MDedge Endocrinology

A Food and Drug Administration advisory panel has endorsed a pancreatic islet cell transplant therapy for the treatment of people with type 1 diabetes that can’t be managed with current therapies.

On April 15, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted 12 to 4 in favor of approval of donislecel (Lantidra). There was one abstention. The panel regarded the drug as having “an overall favorable benefit-risk profile for some patients with type 1 diabetes.” The product consists of purified allogeneic pancreatic islets of Langerhans derived from cadaveric donors and is infused into the portal vein of the liver.

Benefits of the treatment include the potential for insulin independence and elimination of severe hypoglycemia. Risks are those associated with the surgical procedure and with long-term immunosuppression.

The therapy is manufactured by CellTrans. According to Jose Oberholzer, MD, the founder of CellTrans, the proposed indication is for adults with “brittle” type 1 diabetes who meet the American Diabetes Association’s (ADA) criteria for whole-organ pancreas-alone transplant (i.e., transplant of pancreas but not kidney).

The ADA criteria include the following: frequent, severe hypoglycemia, hyperglycemia, and/or ketoacidosis that requires medical attention; clinical or emotional problems regarding the use of exogenous insulin; and consistent failure of insulin-based management to prevent acute diabetes complications.
 

Success in two-thirds of patients in small studies

Dr. Oberholzer presented data from two single-arm open-label studies: a phase 1/2 trial initiated in 2004 with 10 patients, and a phase 3 study with 20 patients that began in 2007. The inclusion criteria differed somewhat between the two studies, but all 30 patients had hypoglycemic unawareness. Mean follow-up was 7.8 years for the phase 1/2 trial and 4.7 years for the phase 3 trial.

For all of the patients, C-peptide levels were positive after transplant. The composite endpoint for success – an A1c level of ≤ 6.5% and the absence of severe hypoglycemic episodes for 1 year – was met by 19 patients (63.3%). For five patients (16.7%), the target A1c level was not achieved, and seven patients (23.3%) experienced a severe episode of hypoglycemia.

Twenty of the 30 patients achieved insulin independence for at least 1 year.

Improvements were also seen at 1 year in mixed meal test outcomes, fasting blood glucose levels, and overall glycemic control. Graft survival 10 years post transplant was achieved by 60% of patients, Dr. Oberholzer said.
 

Adverse events not unexpected, but still of concern

Two patients died, one as a result of fulminant sepsis at 20 months post transplant, and the other as a result of severe dementia 9 years post transplant. Three patients experienced four serious procedure-related events, including one liver laceration and two hepatic hematomas. Elevations in portal pressure occurred in two patients.

Most adverse events were associated with immunosuppression. These included 178 infections in 26 of the 30 patients. The most common of these were herpes virus infections, Epstein-Barr virus infections, oral candidiasis, and cytomegalovirus infections. Twelve infections were severe. Renal function declined persistently in two patients (20%), and six (20%) experienced new-onset proteinuria at 1 year.

The adverse events related to the procedure and the problems associated with immunosuppression were not unexpected and were consistent with those described for patients receiving whole pancreas transplants, FDA reviewer Patricia Beaston, MD, said in her review of the CellTrans data.
 

Panel members support treatment for a small group of patients

During the discussion, several panel members pointed out that the target patient population for this treatment will likely be smaller today than it was when the two studies were initiated, given advances in diabetes care. Those advances include continuous glucose monitoring devices with alarms and closed-loop insulin delivery systems – the “artificial pancreas” that automatically suspends insulin delivery to prevent hypoglycemia.

Panel chair Lisa Butterfield, PhD, a surgeon and immunologist at the University of California, San Francisco, voted in favor of approval. But, she added, “I do support postapproval gathering of data to learn more about the product. ... I don’t know how many patients will really benefit, but I think it’s to be determined.”

Christopher K. Breuer, MD, a general and pediatric surgeon at the Center for Regenerative Medicine, Nationwide Children’s Hospital, Columbus, Ohio, said he supported approval for “two very small subpopulations where it would provide the only viable therapy”: those who are eligible for pancreas transplant but cannot tolerate a major operation, and those who already use the latest automated insulin delivery systems and still do not achieve acceptable glycemic control.

Temporary voting member David Harlan, MD, director of the University of Massachusetts Diabetes Center of Excellence, Worcester, Mass., voted no.

He noted that only about 100 whole pancreas-only transplants are performed annually in the United States and that such transplants are “very effective, so we’re talking about patients who aren’t pancreas transplant candidates who might get this.”

Moreover, Dr. Harlan said, “I’ve seen the awful things that can happen in posttransplant recipients. It’s really hard to get that informed consent from someone when you’re asking them to consider a future that they don’t know. When it works, it’s great. When it doesn’t work, it can be catastrophic. I just worry about opening Pandora’s box.”

The only other diabetes specialist on the panel, temporary voting member Ellen Leschek, MD, said she “reluctantly voted yes because a few people could benefit, but I think it’s a much smaller number than the company may believe.”

Dr. Leschek, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., said she’s concerned that “if it’s approved, too many people will get treated this way, when in fact, for a lot of those people, the risks will outweigh the benefits.”

Sandy Feng, MD, PhD, of the department of surgery at the University of California, San Francisco, pointed out that with regard to immunosuppressive therapy, “We’re concerned about the toxicity of what we currently use, but there are additional therapies being developed that might mitigate those toxicities that would be beneficial to this population.”

Dr. Feng, who voted yes, also said, “I do pancreas transplants. I can tell you that there is nothing that [patients with type 1 diabetes] like more than the freedom from dealing with the entire insulin issue. That has made a large impression on me over the last 20-plus years of clinical practice, so I do think this can help some people and will be incredibly meaningful to those people.”

FDA advisory panel members are vetted for conflicts of interest, and special waivers are granted if necessary. No such waivers were granted for this meeting.

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

A Food and Drug Administration advisory panel has endorsed a pancreatic islet cell transplant therapy for the treatment of people with type 1 diabetes that can’t be managed with current therapies.

On April 15, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted 12 to 4 in favor of approval of donislecel (Lantidra). There was one abstention. The panel regarded the drug as having “an overall favorable benefit-risk profile for some patients with type 1 diabetes.” The product consists of purified allogeneic pancreatic islets of Langerhans derived from cadaveric donors and is infused into the portal vein of the liver.

Benefits of the treatment include the potential for insulin independence and elimination of severe hypoglycemia. Risks are those associated with the surgical procedure and with long-term immunosuppression.

The therapy is manufactured by CellTrans. According to Jose Oberholzer, MD, the founder of CellTrans, the proposed indication is for adults with “brittle” type 1 diabetes who meet the American Diabetes Association’s (ADA) criteria for whole-organ pancreas-alone transplant (i.e., transplant of pancreas but not kidney).

The ADA criteria include the following: frequent, severe hypoglycemia, hyperglycemia, and/or ketoacidosis that requires medical attention; clinical or emotional problems regarding the use of exogenous insulin; and consistent failure of insulin-based management to prevent acute diabetes complications.
 

Success in two-thirds of patients in small studies

Dr. Oberholzer presented data from two single-arm open-label studies: a phase 1/2 trial initiated in 2004 with 10 patients, and a phase 3 study with 20 patients that began in 2007. The inclusion criteria differed somewhat between the two studies, but all 30 patients had hypoglycemic unawareness. Mean follow-up was 7.8 years for the phase 1/2 trial and 4.7 years for the phase 3 trial.

For all of the patients, C-peptide levels were positive after transplant. The composite endpoint for success – an A1c level of ≤ 6.5% and the absence of severe hypoglycemic episodes for 1 year – was met by 19 patients (63.3%). For five patients (16.7%), the target A1c level was not achieved, and seven patients (23.3%) experienced a severe episode of hypoglycemia.

Twenty of the 30 patients achieved insulin independence for at least 1 year.

