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‘Eye-opening’ experience on the other side of the hospital bed
The 5 days that she spent at her mother’s bedside were eye-opening for an oncologist used to being on the other side of the clinician–patient relationship.
“As a physician, I thought I had a unique perspective of things that were done well – and things that were not,” commented Pamela Kunz, MD.
Dr. Kunz, who was named the 2021 Woman Oncologist of the Year, is director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and of the Yale Cancer Center, New Haven, Conn.
But she was propelled into quite a different role when her mother was admitted to the hospital.
Her mom, who has trouble hearing, was easily confused by jargon and by “all of the people coming in and out with no introductions,” she explained.
“She needed someone to translate what was going on because she didn’t feel well,” she added.
Seeing inpatient care through her mother’s eyes was enlightening, and at times it was “shocking to be on the other side.”
Physicians get used to “checking boxes, getting through the day,” she said. “It’s easy to forget the human side.”
“Seeing a loved one sick, [struggling] through this – I just wished I had seen things done differently,” added Dr. Kunz.
Her thread has since garnered thousands of “likes” and scores of comments and retweets.
She began the Twitter thread explaining what prompted her comments:
“I spent many hours last week observing the practice of medicine while sitting at my mom’s hospital bedside and was reminded of some important communication pearls. Some musings ...”
“1. Introduce yourself by full name, role, and team and have ID badges visible. It can get very confusing for [patients] and family members with the number of people in and out of rooms. E.g. ‘My name is Dr. X. I’m the intern on the primary internal medicine team.’
2. End your patient visit with a summary of the plan for the day.
3. Avoid medical jargon & speak slowly, clearly, and logically. Remember you are a teacher for your [patients] and their family.
4. Masks make it harder to hear, especially for [patients] with hearing loss (and they no longer have the aid of lip reading).
5. Many older [patients] get confused in the hospital. Repetition is a good thing.
6. Speak to a family member at least once per day to relay the plan.
7. Try to avoid last minute or surprise discharges – they make [patients] and family members anxious. Talk about discharge planning from day 1 and what milestones must occur prior to a safe discharge. ‘In order for you to leave the hospital, X, Y, X must happen.’
8. Talk with your [patients] about something other than what brought them to the hospital (a tip I once learned from a wise mentor).
9. When possible, sit at eye level with your patient (I love these stools from @YNHH).
10. Take time to listen.”
Dr. Kunz closed with her golden rule: “Lastly, treat your patients how you would want your own family member treated.”
Twitter user @BrunaPellini replied: “I love this, especially ‘Treat your patients how you would want your own family member treated.’ My mom and grandma always said that to me since I was a med student, and this is definitely one of my core values.”
Other clinicians shared similar experiences, and some added to Dr. Kunz’s list.
“Agree entirely, love the list – and while none of us can always practice perfectly, my experiences with my own mother’s illness taught me an enormous amount about communication,” @hoperugo responded.
Twitter user @mariejacork added: “Everyone in health care please read ... if you are lucky enough to not have had a loved one unwell in hospital, these may get forgotten. Having sat with my dad for a few days before he died a few years ago, I felt a lot of these, and it changed my practice forever.”
@bjcohenmd provided additional advice: “And use the dry erase board that should be in every room. Never start a medication without explaining it. Many docs will see the patient and then go to the computer, decide to order a med, but never go back to explain it.”
Patients also shared experiences and offered suggestions.
“As a chronic pain patient I’d add – we know it’s frustrating you can’t cure us but PLEASE do not SIGH if we say something didn’t work or [tell] us to be more positive. Just say ‘I know this is very hard, I’m here to listen.’ We don’t expect a cure, we do expect to be believed,” said @ppenguinsmt. “It makes me feel like I’m causing distress to you if I say the pain has been unrelenting. I leave feeling worse. ...You may have heard 10 [people] in pain before me but this is MY only [appointment].”
Twitter user @KatieCahoots added: “These are perfect. I wish doctors would do this not only in the hospital but in the doctor’s office, as well. I would add one caveat: When you try not to use medical jargon, don’t dumb it down as though I don’t know anything about science or haven’t done any of my own research.”
Dr. Kunz said she was taken aback but pleased by the response to her Tweet.
“It’s an example of the human side of medicine, so it resonates with physicians and with patients,” she commented. Seeing through her mom’s eyes how care was provided made her realize that medical training should include more emphasis on communication, including “real-time feedback to interns, residents, fellows, and students.”
Yes, it takes time, and “we don’t all have a lot of extra time,” she acknowledged.
“But some of these elements don’t take that much more time to do. They can help build trust and can, in the long run, actually save time if patients understand and family members feel engaged and like they are participants,” she said. “I think a little time investment will go a long way.”
In her case, she very much appreciated the one trainee who tried to call her and update her about her mother’s care each afternoon. “I really valued that,” she said.
A version of this article first appeared on Medscape.com.
The 5 days that she spent at her mother’s bedside were eye-opening for an oncologist used to being on the other side of the clinician–patient relationship.
“As a physician, I thought I had a unique perspective of things that were done well – and things that were not,” commented Pamela Kunz, MD.
Dr. Kunz, who was named the 2021 Woman Oncologist of the Year, is director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and of the Yale Cancer Center, New Haven, Conn.
But she was propelled into quite a different role when her mother was admitted to the hospital.
Her mom, who has trouble hearing, was easily confused by jargon and by “all of the people coming in and out with no introductions,” she explained.
“She needed someone to translate what was going on because she didn’t feel well,” she added.
Seeing inpatient care through her mother’s eyes was enlightening, and at times it was “shocking to be on the other side.”
Physicians get used to “checking boxes, getting through the day,” she said. “It’s easy to forget the human side.”
“Seeing a loved one sick, [struggling] through this – I just wished I had seen things done differently,” added Dr. Kunz.
Her thread has since garnered thousands of “likes” and scores of comments and retweets.
She began the Twitter thread explaining what prompted her comments:
“I spent many hours last week observing the practice of medicine while sitting at my mom’s hospital bedside and was reminded of some important communication pearls. Some musings ...”
“1. Introduce yourself by full name, role, and team and have ID badges visible. It can get very confusing for [patients] and family members with the number of people in and out of rooms. E.g. ‘My name is Dr. X. I’m the intern on the primary internal medicine team.’
2. End your patient visit with a summary of the plan for the day.
3. Avoid medical jargon & speak slowly, clearly, and logically. Remember you are a teacher for your [patients] and their family.
4. Masks make it harder to hear, especially for [patients] with hearing loss (and they no longer have the aid of lip reading).
5. Many older [patients] get confused in the hospital. Repetition is a good thing.
6. Speak to a family member at least once per day to relay the plan.
7. Try to avoid last minute or surprise discharges – they make [patients] and family members anxious. Talk about discharge planning from day 1 and what milestones must occur prior to a safe discharge. ‘In order for you to leave the hospital, X, Y, X must happen.’
8. Talk with your [patients] about something other than what brought them to the hospital (a tip I once learned from a wise mentor).
9. When possible, sit at eye level with your patient (I love these stools from @YNHH).
10. Take time to listen.”
Dr. Kunz closed with her golden rule: “Lastly, treat your patients how you would want your own family member treated.”
Twitter user @BrunaPellini replied: “I love this, especially ‘Treat your patients how you would want your own family member treated.’ My mom and grandma always said that to me since I was a med student, and this is definitely one of my core values.”
Other clinicians shared similar experiences, and some added to Dr. Kunz’s list.
“Agree entirely, love the list – and while none of us can always practice perfectly, my experiences with my own mother’s illness taught me an enormous amount about communication,” @hoperugo responded.
Twitter user @mariejacork added: “Everyone in health care please read ... if you are lucky enough to not have had a loved one unwell in hospital, these may get forgotten. Having sat with my dad for a few days before he died a few years ago, I felt a lot of these, and it changed my practice forever.”
@bjcohenmd provided additional advice: “And use the dry erase board that should be in every room. Never start a medication without explaining it. Many docs will see the patient and then go to the computer, decide to order a med, but never go back to explain it.”
Patients also shared experiences and offered suggestions.
“As a chronic pain patient I’d add – we know it’s frustrating you can’t cure us but PLEASE do not SIGH if we say something didn’t work or [tell] us to be more positive. Just say ‘I know this is very hard, I’m here to listen.’ We don’t expect a cure, we do expect to be believed,” said @ppenguinsmt. “It makes me feel like I’m causing distress to you if I say the pain has been unrelenting. I leave feeling worse. ...You may have heard 10 [people] in pain before me but this is MY only [appointment].”
Twitter user @KatieCahoots added: “These are perfect. I wish doctors would do this not only in the hospital but in the doctor’s office, as well. I would add one caveat: When you try not to use medical jargon, don’t dumb it down as though I don’t know anything about science or haven’t done any of my own research.”
Dr. Kunz said she was taken aback but pleased by the response to her Tweet.
“It’s an example of the human side of medicine, so it resonates with physicians and with patients,” she commented. Seeing through her mom’s eyes how care was provided made her realize that medical training should include more emphasis on communication, including “real-time feedback to interns, residents, fellows, and students.”
Yes, it takes time, and “we don’t all have a lot of extra time,” she acknowledged.
“But some of these elements don’t take that much more time to do. They can help build trust and can, in the long run, actually save time if patients understand and family members feel engaged and like they are participants,” she said. “I think a little time investment will go a long way.”
In her case, she very much appreciated the one trainee who tried to call her and update her about her mother’s care each afternoon. “I really valued that,” she said.
A version of this article first appeared on Medscape.com.
The 5 days that she spent at her mother’s bedside were eye-opening for an oncologist used to being on the other side of the clinician–patient relationship.
“As a physician, I thought I had a unique perspective of things that were done well – and things that were not,” commented Pamela Kunz, MD.
Dr. Kunz, who was named the 2021 Woman Oncologist of the Year, is director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and of the Yale Cancer Center, New Haven, Conn.
But she was propelled into quite a different role when her mother was admitted to the hospital.
Her mom, who has trouble hearing, was easily confused by jargon and by “all of the people coming in and out with no introductions,” she explained.
“She needed someone to translate what was going on because she didn’t feel well,” she added.
Seeing inpatient care through her mother’s eyes was enlightening, and at times it was “shocking to be on the other side.”
Physicians get used to “checking boxes, getting through the day,” she said. “It’s easy to forget the human side.”
“Seeing a loved one sick, [struggling] through this – I just wished I had seen things done differently,” added Dr. Kunz.
Her thread has since garnered thousands of “likes” and scores of comments and retweets.
She began the Twitter thread explaining what prompted her comments:
“I spent many hours last week observing the practice of medicine while sitting at my mom’s hospital bedside and was reminded of some important communication pearls. Some musings ...”
“1. Introduce yourself by full name, role, and team and have ID badges visible. It can get very confusing for [patients] and family members with the number of people in and out of rooms. E.g. ‘My name is Dr. X. I’m the intern on the primary internal medicine team.’
2. End your patient visit with a summary of the plan for the day.
3. Avoid medical jargon & speak slowly, clearly, and logically. Remember you are a teacher for your [patients] and their family.
4. Masks make it harder to hear, especially for [patients] with hearing loss (and they no longer have the aid of lip reading).
5. Many older [patients] get confused in the hospital. Repetition is a good thing.
6. Speak to a family member at least once per day to relay the plan.
7. Try to avoid last minute or surprise discharges – they make [patients] and family members anxious. Talk about discharge planning from day 1 and what milestones must occur prior to a safe discharge. ‘In order for you to leave the hospital, X, Y, X must happen.’
8. Talk with your [patients] about something other than what brought them to the hospital (a tip I once learned from a wise mentor).
9. When possible, sit at eye level with your patient (I love these stools from @YNHH).
10. Take time to listen.”
Dr. Kunz closed with her golden rule: “Lastly, treat your patients how you would want your own family member treated.”
Twitter user @BrunaPellini replied: “I love this, especially ‘Treat your patients how you would want your own family member treated.’ My mom and grandma always said that to me since I was a med student, and this is definitely one of my core values.”
Other clinicians shared similar experiences, and some added to Dr. Kunz’s list.
“Agree entirely, love the list – and while none of us can always practice perfectly, my experiences with my own mother’s illness taught me an enormous amount about communication,” @hoperugo responded.
Twitter user @mariejacork added: “Everyone in health care please read ... if you are lucky enough to not have had a loved one unwell in hospital, these may get forgotten. Having sat with my dad for a few days before he died a few years ago, I felt a lot of these, and it changed my practice forever.”
@bjcohenmd provided additional advice: “And use the dry erase board that should be in every room. Never start a medication without explaining it. Many docs will see the patient and then go to the computer, decide to order a med, but never go back to explain it.”
Patients also shared experiences and offered suggestions.
“As a chronic pain patient I’d add – we know it’s frustrating you can’t cure us but PLEASE do not SIGH if we say something didn’t work or [tell] us to be more positive. Just say ‘I know this is very hard, I’m here to listen.’ We don’t expect a cure, we do expect to be believed,” said @ppenguinsmt. “It makes me feel like I’m causing distress to you if I say the pain has been unrelenting. I leave feeling worse. ...You may have heard 10 [people] in pain before me but this is MY only [appointment].”
Twitter user @KatieCahoots added: “These are perfect. I wish doctors would do this not only in the hospital but in the doctor’s office, as well. I would add one caveat: When you try not to use medical jargon, don’t dumb it down as though I don’t know anything about science or haven’t done any of my own research.”
Dr. Kunz said she was taken aback but pleased by the response to her Tweet.
“It’s an example of the human side of medicine, so it resonates with physicians and with patients,” she commented. Seeing through her mom’s eyes how care was provided made her realize that medical training should include more emphasis on communication, including “real-time feedback to interns, residents, fellows, and students.”
Yes, it takes time, and “we don’t all have a lot of extra time,” she acknowledged.
“But some of these elements don’t take that much more time to do. They can help build trust and can, in the long run, actually save time if patients understand and family members feel engaged and like they are participants,” she said. “I think a little time investment will go a long way.”
In her case, she very much appreciated the one trainee who tried to call her and update her about her mother’s care each afternoon. “I really valued that,” she said.
A version of this article first appeared on Medscape.com.
Moderna reports positive COVID-19 vaccine response in kids down to 6 months
Moderna on March 23 released interim results indicating that its mRNA-1273 COVID vaccine produced “robust” neutralizing antibody titers in children aged 6 months to 6 years – levels similar to those seen in adults.
Vaccine efficacy against infection was 43.7% in children aged 6 months to 2 years and 37.5% among children aged 2-6 years, the new data from its phase 2/3 KidCOVE study show.
The company explained the lower efficacy numbers by noting that its study involving these younger children was conducted during the Omicron wave. The same decrease in efficacy against infection was reported in adults during the Omicron surge.
A majority of COVID-19 cases were mild in the approximately 6,900 children aged 6 months to 6 years in the study. No severe COVID-19 cases, hospitalizations, or deaths were reported.
The primary series of two 25-mcg doses of the vaccine given 28 days apart was generally well tolerated. Most adverse events were mild to moderate. For example, temperature greater than 38° C (>100.4° F) was reported for 17.0% of the 6-month-old to 2-year-old group and for 14.6% of the 2- to 6-year-old group. A few children, 0.2% of each group, experienced a temperature greater than 40° C (>104° F).
Moderna plans to include these response, efficacy, and safety data in an application to the Food and Drug Administration for emergency use authorization (EUA) of the vaccine in these younger children in the coming weeks.
“We now have clinical data on the performance of our vaccine from infants 6 months of age through older adults,” Moderna CEO Stephane Bancel said in a news release. He described the interim results as “good news for parents of children under 6 years of age.”
In other news
Moderna also announced that it began the FDA EUA submission process for a 50-μg two-dose primary series for children aged 6-12 years.
The company is also updating its EUA submission for a 100-mcg two-dose primary series for children and adolescents aged 12-18 years.
Similar to its booster research in adults, Moderna plans to evaluate the potential of a booster dose for all pediatric populations, including those aged 6 months to 6 years, 6-12 years, and adolescents. The company is evaluating both a booster dose of mRNA-1273 and its bivalent booster candidate (mRNA1273.214), which includes an Omicron variant booster and mRNA-1273.
A version of this article first appeared on Medscape.com.
Moderna on March 23 released interim results indicating that its mRNA-1273 COVID vaccine produced “robust” neutralizing antibody titers in children aged 6 months to 6 years – levels similar to those seen in adults.
Vaccine efficacy against infection was 43.7% in children aged 6 months to 2 years and 37.5% among children aged 2-6 years, the new data from its phase 2/3 KidCOVE study show.
The company explained the lower efficacy numbers by noting that its study involving these younger children was conducted during the Omicron wave. The same decrease in efficacy against infection was reported in adults during the Omicron surge.
A majority of COVID-19 cases were mild in the approximately 6,900 children aged 6 months to 6 years in the study. No severe COVID-19 cases, hospitalizations, or deaths were reported.
The primary series of two 25-mcg doses of the vaccine given 28 days apart was generally well tolerated. Most adverse events were mild to moderate. For example, temperature greater than 38° C (>100.4° F) was reported for 17.0% of the 6-month-old to 2-year-old group and for 14.6% of the 2- to 6-year-old group. A few children, 0.2% of each group, experienced a temperature greater than 40° C (>104° F).
Moderna plans to include these response, efficacy, and safety data in an application to the Food and Drug Administration for emergency use authorization (EUA) of the vaccine in these younger children in the coming weeks.
“We now have clinical data on the performance of our vaccine from infants 6 months of age through older adults,” Moderna CEO Stephane Bancel said in a news release. He described the interim results as “good news for parents of children under 6 years of age.”
In other news
Moderna also announced that it began the FDA EUA submission process for a 50-μg two-dose primary series for children aged 6-12 years.
The company is also updating its EUA submission for a 100-mcg two-dose primary series for children and adolescents aged 12-18 years.
Similar to its booster research in adults, Moderna plans to evaluate the potential of a booster dose for all pediatric populations, including those aged 6 months to 6 years, 6-12 years, and adolescents. The company is evaluating both a booster dose of mRNA-1273 and its bivalent booster candidate (mRNA1273.214), which includes an Omicron variant booster and mRNA-1273.
A version of this article first appeared on Medscape.com.
Moderna on March 23 released interim results indicating that its mRNA-1273 COVID vaccine produced “robust” neutralizing antibody titers in children aged 6 months to 6 years – levels similar to those seen in adults.
