mount Sinai Health System and professor of medicine at the Icahn School of Medicine at Mount Sinai, New York. “As it stood, a transgender man with his uterus and ovaries in place might be missed in the pregnancy surveillance system because he could simply be labeled a man and not followed further. At the same time, both transgender women and cisgender women who were at no risk of pregnancy could be subject to more medical scrutiny that might have been consider intrusive.”
The change “validates the important point that pregnancy potential is not exclusively defined by sociocultural constructs of gender and allow dermatologists to focus purely on what matters when prescribing isotretinoin – whether an individual is able to become pregnant or not, regardless of their gender identity,” Klint Peebles, MD, a dermatologist at Kaiser Permanente in Washington, D.C., and suburban Maryland, who has also advocated for the change, said in an interview.
FDA elaborates
The modification includes important changes for doctors, pharmacists, and patients alike, according to the FDA.
Health care providers must assign and confirm their currently enrolled patient’s risk category when they first log in to the IPLEDGE REMS website on or after Dec. 13, the effective date. They should be sure any patient whose prescription RMA (iPLEDGE authorization) expires on Dec. 11-12 is told to obtain their prescription before midnight, Eastern time, Dec. 10.
Pharmacists will be affected, too, since the iPLEDGE REMS changed to a new platform vendor and the current “switch” pharmacy management system will be removed as a method to verify authorization to dispense isotretinoin. With these changes, as of Dec. 13, pharmacists can’t use the switch system to obtain a predispense authorization, or RMA (risk management authorization). They will need to obtain an RMA online by accessing the iPLEDGE REMS website or via telephone to the PLEDGE REMS center, 866-495-0654, before dispensing the prescription.
Patients, beginning Dec. 13, will have the option of presenting a unique QR code at the pharmacy on their smartphone rather than providing the iPLEDGE identification number. The code can be accessed by logging into their account on the iPLEDGE REMS website.
Patients with an isotretinoin prescription RMA that expires Dec. 11-12, must obtain the prescription before 11:59 p.m. Eastern time on Dec. 10. If the RMA expires before the prescription is picked up, the patient must begin the authorization process all over again.
Dr. Safer, Dr. Yeung, and Dr. Peebles have no relevant disclosures.
More information on the update and the isotretinoin REMS program is available on the FDA website.
The Food and Drug Administration has approved a modification to the isotretinoin risk-mitigation program to make it more inclusive for transgender patients.
Beginning on Dec. 13, 2021, Previously, there were three risk categories: females of reproductive potential, females not of reproductive potential, and males.
In recent years, dermatologists and others have advocated for the change, hoping to make the process more inclusive and less intrusive for their transgender patients.
Isotretinoin (Accutane, Absorica, Amnesteem, Claravis, others) has a high risk of severe birth defects, and has been linked with other health issues, making it crucial for those with the ability to become pregnant to take contraceptive precautions while on the medication. Under the iPLEDGE program, physicians, patients, and pharmacies prescribing, using, or dispensing the drug must all be registered, with requirements that include the use of two forms of an effective contraceptive and regular pregnancy testing for patients who can become pregnant.
The FDA had given notification in June 2018 that the REMS modification and labeling change would be required, replacing the gender-specific language with gender-neutral language, according to an FDA spokesperson. The change was based on feedback that the gender-specific language can be a barrier to access for some patients. The FDA approved the modification on Oct. 8.
Expert reactions
“This is an exciting and welcome change from the FDA on iPLEDGE that many dermatologists, myself included, have advocated for quite a few years,” Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, said in an interview.
In a report on the dermatologic care for lesbian, gay, bisexual, and transgender persons published in the Journal of the American Academy of Dermatology, Dr. Yeung and his colleagues noted that more than 10 million lesbian, gay, bisexual and transgender people live in the United States and that improving their health is a public health priority.
“For cisgender patients, nothing has changed – patients will continue to receive appropriate educational material related to isotretinoin based on their pregnancy potential,” Dr. Yeung said. “For transgender and gender diverse patients, this is a huge step forward.”
Under the previous system, doctors were asked to register patients using gender binary categories, “which were confusing when they did not reflect reality” for these patients, Dr. Yeung said. The new system, Dr. Yeung added, “will make my job easier. I no longer have to struggle between respecting the patient’s gender identity and providing medically necessary care for patients with severe acne.”
“The new terminology is not just respectful, it also is simpler and makes more sense,” agreed Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery at Mount Sinai Health System and professor of medicine at the Icahn School of Medicine at Mount Sinai, New York. “As it stood, a transgender man with his uterus and ovaries in place might be missed in the pregnancy surveillance system because he could simply be labeled a man and not followed further. At the same time, both transgender women and cisgender women who were at no risk of pregnancy could be subject to more medical scrutiny that might have been consider intrusive.”
The change “validates the important point that pregnancy potential is not exclusively defined by sociocultural constructs of gender and allow dermatologists to focus purely on what matters when prescribing isotretinoin – whether an individual is able to become pregnant or not, regardless of their gender identity,” Klint Peebles, MD, a dermatologist at Kaiser Permanente in Washington, D.C., and suburban Maryland, who has also advocated for the change, said in an interview.
FDA elaborates
The modification includes important changes for doctors, pharmacists, and patients alike, according to the FDA.
Health care providers must assign and confirm their currently enrolled patient’s risk category when they first log in to the IPLEDGE REMS website on or after Dec. 13, the effective date. They should be sure any patient whose prescription RMA (iPLEDGE authorization) expires on Dec. 11-12 is told to obtain their prescription before midnight, Eastern time, Dec. 10.