Improvements were also seen at 1 year in mixed meal test outcomes, fasting blood glucose levels, and overall glycemic control. Graft survival 10 years post transplant was achieved by 60% of patients, Dr. Oberholzer said.
 

Adverse events not unexpected, but still of concern

Two patients died, one as a result of fulminant sepsis at 20 months post transplant, and the other as a result of severe dementia 9 years post transplant. Three patients experienced four serious procedure-related events, including one liver laceration and two hepatic hematomas. Elevations in portal pressure occurred in two patients.

Most adverse events were associated with immunosuppression. These included 178 infections in 26 of the 30 patients. The most common of these were herpes virus infections, Epstein-Barr virus infections, oral candidiasis, and cytomegalovirus infections. Twelve infections were severe. Renal function declined persistently in two patients (20%), and six (20%) experienced new-onset proteinuria at 1 year.

The adverse events related to the procedure and the problems associated with immunosuppression were not unexpected and were consistent with those described for patients receiving whole pancreas transplants, FDA reviewer Patricia Beaston, MD, said in her review of the CellTrans data.
 

Panel members support treatment for a small group of patients

During the discussion, several panel members pointed out that the target patient population for this treatment will likely be smaller today than it was when the two studies were initiated, given advances in diabetes care. Those advances include continuous glucose monitoring devices with alarms and closed-loop insulin delivery systems – the “artificial pancreas” that automatically suspends insulin delivery to prevent hypoglycemia.

Panel chair Lisa Butterfield, PhD, a surgeon and immunologist at the University of California, San Francisco, voted in favor of approval. But, she added, “I do support postapproval gathering of data to learn more about the product. ... I don’t know how many patients will really benefit, but I think it’s to be determined.”

Christopher K. Breuer, MD, a general and pediatric surgeon at the Center for Regenerative Medicine, Nationwide Children’s Hospital, Columbus, Ohio, said he supported approval for “two very small subpopulations where it would provide the only viable therapy”: those who are eligible for pancreas transplant but cannot tolerate a major operation, and those who already use the latest automated insulin delivery systems and still do not achieve acceptable glycemic control.

Temporary voting member David Harlan, MD, director of the University of Massachusetts Diabetes Center of Excellence, Worcester, Mass., voted no.

He noted that only about 100 whole pancreas-only transplants are performed annually in the United States and that such transplants are “very effective, so we’re talking about patients who aren’t pancreas transplant candidates who might get this.”

Moreover, Dr. Harlan said, “I’ve seen the awful things that can happen in posttransplant recipients. It’s really hard to get that informed consent from someone when you’re asking them to consider a future that they don’t know. When it works, it’s great. When it doesn’t work, it can be catastrophic. I just worry about opening Pandora’s box.”

The only other diabetes specialist on the panel, temporary voting member Ellen Leschek, MD, said she “reluctantly voted yes because a few people could benefit, but I think it’s a much smaller number than the company may believe.”

Dr. Leschek, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., said she’s concerned that “if it’s approved, too many people will get treated this way, when in fact, for a lot of those people, the risks will outweigh the benefits.”

Sandy Feng, MD, PhD, of the department of surgery at the University of California, San Francisco, pointed out that with regard to immunosuppressive therapy, “We’re concerned about the toxicity of what we currently use, but there are additional therapies being developed that might mitigate those toxicities that would be beneficial to this population.”

Dr. Feng, who voted yes, also said, “I do pancreas transplants. I can tell you that there is nothing that [patients with type 1 diabetes] like more than the freedom from dealing with the entire insulin issue. That has made a large impression on me over the last 20-plus years of clinical practice, so I do think this can help some people and will be incredibly meaningful to those people.”

FDA advisory panel members are vetted for conflicts of interest, and special waivers are granted if necessary. No such waivers were granted for this meeting.

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

A Food and Drug Administration advisory panel has endorsed a pancreatic islet cell transplant therapy for the treatment of people with type 1 diabetes that can’t be managed with current therapies.

On April 15, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted 12 to 4 in favor of approval of donislecel (Lantidra). There was one abstention. The panel regarded the drug as having “an overall favorable benefit-risk profile for some patients with type 1 diabetes.” The product consists of purified allogeneic pancreatic islets of Langerhans derived from cadaveric donors and is infused into the portal vein of the liver.

Benefits of the treatment include the potential for insulin independence and elimination of severe hypoglycemia. Risks are those associated with the surgical procedure and with long-term immunosuppression.

The therapy is manufactured by CellTrans. According to Jose Oberholzer, MD, the founder of CellTrans, the proposed indication is for adults with “brittle” type 1 diabetes who meet the American Diabetes Association’s (ADA) criteria for whole-organ pancreas-alone transplant (i.e., transplant of pancreas but not kidney).

The ADA criteria include the following: frequent, severe hypoglycemia, hyperglycemia, and/or ketoacidosis that requires medical attention; clinical or emotional problems regarding the use of exogenous insulin; and consistent failure of insulin-based management to prevent acute diabetes complications.
 

Success in two-thirds of patients in small studies

Dr. Oberholzer presented data from two single-arm open-label studies: a phase 1/2 trial initiated in 2004 with 10 patients, and a phase 3 study with 20 patients that began in 2007. The inclusion criteria differed somewhat between the two studies, but all 30 patients had hypoglycemic unawareness. Mean follow-up was 7.8 years for the phase 1/2 trial and 4.7 years for the phase 3 trial.

For all of the patients, C-peptide levels were positive after transplant. The composite endpoint for success – an A1c level of ≤ 6.5% and the absence of severe hypoglycemic episodes for 1 year – was met by 19 patients (63.3%). For five patients (16.7%), the target A1c level was not achieved, and seven patients (23.3%) experienced a severe episode of hypoglycemia.

Twenty of the 30 patients achieved insulin independence for at least 1 year.

Improvements were also seen at 1 year in mixed meal test outcomes, fasting blood glucose levels, and overall glycemic control. Graft survival 10 years post transplant was achieved by 60% of patients, Dr. Oberholzer said.
 

Adverse events not unexpected, but still of concern

Two patients died, one as a result of fulminant sepsis at 20 months post transplant, and the other as a result of severe dementia 9 years post transplant. Three patients experienced four serious procedure-related events, including one liver laceration and two hepatic hematomas. Elevations in portal pressure occurred in two patients.

Most adverse events were associated with immunosuppression. These included 178 infections in 26 of the 30 patients. The most common of these were herpes virus infections, Epstein-Barr virus infections, oral candidiasis, and cytomegalovirus infections. Twelve infections were severe. Renal function declined persistently in two patients (20%), and six (20%) experienced new-onset proteinuria at 1 year.

The adverse events related to the procedure and the problems associated with immunosuppression were not unexpected and were consistent with those described for patients receiving whole pancreas transplants, FDA reviewer Patricia Beaston, MD, said in her review of the CellTrans data.
 

Panel members support treatment for a small group of patients

During the discussion, several panel members pointed out that the target patient population for this treatment will likely be smaller today than it was when the two studies were initiated, given advances in diabetes care. Those advances include continuous glucose monitoring devices with alarms and closed-loop insulin delivery systems – the “artificial pancreas” that automatically suspends insulin delivery to prevent hypoglycemia.

Panel chair Lisa Butterfield, PhD, a surgeon and immunologist at the University of California, San Francisco, voted in favor of approval. But, she added, “I do support postapproval gathering of data to learn more about the product. ... I don’t know how many patients will really benefit, but I think it’s to be determined.”

Christopher K. Breuer, MD, a general and pediatric surgeon at the Center for Regenerative Medicine, Nationwide Children’s Hospital, Columbus, Ohio, said he supported approval for “two very small subpopulations where it would provide the only viable therapy”: those who are eligible for pancreas transplant but cannot tolerate a major operation, and those who already use the latest automated insulin delivery systems and still do not achieve acceptable glycemic control.