Vaccine efficacy against infection was 43.7% in children aged 6 months to 2 years and 37.5% among children aged 2-6 years, the new data from its phase 2/3 KidCOVE study show.
The company explained the lower efficacy numbers by noting that its study involving these younger children was conducted during the Omicron wave. The same decrease in efficacy against infection was reported in adults during the Omicron surge.
A majority of COVID-19 cases were mild in the approximately 6,900 children aged 6 months to 6 years in the study. No severe COVID-19 cases, hospitalizations, or deaths were reported.
The primary series of two 25-mcg doses of the vaccine given 28 days apart was generally well tolerated. Most adverse events were mild to moderate. For example, temperature greater than 38° C (>100.4° F) was reported for 17.0% of the 6-month-old to 2-year-old group and for 14.6% of the 2- to 6-year-old group. A few children, 0.2% of each group, experienced a temperature greater than 40° C (>104° F).
Moderna plans to include these response, efficacy, and safety data in an application to the Food and Drug Administration for emergency use authorization (EUA) of the vaccine in these younger children in the coming weeks.
“We now have clinical data on the performance of our vaccine from infants 6 months of age through older adults,” Moderna CEO Stephane Bancel said in a news release. He described the interim results as “good news for parents of children under 6 years of age.”
In other news
Moderna also announced that it began the FDA EUA submission process for a 50-μg two-dose primary series for children aged 6-12 years.
The company is also updating its EUA submission for a 100-mcg two-dose primary series for children and adolescents aged 12-18 years.
Similar to its booster research in adults, Moderna plans to evaluate the potential of a booster dose for all pediatric populations, including those aged 6 months to 6 years, 6-12 years, and adolescents. The company is evaluating both a booster dose of mRNA-1273 and its bivalent booster candidate (mRNA1273.214), which includes an Omicron variant booster and mRNA-1273.
A version of this article first appeared on Medscape.com.
What’s the future of microbiome therapies in C. diff, cancer?
WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.
Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.
Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
New approaches for CDI
“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”
Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.
The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.
Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”
The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.
One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.
The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.
Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.
Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.
And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”
Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”
In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.
Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”
Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.
The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
Gut microbiome manipulation for cancer
Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.
Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.
Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.
Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.
“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.
Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.
WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.
Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.
Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
New approaches for CDI
“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”
Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.
The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.
Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”
The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.
One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.
The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.
Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.
Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.
And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”
Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”
In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.
Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”
Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.
The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
Gut microbiome manipulation for cancer
Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.
Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.
Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.
Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.
“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.
Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.
WASHINGTON – Research on standardized microbiome-based therapies designed to prevent the recurrence of Clostridioides difficile infection (CDI) is moving “with a lot of momentum,” according to one expert, and modulation of the gut microbiome may even enhance responses to immunotherapy and/or abrogate toxicity, according to another.
Several products for prevention of CDI recurrence are poised for either phase 3 trials or upcoming Food and Drug Administration approval, Sahil Khanna, MBBS, MS, professor of medicine, gastroenterology, and hepatology at the Mayo Clinic in Rochester, Minn., reported at the annual Gut Microbiota for Health World Summit.
Jennifer A. Wargo, MD, MMSc, of the University of Texas MD Anderson Cancer Center, Houston, described her investigations of microbiome modulation’s role in cancer treatment. “I used to say yes [we can do this] somewhat enthusiastically without data, but now we have data to support this,” she said at the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “The answer now is totally yes.”
New approaches for CDI
“Based on how the field is moving, we might be able to [offer our patients] earlier microbiome restoration” than is currently afforded with fecal microbiota transplantation (FMT), he said. “Right now the [Food and Drug Administration] and our clinical guidelines say we should do FMT after three or more episodes [of CDI] – that’s heartbreaking for patients.”
Several of the microbiome-based therapies under investigation – including two poised for phase 3 trials – have shown efficacy after a second episode of CDI, and one of these two has also had positive results after one episode of CDI in patients 65 at older, a group at particularly high risk of recurrence, said Dr. Khanna.
The value of standardized, mostly pill-form microbiome therapies has been heightened during the pandemic. “We’ve been doing conventional FMT for recurrent C. difficile for over a decade now, and it’s probably the most effective treatment we have,” said Colleen R. Kelly, MD, associate professor of medicine at Brown University, Providence, R.I., and moderator of the session on microbiota-based therapies.
Prepandemic “it got really hard, with issues of identifying donors, and quality control and safety ... And then when COVID hit the stool banks shut down,” she said in an interview after the meeting. With stool testing for SARS-CoV-2 now in place, some stool is again available, “but it made me realize how fragile our current system is,” Dr. Kelly said. “The fact that companies are putting these products through the FDA pipeline and investigating them in rigorous, scientific randomized controlled trials is really good for the field.”
The products vary in composition; some are live multi-strain biotherapeutics derived from donor stool, for instance, while others are defined live bacterial consortia not from stool. Most are oral formulations, given one or multiple times, that do not require any bowel preparation.
One of the products most advanced in the pipeline, RBX2660 (Rebiotix, Ferring Pharmaceuticals) is stool derived and rectally administered. In phase 3 research, 70.5% of patients who received one active enema after having had two or more CDI recurrences and standard-of-care antibiotic treatment had no additional recurrence at 8 weeks compared to 58.1% in the placebo group, Dr. Khanna said.
The other product with positive phase 3 results, SER-109 (Seres Therapeutics), is a donor stool-derived oral formulation of purified Firmicutes spores that is administered after bowel prep. In results published earlier this year, the percentage of patients with recurrence of CDI up to 8 weeks after standard antibiotic treatment was 12% in the SER-109 group and 40% in the placebo group.
Patients in this trial were required to have had three episodes of CDI, and interestingly, Dr. Khanna said, the diagnosis of CDI was made only by toxin enzyme immunoassay (EIA). Earlier phase 2 research, which allowed either toxin EIA or polymerase chain reaction testing for the diagnosis of CDI (as other trials have done), produced negative results, leading investigators to surmise that some of the included patients had been colonized with C. difficile rather than being actively infected, Dr. Khanna said.
Researchers of these trials are documenting not only resolution of CDI but what they believe are positive shifts in the gut microbiota after microbiome-based therapy, he said. For instance, a phase 1 trial he led of the product RBX7455 (Rebiotix, Ferring Pharmaceuticals) – an oral capsule of lyophilized stool-based bacteria that can be kept for several days at room temperature – showed increases in Bacteroidia and Clostridia.
And other trials’ analyses of microbiome engraftment have demonstrated that “you can restore [species] even when these bacteria aren’t [included in the therapy],” he noted. “As the milieu of the gut improves, species that were not detected start coming back up.”
Asked about rates of efficacy in the trials’ placebo arms, Dr. Khanna said that “we’ve become smarter with our antibiotic regimens ... the placebo response rate is the response to newer guideline-based therapies.”
In addition to CDI, microbiome-based therapies are being studied, mostly in phase 1 research, for indications such as Crohn’s disease, ulcerative colitis, autism spectrum disorder, hepatitis B, and hepatic encephalopathy, Dr. Khanna noted.
Dr. Kelly, whose own research has focused on FMT for CDI, said she anticipates an expansion of research into other indications once products to prevent CDI recurrence are on the market. “There have been a couple of promising ulcerative colitis trials that haven’t gone anywhere clinically yet,” she said in the interview. “But will we now identify patients with UC who may be more sensitive to microbial manipulation, for whom we can use these microbial therapies along with a biologic?”
Some of her patients with IBD and CDI who are treated with FMT have not only had their CDI eradicated but have subsequently seen improvements in their IBD, she noted.
The role of traditional FMT and of stool banks will likely change in the future with new standardized oral microbiome-based therapies that can be approved and regulated by the FDA, she said. However, “we think the stool banks will still have some value,” she said, certainly for clinical research and probably for some treatment purposes as well. Regarding new therapies, “I just really hope they’re affordable,” she said.
Gut microbiome manipulation for cancer
Dr. Wargo’s research at MD Anderson has focused on metastatic breast cancer and immunotherapeutic checkpoint blockade. By sequencing microbiota samples and performing immune profiling in hundreds of patients, her team found that responders to PD-1 blockage have a greater diversity of gut bacteria and that “favorable signatures in the gut microbiome” are associated with enhanced immune responses in the tumor microenvironment.
Studies published last year in Science from investigators in Israel (2021 Feb 5;371[6529]:602-9) and Pittsburgh (2021 Feb 5;371[6529]:595-602), demonstrated that FMT promotes response in immunotherapy-refractory melanoma patients. In one study, FMT provided clinical benefit in 6 of 15 patients whose cancer had progressed on prior anti-PD-1 therapy, “which is pretty remarkable,” Dr. Wargo said.
Both research groups, she noted, saw favorable changes in the gut microbiome and immune cell infiltrates both at the level of the colon and the tumor.
Current research on FMT and other microbiome modulation strategies for cancer is guided in part by knowledge that tumors have microbial signatures – these signatures are now being identified across all tumor types – and by findings of “cross talk” between the gut and tumor microbiomes, she explained.
“Researchers are working hard to identify optimal consortia to enhance immune responses in the cancer setting, with promising work in preclinical models,” she said, and clinical trials are in progress. The role of diet in modulating the microbiome and enhancing anti-tumor immunity, with a focus on high dietary fiber intake, is also being investigated, she said.
Dr. Wargo reported that she serves on the advisory boards and is a paid speaker of numerous pharmaceutical and biotechnology companies, and is the coinventor of a patent submitted by the Texas MD Anderson Cancer Center on modulating the microbiome to enhance response to checkpoint blockade, and another related patent. Dr. Khanna reported that he is involved in research with Ferring/Rebiotix, Finch, Seres, Pfizer and Vendata, and does consulting for Immuron and several other companies. Dr. Kelly said she serves as an unpaid adviser for OpenBiome, a nonprofit stool bank, and that her site has enrolled patients in two of the trials testing products for CDI.
REPORTING FROM GMFH 2022
Excess weight over lifetime hikes risk for colorectal cancer
Excess weight over a lifetime may play a greater role in a person’s risk for colorectal cancer (CRC) than previously thought, according to new research.
In their paper published online March 17 in JAMA Oncology, the authors liken the cumulative effects of a lifetime with overweight or obesity to the increased risk of cancer the more people smoke over time.
This population-based, case-control study was led by Xiangwei Li, MSc, of the division of clinical epidemiology and aging research at the German Cancer Research Center in Heidelberg.
It looked at height and self-reported weight documented in 10-year increments starting at age 20 years up to the current age for 5,635 people with CRC compared with 4,515 people in a control group.
Odds for colorectal cancer increased substantially over the decades when people carried the excess weight long term compared with participants who remained within the normal weight range during the period.
Coauthor Hermann Brenner, MD, MPH, a colleague in Li’s division at the German Cancer Research Center, said in an interview that a key message in the research is that “overweight and obesity are likely to increase the risk of colorectal cancer more strongly than suggested by previous studies that typically had considered body weight only at a single point of time.”
The researchers used a measure of weighted number of years lived with overweight or obesity (WYOs) determined by multiplying excess body mass index by number of years the person carried the excess weight.
They found a link between WYOs and CRC risk, with adjusted odds ratios (ORs) increasing from 1.25 (95% confidence interval [CI], 1.09-1.44) to 2.54 (95% CI, 2.24-2.89) from the first to the fourth quartile of WYOs, compared with people who stayed within normal weight parameters.
The odds went up substantially the longer the time carrying the excess weight.
“Each SD increment in WYOs was associated with an increase of CRC risk by 55% (adjusted OR, 1.55; 95% CI, 1.46-1.64),” the authors wrote. “This OR was higher than the OR per SD increase of excess body mass index at any single point of time, which ranged from 1.04 (95% CI, 0.93-1.16) to 1.27 (95% CI 1.16-1.39).”
Dr. Brenner said that although this study focused on colorectal cancer, “the same is likely to apply for other cancers and other chronic diseases.”
Prevention of overweight and obesity to reduce burden of cancer and other chronic diseases “should become a public health priority,” he said.
Preventing overweight in childhood is important
Overweight and obesity increasingly are starting in childhood, he noted, and may be a lifelong burden.
Therefore, “efforts to prevent their development in childhood, adolescence, and young adulthood are particularly important,” Dr. Brenner said.
The average age of the patients was 68 years in both the CRC and control groups. There were more men than women in both groups: 59.7% were men in the CRC group and 61.1% were men in the control group.
“Our proposed concept of WYOs is comparable to the concept of pack-years in that WYOs can be considered a weighted measure of years lived with the exposure, with weights reflecting the intensity of exposure,” the authors wrote.
Study helps confirm what is becoming more clear to researchers
Kimmie Ng, MD, MPH, a professor at Harvard Medical School and oncologist at Dana-Farber Cancer Institute, both in Boston, said in an interview that the study helps confirm what is becoming more clear to researchers.
“We do think that exposures over the life course are the ones that will be most strongly contributing to a risk of colorectal cancer as an adult,” she said. “With obesity, what we think is happening is that it’s setting up this milieu of chronic inflammation and insulin resistance and we know those two factors can lead to higher rates of colorectal cancer development and increased tumor growth.”
She said the ideal, but impractical, way to do the study would be to follow healthy people from childhood and document their weight over a lifetime. In this case-control study, people were asked to recall their weight at different time periods, which is a limitation and could lead to recall bias.
But the study is important, Dr. Ng said, and it adds convincing evidence that addressing the link between excess weight and CRC and chronic diseases should be a public health priority. “With the recent rise in young-onset colorectal cancer since the 1990s there has been a lot of interest in looking at whether obesity is a major contributor to that rising trend,” Dr. Ng noted. “If obesity is truly linked to colorectal cancer, these rising rates of obesity are very worrisome for potentially leading to more colorectal cancers in young adulthood and beyond.“
The study authors and Dr. Ng report no relevant financial relationships.
The new research was funded by the German Research Council, the Interdisciplinary Research Program of the National Center for Tumor Diseases, Germany, and the German Federal Ministry of Education and Research.
Excess weight over a lifetime may play a greater role in a person’s risk for colorectal cancer (CRC) than previously thought, according to new research.
In their paper published online March 17 in JAMA Oncology, the authors liken the cumulative effects of a lifetime with overweight or obesity to the increased risk of cancer the more people smoke over time.
This population-based, case-control study was led by Xiangwei Li, MSc, of the division of clinical epidemiology and aging research at the German Cancer Research Center in Heidelberg.
It looked at height and self-reported weight documented in 10-year increments starting at age 20 years up to the current age for 5,635 people with CRC compared with 4,515 people in a control group.
Odds for colorectal cancer increased substantially over the decades when people carried the excess weight long term compared with participants who remained within the normal weight range during the period.
Coauthor Hermann Brenner, MD, MPH, a colleague in Li’s division at the German Cancer Research Center, said in an interview that a key message in the research is that “overweight and obesity are likely to increase the risk of colorectal cancer more strongly than suggested by previous studies that typically had considered body weight only at a single point of time.”
The researchers used a measure of weighted number of years lived with overweight or obesity (WYOs) determined by multiplying excess body mass index by number of years the person carried the excess weight.
They found a link between WYOs and CRC risk, with adjusted odds ratios (ORs) increasing from 1.25 (95% confidence interval [CI], 1.09-1.44) to 2.54 (95% CI, 2.24-2.89) from the first to the fourth quartile of WYOs, compared with people who stayed within normal weight parameters.
The odds went up substantially the longer the time carrying the excess weight.
“Each SD increment in WYOs was associated with an increase of CRC risk by 55% (adjusted OR, 1.55; 95% CI, 1.46-1.64),” the authors wrote. “This OR was higher than the OR per SD increase of excess body mass index at any single point of time, which ranged from 1.04 (95% CI, 0.93-1.16) to 1.27 (95% CI 1.16-1.39).”
Dr. Brenner said that although this study focused on colorectal cancer, “the same is likely to apply for other cancers and other chronic diseases.”
Prevention of overweight and obesity to reduce burden of cancer and other chronic diseases “should become a public health priority,” he said.
Preventing overweight in childhood is important
Overweight and obesity increasingly are starting in childhood, he noted, and may be a lifelong burden.
Therefore, “efforts to prevent their development in childhood, adolescence, and young adulthood are particularly important,” Dr. Brenner said.
The average age of the patients was 68 years in both the CRC and control groups. There were more men than women in both groups: 59.7% were men in the CRC group and 61.1% were men in the control group.
“Our proposed concept of WYOs is comparable to the concept of pack-years in that WYOs can be considered a weighted measure of years lived with the exposure, with weights reflecting the intensity of exposure,” the authors wrote.
Study helps confirm what is becoming more clear to researchers
Kimmie Ng, MD, MPH, a professor at Harvard Medical School and oncologist at Dana-Farber Cancer Institute, both in Boston, said in an interview that the study helps confirm what is becoming more clear to researchers.
“We do think that exposures over the life course are the ones that will be most strongly contributing to a risk of colorectal cancer as an adult,” she said. “With obesity, what we think is happening is that it’s setting up this milieu of chronic inflammation and insulin resistance and we know those two factors can lead to higher rates of colorectal cancer development and increased tumor growth.”
She said the ideal, but impractical, way to do the study would be to follow healthy people from childhood and document their weight over a lifetime. In this case-control study, people were asked to recall their weight at different time periods, which is a limitation and could lead to recall bias.
But the study is important, Dr. Ng said, and it adds convincing evidence that addressing the link between excess weight and CRC and chronic diseases should be a public health priority. “With the recent rise in young-onset colorectal cancer since the 1990s there has been a lot of interest in looking at whether obesity is a major contributor to that rising trend,” Dr. Ng noted. “If obesity is truly linked to colorectal cancer, these rising rates of obesity are very worrisome for potentially leading to more colorectal cancers in young adulthood and beyond.“
The study authors and Dr. Ng report no relevant financial relationships.
The new research was funded by the German Research Council, the Interdisciplinary Research Program of the National Center for Tumor Diseases, Germany, and the German Federal Ministry of Education and Research.
Excess weight over a lifetime may play a greater role in a person’s risk for colorectal cancer (CRC) than previously thought, according to new research.
In their paper published online March 17 in JAMA Oncology, the authors liken the cumulative effects of a lifetime with overweight or obesity to the increased risk of cancer the more people smoke over time.