Pharmacists will be affected, too, since the iPLEDGE REMS changed to a new platform vendor and the current “switch” pharmacy management system will be removed as a method to verify authorization to dispense isotretinoin. With these changes, as of Dec. 13, pharmacists can’t use the switch system to obtain a predispense authorization, or RMA (risk management authorization). They will need to obtain an RMA online by accessing the iPLEDGE REMS website or via telephone to the PLEDGE REMS center, 866-495-0654, before dispensing the prescription.
Patients, beginning Dec. 13, will have the option of presenting a unique QR code at the pharmacy on their smartphone rather than providing the iPLEDGE identification number. The code can be accessed by logging into their account on the iPLEDGE REMS website.
Patients with an isotretinoin prescription RMA that expires Dec. 11-12, must obtain the prescription before 11:59 p.m. Eastern time on Dec. 10. If the RMA expires before the prescription is picked up, the patient must begin the authorization process all over again.
Dr. Safer, Dr. Yeung, and Dr. Peebles have no relevant disclosures.
More information on the update and the isotretinoin REMS program is available on the FDA website.
The Food and Drug Administration has approved a modification to the isotretinoin risk-mitigation program to make it more inclusive for transgender patients.
Beginning on Dec. 13, 2021, Previously, there were three risk categories: females of reproductive potential, females not of reproductive potential, and males.
In recent years, dermatologists and others have advocated for the change, hoping to make the process more inclusive and less intrusive for their transgender patients.
Isotretinoin (Accutane, Absorica, Amnesteem, Claravis, others) has a high risk of severe birth defects, and has been linked with other health issues, making it crucial for those with the ability to become pregnant to take contraceptive precautions while on the medication. Under the iPLEDGE program, physicians, patients, and pharmacies prescribing, using, or dispensing the drug must all be registered, with requirements that include the use of two forms of an effective contraceptive and regular pregnancy testing for patients who can become pregnant.
The FDA had given notification in June 2018 that the REMS modification and labeling change would be required, replacing the gender-specific language with gender-neutral language, according to an FDA spokesperson. The change was based on feedback that the gender-specific language can be a barrier to access for some patients. The FDA approved the modification on Oct. 8.
Expert reactions
“This is an exciting and welcome change from the FDA on iPLEDGE that many dermatologists, myself included, have advocated for quite a few years,” Howa Yeung, MD, MSc, assistant professor of dermatology at Emory University, Atlanta, said in an interview.
In a report on the dermatologic care for lesbian, gay, bisexual, and transgender persons published in the Journal of the American Academy of Dermatology, Dr. Yeung and his colleagues noted that more than 10 million lesbian, gay, bisexual and transgender people live in the United States and that improving their health is a public health priority.
“For cisgender patients, nothing has changed – patients will continue to receive appropriate educational material related to isotretinoin based on their pregnancy potential,” Dr. Yeung said. “For transgender and gender diverse patients, this is a huge step forward.”
Under the previous system, doctors were asked to register patients using gender binary categories, “which were confusing when they did not reflect reality” for these patients, Dr. Yeung said. The new system, Dr. Yeung added, “will make my job easier. I no longer have to struggle between respecting the patient’s gender identity and providing medically necessary care for patients with severe acne.”
“The new terminology is not just respectful, it also is simpler and makes more sense,” agreed Joshua D. Safer, MD, executive director of the Center for Transgender Medicine and Surgery at Mount Sinai Health System and professor of medicine at the Icahn School of Medicine at Mount Sinai, New York. “As it stood, a transgender man with his uterus and ovaries in place might be missed in the pregnancy surveillance system because he could simply be labeled a man and not followed further. At the same time, both transgender women and cisgender women who were at no risk of pregnancy could be subject to more medical scrutiny that might have been consider intrusive.”
The change “validates the important point that pregnancy potential is not exclusively defined by sociocultural constructs of gender and allow dermatologists to focus purely on what matters when prescribing isotretinoin – whether an individual is able to become pregnant or not, regardless of their gender identity,” Klint Peebles, MD, a dermatologist at Kaiser Permanente in Washington, D.C., and suburban Maryland, who has also advocated for the change, said in an interview.
FDA elaborates
The modification includes important changes for doctors, pharmacists, and patients alike, according to the FDA.
Health care providers must assign and confirm their currently enrolled patient’s risk category when they first log in to the IPLEDGE REMS website on or after Dec. 13, the effective date. They should be sure any patient whose prescription RMA (iPLEDGE authorization) expires on Dec. 11-12 is told to obtain their prescription before midnight, Eastern time, Dec. 10.
Pharmacists will be affected, too, since the iPLEDGE REMS changed to a new platform vendor and the current “switch” pharmacy management system will be removed as a method to verify authorization to dispense isotretinoin. With these changes, as of Dec. 13, pharmacists can’t use the switch system to obtain a predispense authorization, or RMA (risk management authorization). They will need to obtain an RMA online by accessing the iPLEDGE REMS website or via telephone to the PLEDGE REMS center, 866-495-0654, before dispensing the prescription.
Patients, beginning Dec. 13, will have the option of presenting a unique QR code at the pharmacy on their smartphone rather than providing the iPLEDGE identification number. The code can be accessed by logging into their account on the iPLEDGE REMS website.
Patients with an isotretinoin prescription RMA that expires Dec. 11-12, must obtain the prescription before 11:59 p.m. Eastern time on Dec. 10. If the RMA expires before the prescription is picked up, the patient must begin the authorization process all over again.
Dr. Safer, Dr. Yeung, and Dr. Peebles have no relevant disclosures.
More information on the update and the isotretinoin REMS program is available on the FDA website.