Temporary voting member David Harlan, MD, director of the University of Massachusetts Diabetes Center of Excellence, Worcester, Mass., voted no.

He noted that only about 100 whole pancreas-only transplants are performed annually in the United States and that such transplants are “very effective, so we’re talking about patients who aren’t pancreas transplant candidates who might get this.”

Moreover, Dr. Harlan said, “I’ve seen the awful things that can happen in posttransplant recipients. It’s really hard to get that informed consent from someone when you’re asking them to consider a future that they don’t know. When it works, it’s great. When it doesn’t work, it can be catastrophic. I just worry about opening Pandora’s box.”

The only other diabetes specialist on the panel, temporary voting member Ellen Leschek, MD, said she “reluctantly voted yes because a few people could benefit, but I think it’s a much smaller number than the company may believe.”

Dr. Leschek, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md., said she’s concerned that “if it’s approved, too many people will get treated this way, when in fact, for a lot of those people, the risks will outweigh the benefits.”

Sandy Feng, MD, PhD, of the department of surgery at the University of California, San Francisco, pointed out that with regard to immunosuppressive therapy, “We’re concerned about the toxicity of what we currently use, but there are additional therapies being developed that might mitigate those toxicities that would be beneficial to this population.”

Dr. Feng, who voted yes, also said, “I do pancreas transplants. I can tell you that there is nothing that [patients with type 1 diabetes] like more than the freedom from dealing with the entire insulin issue. That has made a large impression on me over the last 20-plus years of clinical practice, so I do think this can help some people and will be incredibly meaningful to those people.”

FDA advisory panel members are vetted for conflicts of interest, and special waivers are granted if necessary. No such waivers were granted for this meeting.

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

For patients with obesity who want to lose weight but for whom conventional weight-loss strategies have failed, the combination of intragastric balloon placement and lifestyle modifications may be preferable to lifestyle modifications alone, according to new clinical practice guidelines from the American Gastroenterological Association.

In randomized clinical trials of patients with obesity (body mass index >30 kg/m²), placing an intragastric balloon (IGB) significantly improved key outcomes such as weight loss, metabolic parameters (such as fasting blood glucose, hemoglobin A1c), and rates of remission of diabetes, hypertension, and dyslipidemia, compared with standard noninvasive weight loss interventions, Thiruvengadam Muniraj, MD, MRCP, of Yale University in New Haven, Conn., and associates wrote in Gastroenterology. However, concomitant lifestyle modifications of “moderate to high intensity” are strongly recommended “to maintain and augment weight loss” after IGB placement, according to the guidelines published in Gastroenterology.

Obesity (BMI >30), affects approximately 40% of U.S. adults, but only about 1.1% of eligible patients receive bariatric weight-loss surgery, and few are aware that endoscopic treatment is an option, according to the guideline. Early IGB models were associated with “a number of devastating adverse events,” spurring their removal from the U.S. market in the 1980s and 1990s. Since then, however, several new models of IGBs have become available. The guidelines noted that, in seven randomized, controlled trials of these newer IGBs, there were no deaths and only a 5.6% overall rate of serious adverse events – most commonly injury to the gastrointestinal tract at 6-8 months’ follow-up. “More recently, postmarketing surveillance of IGB has reported additional rare adverse events of hyperinflation, acute pancreatitis, and death,” but overall, “IGBs appear to be associated with both a favorable adverse event and patient tolerability profile.”

Three models of fluid-filled balloons and two models of gas-filled balloons are currently available in the United States, the guidelines noted. The authors did not recommend one specific type or model over another. They cite limited data indicating that “fluid-filled balloons may be associated with more weight loss, lower tolerability, and less favorable safety profile, than gas filled balloons. Shared decision-making is suggested for determining device choice.”

Relatively few studies have evaluated lifestyle modifications after IGB placement. In one study of 80 patients, a very-low-calorie ketogenic diet led to significantly more weight loss (on average, 7.1 kg), compared with a conventional low-calorie diet. “Although diet does augment and sustain weight loss in patients receiving IGB therapy, it is unclear whether other lifestyle modifications (e.g., exercise) would have the same impact,” the guideline authors wrote.

They strongly recommended prophylactic proton pump inhibitor (PPI) therapy after IGB placement. The procedure can erode the gastrointestinal mucosa, and studies in which patients received prophylactic PPIs reported lower rates of serious adverse events, most notably upper GI bleeding. However, the numerous short- and long-term risks of these drugs make it “imperative that the lowest dose, frequency, and duration of PPIs be used in patients undergoing IGB therapy.”

Intragastric balloons can cause nausea and vomiting, leading to their premature removal. Therefore, when placing an IGB, concomitant antiemetic therapy is recommended along with an anesthetic that is unlikely to cause nausea. “Evidence is insufficient to recommend a specific antiemetic regimen” and “choice of regimen [should be] based on institutional policy, clinical context, and availability,” according to the guidelines.

Based on low-quality evidence, they included a conditional recommendation for daily vitamin supplementation with one to two adult-dose multivitamins after IGB placement. They suggest against perioperative laboratory screening for nutritional deficiencies, based on a lack of supporting evidence. However, since nutritional deficiencies with IGB placement have been reported, decisions about screening for nutritional deficiencies should be tailored based on clinical judgment.

To create the guideline, the authors reviewed databases for studies published through January 2020 in which patients with obesity had an IGB placed for at least 6 months. In all, 79 articles were cited, including more than 10 randomized clinical trials.

An update of the clinical practice guidelines is expected in 2024. The AGA Institute provided the only funding. Dr. Muniraj and five coauthors reported having no conflicts of interest. The other two coauthors disclosed relationships with Nestle Health Sciences, the American Society for Gastrointestinal Endoscopy, the American College of Gastroenterology, and the Association of American Indian Physicians.
 

For patients with obesity who want to lose weight but for whom conventional weight-loss strategies have failed, the combination of intragastric balloon placement and lifestyle modifications may be preferable to lifestyle modifications alone, according to new clinical practice guidelines from the American Gastroenterological Association.

In randomized clinical trials of patients with obesity (body mass index >30 kg/m²), placing an intragastric balloon (IGB) significantly improved key outcomes such as weight loss, metabolic parameters (such as fasting blood glucose, hemoglobin A1c), and rates of remission of diabetes, hypertension, and dyslipidemia, compared with standard noninvasive weight loss interventions, Thiruvengadam Muniraj, MD, MRCP, of Yale University in New Haven, Conn., and associates wrote in Gastroenterology. However, concomitant lifestyle modifications of “moderate to high intensity” are strongly recommended “to maintain and augment weight loss” after IGB placement, according to the guidelines published in Gastroenterology.

Obesity (BMI >30), affects approximately 40% of U.S. adults, but only about 1.1% of eligible patients receive bariatric weight-loss surgery, and few are aware that endoscopic treatment is an option, according to the guideline. Early IGB models were associated with “a number of devastating adverse events,” spurring their removal from the U.S. market in the 1980s and 1990s. Since then, however, several new models of IGBs have become available. The guidelines noted that, in seven randomized, controlled trials of these newer IGBs, there were no deaths and only a 5.6% overall rate of serious adverse events – most commonly injury to the gastrointestinal tract at 6-8 months’ follow-up. “More recently, postmarketing surveillance of IGB has reported additional rare adverse events of hyperinflation, acute pancreatitis, and death,” but overall, “IGBs appear to be associated with both a favorable adverse event and patient tolerability profile.”

Three models of fluid-filled balloons and two models of gas-filled balloons are currently available in the United States, the guidelines noted. The authors did not recommend one specific type or model over another. They cite limited data indicating that “fluid-filled balloons may be associated with more weight loss, lower tolerability, and less favorable safety profile, than gas filled balloons. Shared decision-making is suggested for determining device choice.”