This population-based, case-control study was led by Xiangwei Li, MSc, of the division of clinical epidemiology and aging research at the German Cancer Research Center in Heidelberg.
It looked at height and self-reported weight documented in 10-year increments starting at age 20 years up to the current age for 5,635 people with CRC compared with 4,515 people in a control group.
Odds for colorectal cancer increased substantially over the decades when people carried the excess weight long term compared with participants who remained within the normal weight range during the period.
Coauthor Hermann Brenner, MD, MPH, a colleague in Li’s division at the German Cancer Research Center, said in an interview that a key message in the research is that “overweight and obesity are likely to increase the risk of colorectal cancer more strongly than suggested by previous studies that typically had considered body weight only at a single point of time.”
The researchers used a measure of weighted number of years lived with overweight or obesity (WYOs) determined by multiplying excess body mass index by number of years the person carried the excess weight.
They found a link between WYOs and CRC risk, with adjusted odds ratios (ORs) increasing from 1.25 (95% confidence interval [CI], 1.09-1.44) to 2.54 (95% CI, 2.24-2.89) from the first to the fourth quartile of WYOs, compared with people who stayed within normal weight parameters.
The odds went up substantially the longer the time carrying the excess weight.
“Each SD increment in WYOs was associated with an increase of CRC risk by 55% (adjusted OR, 1.55; 95% CI, 1.46-1.64),” the authors wrote. “This OR was higher than the OR per SD increase of excess body mass index at any single point of time, which ranged from 1.04 (95% CI, 0.93-1.16) to 1.27 (95% CI 1.16-1.39).”
Dr. Brenner said that although this study focused on colorectal cancer, “the same is likely to apply for other cancers and other chronic diseases.”
Prevention of overweight and obesity to reduce burden of cancer and other chronic diseases “should become a public health priority,” he said.
Preventing overweight in childhood is important
Overweight and obesity increasingly are starting in childhood, he noted, and may be a lifelong burden.
Therefore, “efforts to prevent their development in childhood, adolescence, and young adulthood are particularly important,” Dr. Brenner said.
The average age of the patients was 68 years in both the CRC and control groups. There were more men than women in both groups: 59.7% were men in the CRC group and 61.1% were men in the control group.
“Our proposed concept of WYOs is comparable to the concept of pack-years in that WYOs can be considered a weighted measure of years lived with the exposure, with weights reflecting the intensity of exposure,” the authors wrote.
Study helps confirm what is becoming more clear to researchers
Kimmie Ng, MD, MPH, a professor at Harvard Medical School and oncologist at Dana-Farber Cancer Institute, both in Boston, said in an interview that the study helps confirm what is becoming more clear to researchers.
“We do think that exposures over the life course are the ones that will be most strongly contributing to a risk of colorectal cancer as an adult,” she said. “With obesity, what we think is happening is that it’s setting up this milieu of chronic inflammation and insulin resistance and we know those two factors can lead to higher rates of colorectal cancer development and increased tumor growth.”
She said the ideal, but impractical, way to do the study would be to follow healthy people from childhood and document their weight over a lifetime. In this case-control study, people were asked to recall their weight at different time periods, which is a limitation and could lead to recall bias.
But the study is important, Dr. Ng said, and it adds convincing evidence that addressing the link between excess weight and CRC and chronic diseases should be a public health priority. “With the recent rise in young-onset colorectal cancer since the 1990s there has been a lot of interest in looking at whether obesity is a major contributor to that rising trend,” Dr. Ng noted. “If obesity is truly linked to colorectal cancer, these rising rates of obesity are very worrisome for potentially leading to more colorectal cancers in young adulthood and beyond.“
The study authors and Dr. Ng report no relevant financial relationships.
The new research was funded by the German Research Council, the Interdisciplinary Research Program of the National Center for Tumor Diseases, Germany, and the German Federal Ministry of Education and Research.
FROM JAMA ONCOLOGY
Hematocrit, White Blood Cells, and Thrombotic Events in the Veteran Population With Polycythemia Vera
Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.2 Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.3,8-10
Blood Cell Counts and Thrombotic Events in PV
Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.11 Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.12 Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).12
Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 109/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.13 In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 109/L vs reference level of < 7 × 109/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).14 Likewise, WBC count ≥ 11 × 109/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.8
Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.
The Veteran Population with PV
Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.
In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.17 The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).
In the second analysis, the authors investigated the relationship between WBC counts and thrombotic events.16 Evaluable patients (N = 1565) were grouped into 1 of 4 cohorts based on the last WBC measurement taken during the study period before a thrombotic event or through the end of follow-up: (1) WBC < 7.0 × 109/L, (2) 7.0 to 8.4 × 109/L, (3) 8.5 to < 11.0 × 109/L, or (4) ≥ 11.0 × 109/L. Mean follow-up time ranged from 3.6 to 4.5 years among WBC count cohorts, during which 24.9% of patients experienced a thrombotic event. Compared with the reference cohort (WBC < 7.0 × 109/L), a significant positive association between WBC counts and thrombotic event occurrence was observed among patients with WBC counts of 8.5 to < 11.0 × 109/L (HR, 1.47; 95% CI, 1.10-1.96; P < .01) and ≥ 11 × 109/L (HR, 1.87; 95% CI, 1.44-2.43; P < .001) (Figure 2).16 When including all patients in a sensitivity analysis regardless of whether they experienced thrombotic events before the index date (N = 1876), similar results were obtained (7.0-8.4 × 109/L group: HR, 1.22; 95% CI, 0.97-1.55; P = .0959; 8.5 - 11.0 × 109/L group: HR, 1.41; 95% CI, 1.10-1.81; P = .0062; ≥ 11.0 × 109/L group: HR, 1.53; 95% CI, 1.23-1.91; P < .001; compared with < 7.0 × 109/L reference group). Rates of phlebotomy and cytoreductive treatments were similar across groups.16
Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 109/L) compared with those reported in CYTO-PV (≥ 11 × 109/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.
Current PV Management and Future Implications
The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.11 Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).
Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.21 In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.22 The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.24
However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.25
Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.
Acknowledgments
Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).
1. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma. 2014;55(3):595-600. doi:10.3109/10428194.2013.813500
2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544
3. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874-1881. doi:10.1038/leu.2013.163
4. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23(10):2224-2232. doi:10.1200/JCO.2005.07.062
5. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110(3):840-846. doi:10.1182/blood-2006-12-064287
6. Goyal RK, Davis KL, Cote I, Mounedji N, Kaye JA. Increased incidence of thromboembolic event rates in patients diagnosed with polycythemia vera: results from an observational cohort study. Blood (ASH Annual Meeting Abstracts). 2014;124:4840. doi:10.1182/blood.V124.21.4840.4840
7. Barbui T, Carobbio A, Rumi E, et al. In contemporary patients with polycythemia vera, rates of thrombosis and risk factors delineate a new clinical epidemiology. Blood. 2014;124(19):3021-3023. doi:10.1182/blood-2014-07-591610 8. Cerquozzi S, Barraco D, Lasho T, et al. Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. Blood Cancer J. 2017;7(12):662. doi:10.1038/s41408-017-0035-6
9. Stein BL, Moliterno AR, Tiu RV. Polycythemia vera disease burden: contributing factors, impact on quality of life, and emerging treatment options. Ann Hematol. 2014;93(12):1965-1976. doi:10.1007/s00277-014-2205-y
10. Hultcrantz M, Kristinsson SY, Andersson TM-L, et al. Patterns of survival among patients with myeloproliferative neoplasms diagnosed in Sweden from 1973 to 2008: a population-based study. J Clin Oncol. 2012;30(24):2995-3001. doi:10.1200/JCO.2012.42.1925
11. National Comprehensive Cancer Network. NCCN clinical practice guidelines in myeloproliferative neoplasms (Version 1.2020). Accessed March 3, 2022. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf
12. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. doi:10.1056/NEJMoa1208500
13. Landolfi R, Di Gennaro L, Barbui T, et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood. 2007;109(6):2446-2452. doi:10.1182/blood-2006-08-042515
14. Barbui T, Masciulli A, Marfisi MR, et al. White blood cell counts and thrombosis in polycythemia vera: a subanalysis of the CYTO-PV study. Blood. 2015;126(4):560-561. doi:10.1182/blood-2015-04-638593
15. Prchal JT, Gordeuk VR. Treatment target in polycythemia vera. N Engl J Med. 2013;368(16):1555-1556. doi:10.1056/NEJMc1301262
16. Parasuraman S, Yu J, Paranagama D, et al. Elevated white blood cell levels and thrombotic events in patients with polycythemia vera: a real-world analysis of Veterans Health Administration data. Clin Lymphoma Myeloma Leuk. 2020;20(2):63-69. doi:10.1016/j.clml.2019.11.010
17. Parasuraman S, Yu J, Paranagama D, et al. Hematocrit levels and thrombotic events in patients with polycythemia vera: an analysis of Veterans Health Administration data. Ann Hematol. 2019;98(11):2533-2539. doi:10.1007/s00277-019-03793-w
18. WHO CVD Risk Chart Working Group. World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions. Lancet Glob Health. 2019;7(10):e1332-e1345. doi:10.1016/S2214-109X(19)30318-3.
19. D’Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743-753. doi:10.1161/CIRCULATIONAHA.107.699579
20. Jakafi. Package insert. Incyte Corporation; 2020.
21. Gordeuk VR, Key NS, Prchal JT. Re-evaluation of hematocrit as a determinant of thrombotic risk in erythrocytosis. Haematologica. 2019;104(4):653-658. doi:10.3324/haematol.2018.210732
22. Carobbio A, Thiele J, Passamonti F, et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood. 2011;117(22):5857-5859. doi:10.1182/blood-2011-02-339002
23. Perloff JK, Marelli AJ, Miner PD. Risk of stroke in adults with cyanotic congenital heart disease. Circulation. 1993;87(6):1954-1959. doi:10.1161/01.cir.87.6.1954
24. Gordeuk VR, Miasnikova GY, Sergueeva AI, et al. Thrombotic risk in congenital erythrocytosis due to up-regulated hypoxia sensing is not associated with elevated hematocrit. Haematologica. 2020;105(3):e87-e90. doi:10.3324/haematol.2019.216267
25. Kroll MH, Michaelis LC, Verstovsek S. Mechanisms of thrombogenesis in polycythemia vera. Blood Rev. 2015;29(4):215-221. doi:10.1016/j.blre.2014.12.002
26. Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018;32(5):1057-1069. doi:10.1038/s41375-018-0077-1
27. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood. 2013;121(23):4778-4781. doi:10.1182/blood-2013-01-478891
Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.2 Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.3,8-10
Blood Cell Counts and Thrombotic Events in PV
Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.11 Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.12 Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).12
Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 109/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.13 In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 109/L vs reference level of < 7 × 109/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).14 Likewise, WBC count ≥ 11 × 109/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.8
Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.
The Veteran Population with PV
Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.
In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.17 The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).
In the second analysis, the authors investigated the relationship between WBC counts and thrombotic events.16 Evaluable patients (N = 1565) were grouped into 1 of 4 cohorts based on the last WBC measurement taken during the study period before a thrombotic event or through the end of follow-up: (1) WBC < 7.0 × 109/L, (2) 7.0 to 8.4 × 109/L, (3) 8.5 to < 11.0 × 109/L, or (4) ≥ 11.0 × 109/L. Mean follow-up time ranged from 3.6 to 4.5 years among WBC count cohorts, during which 24.9% of patients experienced a thrombotic event. Compared with the reference cohort (WBC < 7.0 × 109/L), a significant positive association between WBC counts and thrombotic event occurrence was observed among patients with WBC counts of 8.5 to < 11.0 × 109/L (HR, 1.47; 95% CI, 1.10-1.96; P < .01) and ≥ 11 × 109/L (HR, 1.87; 95% CI, 1.44-2.43; P < .001) (Figure 2).16 When including all patients in a sensitivity analysis regardless of whether they experienced thrombotic events before the index date (N = 1876), similar results were obtained (7.0-8.4 × 109/L group: HR, 1.22; 95% CI, 0.97-1.55; P = .0959; 8.5 - 11.0 × 109/L group: HR, 1.41; 95% CI, 1.10-1.81; P = .0062; ≥ 11.0 × 109/L group: HR, 1.53; 95% CI, 1.23-1.91; P < .001; compared with < 7.0 × 109/L reference group). Rates of phlebotomy and cytoreductive treatments were similar across groups.16
Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 109/L) compared with those reported in CYTO-PV (≥ 11 × 109/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.
Current PV Management and Future Implications
The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.11 Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).
Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.21 In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.22 The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.24
However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.25
Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.
Acknowledgments
Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).
Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.2 Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.3,8-10
Blood Cell Counts and Thrombotic Events in PV
Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.11 Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.12 Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).12
Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 109/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.13 In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 109/L vs reference level of < 7 × 109/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).14 Likewise, WBC count ≥ 11 × 109/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.8
Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.
The Veteran Population with PV
Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.
In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.17 The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).
In the second analysis, the authors investigated the relationship between WBC counts and thrombotic events.16 Evaluable patients (N = 1565) were grouped into 1 of 4 cohorts based on the last WBC measurement taken during the study period before a thrombotic event or through the end of follow-up: (1) WBC < 7.0 × 109/L, (2) 7.0 to 8.4 × 109/L, (3) 8.5 to < 11.0 × 109/L, or (4) ≥ 11.0 × 109/L. Mean follow-up time ranged from 3.6 to 4.5 years among WBC count cohorts, during which 24.9% of patients experienced a thrombotic event. Compared with the reference cohort (WBC < 7.0 × 109/L), a significant positive association between WBC counts and thrombotic event occurrence was observed among patients with WBC counts of 8.5 to < 11.0 × 109/L (HR, 1.47; 95% CI, 1.10-1.96; P < .01) and ≥ 11 × 109/L (HR, 1.87; 95% CI, 1.44-2.43; P < .001) (Figure 2).16 When including all patients in a sensitivity analysis regardless of whether they experienced thrombotic events before the index date (N = 1876), similar results were obtained (7.0-8.4 × 109/L group: HR, 1.22; 95% CI, 0.97-1.55; P = .0959; 8.5 - 11.0 × 109/L group: HR, 1.41; 95% CI, 1.10-1.81; P = .0062; ≥ 11.0 × 109/L group: HR, 1.53; 95% CI, 1.23-1.91; P < .001; compared with < 7.0 × 109/L reference group). Rates of phlebotomy and cytoreductive treatments were similar across groups.16
Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 109/L) compared with those reported in CYTO-PV (≥ 11 × 109/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.
Current PV Management and Future Implications
The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.11 Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).
Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.21 In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.22 The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.24
However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.25
Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.
Acknowledgments
Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).
1. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma. 2014;55(3):595-600. doi:10.3109/10428194.2013.813500
2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544
3. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874-1881. doi:10.1038/leu.2013.163
4. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23(10):2224-2232. doi:10.1200/JCO.2005.07.062
5. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110(3):840-846. doi:10.1182/blood-2006-12-064287
6. Goyal RK, Davis KL, Cote I, Mounedji N, Kaye JA. Increased incidence of thromboembolic event rates in patients diagnosed with polycythemia vera: results from an observational cohort study. Blood (ASH Annual Meeting Abstracts). 2014;124:4840. doi:10.1182/blood.V124.21.4840.4840
7. Barbui T, Carobbio A, Rumi E, et al. In contemporary patients with polycythemia vera, rates of thrombosis and risk factors delineate a new clinical epidemiology. Blood. 2014;124(19):3021-3023. doi:10.1182/blood-2014-07-591610 8. Cerquozzi S, Barraco D, Lasho T, et al. Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. Blood Cancer J. 2017;7(12):662. doi:10.1038/s41408-017-0035-6
9. Stein BL, Moliterno AR, Tiu RV. Polycythemia vera disease burden: contributing factors, impact on quality of life, and emerging treatment options. Ann Hematol. 2014;93(12):1965-1976. doi:10.1007/s00277-014-2205-y
10. Hultcrantz M, Kristinsson SY, Andersson TM-L, et al. Patterns of survival among patients with myeloproliferative neoplasms diagnosed in Sweden from 1973 to 2008: a population-based study. J Clin Oncol. 2012;30(24):2995-3001. doi:10.1200/JCO.2012.42.1925
11. National Comprehensive Cancer Network. NCCN clinical practice guidelines in myeloproliferative neoplasms (Version 1.2020). Accessed March 3, 2022. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf
12. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. doi:10.1056/NEJMoa1208500
13. Landolfi R, Di Gennaro L, Barbui T, et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood. 2007;109(6):2446-2452. doi:10.1182/blood-2006-08-042515
14. Barbui T, Masciulli A, Marfisi MR, et al. White blood cell counts and thrombosis in polycythemia vera: a subanalysis of the CYTO-PV study. Blood. 2015;126(4):560-561. doi:10.1182/blood-2015-04-638593
15. Prchal JT, Gordeuk VR. Treatment target in polycythemia vera. N Engl J Med. 2013;368(16):1555-1556. doi:10.1056/NEJMc1301262
16. Parasuraman S, Yu J, Paranagama D, et al. Elevated white blood cell levels and thrombotic events in patients with polycythemia vera: a real-world analysis of Veterans Health Administration data. Clin Lymphoma Myeloma Leuk. 2020;20(2):63-69. doi:10.1016/j.clml.2019.11.010
17. Parasuraman S, Yu J, Paranagama D, et al. Hematocrit levels and thrombotic events in patients with polycythemia vera: an analysis of Veterans Health Administration data. Ann Hematol. 2019;98(11):2533-2539. doi:10.1007/s00277-019-03793-w
18. WHO CVD Risk Chart Working Group. World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions. Lancet Glob Health. 2019;7(10):e1332-e1345. doi:10.1016/S2214-109X(19)30318-3.