Relatively few studies have evaluated lifestyle modifications after IGB placement. In one study of 80 patients, a very-low-calorie ketogenic diet led to significantly more weight loss (on average, 7.1 kg), compared with a conventional low-calorie diet. “Although diet does augment and sustain weight loss in patients receiving IGB therapy, it is unclear whether other lifestyle modifications (e.g., exercise) would have the same impact,” the guideline authors wrote.

They strongly recommended prophylactic proton pump inhibitor (PPI) therapy after IGB placement. The procedure can erode the gastrointestinal mucosa, and studies in which patients received prophylactic PPIs reported lower rates of serious adverse events, most notably upper GI bleeding. However, the numerous short- and long-term risks of these drugs make it “imperative that the lowest dose, frequency, and duration of PPIs be used in patients undergoing IGB therapy.”

Intragastric balloons can cause nausea and vomiting, leading to their premature removal. Therefore, when placing an IGB, concomitant antiemetic therapy is recommended along with an anesthetic that is unlikely to cause nausea. “Evidence is insufficient to recommend a specific antiemetic regimen” and “choice of regimen [should be] based on institutional policy, clinical context, and availability,” according to the guidelines.

Based on low-quality evidence, they included a conditional recommendation for daily vitamin supplementation with one to two adult-dose multivitamins after IGB placement. They suggest against perioperative laboratory screening for nutritional deficiencies, based on a lack of supporting evidence. However, since nutritional deficiencies with IGB placement have been reported, decisions about screening for nutritional deficiencies should be tailored based on clinical judgment.

To create the guideline, the authors reviewed databases for studies published through January 2020 in which patients with obesity had an IGB placed for at least 6 months. In all, 79 articles were cited, including more than 10 randomized clinical trials.

An update of the clinical practice guidelines is expected in 2024. The AGA Institute provided the only funding. Dr. Muniraj and five coauthors reported having no conflicts of interest. The other two coauthors disclosed relationships with Nestle Health Sciences, the American Society for Gastrointestinal Endoscopy, the American College of Gastroenterology, and the Association of American Indian Physicians.
 

For patients with obesity who want to lose weight but for whom conventional weight-loss strategies have failed, the combination of intragastric balloon placement and lifestyle modifications may be preferable to lifestyle modifications alone, according to new clinical practice guidelines from the American Gastroenterological Association.

In randomized clinical trials of patients with obesity (body mass index >30 kg/m²), placing an intragastric balloon (IGB) significantly improved key outcomes such as weight loss, metabolic parameters (such as fasting blood glucose, hemoglobin A1c), and rates of remission of diabetes, hypertension, and dyslipidemia, compared with standard noninvasive weight loss interventions, Thiruvengadam Muniraj, MD, MRCP, of Yale University in New Haven, Conn., and associates wrote in Gastroenterology. However, concomitant lifestyle modifications of “moderate to high intensity” are strongly recommended “to maintain and augment weight loss” after IGB placement, according to the guidelines published in Gastroenterology.

Obesity (BMI >30), affects approximately 40% of U.S. adults, but only about 1.1% of eligible patients receive bariatric weight-loss surgery, and few are aware that endoscopic treatment is an option, according to the guideline. Early IGB models were associated with “a number of devastating adverse events,” spurring their removal from the U.S. market in the 1980s and 1990s. Since then, however, several new models of IGBs have become available. The guidelines noted that, in seven randomized, controlled trials of these newer IGBs, there were no deaths and only a 5.6% overall rate of serious adverse events – most commonly injury to the gastrointestinal tract at 6-8 months’ follow-up. “More recently, postmarketing surveillance of IGB has reported additional rare adverse events of hyperinflation, acute pancreatitis, and death,” but overall, “IGBs appear to be associated with both a favorable adverse event and patient tolerability profile.”

Three models of fluid-filled balloons and two models of gas-filled balloons are currently available in the United States, the guidelines noted. The authors did not recommend one specific type or model over another. They cite limited data indicating that “fluid-filled balloons may be associated with more weight loss, lower tolerability, and less favorable safety profile, than gas filled balloons. Shared decision-making is suggested for determining device choice.”

Relatively few studies have evaluated lifestyle modifications after IGB placement. In one study of 80 patients, a very-low-calorie ketogenic diet led to significantly more weight loss (on average, 7.1 kg), compared with a conventional low-calorie diet. “Although diet does augment and sustain weight loss in patients receiving IGB therapy, it is unclear whether other lifestyle modifications (e.g., exercise) would have the same impact,” the guideline authors wrote.

They strongly recommended prophylactic proton pump inhibitor (PPI) therapy after IGB placement. The procedure can erode the gastrointestinal mucosa, and studies in which patients received prophylactic PPIs reported lower rates of serious adverse events, most notably upper GI bleeding. However, the numerous short- and long-term risks of these drugs make it “imperative that the lowest dose, frequency, and duration of PPIs be used in patients undergoing IGB therapy.”

Intragastric balloons can cause nausea and vomiting, leading to their premature removal. Therefore, when placing an IGB, concomitant antiemetic therapy is recommended along with an anesthetic that is unlikely to cause nausea. “Evidence is insufficient to recommend a specific antiemetic regimen” and “choice of regimen [should be] based on institutional policy, clinical context, and availability,” according to the guidelines.

Based on low-quality evidence, they included a conditional recommendation for daily vitamin supplementation with one to two adult-dose multivitamins after IGB placement. They suggest against perioperative laboratory screening for nutritional deficiencies, based on a lack of supporting evidence. However, since nutritional deficiencies with IGB placement have been reported, decisions about screening for nutritional deficiencies should be tailored based on clinical judgment.

To create the guideline, the authors reviewed databases for studies published through January 2020 in which patients with obesity had an IGB placed for at least 6 months. In all, 79 articles were cited, including more than 10 randomized clinical trials.

An update of the clinical practice guidelines is expected in 2024. The AGA Institute provided the only funding. Dr. Muniraj and five coauthors reported having no conflicts of interest. The other two coauthors disclosed relationships with Nestle Health Sciences, the American Society for Gastrointestinal Endoscopy, the American College of Gastroenterology, and the Association of American Indian Physicians.
 

Most patients who are receiving maintenance hemodialysis develop a good antibody response after being given two doses of the Pfizer-BioNTech COVID-19 vaccine, but their responses are still significantly lower than those of health care workers who do not have kidney disease, the first study of its kind shows.

“It is well known that patients on dialysis may have a reduced response to vaccination,” Ayelet Grupper, MD, of Tel Aviv Medical Center, and colleagues observe. Their study was published online April 6 in the Clinical Journal of the American Society of Nephrology.

“I believe our findings should encourage patients with kidney failure treated with dialysis to be vaccinated as soon as vaccination becomes available for them, while we as caregivers should explore ways to enhance its efficacy in our patients,” senior author Moshe Shashar, MD, noted in a statement from the American Society of Nephrology.

Asked to comment, Peter Blake, MD, professor of medicine, University of Western Ontario, London, pointed out that COVID-19 is very common among hemodialysis patients and that the likelihood of these patients dying from it is very high. Indeed, 1.5% of approximately 12,500 patients receiving dialysis in the province of Ontario have died of COVID-19 – “a horrifying statistic and one that only long-term care home residents can compare with,” he told this news organization.

In the Israeli study, almost all dialysis patients mounted a serologic response to the Pfizer-BioNTech vaccine, which is “good news” overall, Dr. Blake said.

Also commenting on the study, Anushree Shirali, MD, of Yale University, New Haven, Conn., said she was impressed by the fact that most of the dialysis patients in the study mounted at least some IgG response to vaccination, which she said was good “in and of itself,” because that is not always the case with other vaccines.
 

Study compared dialysis patients with health care workers

The Israeli study included 56 patients who were receiving maintenance hemodialysis and 95 health care workers, who served as control persons.

“All participants had been previously vaccinated with the [Pfizer-BioNTech] vaccine, with the recommended dosing interval of 21 days between the first and second doses,” the investigators note. Immunogenicity was assessed using a dedicated immunoassay to quantify the level of IgG antibodies from participants’ plasma.

A cutoff for a positive antibody response was greater than or equal to 50 arbitrary units per milliliter (AU/mL). “All subjects in the control group developed a positive antibody response (≥50 AU/mL) as compared with 96% (54 of 56) in the dialysis group,” Dr. Shashar and colleagues report.

The median IgG level in the dialysis group was 2,900 AU/mL, which is significantly lower than the median of 7,401 AU/mL in the control group (P < .001), they report.

The investigators also observed a significant inverse correlation between older age and antibody levels in both groups.

The odds of being in the lower quartile were significantly higher for older individuals (odds ratio, 1.11 per year of age; P = .004) and for the dialysis group compared with the control group (OR, 2.7; P = .05).

Among the dialysis patients, older age and lower lymphocyte count were associated with antibody response in the lower quartile (OR, 1.22 per 1 year older; P = .03; and OR, 0.83 per 10-e3/mL-higher lymphocyte count; P = .05).

Among recipients older than 70 years, there was little difference in antibody response between the dialysis patients and the control group. Thus, age is clearly an important contributor to a robust humoral response, the authors observe.

For more than 90% of the patients receiving dialysis, the antibody response was well above 50 AU/mL, which was the cutoff for having a positive response.

Nevertheless, the authors suggest that their findings should prompt clinicians to consider either changing the dose or the schedule of COVID-19 vaccination for dialysis patients, as was done, for example, with the hepatitis B vaccine Engerix-B.

Dialysis patients now receive double doses of the hepatitis B vaccine, which is given in a four-series vaccine schedule rather than a three-series vaccine schedule, as is given to healthy individuals.

The authors also call for studies to assess the longevity of vaccine efficacy for dialysis patients and whether current vaccines are effective against variant strains among patients undergoing dialysis.
 

Some suggestion COVID-19 vaccines also elicit T-cell responses

Dr. Shirali said the news regarding the COVID-19 vaccine for dialysis patients is good, given the fact that such patients exhibit a poor response to the hepatitis B vaccine.

“There isn’t a large percentage of dialysis patients who mount a humoral response to the hepatitis B vaccine, even with the change in dosing that we use that is different than it is for the general population,” she told this news organization.

Dr. Shirali also noted that preliminary evidence suggests that COVID-19 vaccines elicit nonantibody and antibody T-cell responses and that such immunity is going to be just as important for protecting dialysis patients against COVID-19 as it is for protecting patients who are not receiving dialysis.

“Antibody responses are just one arm of vaccination,” she explained. “People can form memory T-cell responses with vaccination, and while this has not been well studied with COVID-19, there are preliminary data to suggest that T-cell responses are likely to be effective in the fight against COVID-19.” There is also the possibility that this type of response “may even be more durable than antibody responses,” she said.

The study received no funding. The authors, Dr. Blake and Dr. Shirali, have disclosed no relevant financial relationships.

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

Most patients who are receiving maintenance hemodialysis develop a good antibody response after being given two doses of the Pfizer-BioNTech COVID-19 vaccine, but their responses are still significantly lower than those of health care workers who do not have kidney disease, the first study of its kind shows.

“It is well known that patients on dialysis may have a reduced response to vaccination,” Ayelet Grupper, MD, of Tel Aviv Medical Center, and colleagues observe. Their study was published online April 6 in the Clinical Journal of the American Society of Nephrology.

“I believe our findings should encourage patients with kidney failure treated with dialysis to be vaccinated as soon as vaccination becomes available for them, while we as caregivers should explore ways to enhance its efficacy in our patients,” senior author Moshe Shashar, MD, noted in a statement from the American Society of Nephrology.

Asked to comment, Peter Blake, MD, professor of medicine, University of Western Ontario, London, pointed out that COVID-19 is very common among hemodialysis patients and that the likelihood of these patients dying from it is very high. Indeed, 1.5% of approximately 12,500 patients receiving dialysis in the province of Ontario have died of COVID-19 – “a horrifying statistic and one that only long-term care home residents can compare with,” he told this news organization.

In the Israeli study, almost all dialysis patients mounted a serologic response to the Pfizer-BioNTech vaccine, which is “good news” overall, Dr. Blake said.

Also commenting on the study, Anushree Shirali, MD, of Yale University, New Haven, Conn., said she was impressed by the fact that most of the dialysis patients in the study mounted at least some IgG response to vaccination, which she said was good “in and of itself,” because that is not always the case with other vaccines.
 

Study compared dialysis patients with health care workers

The Israeli study included 56 patients who were receiving maintenance hemodialysis and 95 health care workers, who served as control persons.

“All participants had been previously vaccinated with the [Pfizer-BioNTech] vaccine, with the recommended dosing interval of 21 days between the first and second doses,” the investigators note. Immunogenicity was assessed using a dedicated immunoassay to quantify the level of IgG antibodies from participants’ plasma.

A cutoff for a positive antibody response was greater than or equal to 50 arbitrary units per milliliter (AU/mL). “All subjects in the control group developed a positive antibody response (≥50 AU/mL) as compared with 96% (54 of 56) in the dialysis group,” Dr. Shashar and colleagues report.

The median IgG level in the dialysis group was 2,900 AU/mL, which is significantly lower than the median of 7,401 AU/mL in the control group (P < .001), they report.

The investigators also observed a significant inverse correlation between older age and antibody levels in both groups.

The odds of being in the lower quartile were significantly higher for older individuals (odds ratio, 1.11 per year of age; P = .004) and for the dialysis group compared with the control group (OR, 2.7; P = .05).

Among the dialysis patients, older age and lower lymphocyte count were associated with antibody response in the lower quartile (OR, 1.22 per 1 year older; P = .03; and OR, 0.83 per 10-e3/mL-higher lymphocyte count; P = .05).

Among recipients older than 70 years, there was little difference in antibody response between the dialysis patients and the control group. Thus, age is clearly an important contributor to a robust humoral response, the authors observe.

For more than 90% of the patients receiving dialysis, the antibody response was well above 50 AU/mL, which was the cutoff for having a positive response.

Nevertheless, the authors suggest that their findings should prompt clinicians to consider either changing the dose or the schedule of COVID-19 vaccination for dialysis patients, as was done, for example, with the hepatitis B vaccine Engerix-B.

Dialysis patients now receive double doses of the hepatitis B vaccine, which is given in a four-series vaccine schedule rather than a three-series vaccine schedule, as is given to healthy individuals.

The authors also call for studies to assess the longevity of vaccine efficacy for dialysis patients and whether current vaccines are effective against variant strains among patients undergoing dialysis.
 

Some suggestion COVID-19 vaccines also elicit T-cell responses

Dr. Shirali said the news regarding the COVID-19 vaccine for dialysis patients is good, given the fact that such patients exhibit a poor response to the hepatitis B vaccine.

“There isn’t a large percentage of dialysis patients who mount a humoral response to the hepatitis B vaccine, even with the change in dosing that we use that is different than it is for the general population,” she told this news organization.

Dr. Shirali also noted that preliminary evidence suggests that COVID-19 vaccines elicit nonantibody and antibody T-cell responses and that such immunity is going to be just as important for protecting dialysis patients against COVID-19 as it is for protecting patients who are not receiving dialysis.

“Antibody responses are just one arm of vaccination,” she explained. “People can form memory T-cell responses with vaccination, and while this has not been well studied with COVID-19, there are preliminary data to suggest that T-cell responses are likely to be effective in the fight against COVID-19.” There is also the possibility that this type of response “may even be more durable than antibody responses,” she said.

The study received no funding. The authors, Dr. Blake and Dr. Shirali, have disclosed no relevant financial relationships.