19. D’Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743-753. doi:10.1161/CIRCULATIONAHA.107.699579
20. Jakafi. Package insert. Incyte Corporation; 2020.
21. Gordeuk VR, Key NS, Prchal JT. Re-evaluation of hematocrit as a determinant of thrombotic risk in erythrocytosis. Haematologica. 2019;104(4):653-658. doi:10.3324/haematol.2018.210732
22. Carobbio A, Thiele J, Passamonti F, et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood. 2011;117(22):5857-5859. doi:10.1182/blood-2011-02-339002
23. Perloff JK, Marelli AJ, Miner PD. Risk of stroke in adults with cyanotic congenital heart disease. Circulation. 1993;87(6):1954-1959. doi:10.1161/01.cir.87.6.1954
24. Gordeuk VR, Miasnikova GY, Sergueeva AI, et al. Thrombotic risk in congenital erythrocytosis due to up-regulated hypoxia sensing is not associated with elevated hematocrit. Haematologica. 2020;105(3):e87-e90. doi:10.3324/haematol.2019.216267
25. Kroll MH, Michaelis LC, Verstovsek S. Mechanisms of thrombogenesis in polycythemia vera. Blood Rev. 2015;29(4):215-221. doi:10.1016/j.blre.2014.12.002
26. Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018;32(5):1057-1069. doi:10.1038/s41375-018-0077-1
27. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood. 2013;121(23):4778-4781. doi:10.1182/blood-2013-01-478891
1. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma. 2014;55(3):595-600. doi:10.3109/10428194.2013.813500
2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544
3. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874-1881. doi:10.1038/leu.2013.163
4. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23(10):2224-2232. doi:10.1200/JCO.2005.07.062
5. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110(3):840-846. doi:10.1182/blood-2006-12-064287
6. Goyal RK, Davis KL, Cote I, Mounedji N, Kaye JA. Increased incidence of thromboembolic event rates in patients diagnosed with polycythemia vera: results from an observational cohort study. Blood (ASH Annual Meeting Abstracts). 2014;124:4840. doi:10.1182/blood.V124.21.4840.4840
7. Barbui T, Carobbio A, Rumi E, et al. In contemporary patients with polycythemia vera, rates of thrombosis and risk factors delineate a new clinical epidemiology. Blood. 2014;124(19):3021-3023. doi:10.1182/blood-2014-07-591610 8. Cerquozzi S, Barraco D, Lasho T, et al. Risk factors for arterial versus venous thrombosis in polycythemia vera: a single center experience in 587 patients. Blood Cancer J. 2017;7(12):662. doi:10.1038/s41408-017-0035-6
9. Stein BL, Moliterno AR, Tiu RV. Polycythemia vera disease burden: contributing factors, impact on quality of life, and emerging treatment options. Ann Hematol. 2014;93(12):1965-1976. doi:10.1007/s00277-014-2205-y
10. Hultcrantz M, Kristinsson SY, Andersson TM-L, et al. Patterns of survival among patients with myeloproliferative neoplasms diagnosed in Sweden from 1973 to 2008: a population-based study. J Clin Oncol. 2012;30(24):2995-3001. doi:10.1200/JCO.2012.42.1925
11. National Comprehensive Cancer Network. NCCN clinical practice guidelines in myeloproliferative neoplasms (Version 1.2020). Accessed March 3, 2022. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf
12. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. doi:10.1056/NEJMoa1208500
13. Landolfi R, Di Gennaro L, Barbui T, et al. Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood. 2007;109(6):2446-2452. doi:10.1182/blood-2006-08-042515
14. Barbui T, Masciulli A, Marfisi MR, et al. White blood cell counts and thrombosis in polycythemia vera: a subanalysis of the CYTO-PV study. Blood. 2015;126(4):560-561. doi:10.1182/blood-2015-04-638593
15. Prchal JT, Gordeuk VR. Treatment target in polycythemia vera. N Engl J Med. 2013;368(16):1555-1556. doi:10.1056/NEJMc1301262
16. Parasuraman S, Yu J, Paranagama D, et al. Elevated white blood cell levels and thrombotic events in patients with polycythemia vera: a real-world analysis of Veterans Health Administration data. Clin Lymphoma Myeloma Leuk. 2020;20(2):63-69. doi:10.1016/j.clml.2019.11.010
17. Parasuraman S, Yu J, Paranagama D, et al. Hematocrit levels and thrombotic events in patients with polycythemia vera: an analysis of Veterans Health Administration data. Ann Hematol. 2019;98(11):2533-2539. doi:10.1007/s00277-019-03793-w
18. WHO CVD Risk Chart Working Group. World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions. Lancet Glob Health. 2019;7(10):e1332-e1345. doi:10.1016/S2214-109X(19)30318-3.
19. D’Agostino RB Sr, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743-753. doi:10.1161/CIRCULATIONAHA.107.699579
20. Jakafi. Package insert. Incyte Corporation; 2020.
21. Gordeuk VR, Key NS, Prchal JT. Re-evaluation of hematocrit as a determinant of thrombotic risk in erythrocytosis. Haematologica. 2019;104(4):653-658. doi:10.3324/haematol.2018.210732
22. Carobbio A, Thiele J, Passamonti F, et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood. 2011;117(22):5857-5859. doi:10.1182/blood-2011-02-339002
23. Perloff JK, Marelli AJ, Miner PD. Risk of stroke in adults with cyanotic congenital heart disease. Circulation. 1993;87(6):1954-1959. doi:10.1161/01.cir.87.6.1954
24. Gordeuk VR, Miasnikova GY, Sergueeva AI, et al. Thrombotic risk in congenital erythrocytosis due to up-regulated hypoxia sensing is not associated with elevated hematocrit. Haematologica. 2020;105(3):e87-e90. doi:10.3324/haematol.2019.216267
25. Kroll MH, Michaelis LC, Verstovsek S. Mechanisms of thrombogenesis in polycythemia vera. Blood Rev. 2015;29(4):215-221. doi:10.1016/j.blre.2014.12.002
26. Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018;32(5):1057-1069. doi:10.1038/s41375-018-0077-1
27. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood. 2013;121(23):4778-4781. doi:10.1182/blood-2013-01-478891
Reactivation of a BCG Vaccination Scar Following the First Dose of the Moderna COVID-19 Vaccine
The COVID-19 pandemic has resulted in notable morbidity and mortality worldwide. In December 2020, the US Food and Drug Administration issued an Emergency Use Authorization for 2 messenger RNA (mRNA) vaccines—produced by Pfizer-BioNTech and Moderna—for the prevention of COVID-19. Phase 3 trials of the vaccine developed by Moderna showed 94.1% efficacy at preventing COVID-19 after 2 doses.1
Common cutaneous adverse effects of the Moderna COVID-19 Vaccine include injection-site reactions, such as pain, induration, and erythema. Less frequently reported dermatologic adverse effects include diffuse bullous rash and hypersensitivity reactions.1 We report a case of reactivation of a BCG vaccination scar after the first dose of the Moderna COVID-19 Vaccine.
Case Report
A 48-year-old Asian man who was otherwise healthy presented with erythema, induration, and mild pruritus on the deltoid muscle of the left arm, near the scar from an earlier BCG vaccine, which he received at approximately 5 years of age when living in Taiwan. The patient received the first dose of the Moderna COVID-19 Vaccine approximately 5 to 7 cm distant from the BCG vaccination scar. One to 2 days after inoculation, the patient endorsed tenderness at the site of COVID-19 vaccination but denied systemic symptoms. He had never been given a diagnosis of COVID-19. His SARS-CoV-2 antibody status was unknown.
Eight days later, the patient noticed a well-defined, erythematous, indurated plaque with mild itchiness overlying and around the BCG vaccination scar that did not involve the COVID-19 vaccination site. The following day, the redness and induration became worse (Figure).
The patient was otherwise well. Vital signs were normal; there was no lymphadenopathy. The rash resolved without treatment over the next 4 days.
Comment
The BCG vaccine is an intradermal live attenuated virus vaccine used to prevent certain forms of tuberculosis and potentially other Mycobacterium infections. Although the vaccine is not routinely administered in the United States, it is part of the vaccination schedule in most countries, administered most often to newborns and infants. Administration of the BCG vaccine commonly results in mild localized erythema, swelling, and pain at the injection site. Most inoculated patients also develop an ulcer that heals with the characteristic BCG vaccination scar.2,3
There is evidence that the BCG vaccine can enhance the innate immune system response and might decrease the rate of infection by unrelated pathogens, including viruses.4 Several epidemiologic studies have suggested that the BCG vaccine might offer some protection against COVID-19, possibly due to a resemblance of the amino acid sequences of BCG and SARS-CoV-2, which might provoke cross-reactive T cells.5,6 Further studies are underway to determine whether the BCG vaccine is truly protective against COVID-19.
BCG vaccination scar reactivation presents as redness, swelling, or ulceration at the BCG injection site months to years after inoculation. Although erythema and induration of the BCG scar are not included in the diagnostic criteria of Kawasaki disease, likely due to variable vaccine requirements in different countries, these findings are largely recognized as specific for Kawasaki disease and present in approximately half of affected patients who received the BCG vaccine.2
Heat Shock Proteins—Heat shock proteins (HSPs) are produced by cells in response to stressors. The proposed mechanism of BCG vaccination scar reactivation is a cross-reaction between human homologue HSP 63 and Mycobacterium HSP 65, leading to hyperactivity of the immune system against BCG.7 There also are reports of reactivation of a BCG vaccination scar from measles infection and influenza vaccination.2,8,9 Most prior reports of BCG vaccination scar reactivation have been in pediatric patients; our patient is an adult who received the BCG vaccine more than 40 years ago.
Mechanism of Reactivation—The mechanism of BCG vaccination scar reactivation in our patient, who received the Moderna COVID-19 Vaccine, is unclear. Possible mechanisms include (1) release of HSP mediated by the COVID-19 vaccine, leading to an immune response at the BCG vaccine scar, or (2) another immune-mediated cross-reaction between BCG and the Moderna COVID-19 Vaccine mRNA nanoparticle or encoded spike protein antigen. It has been hypothesized that the BCG vaccine might offer some protection against COVID-19; this remains uncertain and is under further investigation.10 A recent retrospective cohort study showed that a BCG vaccination booster may decrease COVID-19 infection rates in higher-risk populations.11
Conclusion
We present a case of BCG vaccine scar reactivation occurring after a dose of the Moderna COVID-19 Vaccine, a likely underreported, self-limiting, cutaneous adverse effect of this mRNA vaccine.
- Baden LR, El Sahly HM, Essink B, et al; COVE Study Group. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2020;384:403-416. doi:10.1056/NEJMoa2035389
- Muthuvelu S, Lim KS, Huang L-Y, et al. Measles infection causing bacillus Calmette-Guérin reactivation: a case report. BMC Pediatr. 2019;19:251. doi:10.1186/s12887-019-1635-z
- Fatima S, Kumari A, Das G, et al. Tuberculosis vaccine: a journey from BCG to present. Life Sci. 2020;252:117594. doi:10.1016/j.lfs.2020.117594
- O’Neill LAJ, Netea MG. BCG-induced trained immunity: can it offer protection against COVID-19? Nat Rev Immunol. 2020;20:335-337. doi:10.1038/s41577-020-0337-y
- Brooks NA, Puri A, Garg S, et al. The association of coronavirus disease-19 mortality and prior bacille Calmette-Guérin vaccination: a robust ecological analysis using unsupervised machine learning. Sci Rep. 2021;11:774. doi:10.1038/s41598-020-80787-z
- Tomita Y, Sato R, Ikeda T, et al. BCG vaccine may generate cross-reactive T-cells against SARS-CoV-2: in silico analyses and a hypothesis. Vaccine. 2020;38:6352-6356. doi:10.1016/j.vaccine.2020.08.045
- Lim KYY, Chua MC, Tan NWH, et al. Reactivation of BCG inoculation site in a child with febrile exanthema of 3 days duration: an early indicator of incomplete Kawasaki disease. BMJ Case Rep. 2020;13:E239648. doi:10.1136/bcr-2020-239648
- Kondo M, Goto H, Yamamoto S. First case of redness and erosion at bacillus Calmette-Guérin inoculation site after vaccination against influenza. J Dermatol. 2016;43:1229-1231. doi:10.1111/1346-8138.13365
- Chavarri-Guerra Y, Soto-Pérez-de-Celis E. Erythema at the bacillus Calmette-Guerin scar after influenza vaccination. Rev Soc Bras Med Trop. 2019;53:E20190390. doi:10.1590/0037-8682-0390-2019
- Fu W, Ho P-C, Liu C-L, et al. Reconcile the debate over protective effects of BCG vaccine against COVID-19. Sci Rep. 2021;11:8356. doi:10.1038/s41598-021-87731-9
- Amirlak L, Haddad R, Hardy JD, et al. Effectiveness of booster BCG vaccination in preventing COVID-19 infection. Hum Vaccin Immunother. 2021;17:3913-3915. doi:10.1080/21645515.2021.1956228
The COVID-19 pandemic has resulted in notable morbidity and mortality worldwide. In December 2020, the US Food and Drug Administration issued an Emergency Use Authorization for 2 messenger RNA (mRNA) vaccines—produced by Pfizer-BioNTech and Moderna—for the prevention of COVID-19. Phase 3 trials of the vaccine developed by Moderna showed 94.1% efficacy at preventing COVID-19 after 2 doses.1
Common cutaneous adverse effects of the Moderna COVID-19 Vaccine include injection-site reactions, such as pain, induration, and erythema. Less frequently reported dermatologic adverse effects include diffuse bullous rash and hypersensitivity reactions.1 We report a case of reactivation of a BCG vaccination scar after the first dose of the Moderna COVID-19 Vaccine.
Case Report
A 48-year-old Asian man who was otherwise healthy presented with erythema, induration, and mild pruritus on the deltoid muscle of the left arm, near the scar from an earlier BCG vaccine, which he received at approximately 5 years of age when living in Taiwan. The patient received the first dose of the Moderna COVID-19 Vaccine approximately 5 to 7 cm distant from the BCG vaccination scar. One to 2 days after inoculation, the patient endorsed tenderness at the site of COVID-19 vaccination but denied systemic symptoms. He had never been given a diagnosis of COVID-19. His SARS-CoV-2 antibody status was unknown.
Eight days later, the patient noticed a well-defined, erythematous, indurated plaque with mild itchiness overlying and around the BCG vaccination scar that did not involve the COVID-19 vaccination site. The following day, the redness and induration became worse (Figure).
The patient was otherwise well. Vital signs were normal; there was no lymphadenopathy. The rash resolved without treatment over the next 4 days.
Comment
The BCG vaccine is an intradermal live attenuated virus vaccine used to prevent certain forms of tuberculosis and potentially other Mycobacterium infections. Although the vaccine is not routinely administered in the United States, it is part of the vaccination schedule in most countries, administered most often to newborns and infants. Administration of the BCG vaccine commonly results in mild localized erythema, swelling, and pain at the injection site. Most inoculated patients also develop an ulcer that heals with the characteristic BCG vaccination scar.2,3
There is evidence that the BCG vaccine can enhance the innate immune system response and might decrease the rate of infection by unrelated pathogens, including viruses.4 Several epidemiologic studies have suggested that the BCG vaccine might offer some protection against COVID-19, possibly due to a resemblance of the amino acid sequences of BCG and SARS-CoV-2, which might provoke cross-reactive T cells.5,6 Further studies are underway to determine whether the BCG vaccine is truly protective against COVID-19.
BCG vaccination scar reactivation presents as redness, swelling, or ulceration at the BCG injection site months to years after inoculation. Although erythema and induration of the BCG scar are not included in the diagnostic criteria of Kawasaki disease, likely due to variable vaccine requirements in different countries, these findings are largely recognized as specific for Kawasaki disease and present in approximately half of affected patients who received the BCG vaccine.2
Heat Shock Proteins—Heat shock proteins (HSPs) are produced by cells in response to stressors. The proposed mechanism of BCG vaccination scar reactivation is a cross-reaction between human homologue HSP 63 and Mycobacterium HSP 65, leading to hyperactivity of the immune system against BCG.7 There also are reports of reactivation of a BCG vaccination scar from measles infection and influenza vaccination.2,8,9 Most prior reports of BCG vaccination scar reactivation have been in pediatric patients; our patient is an adult who received the BCG vaccine more than 40 years ago.
Mechanism of Reactivation—The mechanism of BCG vaccination scar reactivation in our patient, who received the Moderna COVID-19 Vaccine, is unclear. Possible mechanisms include (1) release of HSP mediated by the COVID-19 vaccine, leading to an immune response at the BCG vaccine scar, or (2) another immune-mediated cross-reaction between BCG and the Moderna COVID-19 Vaccine mRNA nanoparticle or encoded spike protein antigen. It has been hypothesized that the BCG vaccine might offer some protection against COVID-19; this remains uncertain and is under further investigation.10 A recent retrospective cohort study showed that a BCG vaccination booster may decrease COVID-19 infection rates in higher-risk populations.11
Conclusion
We present a case of BCG vaccine scar reactivation occurring after a dose of the Moderna COVID-19 Vaccine, a likely underreported, self-limiting, cutaneous adverse effect of this mRNA vaccine.
The COVID-19 pandemic has resulted in notable morbidity and mortality worldwide. In December 2020, the US Food and Drug Administration issued an Emergency Use Authorization for 2 messenger RNA (mRNA) vaccines—produced by Pfizer-BioNTech and Moderna—for the prevention of COVID-19. Phase 3 trials of the vaccine developed by Moderna showed 94.1% efficacy at preventing COVID-19 after 2 doses.1
Common cutaneous adverse effects of the Moderna COVID-19 Vaccine include injection-site reactions, such as pain, induration, and erythema. Less frequently reported dermatologic adverse effects include diffuse bullous rash and hypersensitivity reactions.1 We report a case of reactivation of a BCG vaccination scar after the first dose of the Moderna COVID-19 Vaccine.
Case Report
A 48-year-old Asian man who was otherwise healthy presented with erythema, induration, and mild pruritus on the deltoid muscle of the left arm, near the scar from an earlier BCG vaccine, which he received at approximately 5 years of age when living in Taiwan. The patient received the first dose of the Moderna COVID-19 Vaccine approximately 5 to 7 cm distant from the BCG vaccination scar. One to 2 days after inoculation, the patient endorsed tenderness at the site of COVID-19 vaccination but denied systemic symptoms. He had never been given a diagnosis of COVID-19. His SARS-CoV-2 antibody status was unknown.
Eight days later, the patient noticed a well-defined, erythematous, indurated plaque with mild itchiness overlying and around the BCG vaccination scar that did not involve the COVID-19 vaccination site. The following day, the redness and induration became worse (Figure).
The patient was otherwise well. Vital signs were normal; there was no lymphadenopathy. The rash resolved without treatment over the next 4 days.