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

Most patients who are receiving maintenance hemodialysis develop a good antibody response after being given two doses of the Pfizer-BioNTech COVID-19 vaccine, but their responses are still significantly lower than those of health care workers who do not have kidney disease, the first study of its kind shows.

“It is well known that patients on dialysis may have a reduced response to vaccination,” Ayelet Grupper, MD, of Tel Aviv Medical Center, and colleagues observe. Their study was published online April 6 in the Clinical Journal of the American Society of Nephrology.

“I believe our findings should encourage patients with kidney failure treated with dialysis to be vaccinated as soon as vaccination becomes available for them, while we as caregivers should explore ways to enhance its efficacy in our patients,” senior author Moshe Shashar, MD, noted in a statement from the American Society of Nephrology.

Asked to comment, Peter Blake, MD, professor of medicine, University of Western Ontario, London, pointed out that COVID-19 is very common among hemodialysis patients and that the likelihood of these patients dying from it is very high. Indeed, 1.5% of approximately 12,500 patients receiving dialysis in the province of Ontario have died of COVID-19 – “a horrifying statistic and one that only long-term care home residents can compare with,” he told this news organization.

In the Israeli study, almost all dialysis patients mounted a serologic response to the Pfizer-BioNTech vaccine, which is “good news” overall, Dr. Blake said.

Also commenting on the study, Anushree Shirali, MD, of Yale University, New Haven, Conn., said she was impressed by the fact that most of the dialysis patients in the study mounted at least some IgG response to vaccination, which she said was good “in and of itself,” because that is not always the case with other vaccines.
 

Study compared dialysis patients with health care workers

The Israeli study included 56 patients who were receiving maintenance hemodialysis and 95 health care workers, who served as control persons.

“All participants had been previously vaccinated with the [Pfizer-BioNTech] vaccine, with the recommended dosing interval of 21 days between the first and second doses,” the investigators note. Immunogenicity was assessed using a dedicated immunoassay to quantify the level of IgG antibodies from participants’ plasma.

A cutoff for a positive antibody response was greater than or equal to 50 arbitrary units per milliliter (AU/mL). “All subjects in the control group developed a positive antibody response (≥50 AU/mL) as compared with 96% (54 of 56) in the dialysis group,” Dr. Shashar and colleagues report.

The median IgG level in the dialysis group was 2,900 AU/mL, which is significantly lower than the median of 7,401 AU/mL in the control group (P < .001), they report.

The investigators also observed a significant inverse correlation between older age and antibody levels in both groups.

The odds of being in the lower quartile were significantly higher for older individuals (odds ratio, 1.11 per year of age; P = .004) and for the dialysis group compared with the control group (OR, 2.7; P = .05).

Among the dialysis patients, older age and lower lymphocyte count were associated with antibody response in the lower quartile (OR, 1.22 per 1 year older; P = .03; and OR, 0.83 per 10-e3/mL-higher lymphocyte count; P = .05).

Among recipients older than 70 years, there was little difference in antibody response between the dialysis patients and the control group. Thus, age is clearly an important contributor to a robust humoral response, the authors observe.

For more than 90% of the patients receiving dialysis, the antibody response was well above 50 AU/mL, which was the cutoff for having a positive response.

Nevertheless, the authors suggest that their findings should prompt clinicians to consider either changing the dose or the schedule of COVID-19 vaccination for dialysis patients, as was done, for example, with the hepatitis B vaccine Engerix-B.

Dialysis patients now receive double doses of the hepatitis B vaccine, which is given in a four-series vaccine schedule rather than a three-series vaccine schedule, as is given to healthy individuals.

The authors also call for studies to assess the longevity of vaccine efficacy for dialysis patients and whether current vaccines are effective against variant strains among patients undergoing dialysis.
 

Some suggestion COVID-19 vaccines also elicit T-cell responses

Dr. Shirali said the news regarding the COVID-19 vaccine for dialysis patients is good, given the fact that such patients exhibit a poor response to the hepatitis B vaccine.

“There isn’t a large percentage of dialysis patients who mount a humoral response to the hepatitis B vaccine, even with the change in dosing that we use that is different than it is for the general population,” she told this news organization.

Dr. Shirali also noted that preliminary evidence suggests that COVID-19 vaccines elicit nonantibody and antibody T-cell responses and that such immunity is going to be just as important for protecting dialysis patients against COVID-19 as it is for protecting patients who are not receiving dialysis.

“Antibody responses are just one arm of vaccination,” she explained. “People can form memory T-cell responses with vaccination, and while this has not been well studied with COVID-19, there are preliminary data to suggest that T-cell responses are likely to be effective in the fight against COVID-19.” There is also the possibility that this type of response “may even be more durable than antibody responses,” she said.

The study received no funding. The authors, Dr. Blake and Dr. Shirali, have disclosed no relevant financial relationships.

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

The high-density lipoprotein particle’s complexity as a mediator of cardiovascular risk was on display in a case-control study that, the researchers say, points to its anti-inflammatory capacity as potentially a worthy addition to standard CV risk assessments.

A measure of HDL anti-inflammatory capacity in a prospective community cohort was inversely related to future CV risk independent of HDL’s role in cholesterol transport, total cholesterol, and other established biomarkers, as well as any lipid-modifying therapy.

The current analysis “identified an impaired HDL anti-inflammatory capacity as a functional metric prospectively associated with increased cardiovascular risk in the general population,” observed the authors of the study, published April 12, 2021, in Circulation, led by Congzhuo Jia, MD, University of Groningen (the Netherlands).

“In contrast with the cholesterol efflux function of HDL that tracks moderately with HDL cholesterol levels,” they wrote, HDL anti-inflammatory capacity was not significantly correlated with actual levels of the lipoprotein or a major constituent, apolipoprotein A1 (apoA1). Nor was it correlated with levels of a more generalized inflammatory biomarker, C-reactive protein by high-sensitivity assay (hsCRP).

In a test of its independence as a prognosticator, HDL anti-inflammatory capacity significantly and meaningfully improved prediction of CV events in the study after it was added to the familiar Framingham risk equations.

Measurement of HDL anti-inflammatory properties, therefore, has the potential to improve current CV risk assessments in people without clinical heart disease, the authors proposed.

The study “adds to our understanding of the potential cardioprotective role of HDL,” Michael Miller, MD, University of Maryland, Baltimore, said in an interview.

“We’ve known for some time that HDL has anti-inflammatory properties in vitro, and my understanding is this is the first study to assess these anti-inflammatory properties in a clinical trial,” said Dr. Miller, who studies lipid metabolism and directs the Center for Preventive Cardiology at his center but isn’t an author of the report.

The study is part of a long line of research aiming to “untangle the complexities of HDL and try to get a better handle as to the properties that make it cardioprotective,” he said. For example, “high levels are not always associated with cardioprotection, and low levels don’t always imply increased risk.”

The current findings highlight a quality of HDL that might be prognostic but also independent of its concentrations, apoA1 content, or cholesterol efflux capacity, Dr. Miller noted. That makes HDL anti-inflammatory capacity a “promising feature” of HDL that, if confirmed in further studies, could potentially be brought into the mainstream for CV risk prediction. “But it’s too premature at this time.”

The study of participants in the population-based PREVEND cohort study compared 340 patients with a first CV event – CV death, ischemic heart disease, nonfatal MI, or coronary revascularization – over a median of about 10 years with the same number of participants without such events. The two cohorts of people from the same city in the Netherlands had been matched according to sex, smoking status, age, and HDL cholesterol levels at baseline.

No measured clinical or laboratory value, the group wrote, was significantly correlated with HDL anti-inflammatory capacity, defined here as ability to suppress vascular cell adhesion molecule-1 (VCAM-1) mRNA expression as induced by tumor necrosis factor–alpha in endothelial cells in vitro.