Comment
The BCG vaccine is an intradermal live attenuated virus vaccine used to prevent certain forms of tuberculosis and potentially other Mycobacterium infections. Although the vaccine is not routinely administered in the United States, it is part of the vaccination schedule in most countries, administered most often to newborns and infants. Administration of the BCG vaccine commonly results in mild localized erythema, swelling, and pain at the injection site. Most inoculated patients also develop an ulcer that heals with the characteristic BCG vaccination scar.2,3
There is evidence that the BCG vaccine can enhance the innate immune system response and might decrease the rate of infection by unrelated pathogens, including viruses.4 Several epidemiologic studies have suggested that the BCG vaccine might offer some protection against COVID-19, possibly due to a resemblance of the amino acid sequences of BCG and SARS-CoV-2, which might provoke cross-reactive T cells.5,6 Further studies are underway to determine whether the BCG vaccine is truly protective against COVID-19.
BCG vaccination scar reactivation presents as redness, swelling, or ulceration at the BCG injection site months to years after inoculation. Although erythema and induration of the BCG scar are not included in the diagnostic criteria of Kawasaki disease, likely due to variable vaccine requirements in different countries, these findings are largely recognized as specific for Kawasaki disease and present in approximately half of affected patients who received the BCG vaccine.2
Heat Shock Proteins—Heat shock proteins (HSPs) are produced by cells in response to stressors. The proposed mechanism of BCG vaccination scar reactivation is a cross-reaction between human homologue HSP 63 and Mycobacterium HSP 65, leading to hyperactivity of the immune system against BCG.7 There also are reports of reactivation of a BCG vaccination scar from measles infection and influenza vaccination.2,8,9 Most prior reports of BCG vaccination scar reactivation have been in pediatric patients; our patient is an adult who received the BCG vaccine more than 40 years ago.
Mechanism of Reactivation—The mechanism of BCG vaccination scar reactivation in our patient, who received the Moderna COVID-19 Vaccine, is unclear. Possible mechanisms include (1) release of HSP mediated by the COVID-19 vaccine, leading to an immune response at the BCG vaccine scar, or (2) another immune-mediated cross-reaction between BCG and the Moderna COVID-19 Vaccine mRNA nanoparticle or encoded spike protein antigen. It has been hypothesized that the BCG vaccine might offer some protection against COVID-19; this remains uncertain and is under further investigation.10 A recent retrospective cohort study showed that a BCG vaccination booster may decrease COVID-19 infection rates in higher-risk populations.11
Conclusion
We present a case of BCG vaccine scar reactivation occurring after a dose of the Moderna COVID-19 Vaccine, a likely underreported, self-limiting, cutaneous adverse effect of this mRNA vaccine.
- Baden LR, El Sahly HM, Essink B, et al; COVE Study Group. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2020;384:403-416. doi:10.1056/NEJMoa2035389
- Muthuvelu S, Lim KS, Huang L-Y, et al. Measles infection causing bacillus Calmette-Guérin reactivation: a case report. BMC Pediatr. 2019;19:251. doi:10.1186/s12887-019-1635-z
- Fatima S, Kumari A, Das G, et al. Tuberculosis vaccine: a journey from BCG to present. Life Sci. 2020;252:117594. doi:10.1016/j.lfs.2020.117594
- O’Neill LAJ, Netea MG. BCG-induced trained immunity: can it offer protection against COVID-19? Nat Rev Immunol. 2020;20:335-337. doi:10.1038/s41577-020-0337-y
- Brooks NA, Puri A, Garg S, et al. The association of coronavirus disease-19 mortality and prior bacille Calmette-Guérin vaccination: a robust ecological analysis using unsupervised machine learning. Sci Rep. 2021;11:774. doi:10.1038/s41598-020-80787-z
- Tomita Y, Sato R, Ikeda T, et al. BCG vaccine may generate cross-reactive T-cells against SARS-CoV-2: in silico analyses and a hypothesis. Vaccine. 2020;38:6352-6356. doi:10.1016/j.vaccine.2020.08.045
- Lim KYY, Chua MC, Tan NWH, et al. Reactivation of BCG inoculation site in a child with febrile exanthema of 3 days duration: an early indicator of incomplete Kawasaki disease. BMJ Case Rep. 2020;13:E239648. doi:10.1136/bcr-2020-239648
- Kondo M, Goto H, Yamamoto S. First case of redness and erosion at bacillus Calmette-Guérin inoculation site after vaccination against influenza. J Dermatol. 2016;43:1229-1231. doi:10.1111/1346-8138.13365
- Chavarri-Guerra Y, Soto-Pérez-de-Celis E. Erythema at the bacillus Calmette-Guerin scar after influenza vaccination. Rev Soc Bras Med Trop. 2019;53:E20190390. doi:10.1590/0037-8682-0390-2019
- Fu W, Ho P-C, Liu C-L, et al. Reconcile the debate over protective effects of BCG vaccine against COVID-19. Sci Rep. 2021;11:8356. doi:10.1038/s41598-021-87731-9
- Amirlak L, Haddad R, Hardy JD, et al. Effectiveness of booster BCG vaccination in preventing COVID-19 infection. Hum Vaccin Immunother. 2021;17:3913-3915. doi:10.1080/21645515.2021.1956228
- Baden LR, El Sahly HM, Essink B, et al; COVE Study Group. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2020;384:403-416. doi:10.1056/NEJMoa2035389
- Muthuvelu S, Lim KS, Huang L-Y, et al. Measles infection causing bacillus Calmette-Guérin reactivation: a case report. BMC Pediatr. 2019;19:251. doi:10.1186/s12887-019-1635-z
- Fatima S, Kumari A, Das G, et al. Tuberculosis vaccine: a journey from BCG to present. Life Sci. 2020;252:117594. doi:10.1016/j.lfs.2020.117594
- O’Neill LAJ, Netea MG. BCG-induced trained immunity: can it offer protection against COVID-19? Nat Rev Immunol. 2020;20:335-337. doi:10.1038/s41577-020-0337-y
- Brooks NA, Puri A, Garg S, et al. The association of coronavirus disease-19 mortality and prior bacille Calmette-Guérin vaccination: a robust ecological analysis using unsupervised machine learning. Sci Rep. 2021;11:774. doi:10.1038/s41598-020-80787-z
- Tomita Y, Sato R, Ikeda T, et al. BCG vaccine may generate cross-reactive T-cells against SARS-CoV-2: in silico analyses and a hypothesis. Vaccine. 2020;38:6352-6356. doi:10.1016/j.vaccine.2020.08.045
- Lim KYY, Chua MC, Tan NWH, et al. Reactivation of BCG inoculation site in a child with febrile exanthema of 3 days duration: an early indicator of incomplete Kawasaki disease. BMJ Case Rep. 2020;13:E239648. doi:10.1136/bcr-2020-239648
- Kondo M, Goto H, Yamamoto S. First case of redness and erosion at bacillus Calmette-Guérin inoculation site after vaccination against influenza. J Dermatol. 2016;43:1229-1231. doi:10.1111/1346-8138.13365
- Chavarri-Guerra Y, Soto-Pérez-de-Celis E. Erythema at the bacillus Calmette-Guerin scar after influenza vaccination. Rev Soc Bras Med Trop. 2019;53:E20190390. doi:10.1590/0037-8682-0390-2019
- Fu W, Ho P-C, Liu C-L, et al. Reconcile the debate over protective effects of BCG vaccine against COVID-19. Sci Rep. 2021;11:8356. doi:10.1038/s41598-021-87731-9
- Amirlak L, Haddad R, Hardy JD, et al. Effectiveness of booster BCG vaccination in preventing COVID-19 infection. Hum Vaccin Immunother. 2021;17:3913-3915. doi:10.1080/21645515.2021.1956228
Practice Points
- BCG vaccination scar reactivation is a potential benign, self-limited reaction in patients who receive the Moderna COVID-19 Vaccine.
- Symptoms of BCG vaccination scar reactivation, which is seen more commonly in children with Kawasaki disease, include redness, swelling, and ulceration.
NY radiation oncologist loses license, poses ‘potential danger’
The state Board for Professional Medical Conduct has revoked the medical license of Won Sam Yi, MD, following a lengthy review of the care he provided to seven cancer patients; six of them died.
“He is a danger to potential new patients should he be reinstated as a radiation oncologist,” board members wrote, according to a news report in the Buffalo News.
Dr. Yi’s lawyer said that he is appealing the decision.
Dr. Yi was the former CEO of the now-defunct private cancer practice CCS Oncology, located in western New York.
In 2018, the state health department brought numerous charges of professional misconduct against Dr. Yi, including charges that he had failed to “account for prior doses of radiotherapy” as well as exceeding “appropriate tissue tolerances” during the treatment.
Now, the state’s Board for Professional Medical Conduct has upheld nearly all of the departmental charges that had been levied against him, and also found that Dr. Yi failed to take responsibility or show contrition for his treatment decisions.
However, whistleblower claims from a former CSS Oncology employee were dismissed.
Troubled history
CCS Oncology was once one of the largest private cancer practices in Erie and Niagara counties, both in the Buffalo metropolitan area.
Dr. Yi purchased CCS Oncology in 2008 and was its sole shareholder, and in 2012 he also acquired CCS Medical. As of 2016, the practices provided care to about 30% of cancer patients in the region. CCS also began acquiring other practices as it expanded into noncancer specialties, including primary care.
However, CCS began to struggle financially in late 2016, when health insurance provider Independent Health announced it was removing CCS Oncology from its network, and several vendors and lenders subsequently sued CCS and Dr. Yi for nonpayment.
The announcement from Independent Health was “financially devastating to CCS,” and also was “the direct cause” of the practice defaulting on its Bank of America loan and of the practice’s inability to pay not only its vendors but state and federal tax agencies, the Buffalo News reported. As a result, several vendors and lenders had sued CCS and Dr. Yi for nonpayment.
The FBI raided numerous CCS locations in March 2018, seizing financial and other data as part of an investigation into possible Medicare billing fraud. The following month, CCS filed for Chapter 11 bankruptcy, citing it owed millions of dollars to Bank of America and other creditors. Shortly afterward, the practice closed.
Medical misconduct
The state’s charges of professional misconduct accused Dr. Yi of “gross negligence,” “gross incompetence,” and several other cases of misconduct in treating seven patients between 2009 and 2013 at various CCS locations. The patients ranged in age from 27 to 72. Six of the seven patients died.
In one case, Dr. Yi was accused of providing whole-brain radiation therapy to a 43-year-old woman for about 6 weeks in 2012, but the treatment was “contrary to medical indications” and did not take into account prior doses of such treatment. The patient died in December of that year, and the board concluded that Dr. Yi had improperly treated her with a high dose of radiation that was intended to cure her cancer even though she was at a stage where her disease was incurable.
The state board eventually concluded that for all but one of the patients in question, Dr. Yi was guilty of misconduct in his treatment decisions. They wrote that Dr. Yi had frequently administered radiation doses without taking into account how much radiation therapy the patients had received previously and without considering the risk of serious complications for them.
Dr. Yi plans to appeal the board’s decision in state court, according to his attorney, Anthony Scher.
“Dr Yi has treated over 10,000 patients in his career,” Mr. Scher told the Buffalo News. “These handful of cases don’t represent the thousands of success stories that he’s had.”
A version of this article first appeared on Medscape.com.
The state Board for Professional Medical Conduct has revoked the medical license of Won Sam Yi, MD, following a lengthy review of the care he provided to seven cancer patients; six of them died.
“He is a danger to potential new patients should he be reinstated as a radiation oncologist,” board members wrote, according to a news report in the Buffalo News.
Dr. Yi’s lawyer said that he is appealing the decision.
Dr. Yi was the former CEO of the now-defunct private cancer practice CCS Oncology, located in western New York.
In 2018, the state health department brought numerous charges of professional misconduct against Dr. Yi, including charges that he had failed to “account for prior doses of radiotherapy” as well as exceeding “appropriate tissue tolerances” during the treatment.
Now, the state’s Board for Professional Medical Conduct has upheld nearly all of the departmental charges that had been levied against him, and also found that Dr. Yi failed to take responsibility or show contrition for his treatment decisions.
However, whistleblower claims from a former CSS Oncology employee were dismissed.
Troubled history
CCS Oncology was once one of the largest private cancer practices in Erie and Niagara counties, both in the Buffalo metropolitan area.
Dr. Yi purchased CCS Oncology in 2008 and was its sole shareholder, and in 2012 he also acquired CCS Medical. As of 2016, the practices provided care to about 30% of cancer patients in the region. CCS also began acquiring other practices as it expanded into noncancer specialties, including primary care.
However, CCS began to struggle financially in late 2016, when health insurance provider Independent Health announced it was removing CCS Oncology from its network, and several vendors and lenders subsequently sued CCS and Dr. Yi for nonpayment.
The announcement from Independent Health was “financially devastating to CCS,” and also was “the direct cause” of the practice defaulting on its Bank of America loan and of the practice’s inability to pay not only its vendors but state and federal tax agencies, the Buffalo News reported. As a result, several vendors and lenders had sued CCS and Dr. Yi for nonpayment.
The FBI raided numerous CCS locations in March 2018, seizing financial and other data as part of an investigation into possible Medicare billing fraud. The following month, CCS filed for Chapter 11 bankruptcy, citing it owed millions of dollars to Bank of America and other creditors. Shortly afterward, the practice closed.
Medical misconduct
The state’s charges of professional misconduct accused Dr. Yi of “gross negligence,” “gross incompetence,” and several other cases of misconduct in treating seven patients between 2009 and 2013 at various CCS locations. The patients ranged in age from 27 to 72. Six of the seven patients died.
In one case, Dr. Yi was accused of providing whole-brain radiation therapy to a 43-year-old woman for about 6 weeks in 2012, but the treatment was “contrary to medical indications” and did not take into account prior doses of such treatment. The patient died in December of that year, and the board concluded that Dr. Yi had improperly treated her with a high dose of radiation that was intended to cure her cancer even though she was at a stage where her disease was incurable.
The state board eventually concluded that for all but one of the patients in question, Dr. Yi was guilty of misconduct in his treatment decisions. They wrote that Dr. Yi had frequently administered radiation doses without taking into account how much radiation therapy the patients had received previously and without considering the risk of serious complications for them.
Dr. Yi plans to appeal the board’s decision in state court, according to his attorney, Anthony Scher.
“Dr Yi has treated over 10,000 patients in his career,” Mr. Scher told the Buffalo News. “These handful of cases don’t represent the thousands of success stories that he’s had.”
A version of this article first appeared on Medscape.com.
The state Board for Professional Medical Conduct has revoked the medical license of Won Sam Yi, MD, following a lengthy review of the care he provided to seven cancer patients; six of them died.
“He is a danger to potential new patients should he be reinstated as a radiation oncologist,” board members wrote, according to a news report in the Buffalo News.
Dr. Yi’s lawyer said that he is appealing the decision.
Dr. Yi was the former CEO of the now-defunct private cancer practice CCS Oncology, located in western New York.
In 2018, the state health department brought numerous charges of professional misconduct against Dr. Yi, including charges that he had failed to “account for prior doses of radiotherapy” as well as exceeding “appropriate tissue tolerances” during the treatment.
Now, the state’s Board for Professional Medical Conduct has upheld nearly all of the departmental charges that had been levied against him, and also found that Dr. Yi failed to take responsibility or show contrition for his treatment decisions.
However, whistleblower claims from a former CSS Oncology employee were dismissed.
Troubled history
CCS Oncology was once one of the largest private cancer practices in Erie and Niagara counties, both in the Buffalo metropolitan area.
Dr. Yi purchased CCS Oncology in 2008 and was its sole shareholder, and in 2012 he also acquired CCS Medical. As of 2016, the practices provided care to about 30% of cancer patients in the region. CCS also began acquiring other practices as it expanded into noncancer specialties, including primary care.
However, CCS began to struggle financially in late 2016, when health insurance provider Independent Health announced it was removing CCS Oncology from its network, and several vendors and lenders subsequently sued CCS and Dr. Yi for nonpayment.
The announcement from Independent Health was “financially devastating to CCS,” and also was “the direct cause” of the practice defaulting on its Bank of America loan and of the practice’s inability to pay not only its vendors but state and federal tax agencies, the Buffalo News reported. As a result, several vendors and lenders had sued CCS and Dr. Yi for nonpayment.
The FBI raided numerous CCS locations in March 2018, seizing financial and other data as part of an investigation into possible Medicare billing fraud. The following month, CCS filed for Chapter 11 bankruptcy, citing it owed millions of dollars to Bank of America and other creditors. Shortly afterward, the practice closed.
Medical misconduct
The state’s charges of professional misconduct accused Dr. Yi of “gross negligence,” “gross incompetence,” and several other cases of misconduct in treating seven patients between 2009 and 2013 at various CCS locations. The patients ranged in age from 27 to 72. Six of the seven patients died.
In one case, Dr. Yi was accused of providing whole-brain radiation therapy to a 43-year-old woman for about 6 weeks in 2012, but the treatment was “contrary to medical indications” and did not take into account prior doses of such treatment. The patient died in December of that year, and the board concluded that Dr. Yi had improperly treated her with a high dose of radiation that was intended to cure her cancer even though she was at a stage where her disease was incurable.
The state board eventually concluded that for all but one of the patients in question, Dr. Yi was guilty of misconduct in his treatment decisions. They wrote that Dr. Yi had frequently administered radiation doses without taking into account how much radiation therapy the patients had received previously and without considering the risk of serious complications for them.
Dr. Yi plans to appeal the board’s decision in state court, according to his attorney, Anthony Scher.
“Dr Yi has treated over 10,000 patients in his career,” Mr. Scher told the Buffalo News. “These handful of cases don’t represent the thousands of success stories that he’s had.”
A version of this article first appeared on Medscape.com.
Why pregnant people were left behind while vaccines moved at ‘warp speed’ to help the masses
Kia Slade was 7 months pregnant, unvaccinated, and fighting for breath, her oxygen levels plummeting, when her son came into the world last May.
A severe case of COVID-19 pneumonia had left Ms. Slade delirious. When the intensive care team tried to place an oxygen mask on her face, she snatched it away, she recalled. Her baby’s heart rate began to drop.
Ms. Slade’s doctor performed an emergency cesarean section at her bedside in the intensive care unit, delivering baby Tristan 10 weeks early. He weighed just 2 pounds, 14 ounces, about half the size of small full-term baby.
But Ms. Slade wouldn’t meet him until July. She was on a ventilator in a medically-induced coma for 8 weeks, and she developed a serious infection and blood clot while unconscious. It was only after a perilous 2½ months in the hospital, during which her heart stopped twice, that Ms. Slade was vaccinated against COVID-19.
“I wish I had gotten the vaccine earlier,” said Ms. Slade, 42, who remains too sick to return to work as a special education teacher in Baltimore. Doctors “kept pushing me to get vaccinated, but there just wasn’t enough information out there for me to do it.”
A year ago, there was little to no vaccine safety data for pregnant people like Ms. Slade, because they had been excluded from clinical trials run by Pfizer, Moderna, and other vaccine makers.
Lacking data, health experts were unsure and divided about how to advise expectant parents. Although U.S. health officials permitted pregnant people to be vaccinated, the World Health Organization in January 2021 actually discouraged them from doing so; it later reversed that recommendation.
The uncertainty led many women to delay vaccination, and only about two-thirds of the pregnant people who have been tracked by the Centers for Disease Control and Prevention were fully vaccinated as of Feb. 5, 2022, leaving many expectant moms at a high risk of infection and life-threatening complications.
More than 29,000 pregnant people have been hospitalized with COVID-19 and 274 have died, according to the CDC.
“There were surely women who were hospitalized because there wasn’t information available to them,” said Paul A. Offit, MD, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia.
Vaccine developers say that pregnant people – who have special health needs and risks – were excluded from clinical trials to protect them from potential side effects of novel technologies, including the Pfizer and Moderna mRNA vaccines and formulations made with cold viruses, such as the Johnson & Johnson vaccine.
But a KHN analysis also shows that pregnant people were left behind because including them in vaccine studies would have complicated and potentially delayed the delivery of COVID-19 vaccines to the broader population.
A growing number of women’s health researchers and advocates say that excluding pregnant people – and the months-long delay in recommending that they be immunized – helped fuel widespread vaccine hesitancy in this vulnerable group.
“Women and their unborn fetuses are dying of COVID infection,” said Jane Van Dis, MD, an ob.gyn. at the University of Rochester (N.Y.) Medical Center who has treated many patients like Ms. Slade. “Our failure as a society to vaccinate women in pregnancy will be remembered by the children and families who lost their mothers to this disease.”
New technology, uncertain risks
At the time COVID-19 vaccines were being developed, scientists had very little experience using mRNA vaccines in pregnant women, said Jacqueline Miller, MD, a senior vice president involved in vaccine research at Moderna.
“When you study anything in pregnant women, you have two patients, the mom and the unborn child,” Dr. Miller said. “Until we had more safety data on the platform, it wasn’t something we wanted to undertake.”
But Dr. Offit noted that vaccines have a strong record of safety in pregnancy and he sees no reason to have excluded pregnant people. None of the vaccines currently in use – including the chickenpox and rubella vaccines, which contain live viruses – have been shown to harm fetuses, he said. Doctors routinely recommend that pregnant people receive pertussis and flu vaccinations.
Dr. Offit, the coinventor of a rotavirus vaccine, said that some concerns about vaccines stem from commercial, not medical, interests. Drug makers don’t want to risk that their product will be blamed for any problems occurring in pregnant people, even if coincidental, he said.
“These companies don’t want bad news,” Dr. Offit said.
In the United States, health officials typically would have told expectant mothers not to take a vaccine that was untested during pregnancy, said Dr. Offit, a member of a committee that advises the Food and Drug Administration on vaccines.
Due to the urgency of the pandemic, health agencies instead permitted pregnant people to make up their own minds about vaccines without recommending them.
Women’s medical associations were also hampered by the lack of data. Neither the American College of Obstetricians and Gynecologists nor the Society for Maternal-Fetal Medicine actively encouraged pregnant people to be vaccinated until July 30, 2021, after the first real-world vaccine studies had been published. The CDC followed suit in August of 2021.
“If we had had this data in the beginning, we would have been able to vaccinate more women,” said Kelli Burroughs, MD, the department chair of obstetrics and gynecology at Memorial Hermann Sugar Land Hospital near Houston.
Yet anti-vaccine groups wasted no time in scaring pregnant people, flooding social media with misinformation about impaired fertility and harm to the fetus.
In the first few months after the COVID-19 vaccines were approved, some doctors were ambivalent about recommending them, and some still advise pregnant patients against vaccination.
An estimated 67% of pregnant people today are fully vaccinated, compared with about 89% of people 65 and older, another high-risk group, and 65% of Americans overall. Vaccination rates are lower among minorities, with 65% of expectant Hispanic mothers and 53% of pregnant African Americans fully vaccinated, according to the CDC.
Vaccination is especially important during pregnancy, because of increased risks of hospitalization, ICU admission, and mechanical ventilation, Dr. Burroughs said. A study released in February from the National Institutes of Health found that pregnant people with a moderate to severe COVID-19 infection also were more likely to have a C-section, deliver preterm, or develop a postpartum hemorrhage.
Black moms such as Ms. Slade were already at higher risk of maternal and infant mortality before the pandemic, because of higher underlying risks, unequal access to health care, and other factors. COVID-19 has magnified those risks, said Dr. Burroughs, who has persuaded reluctant patients by revealing that she had a healthy pregnancy and child after being vaccinated.
Ms. Slade said she has never opposed vaccines and had no hesitation about receiving other vaccines while pregnant. But she said she “just wasn’t comfortable” with COVID-19 shots.
“If there had been data out there saying the COVID shot was safe, and that nothing would happen to my baby and there was no risk of birth defects, I would have taken it,” said Ms. Slade, who has had type 2 diabetes for 12 years.
Working at warp speed
Government scientists at the NIH were concerned about the risk of COVID-19 to pregnant people from the very beginning and knew that expectant moms needed vaccines as much or more than anyone else, said Larry Corey, MD, a leader of the COVID-19 Prevention Network, which coordinated COVID-19 vaccine trials for the federal government.
But including pregnant volunteers in the larger vaccine trials could have led to interruptions and delays, Dr. Corey said. Researchers would have had to enroll thousands of pregnant volunteers to achieve statistically robust results that weren’t due to chance, he said.
Pregnancy can bring on a wide range of complications: gestational diabetes, hypertension, anemia, bleeding, blood clots, or problems with the placenta, for example. Up to 20% of people who know they’re pregnant miscarry. Because researchers would have been obliged to investigate any medical problem to make sure it wasn’t caused by one of the COVID-19 vaccines, including pregnant people might have meant having to hit pause on those trials, Dr. Corey said.
With death tolls from the pandemic mounting, “we had a mission to do this as quickly and as thoroughly as possible,” Dr. Corey said. Making COVID-19 vaccines available within a year “saved hundreds of thousands of lives.”
The first data on COVID-19 vaccine safety in pregnancy was published in April of 2021 when the CDC released an analysis of nearly 36,000 vaccinated pregnant people who had enrolled in a registry called V-safe, which allows users to log the dates of their vaccinations and any subsequent symptoms.
Later research showed that COVID-19 vaccines weren’t associated with increased risk of miscarriage or premature delivery.
Brenna Hughes, MD, a maternal-fetal medicine specialist and member of the American College of Obstetricians and Gynecologists’ COVID-19 expert group, agrees that adding pregnant people to large-scale COVID-19 vaccine and drug trials may have been impractical. But researchers could have launched parallel trials of pregnant women, once early studies showed the vaccines were safe in humans, she said.
“Would it have been hard? Everything with COVID is hard,” Dr. Hughes said. “But it would have been feasible.”
The FDA requires that researchers perform additional animal studies – called developmental and reproductive toxicity studies – before testing vaccines in pregnant people. Although these studies are essential, they take 5-6 months, and weren’t completed until late 2020, around the time the first COVID-19 vaccines were authorized for adults, said Emily Erbelding, MD, director of microbiology and infectious diseases at the National Institute of Allergy and Infectious Diseases, part of the NIH.
Pregnancy studies “were an afterthought,” said Irina Burd, MD, director of Johns Hopkins’ Integrated Research Center for Fetal Medicine and a professor of gynecology and obstetrics. “They should have been done sooner.”
The NIH is conducting a study of pregnant and postpartum people who decided on their own to be vaccinated, Dr. Erbelding said. The study is due to be completed by July 2023.
Janssen and Moderna are also conducting studies in pregnant people, both due to be completed in 2024.
Pfizer scientists encountered problems when they initiated a clinical trial, which would have randomly assigned pregnant people to receive either a vaccine or placebo. Once vaccines were widely available, many patients weren’t willing to take a chance on being unvaccinated until after delivery.
Pfizer has stopped recruiting patients and has not said whether it will publicly report any data from the trial.
Dr. Hughes said vaccine developers need to include pregnant people from the very beginning.
“There is this notion of protecting pregnant people from research,” Dr. Hughes said. “But we should be protecting patients through research, not from research.”
Recovering physically and emotionally
Ms. Slade still regrets being deprived of time with her children while she fought the disease.
Being on a ventilator kept her from spending those early weeks with her newborn, or from seeing her 9-year-old daughter, Zoe.
Even when Ms. Slade was finally able to see her son, she wasn’t able to tell him she loved him or sing a lullaby, or even talk at all, because of a breathing tube in her throat.
Today, Ms. Slade is a strong advocate of COVID-19 vaccinations, urging her friends and family to get their shots to avoid suffering the way she has.
Ms. Slade had to relearn to walk after being bedridden for weeks. Her many weeks on a ventilator may have contributed to her stomach paralysis, which often causes intense pain, nausea, and even vomiting when she eats or drinks. Ms. Slade weighs 50 pounds less today than before she became pregnant and has resorted to going to the emergency department when the pain is unbearable. “Most days, I’m just miserable,” she said.
Her family suffered as well. Like many babies born prematurely, Tristan, now nearly 9 months old and crawling, receives physical therapy to strengthen his muscles. At 15 pounds, Tristan is largely healthy, although his doctor said he has symptoms of asthma.
Ms. Slade said she would like to attend family counseling with Zoe, who rarely complains and tends to keep her feelings to herself. Ms. Slade said she knows her illness must have been terrifying for her little girl.
“The other day she was talking to me,” Ms. Slade said, “and she said, ‘You know, I almost had to bury you.’ ”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
Kia Slade was 7 months pregnant, unvaccinated, and fighting for breath, her oxygen levels plummeting, when her son came into the world last May.
A severe case of COVID-19 pneumonia had left Ms. Slade delirious. When the intensive care team tried to place an oxygen mask on her face, she snatched it away, she recalled. Her baby’s heart rate began to drop.
Ms. Slade’s doctor performed an emergency cesarean section at her bedside in the intensive care unit, delivering baby Tristan 10 weeks early. He weighed just 2 pounds, 14 ounces, about half the size of small full-term baby.
But Ms. Slade wouldn’t meet him until July. She was on a ventilator in a medically-induced coma for 8 weeks, and she developed a serious infection and blood clot while unconscious. It was only after a perilous 2½ months in the hospital, during which her heart stopped twice, that Ms. Slade was vaccinated against COVID-19.
“I wish I had gotten the vaccine earlier,” said Ms. Slade, 42, who remains too sick to return to work as a special education teacher in Baltimore. Doctors “kept pushing me to get vaccinated, but there just wasn’t enough information out there for me to do it.”
A year ago, there was little to no vaccine safety data for pregnant people like Ms. Slade, because they had been excluded from clinical trials run by Pfizer, Moderna, and other vaccine makers.
Lacking data, health experts were unsure and divided about how to advise expectant parents. Although U.S. health officials permitted pregnant people to be vaccinated, the World Health Organization in January 2021 actually discouraged them from doing so; it later reversed that recommendation.
The uncertainty led many women to delay vaccination, and only about two-thirds of the pregnant people who have been tracked by the Centers for Disease Control and Prevention were fully vaccinated as of Feb. 5, 2022, leaving many expectant moms at a high risk of infection and life-threatening complications.
More than 29,000 pregnant people have been hospitalized with COVID-19 and 274 have died, according to the CDC.
“There were surely women who were hospitalized because there wasn’t information available to them,” said Paul A. Offit, MD, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia.
Vaccine developers say that pregnant people – who have special health needs and risks – were excluded from clinical trials to protect them from potential side effects of novel technologies, including the Pfizer and Moderna mRNA vaccines and formulations made with cold viruses, such as the Johnson & Johnson vaccine.
But a KHN analysis also shows that pregnant people were left behind because including them in vaccine studies would have complicated and potentially delayed the delivery of COVID-19 vaccines to the broader population.
A growing number of women’s health researchers and advocates say that excluding pregnant people – and the months-long delay in recommending that they be immunized – helped fuel widespread vaccine hesitancy in this vulnerable group.
“Women and their unborn fetuses are dying of COVID infection,” said Jane Van Dis, MD, an ob.gyn. at the University of Rochester (N.Y.) Medical Center who has treated many patients like Ms. Slade. “Our failure as a society to vaccinate women in pregnancy will be remembered by the children and families who lost their mothers to this disease.”
New technology, uncertain risks
At the time COVID-19 vaccines were being developed, scientists had very little experience using mRNA vaccines in pregnant women, said Jacqueline Miller, MD, a senior vice president involved in vaccine research at Moderna.
“When you study anything in pregnant women, you have two patients, the mom and the unborn child,” Dr. Miller said. “Until we had more safety data on the platform, it wasn’t something we wanted to undertake.”
But Dr. Offit noted that vaccines have a strong record of safety in pregnancy and he sees no reason to have excluded pregnant people. None of the vaccines currently in use – including the chickenpox and rubella vaccines, which contain live viruses – have been shown to harm fetuses, he said. Doctors routinely recommend that pregnant people receive pertussis and flu vaccinations.
Dr. Offit, the coinventor of a rotavirus vaccine, said that some concerns about vaccines stem from commercial, not medical, interests. Drug makers don’t want to risk that their product will be blamed for any problems occurring in pregnant people, even if coincidental, he said.
“These companies don’t want bad news,” Dr. Offit said.
In the United States, health officials typically would have told expectant mothers not to take a vaccine that was untested during pregnancy, said Dr. Offit, a member of a committee that advises the Food and Drug Administration on vaccines.
Due to the urgency of the pandemic, health agencies instead permitted pregnant people to make up their own minds about vaccines without recommending them.
Women’s medical associations were also hampered by the lack of data. Neither the American College of Obstetricians and Gynecologists nor the Society for Maternal-Fetal Medicine actively encouraged pregnant people to be vaccinated until July 30, 2021, after the first real-world vaccine studies had been published. The CDC followed suit in August of 2021.
“If we had had this data in the beginning, we would have been able to vaccinate more women,” said Kelli Burroughs, MD, the department chair of obstetrics and gynecology at Memorial Hermann Sugar Land Hospital near Houston.
Yet anti-vaccine groups wasted no time in scaring pregnant people, flooding social media with misinformation about impaired fertility and harm to the fetus.
In the first few months after the COVID-19 vaccines were approved, some doctors were ambivalent about recommending them, and some still advise pregnant patients against vaccination.
An estimated 67% of pregnant people today are fully vaccinated, compared with about 89% of people 65 and older, another high-risk group, and 65% of Americans overall. Vaccination rates are lower among minorities, with 65% of expectant Hispanic mothers and 53% of pregnant African Americans fully vaccinated, according to the CDC.
Vaccination is especially important during pregnancy, because of increased risks of hospitalization, ICU admission, and mechanical ventilation, Dr. Burroughs said. A study released in February from the National Institutes of Health found that pregnant people with a moderate to severe COVID-19 infection also were more likely to have a C-section, deliver preterm, or develop a postpartum hemorrhage.
Black moms such as Ms. Slade were already at higher risk of maternal and infant mortality before the pandemic, because of higher underlying risks, unequal access to health care, and other factors. COVID-19 has magnified those risks, said Dr. Burroughs, who has persuaded reluctant patients by revealing that she had a healthy pregnancy and child after being vaccinated.
Ms. Slade said she has never opposed vaccines and had no hesitation about receiving other vaccines while pregnant. But she said she “just wasn’t comfortable” with COVID-19 shots.
“If there had been data out there saying the COVID shot was safe, and that nothing would happen to my baby and there was no risk of birth defects, I would have taken it,” said Ms. Slade, who has had type 2 diabetes for 12 years.
Working at warp speed
Government scientists at the NIH were concerned about the risk of COVID-19 to pregnant people from the very beginning and knew that expectant moms needed vaccines as much or more than anyone else, said Larry Corey, MD, a leader of the COVID-19 Prevention Network, which coordinated COVID-19 vaccine trials for the federal government.
But including pregnant volunteers in the larger vaccine trials could have led to interruptions and delays, Dr. Corey said. Researchers would have had to enroll thousands of pregnant volunteers to achieve statistically robust results that weren’t due to chance, he said.
Pregnancy can bring on a wide range of complications: gestational diabetes, hypertension, anemia, bleeding, blood clots, or problems with the placenta, for example. Up to 20% of people who know they’re pregnant miscarry. Because researchers would have been obliged to investigate any medical problem to make sure it wasn’t caused by one of the COVID-19 vaccines, including pregnant people might have meant having to hit pause on those trials, Dr. Corey said.
With death tolls from the pandemic mounting, “we had a mission to do this as quickly and as thoroughly as possible,” Dr. Corey said. Making COVID-19 vaccines available within a year “saved hundreds of thousands of lives.”
The first data on COVID-19 vaccine safety in pregnancy was published in April of 2021 when the CDC released an analysis of nearly 36,000 vaccinated pregnant people who had enrolled in a registry called V-safe, which allows users to log the dates of their vaccinations and any subsequent symptoms.
Later research showed that COVID-19 vaccines weren’t associated with increased risk of miscarriage or premature delivery.
Brenna Hughes, MD, a maternal-fetal medicine specialist and member of the American College of Obstetricians and Gynecologists’ COVID-19 expert group, agrees that adding pregnant people to large-scale COVID-19 vaccine and drug trials may have been impractical. But researchers could have launched parallel trials of pregnant women, once early studies showed the vaccines were safe in humans, she said.
“Would it have been hard? Everything with COVID is hard,” Dr. Hughes said. “But it would have been feasible.”
The FDA requires that researchers perform additional animal studies – called developmental and reproductive toxicity studies – before testing vaccines in pregnant people. Although these studies are essential, they take 5-6 months, and weren’t completed until late 2020, around the time the first COVID-19 vaccines were authorized for adults, said Emily Erbelding, MD, director of microbiology and infectious diseases at the National Institute of Allergy and Infectious Diseases, part of the NIH.