HDL anti-inflammatory capacity was significantly lower in the case cohort, compared with the control cohort (P < .001), and was inversely related to new CV events, at an odds ratio per 1 standard deviation of 0.74 (95% confidence interval, 0.61-0.90; P = .002). Covariate adjustments included body mass index; alcohol intake; diabetes and hypertension status; use of lipid-lowering medicine; levels of total cholesterol, apoA1, triglyceride, and hsCRP; and measures of renal function.

No significant association was seen between HDL anti-inflammatory capacity and cholesterol efflux capacity (coefficient of correlation, −0.02; P > .05). But both metrics were independently associated with CV disease events. The OR per 1 standard deviation was 0.74 (95% CI, 0.61-0.90; P = .002) for cholesterol efflux capacity and 0.66 (95% CI, 0.54-0.81; P < .001) for HDL anti-inflammatory capacity.

Adding HDL anti-inflammatory capacity to the Framingham risk score significantly improved its predictive power; its likelihood-ratio statistic rose from 10.50 to 20.40 (P = .002), the group wrote. The addition of cholesterol efflux capacity further elevated the risk score’s likelihood-ratio statistic to 32.84 (P = .0005).

The analysis has all the limitations of a case-control study, Dr. Miller said, but it does “show a potential reasonable association” between anti-inflammatory capacity and CV risk “that needs to be taken to the next level.”

For example, it could be explored in a controlled trial that tracks anti-inflammatory capacity in individuals who receive an intervention that is likely to improve the biomarker – such as weight loss, he proposed – and follows them for clinical outcomes.

“If you want to elevate the stature of the anti-inflammatory index,” Dr. Miller said, “you will need to show that it’s clinically meaningful.”

Dr. Jia reported no conflicts. Dr. Miller has no relevant disclosures.

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

The high-density lipoprotein particle’s complexity as a mediator of cardiovascular risk was on display in a case-control study that, the researchers say, points to its anti-inflammatory capacity as potentially a worthy addition to standard CV risk assessments.

A measure of HDL anti-inflammatory capacity in a prospective community cohort was inversely related to future CV risk independent of HDL’s role in cholesterol transport, total cholesterol, and other established biomarkers, as well as any lipid-modifying therapy.

The current analysis “identified an impaired HDL anti-inflammatory capacity as a functional metric prospectively associated with increased cardiovascular risk in the general population,” observed the authors of the study, published April 12, 2021, in Circulation, led by Congzhuo Jia, MD, University of Groningen (the Netherlands).

“In contrast with the cholesterol efflux function of HDL that tracks moderately with HDL cholesterol levels,” they wrote, HDL anti-inflammatory capacity was not significantly correlated with actual levels of the lipoprotein or a major constituent, apolipoprotein A1 (apoA1). Nor was it correlated with levels of a more generalized inflammatory biomarker, C-reactive protein by high-sensitivity assay (hsCRP).

In a test of its independence as a prognosticator, HDL anti-inflammatory capacity significantly and meaningfully improved prediction of CV events in the study after it was added to the familiar Framingham risk equations.

Measurement of HDL anti-inflammatory properties, therefore, has the potential to improve current CV risk assessments in people without clinical heart disease, the authors proposed.

The study “adds to our understanding of the potential cardioprotective role of HDL,” Michael Miller, MD, University of Maryland, Baltimore, said in an interview.

“We’ve known for some time that HDL has anti-inflammatory properties in vitro, and my understanding is this is the first study to assess these anti-inflammatory properties in a clinical trial,” said Dr. Miller, who studies lipid metabolism and directs the Center for Preventive Cardiology at his center but isn’t an author of the report.

The study is part of a long line of research aiming to “untangle the complexities of HDL and try to get a better handle as to the properties that make it cardioprotective,” he said. For example, “high levels are not always associated with cardioprotection, and low levels don’t always imply increased risk.”

The current findings highlight a quality of HDL that might be prognostic but also independent of its concentrations, apoA1 content, or cholesterol efflux capacity, Dr. Miller noted. That makes HDL anti-inflammatory capacity a “promising feature” of HDL that, if confirmed in further studies, could potentially be brought into the mainstream for CV risk prediction. “But it’s too premature at this time.”

The study of participants in the population-based PREVEND cohort study compared 340 patients with a first CV event – CV death, ischemic heart disease, nonfatal MI, or coronary revascularization – over a median of about 10 years with the same number of participants without such events. The two cohorts of people from the same city in the Netherlands had been matched according to sex, smoking status, age, and HDL cholesterol levels at baseline.

No measured clinical or laboratory value, the group wrote, was significantly correlated with HDL anti-inflammatory capacity, defined here as ability to suppress vascular cell adhesion molecule-1 (VCAM-1) mRNA expression as induced by tumor necrosis factor–alpha in endothelial cells in vitro.

HDL anti-inflammatory capacity was significantly lower in the case cohort, compared with the control cohort (P < .001), and was inversely related to new CV events, at an odds ratio per 1 standard deviation of 0.74 (95% confidence interval, 0.61-0.90; P = .002). Covariate adjustments included body mass index; alcohol intake; diabetes and hypertension status; use of lipid-lowering medicine; levels of total cholesterol, apoA1, triglyceride, and hsCRP; and measures of renal function.

No significant association was seen between HDL anti-inflammatory capacity and cholesterol efflux capacity (coefficient of correlation, −0.02; P > .05). But both metrics were independently associated with CV disease events. The OR per 1 standard deviation was 0.74 (95% CI, 0.61-0.90; P = .002) for cholesterol efflux capacity and 0.66 (95% CI, 0.54-0.81; P < .001) for HDL anti-inflammatory capacity.

Adding HDL anti-inflammatory capacity to the Framingham risk score significantly improved its predictive power; its likelihood-ratio statistic rose from 10.50 to 20.40 (P = .002), the group wrote. The addition of cholesterol efflux capacity further elevated the risk score’s likelihood-ratio statistic to 32.84 (P = .0005).

The analysis has all the limitations of a case-control study, Dr. Miller said, but it does “show a potential reasonable association” between anti-inflammatory capacity and CV risk “that needs to be taken to the next level.”

For example, it could be explored in a controlled trial that tracks anti-inflammatory capacity in individuals who receive an intervention that is likely to improve the biomarker – such as weight loss, he proposed – and follows them for clinical outcomes.

“If you want to elevate the stature of the anti-inflammatory index,” Dr. Miller said, “you will need to show that it’s clinically meaningful.”

Dr. Jia reported no conflicts. Dr. Miller has no relevant disclosures.

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

The high-density lipoprotein particle’s complexity as a mediator of cardiovascular risk was on display in a case-control study that, the researchers say, points to its anti-inflammatory capacity as potentially a worthy addition to standard CV risk assessments.

A measure of HDL anti-inflammatory capacity in a prospective community cohort was inversely related to future CV risk independent of HDL’s role in cholesterol transport, total cholesterol, and other established biomarkers, as well as any lipid-modifying therapy.

The current analysis “identified an impaired HDL anti-inflammatory capacity as a functional metric prospectively associated with increased cardiovascular risk in the general population,” observed the authors of the study, published April 12, 2021, in Circulation, led by Congzhuo Jia, MD, University of Groningen (the Netherlands).

“In contrast with the cholesterol efflux function of HDL that tracks moderately with HDL cholesterol levels,” they wrote, HDL anti-inflammatory capacity was not significantly correlated with actual levels of the lipoprotein or a major constituent, apolipoprotein A1 (apoA1). Nor was it correlated with levels of a more generalized inflammatory biomarker, C-reactive protein by high-sensitivity assay (hsCRP).

In a test of its independence as a prognosticator, HDL anti-inflammatory capacity significantly and meaningfully improved prediction of CV events in the study after it was added to the familiar Framingham risk equations.

Measurement of HDL anti-inflammatory properties, therefore, has the potential to improve current CV risk assessments in people without clinical heart disease, the authors proposed.

The study “adds to our understanding of the potential cardioprotective role of HDL,” Michael Miller, MD, University of Maryland, Baltimore, said in an interview.