Pregnancy studies “were an afterthought,” said Irina Burd, MD, director of Johns Hopkins’ Integrated Research Center for Fetal Medicine and a professor of gynecology and obstetrics. “They should have been done sooner.”
The NIH is conducting a study of pregnant and postpartum people who decided on their own to be vaccinated, Dr. Erbelding said. The study is due to be completed by July 2023.
Janssen and Moderna are also conducting studies in pregnant people, both due to be completed in 2024.
Pfizer scientists encountered problems when they initiated a clinical trial, which would have randomly assigned pregnant people to receive either a vaccine or placebo. Once vaccines were widely available, many patients weren’t willing to take a chance on being unvaccinated until after delivery.
Pfizer has stopped recruiting patients and has not said whether it will publicly report any data from the trial.
Dr. Hughes said vaccine developers need to include pregnant people from the very beginning.
“There is this notion of protecting pregnant people from research,” Dr. Hughes said. “But we should be protecting patients through research, not from research.”
Recovering physically and emotionally
Ms. Slade still regrets being deprived of time with her children while she fought the disease.
Being on a ventilator kept her from spending those early weeks with her newborn, or from seeing her 9-year-old daughter, Zoe.
Even when Ms. Slade was finally able to see her son, she wasn’t able to tell him she loved him or sing a lullaby, or even talk at all, because of a breathing tube in her throat.
Today, Ms. Slade is a strong advocate of COVID-19 vaccinations, urging her friends and family to get their shots to avoid suffering the way she has.
Ms. Slade had to relearn to walk after being bedridden for weeks. Her many weeks on a ventilator may have contributed to her stomach paralysis, which often causes intense pain, nausea, and even vomiting when she eats or drinks. Ms. Slade weighs 50 pounds less today than before she became pregnant and has resorted to going to the emergency department when the pain is unbearable. “Most days, I’m just miserable,” she said.
Her family suffered as well. Like many babies born prematurely, Tristan, now nearly 9 months old and crawling, receives physical therapy to strengthen his muscles. At 15 pounds, Tristan is largely healthy, although his doctor said he has symptoms of asthma.
Ms. Slade said she would like to attend family counseling with Zoe, who rarely complains and tends to keep her feelings to herself. Ms. Slade said she knows her illness must have been terrifying for her little girl.
“The other day she was talking to me,” Ms. Slade said, “and she said, ‘You know, I almost had to bury you.’ ”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
Kia Slade was 7 months pregnant, unvaccinated, and fighting for breath, her oxygen levels plummeting, when her son came into the world last May.
A severe case of COVID-19 pneumonia had left Ms. Slade delirious. When the intensive care team tried to place an oxygen mask on her face, she snatched it away, she recalled. Her baby’s heart rate began to drop.
Ms. Slade’s doctor performed an emergency cesarean section at her bedside in the intensive care unit, delivering baby Tristan 10 weeks early. He weighed just 2 pounds, 14 ounces, about half the size of small full-term baby.
But Ms. Slade wouldn’t meet him until July. She was on a ventilator in a medically-induced coma for 8 weeks, and she developed a serious infection and blood clot while unconscious. It was only after a perilous 2½ months in the hospital, during which her heart stopped twice, that Ms. Slade was vaccinated against COVID-19.
“I wish I had gotten the vaccine earlier,” said Ms. Slade, 42, who remains too sick to return to work as a special education teacher in Baltimore. Doctors “kept pushing me to get vaccinated, but there just wasn’t enough information out there for me to do it.”
A year ago, there was little to no vaccine safety data for pregnant people like Ms. Slade, because they had been excluded from clinical trials run by Pfizer, Moderna, and other vaccine makers.
Lacking data, health experts were unsure and divided about how to advise expectant parents. Although U.S. health officials permitted pregnant people to be vaccinated, the World Health Organization in January 2021 actually discouraged them from doing so; it later reversed that recommendation.
The uncertainty led many women to delay vaccination, and only about two-thirds of the pregnant people who have been tracked by the Centers for Disease Control and Prevention were fully vaccinated as of Feb. 5, 2022, leaving many expectant moms at a high risk of infection and life-threatening complications.
More than 29,000 pregnant people have been hospitalized with COVID-19 and 274 have died, according to the CDC.
“There were surely women who were hospitalized because there wasn’t information available to them,” said Paul A. Offit, MD, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia.
Vaccine developers say that pregnant people – who have special health needs and risks – were excluded from clinical trials to protect them from potential side effects of novel technologies, including the Pfizer and Moderna mRNA vaccines and formulations made with cold viruses, such as the Johnson & Johnson vaccine.
But a KHN analysis also shows that pregnant people were left behind because including them in vaccine studies would have complicated and potentially delayed the delivery of COVID-19 vaccines to the broader population.
A growing number of women’s health researchers and advocates say that excluding pregnant people – and the months-long delay in recommending that they be immunized – helped fuel widespread vaccine hesitancy in this vulnerable group.
“Women and their unborn fetuses are dying of COVID infection,” said Jane Van Dis, MD, an ob.gyn. at the University of Rochester (N.Y.) Medical Center who has treated many patients like Ms. Slade. “Our failure as a society to vaccinate women in pregnancy will be remembered by the children and families who lost their mothers to this disease.”
New technology, uncertain risks
At the time COVID-19 vaccines were being developed, scientists had very little experience using mRNA vaccines in pregnant women, said Jacqueline Miller, MD, a senior vice president involved in vaccine research at Moderna.
“When you study anything in pregnant women, you have two patients, the mom and the unborn child,” Dr. Miller said. “Until we had more safety data on the platform, it wasn’t something we wanted to undertake.”
But Dr. Offit noted that vaccines have a strong record of safety in pregnancy and he sees no reason to have excluded pregnant people. None of the vaccines currently in use – including the chickenpox and rubella vaccines, which contain live viruses – have been shown to harm fetuses, he said. Doctors routinely recommend that pregnant people receive pertussis and flu vaccinations.
Dr. Offit, the coinventor of a rotavirus vaccine, said that some concerns about vaccines stem from commercial, not medical, interests. Drug makers don’t want to risk that their product will be blamed for any problems occurring in pregnant people, even if coincidental, he said.
“These companies don’t want bad news,” Dr. Offit said.
In the United States, health officials typically would have told expectant mothers not to take a vaccine that was untested during pregnancy, said Dr. Offit, a member of a committee that advises the Food and Drug Administration on vaccines.
Due to the urgency of the pandemic, health agencies instead permitted pregnant people to make up their own minds about vaccines without recommending them.
Women’s medical associations were also hampered by the lack of data. Neither the American College of Obstetricians and Gynecologists nor the Society for Maternal-Fetal Medicine actively encouraged pregnant people to be vaccinated until July 30, 2021, after the first real-world vaccine studies had been published. The CDC followed suit in August of 2021.
“If we had had this data in the beginning, we would have been able to vaccinate more women,” said Kelli Burroughs, MD, the department chair of obstetrics and gynecology at Memorial Hermann Sugar Land Hospital near Houston.
Yet anti-vaccine groups wasted no time in scaring pregnant people, flooding social media with misinformation about impaired fertility and harm to the fetus.
In the first few months after the COVID-19 vaccines were approved, some doctors were ambivalent about recommending them, and some still advise pregnant patients against vaccination.
An estimated 67% of pregnant people today are fully vaccinated, compared with about 89% of people 65 and older, another high-risk group, and 65% of Americans overall. Vaccination rates are lower among minorities, with 65% of expectant Hispanic mothers and 53% of pregnant African Americans fully vaccinated, according to the CDC.
Vaccination is especially important during pregnancy, because of increased risks of hospitalization, ICU admission, and mechanical ventilation, Dr. Burroughs said. A study released in February from the National Institutes of Health found that pregnant people with a moderate to severe COVID-19 infection also were more likely to have a C-section, deliver preterm, or develop a postpartum hemorrhage.
Black moms such as Ms. Slade were already at higher risk of maternal and infant mortality before the pandemic, because of higher underlying risks, unequal access to health care, and other factors. COVID-19 has magnified those risks, said Dr. Burroughs, who has persuaded reluctant patients by revealing that she had a healthy pregnancy and child after being vaccinated.
Ms. Slade said she has never opposed vaccines and had no hesitation about receiving other vaccines while pregnant. But she said she “just wasn’t comfortable” with COVID-19 shots.
“If there had been data out there saying the COVID shot was safe, and that nothing would happen to my baby and there was no risk of birth defects, I would have taken it,” said Ms. Slade, who has had type 2 diabetes for 12 years.
Working at warp speed
Government scientists at the NIH were concerned about the risk of COVID-19 to pregnant people from the very beginning and knew that expectant moms needed vaccines as much or more than anyone else, said Larry Corey, MD, a leader of the COVID-19 Prevention Network, which coordinated COVID-19 vaccine trials for the federal government.
But including pregnant volunteers in the larger vaccine trials could have led to interruptions and delays, Dr. Corey said. Researchers would have had to enroll thousands of pregnant volunteers to achieve statistically robust results that weren’t due to chance, he said.
Pregnancy can bring on a wide range of complications: gestational diabetes, hypertension, anemia, bleeding, blood clots, or problems with the placenta, for example. Up to 20% of people who know they’re pregnant miscarry. Because researchers would have been obliged to investigate any medical problem to make sure it wasn’t caused by one of the COVID-19 vaccines, including pregnant people might have meant having to hit pause on those trials, Dr. Corey said.
With death tolls from the pandemic mounting, “we had a mission to do this as quickly and as thoroughly as possible,” Dr. Corey said. Making COVID-19 vaccines available within a year “saved hundreds of thousands of lives.”
The first data on COVID-19 vaccine safety in pregnancy was published in April of 2021 when the CDC released an analysis of nearly 36,000 vaccinated pregnant people who had enrolled in a registry called V-safe, which allows users to log the dates of their vaccinations and any subsequent symptoms.
Later research showed that COVID-19 vaccines weren’t associated with increased risk of miscarriage or premature delivery.
Brenna Hughes, MD, a maternal-fetal medicine specialist and member of the American College of Obstetricians and Gynecologists’ COVID-19 expert group, agrees that adding pregnant people to large-scale COVID-19 vaccine and drug trials may have been impractical. But researchers could have launched parallel trials of pregnant women, once early studies showed the vaccines were safe in humans, she said.
“Would it have been hard? Everything with COVID is hard,” Dr. Hughes said. “But it would have been feasible.”
The FDA requires that researchers perform additional animal studies – called developmental and reproductive toxicity studies – before testing vaccines in pregnant people. Although these studies are essential, they take 5-6 months, and weren’t completed until late 2020, around the time the first COVID-19 vaccines were authorized for adults, said Emily Erbelding, MD, director of microbiology and infectious diseases at the National Institute of Allergy and Infectious Diseases, part of the NIH.
Pregnancy studies “were an afterthought,” said Irina Burd, MD, director of Johns Hopkins’ Integrated Research Center for Fetal Medicine and a professor of gynecology and obstetrics. “They should have been done sooner.”
The NIH is conducting a study of pregnant and postpartum people who decided on their own to be vaccinated, Dr. Erbelding said. The study is due to be completed by July 2023.
Janssen and Moderna are also conducting studies in pregnant people, both due to be completed in 2024.
Pfizer scientists encountered problems when they initiated a clinical trial, which would have randomly assigned pregnant people to receive either a vaccine or placebo. Once vaccines were widely available, many patients weren’t willing to take a chance on being unvaccinated until after delivery.
Pfizer has stopped recruiting patients and has not said whether it will publicly report any data from the trial.
Dr. Hughes said vaccine developers need to include pregnant people from the very beginning.
“There is this notion of protecting pregnant people from research,” Dr. Hughes said. “But we should be protecting patients through research, not from research.”
Recovering physically and emotionally
Ms. Slade still regrets being deprived of time with her children while she fought the disease.
Being on a ventilator kept her from spending those early weeks with her newborn, or from seeing her 9-year-old daughter, Zoe.
Even when Ms. Slade was finally able to see her son, she wasn’t able to tell him she loved him or sing a lullaby, or even talk at all, because of a breathing tube in her throat.
Today, Ms. Slade is a strong advocate of COVID-19 vaccinations, urging her friends and family to get their shots to avoid suffering the way she has.
Ms. Slade had to relearn to walk after being bedridden for weeks. Her many weeks on a ventilator may have contributed to her stomach paralysis, which often causes intense pain, nausea, and even vomiting when she eats or drinks. Ms. Slade weighs 50 pounds less today than before she became pregnant and has resorted to going to the emergency department when the pain is unbearable. “Most days, I’m just miserable,” she said.
Her family suffered as well. Like many babies born prematurely, Tristan, now nearly 9 months old and crawling, receives physical therapy to strengthen his muscles. At 15 pounds, Tristan is largely healthy, although his doctor said he has symptoms of asthma.
Ms. Slade said she would like to attend family counseling with Zoe, who rarely complains and tends to keep her feelings to herself. Ms. Slade said she knows her illness must have been terrifying for her little girl.
“The other day she was talking to me,” Ms. Slade said, “and she said, ‘You know, I almost had to bury you.’ ”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
Most Americans unaware alcohol can cause cancer
The majority of Americans are not aware that alcohol consumption causes a variety of cancers and especially do not consider wine and beer to have a link with cancer, suggest the results from a national survey.
write lead author Andrew Seidenberg, PhD, MPH, National Cancer Institute, Rockville, Md., and colleagues.
“Increasing awareness of the alcohol-cancer link, such as through multimedia campaigns and patient-provider communication, may be an important new strategy for health advocates working to implement preventive alcohol policies,” they add.
The findings were published in the February issue of the American Journal of Preventive Medicine.
“This is the first study to examine the relationship between alcohol control policy support and awareness of the alcohol-cancer link among a national U.S. sample,” the authors write.
The results show that there is some public support for the idea of adding written warnings about the alcohol-cancer risk to alcoholic beverages, which is something that a number of cancer organizations have been petitioning for.
A petition filed by the American Society of Clinical Oncology, the American Institute for Cancer Research, and Breast Cancer Prevention Partners, all in collaboration with several public health organizations, proposes labeling that would read: “WARNING: According to the Surgeon General, consumption of alcoholic beverages can cause cancer, including breast and colon cancers.”
Such labeling has “the potential to save lives by ensuring that consumers have a more accurate understanding of the link between alcohol and cancer, which will empower them to better protect their health,” the groups said in the petition.
Public support
The findings come from an analysis of the 2020 Health Information National Trends Survey 5 Cycle 4. A total of 3,865 adults participated in the survey, approximately half of whom were nondrinkers.
As well as investigating how aware people were of the alcohol-cancer link, the investigators looked at how prevalent public support might be for the following three communication-focused alcohol policies:
- Banning outdoor alcohol-related advertising
- Requiring health warnings on alcohol beverage containers
- Requiring recommended drinking guidelines on alcoholic beverage containers
“Awareness of the alcohol-cancer link was measured separately for wine, beer, and liquor by asking: In your opinion, how much does drinking the following types of alcohol affect the risk of getting cancer?” the authors explain.
“Awareness of the alcohol-cancer link was low,” the investigators comment; only about one-third (31.8%) of participants were aware that alcohol increases the risk of cancer. The figures were even lower for individual beverage type, at 20.3% for wine, 24.9% for beer, and 31.2% for liquor. Furthermore, approximately half of participants responded with “don’t know” to the three awareness items, investigators noted.
On the other hand, more than half of the Americans surveyed supported adding both health warning labels (65.1%) and information on recommended drinking guidelines (63.9%) to alcoholic beverage containers. Support was lower (34.4% of respondents) for banning outdoor alcohol advertising.
Among Americans who were aware that alcohol increased cancer risk, support was also higher for all three policies.
For example, about 75% of respondents who were aware that alcohol increases cancer risk supported adding health warnings and drinking guidelines to beverage containers, compared with about half of Americans who felt that alcohol consumption had either no effect on or decreased cancer risk.
Even among those who were aware of the alcohol-cancer link, public support for outdoor advertising was not high (37.8%), but it was even lower (23.6%) among respondents who felt alcohol had no effect on or decreased the risk of cancer.
“Policy support was highest among nondrinkers, followed by drinkers, and was lowest among heavier drinkers,” the authors report.
For example, almost 43% of nondrinkers supported restrictions on outdoor alcohol advertising, compared with only about 28.6% of drinkers and 22% of heavier drinkers. More respondents supported adding health warning labels on alcoholic beverages – 70% of nondrinkers, 65% of drinkers, and 57% of heavier drinkers, investigators observe.
The study had no specific funding. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The majority of Americans are not aware that alcohol consumption causes a variety of cancers and especially do not consider wine and beer to have a link with cancer, suggest the results from a national survey.
write lead author Andrew Seidenberg, PhD, MPH, National Cancer Institute, Rockville, Md., and colleagues.
“Increasing awareness of the alcohol-cancer link, such as through multimedia campaigns and patient-provider communication, may be an important new strategy for health advocates working to implement preventive alcohol policies,” they add.
The findings were published in the February issue of the American Journal of Preventive Medicine.
“This is the first study to examine the relationship between alcohol control policy support and awareness of the alcohol-cancer link among a national U.S. sample,” the authors write.
The results show that there is some public support for the idea of adding written warnings about the alcohol-cancer risk to alcoholic beverages, which is something that a number of cancer organizations have been petitioning for.
A petition filed by the American Society of Clinical Oncology, the American Institute for Cancer Research, and Breast Cancer Prevention Partners, all in collaboration with several public health organizations, proposes labeling that would read: “WARNING: According to the Surgeon General, consumption of alcoholic beverages can cause cancer, including breast and colon cancers.”
Such labeling has “the potential to save lives by ensuring that consumers have a more accurate understanding of the link between alcohol and cancer, which will empower them to better protect their health,” the groups said in the petition.
Public support
The findings come from an analysis of the 2020 Health Information National Trends Survey 5 Cycle 4. A total of 3,865 adults participated in the survey, approximately half of whom were nondrinkers.
As well as investigating how aware people were of the alcohol-cancer link, the investigators looked at how prevalent public support might be for the following three communication-focused alcohol policies:
- Banning outdoor alcohol-related advertising
- Requiring health warnings on alcohol beverage containers
- Requiring recommended drinking guidelines on alcoholic beverage containers
“Awareness of the alcohol-cancer link was measured separately for wine, beer, and liquor by asking: In your opinion, how much does drinking the following types of alcohol affect the risk of getting cancer?” the authors explain.
“Awareness of the alcohol-cancer link was low,” the investigators comment; only about one-third (31.8%) of participants were aware that alcohol increases the risk of cancer. The figures were even lower for individual beverage type, at 20.3% for wine, 24.9% for beer, and 31.2% for liquor. Furthermore, approximately half of participants responded with “don’t know” to the three awareness items, investigators noted.
On the other hand, more than half of the Americans surveyed supported adding both health warning labels (65.1%) and information on recommended drinking guidelines (63.9%) to alcoholic beverage containers. Support was lower (34.4% of respondents) for banning outdoor alcohol advertising.
Among Americans who were aware that alcohol increased cancer risk, support was also higher for all three policies.
For example, about 75% of respondents who were aware that alcohol increases cancer risk supported adding health warnings and drinking guidelines to beverage containers, compared with about half of Americans who felt that alcohol consumption had either no effect on or decreased cancer risk.
Even among those who were aware of the alcohol-cancer link, public support for outdoor advertising was not high (37.8%), but it was even lower (23.6%) among respondents who felt alcohol had no effect on or decreased the risk of cancer.
“Policy support was highest among nondrinkers, followed by drinkers, and was lowest among heavier drinkers,” the authors report.
For example, almost 43% of nondrinkers supported restrictions on outdoor alcohol advertising, compared with only about 28.6% of drinkers and 22% of heavier drinkers. More respondents supported adding health warning labels on alcoholic beverages – 70% of nondrinkers, 65% of drinkers, and 57% of heavier drinkers, investigators observe.
The study had no specific funding. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The majority of Americans are not aware that alcohol consumption causes a variety of cancers and especially do not consider wine and beer to have a link with cancer, suggest the results from a national survey.
write lead author Andrew Seidenberg, PhD, MPH, National Cancer Institute, Rockville, Md., and colleagues.
“Increasing awareness of the alcohol-cancer link, such as through multimedia campaigns and patient-provider communication, may be an important new strategy for health advocates working to implement preventive alcohol policies,” they add.
The findings were published in the February issue of the American Journal of Preventive Medicine.
“This is the first study to examine the relationship between alcohol control policy support and awareness of the alcohol-cancer link among a national U.S. sample,” the authors write.
The results show that there is some public support for the idea of adding written warnings about the alcohol-cancer risk to alcoholic beverages, which is something that a number of cancer organizations have been petitioning for.
A petition filed by the American Society of Clinical Oncology, the American Institute for Cancer Research, and Breast Cancer Prevention Partners, all in collaboration with several public health organizations, proposes labeling that would read: “WARNING: According to the Surgeon General, consumption of alcoholic beverages can cause cancer, including breast and colon cancers.”
Such labeling has “the potential to save lives by ensuring that consumers have a more accurate understanding of the link between alcohol and cancer, which will empower them to better protect their health,” the groups said in the petition.
Public support
The findings come from an analysis of the 2020 Health Information National Trends Survey 5 Cycle 4. A total of 3,865 adults participated in the survey, approximately half of whom were nondrinkers.
As well as investigating how aware people were of the alcohol-cancer link, the investigators looked at how prevalent public support might be for the following three communication-focused alcohol policies:
- Banning outdoor alcohol-related advertising
- Requiring health warnings on alcohol beverage containers
- Requiring recommended drinking guidelines on alcoholic beverage containers
“Awareness of the alcohol-cancer link was measured separately for wine, beer, and liquor by asking: In your opinion, how much does drinking the following types of alcohol affect the risk of getting cancer?” the authors explain.
“Awareness of the alcohol-cancer link was low,” the investigators comment; only about one-third (31.8%) of participants were aware that alcohol increases the risk of cancer. The figures were even lower for individual beverage type, at 20.3% for wine, 24.9% for beer, and 31.2% for liquor. Furthermore, approximately half of participants responded with “don’t know” to the three awareness items, investigators noted.
On the other hand, more than half of the Americans surveyed supported adding both health warning labels (65.1%) and information on recommended drinking guidelines (63.9%) to alcoholic beverage containers. Support was lower (34.4% of respondents) for banning outdoor alcohol advertising.
Among Americans who were aware that alcohol increased cancer risk, support was also higher for all three policies.
For example, about 75% of respondents who were aware that alcohol increases cancer risk supported adding health warnings and drinking guidelines to beverage containers, compared with about half of Americans who felt that alcohol consumption had either no effect on or decreased cancer risk.
Even among those who were aware of the alcohol-cancer link, public support for outdoor advertising was not high (37.8%), but it was even lower (23.6%) among respondents who felt alcohol had no effect on or decreased the risk of cancer.
“Policy support was highest among nondrinkers, followed by drinkers, and was lowest among heavier drinkers,” the authors report.
For example, almost 43% of nondrinkers supported restrictions on outdoor alcohol advertising, compared with only about 28.6% of drinkers and 22% of heavier drinkers. More respondents supported adding health warning labels on alcoholic beverages – 70% of nondrinkers, 65% of drinkers, and 57% of heavier drinkers, investigators observe.
The study had no specific funding. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE AMERICAN JOURNAL OF PREVENTIVE MEDICINE
Perinatal deaths from COVID show ‘extensive’ placental damage
Recent evidence has shown that women who contract COVID-19 during pregnancy are at increased risk for pregnancy loss and neonatal death. Now, an analysis of pathology data from dozens of perinatal deaths shows how.
Unlike numerous pathogens that kill the fetus by infecting it directly, SARS-CoV-2 causes “widespread and severe” destruction of the placenta that deprives the fetus of oxygen, a team of 44 researchers in 12 countries concluded after examining 64 stillbirths and four neonatal deaths in which the placentas were infected with the virus. They noted that such damage occurs in a small percentage of pregnant women with COVID and that all the women in the study had not been vaccinated against the disease.
The findings were published online Feb. 10 in the Archives of Pathology & Laboratory Medicine.
Nearly all placentas had each of three features that pathologists have dubbed SARS-CoV-2 placentitis: large deposits of fibrin, a clotting protein that obstructs the flow of blood, death of cells in the trophoblast, and an unusual form of inflammation called chronic histiocytic intervillositis. Some had other abnormalities that could have exacerbated the condition.
The researchers called the extent of damage “striking,” affecting 77.7% of the placenta on average. The virus did not appear to harm fetal tissue, but placental damage “was extensive and highly destructive,” they write. Notably, none of the women in the analysis were known to have severe COVID.
Virus seen ‘chewing up the placenta’
David Schwartz, MD, a pathologist in Atlanta, and the lead author of the study, said COVID appears to be unique in destroying the placenta.
“I don’t know of any infection that does that to this degree or with this uniformity,” Dr. Schwartz told this news organization. “The simple message is that this infection is chewing up the placenta and destroying its capability to oxygenate the fetus.”
In November, the Centers for Disease Control and Prevention reported that maternal COVID increases the risk of losing a pregnancy. From March 2020 to September 2021, 8,154 stillbirths were reported, affecting 0.65% of births by women without COVID and 1.26% of births by women with COVID, for a relative risk of 1.90 (95% confidence interval, 1.69-2.15).
Delta, the variant that dominated in mid-2021, appears to have been particularly harmful. The CDC reported that the relative risk for stillbirth for mothers with COVID-19 during that period increased to 4.04 (95% CI, 3.28-4.97). Many cases in the new analysis coincided with Delta.
Dr. Schwartz and his colleagues said immunization, along with antiviral therapy, might reduce the chance of SARS-CoV-2 infecting the placenta. None of the mothers in the analysis was vaccinated, and Dr. Schwartz said he is not aware of a single case in a vaccinated woman.
The analysis comes on the heels of a study from the National Institutes of Health linking severe to moderate COVID infection to greater risk of other pregnancy complications: cesarean and preterm delivery, death during childbirth, postpartum hemorrhaging, and non-COVID infections.
Diana Bianchi, MD, director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, said those findings underscore the need for pregnant women to be vaccinated. (The shots have been shown to be safe for pregnant women.)
Denise Jamieson, MD, MPH, chair of the department of gynecology and obstetrics at Emory University, Atlanta, who was not involved in the new analysis, said the findings may have important clinical implications. In addition to ensuring that pregnant patients are fully vaccinated, she said “there may be opportunities to more closely monitor the placenta during pregnancy using imaging modalities such as ultrasound.”
Even in the presence of severe abnormalities, a fetus that has reached a viable gestational age could potentially be delivered prior to stillbirth, Dr. Jamieson said. The 64 stillbirths in the analysis ranged from 15 to 39.2 weeks of gestation, with an average of 30 weeks. Eight were delivered at full term.
However, additional studies are needed to support monitoring of placental changes, she said: “It is not ready for prime time now.”
Christopher Zahn, MD, vice president of practice activities the American College of Obstetricians and Gynecologists, cautioned that data on COVID and pregnancy complications remain limited.
The findings in this analysis “do not prove the association between COVID-19 infection and neonatal outcomes,” Dr. Zahn said. “While stillbirth could potentially be another adverse outcome for pregnant people who contract COVID-19, currently we don’t have enough data to confirm that a COVID-19 infection at any point in pregnancy indicates increased risk of stillbirth.”
He added that ACOG continues to strongly recommend vaccination against COVID for women who are pregnant, recently pregnant, or planning to be pregnant.
Dr. Schwartz and Dr. Jamieson have disclosed no relevant financial relationships. One author reported receiving financial support from the Slovak Research and Development Agency. Another reported funding from the Belgian Fund for Scientific Research and the Fetus for Life charity.
A version of this article first appeared on Medscape.com.
Recent evidence has shown that women who contract COVID-19 during pregnancy are at increased risk for pregnancy loss and neonatal death. Now, an analysis of pathology data from dozens of perinatal deaths shows how.
Unlike numerous pathogens that kill the fetus by infecting it directly, SARS-CoV-2 causes “widespread and severe” destruction of the placenta that deprives the fetus of oxygen, a team of 44 researchers in 12 countries concluded after examining 64 stillbirths and four neonatal deaths in which the placentas were infected with the virus. They noted that such damage occurs in a small percentage of pregnant women with COVID and that all the women in the study had not been vaccinated against the disease.
The findings were published online Feb. 10 in the Archives of Pathology & Laboratory Medicine.
Nearly all placentas had each of three features that pathologists have dubbed SARS-CoV-2 placentitis: large deposits of fibrin, a clotting protein that obstructs the flow of blood, death of cells in the trophoblast, and an unusual form of inflammation called chronic histiocytic intervillositis. Some had other abnormalities that could have exacerbated the condition.
The researchers called the extent of damage “striking,” affecting 77.7% of the placenta on average. The virus did not appear to harm fetal tissue, but placental damage “was extensive and highly destructive,” they write. Notably, none of the women in the analysis were known to have severe COVID.
Virus seen ‘chewing up the placenta’
David Schwartz, MD, a pathologist in Atlanta, and the lead author of the study, said COVID appears to be unique in destroying the placenta.
“I don’t know of any infection that does that to this degree or with this uniformity,” Dr. Schwartz told this news organization. “The simple message is that this infection is chewing up the placenta and destroying its capability to oxygenate the fetus.”
In November, the Centers for Disease Control and Prevention reported that maternal COVID increases the risk of losing a pregnancy. From March 2020 to September 2021, 8,154 stillbirths were reported, affecting 0.65% of births by women without COVID and 1.26% of births by women with COVID, for a relative risk of 1.90 (95% confidence interval, 1.69-2.15).
Delta, the variant that dominated in mid-2021, appears to have been particularly harmful. The CDC reported that the relative risk for stillbirth for mothers with COVID-19 during that period increased to 4.04 (95% CI, 3.28-4.97). Many cases in the new analysis coincided with Delta.
Dr. Schwartz and his colleagues said immunization, along with antiviral therapy, might reduce the chance of SARS-CoV-2 infecting the placenta. None of the mothers in the analysis was vaccinated, and Dr. Schwartz said he is not aware of a single case in a vaccinated woman.
The analysis comes on the heels of a study from the National Institutes of Health linking severe to moderate COVID infection to greater risk of other pregnancy complications: cesarean and preterm delivery, death during childbirth, postpartum hemorrhaging, and non-COVID infections.
Diana Bianchi, MD, director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, said those findings underscore the need for pregnant women to be vaccinated. (The shots have been shown to be safe for pregnant women.)
Denise Jamieson, MD, MPH, chair of the department of gynecology and obstetrics at Emory University, Atlanta, who was not involved in the new analysis, said the findings may have important clinical implications. In addition to ensuring that pregnant patients are fully vaccinated, she said “there may be opportunities to more closely monitor the placenta during pregnancy using imaging modalities such as ultrasound.”
Even in the presence of severe abnormalities, a fetus that has reached a viable gestational age could potentially be delivered prior to stillbirth, Dr. Jamieson said. The 64 stillbirths in the analysis ranged from 15 to 39.2 weeks of gestation, with an average of 30 weeks. Eight were delivered at full term.
However, additional studies are needed to support monitoring of placental changes, she said: “It is not ready for prime time now.”
Christopher Zahn, MD, vice president of practice activities the American College of Obstetricians and Gynecologists, cautioned that data on COVID and pregnancy complications remain limited.
The findings in this analysis “do not prove the association between COVID-19 infection and neonatal outcomes,” Dr. Zahn said. “While stillbirth could potentially be another adverse outcome for pregnant people who contract COVID-19, currently we don’t have enough data to confirm that a COVID-19 infection at any point in pregnancy indicates increased risk of stillbirth.”
He added that ACOG continues to strongly recommend vaccination against COVID for women who are pregnant, recently pregnant, or planning to be pregnant.
Dr. Schwartz and Dr. Jamieson have disclosed no relevant financial relationships. One author reported receiving financial support from the Slovak Research and Development Agency. Another reported funding from the Belgian Fund for Scientific Research and the Fetus for Life charity.
A version of this article first appeared on Medscape.com.
Recent evidence has shown that women who contract COVID-19 during pregnancy are at increased risk for pregnancy loss and neonatal death. Now, an analysis of pathology data from dozens of perinatal deaths shows how.
Unlike numerous pathogens that kill the fetus by infecting it directly, SARS-CoV-2 causes “widespread and severe” destruction of the placenta that deprives the fetus of oxygen, a team of 44 researchers in 12 countries concluded after examining 64 stillbirths and four neonatal deaths in which the placentas were infected with the virus. They noted that such damage occurs in a small percentage of pregnant women with COVID and that all the women in the study had not been vaccinated against the disease.
The findings were published online Feb. 10 in the Archives of Pathology & Laboratory Medicine.
Nearly all placentas had each of three features that pathologists have dubbed SARS-CoV-2 placentitis: large deposits of fibrin, a clotting protein that obstructs the flow of blood, death of cells in the trophoblast, and an unusual form of inflammation called chronic histiocytic intervillositis. Some had other abnormalities that could have exacerbated the condition.
The researchers called the extent of damage “striking,” affecting 77.7% of the placenta on average. The virus did not appear to harm fetal tissue, but placental damage “was extensive and highly destructive,” they write. Notably, none of the women in the analysis were known to have severe COVID.
Virus seen ‘chewing up the placenta’
David Schwartz, MD, a pathologist in Atlanta, and the lead author of the study, said COVID appears to be unique in destroying the placenta.
“I don’t know of any infection that does that to this degree or with this uniformity,” Dr. Schwartz told this news organization. “The simple message is that this infection is chewing up the placenta and destroying its capability to oxygenate the fetus.”
In November, the Centers for Disease Control and Prevention reported that maternal COVID increases the risk of losing a pregnancy. From March 2020 to September 2021, 8,154 stillbirths were reported, affecting 0.65% of births by women without COVID and 1.26% of births by women with COVID, for a relative risk of 1.90 (95% confidence interval, 1.69-2.15).
Delta, the variant that dominated in mid-2021, appears to have been particularly harmful. The CDC reported that the relative risk for stillbirth for mothers with COVID-19 during that period increased to 4.04 (95% CI, 3.28-4.97). Many cases in the new analysis coincided with Delta.
Dr. Schwartz and his colleagues said immunization, along with antiviral therapy, might reduce the chance of SARS-CoV-2 infecting the placenta. None of the mothers in the analysis was vaccinated, and Dr. Schwartz said he is not aware of a single case in a vaccinated woman.
The analysis comes on the heels of a study from the National Institutes of Health linking severe to moderate COVID infection to greater risk of other pregnancy complications: cesarean and preterm delivery, death during childbirth, postpartum hemorrhaging, and non-COVID infections.
Diana Bianchi, MD, director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, said those findings underscore the need for pregnant women to be vaccinated. (The shots have been shown to be safe for pregnant women.)
Denise Jamieson, MD, MPH, chair of the department of gynecology and obstetrics at Emory University, Atlanta, who was not involved in the new analysis, said the findings may have important clinical implications. In addition to ensuring that pregnant patients are fully vaccinated, she said “there may be opportunities to more closely monitor the placenta during pregnancy using imaging modalities such as ultrasound.”
Even in the presence of severe abnormalities, a fetus that has reached a viable gestational age could potentially be delivered prior to stillbirth, Dr. Jamieson said. The 64 stillbirths in the analysis ranged from 15 to 39.2 weeks of gestation, with an average of 30 weeks. Eight were delivered at full term.
However, additional studies are needed to support monitoring of placental changes, she said: “It is not ready for prime time now.”
Christopher Zahn, MD, vice president of practice activities the American College of Obstetricians and Gynecologists, cautioned that data on COVID and pregnancy complications remain limited.
The findings in this analysis “do not prove the association between COVID-19 infection and neonatal outcomes,” Dr. Zahn said. “While stillbirth could potentially be another adverse outcome for pregnant people who contract COVID-19, currently we don’t have enough data to confirm that a COVID-19 infection at any point in pregnancy indicates increased risk of stillbirth.”
He added that ACOG continues to strongly recommend vaccination against COVID for women who are pregnant, recently pregnant, or planning to be pregnant.
Dr. Schwartz and Dr. Jamieson have disclosed no relevant financial relationships. One author reported receiving financial support from the Slovak Research and Development Agency. Another reported funding from the Belgian Fund for Scientific Research and the Fetus for Life charity.
A version of this article first appeared on Medscape.com.