“We’ve known for some time that HDL has anti-inflammatory properties in vitro, and my understanding is this is the first study to assess these anti-inflammatory properties in a clinical trial,” said Dr. Miller, who studies lipid metabolism and directs the Center for Preventive Cardiology at his center but isn’t an author of the report.

The study is part of a long line of research aiming to “untangle the complexities of HDL and try to get a better handle as to the properties that make it cardioprotective,” he said. For example, “high levels are not always associated with cardioprotection, and low levels don’t always imply increased risk.”

The current findings highlight a quality of HDL that might be prognostic but also independent of its concentrations, apoA1 content, or cholesterol efflux capacity, Dr. Miller noted. That makes HDL anti-inflammatory capacity a “promising feature” of HDL that, if confirmed in further studies, could potentially be brought into the mainstream for CV risk prediction. “But it’s too premature at this time.”

The study of participants in the population-based PREVEND cohort study compared 340 patients with a first CV event – CV death, ischemic heart disease, nonfatal MI, or coronary revascularization – over a median of about 10 years with the same number of participants without such events. The two cohorts of people from the same city in the Netherlands had been matched according to sex, smoking status, age, and HDL cholesterol levels at baseline.

No measured clinical or laboratory value, the group wrote, was significantly correlated with HDL anti-inflammatory capacity, defined here as ability to suppress vascular cell adhesion molecule-1 (VCAM-1) mRNA expression as induced by tumor necrosis factor–alpha in endothelial cells in vitro.

HDL anti-inflammatory capacity was significantly lower in the case cohort, compared with the control cohort (P < .001), and was inversely related to new CV events, at an odds ratio per 1 standard deviation of 0.74 (95% confidence interval, 0.61-0.90; P = .002). Covariate adjustments included body mass index; alcohol intake; diabetes and hypertension status; use of lipid-lowering medicine; levels of total cholesterol, apoA1, triglyceride, and hsCRP; and measures of renal function.

No significant association was seen between HDL anti-inflammatory capacity and cholesterol efflux capacity (coefficient of correlation, −0.02; P > .05). But both metrics were independently associated with CV disease events. The OR per 1 standard deviation was 0.74 (95% CI, 0.61-0.90; P = .002) for cholesterol efflux capacity and 0.66 (95% CI, 0.54-0.81; P < .001) for HDL anti-inflammatory capacity.

Adding HDL anti-inflammatory capacity to the Framingham risk score significantly improved its predictive power; its likelihood-ratio statistic rose from 10.50 to 20.40 (P = .002), the group wrote. The addition of cholesterol efflux capacity further elevated the risk score’s likelihood-ratio statistic to 32.84 (P = .0005).

The analysis has all the limitations of a case-control study, Dr. Miller said, but it does “show a potential reasonable association” between anti-inflammatory capacity and CV risk “that needs to be taken to the next level.”

For example, it could be explored in a controlled trial that tracks anti-inflammatory capacity in individuals who receive an intervention that is likely to improve the biomarker – such as weight loss, he proposed – and follows them for clinical outcomes.

“If you want to elevate the stature of the anti-inflammatory index,” Dr. Miller said, “you will need to show that it’s clinically meaningful.”

Dr. Jia reported no conflicts. Dr. Miller has no relevant disclosures.

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

The recommended pause in use of the Johnson & Johnson COVID-19 vaccine will last at least another week after a Centers for Disease Control and Prevention advisory committee on April 14 decided not to take action.

Johnson &amp; Johnson

The Advisory Committee on Immunization Practices decided there was not adequate information to change again recommend use of the Johnson & Johnson vaccine.

The committee’s decision comes the day after the CDC and Food and Drug Administration recommended that J&J injections be paused after reports of rare, but serious types of blood clots in six patients among the 6.8 million people who had received the J&J vaccine in the United States.

A member of the committee, Beth Bell, MD, said: “I do not want to be sending a message that there is some huge concern here on a different order of magnitude than any other vaccine safety signals that we evaluate. And I don’t want to send a message that there is something fundamentally wrong with the vaccine because that also I don’t agree with.”

At the end of the 4-hour meeting, ACIP members decided to call a meeting in 1 or 2 weeks and evaluate more safety data, specifically reports of people who have received the J&J vaccine in the past 2 weeks.

Some, however, pointed out that delaying a decision could have substantial consequences as well in terms of unused vaccine doses and public confidence.

Committee member Camiile Kotton, MD, described the pause as “devastating.”

“Putting this vaccine on pause for those of us that are frontline health care workers has really been devastating,” she said. “I agree in general that we don’t have enough data to make a decision at this time but we were planning on using this vaccine in the state of Massachusetts for people who were homebound and otherwise not able to get a vaccine. We were planning on using it for our vulnerable inpatient population often with many comorbidities and at high risk for disease but haven’t been able to get vaccinated otherwise.”

Pausing the one-and-done vaccine that doesn’t have the significant refrigeration requirements of the others “is a significant loss,” she said.
 

What is known, not known

Sara Oliver, MD, who leads the COVID-19 Vaccines ACIP Work Group, summarized what is known and unknown about the blood clots.

Among the six cases of cerebral venous sinus thrombosis reported to the Vaccine Adverse Event Reporting System after the J&J shot, all were women aged 18-48 years and all developed the clots 6-13 days after receiving the vaccine.

No cases of these clots have been reported from either the Pfizer or Moderna shots, she noted.

In the United States, the two mRNA vaccine alternatives – the Moderna and Pfizer vaccines – are available “and based on current projections supply of both vaccines are expected to be relatively stable in the near future,” she said.

She said 14 million doses of Pfizer and Moderna are expected each week in the United States and J&J vaccines makes up less than 5% of vaccines administered in the country.

Approximately 13 million J&J doses are available to order or are already at administration sites, she said.

But much more is unknown, she said.

“There may be more cases identified in the coming days to weeks,” Dr. Oliver said, referring back to the average time from vaccination to symptom onset.

Scott Ratzan, MD, editor-in-chief of the Journal of Health Communication: International Perspectives and executive director of Business Partners to CONVINCE (BP2C), a global network of employers that promotes COVID-19 vaccination among employees, suppliers, and customers, applauded ACIP’s delay on making a decision.

Dr. Ratzan, who watched the deliberations online, said in an interview the decision “shows an admirable abundance of caution in the distribution of COVID-19 vaccines.”

“Unfortunately,” he said, “the pause also worsens the existing and pervasive vaccine hesitancy issue.

“We need a rational strategy regarding who should or should not get the J&J/Janssen vaccine since these rare adverse events appear to affect a particular group of people, females aged 18-48. It is essential that we build vaccine confidence and retain the option of using this vaccine for people who are not in this risk group.”

He pointed out there are safety red flags with the Pfizer and Moderna COVID-19 vaccines.

“We should feel reassured about the process of ensuring vaccine safety as the FDA and CDC have quickly addressed risk and shared the data transparently of the J&J vaccine and taken appropriate action,” he said.

ACIP’s executive secretary, Amanda Cohn, MD, said the date for the next meeting would be set by April 16.

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

The recommended pause in use of the Johnson & Johnson COVID-19 vaccine will last at least another week after a Centers for Disease Control and Prevention advisory committee on April 14 decided not to take action.

Johnson &amp; Johnson

The Advisory Committee on Immunization Practices decided there was not adequate information to change again recommend use of the Johnson & Johnson vaccine.

The committee’s decision comes the day after the CDC and Food and Drug Administration recommended that J&J injections be paused after reports of rare, but serious types of blood clots in six patients among the 6.8 million people who had received the J&J vaccine in the United States.

A member of the committee, Beth Bell, MD, said: “I do not want to be sending a message that there is some huge concern here on a different order of magnitude than any other vaccine safety signals that we evaluate. And I don’t want to send a message that there is something fundamentally wrong with the vaccine because that also I don’t agree with.”

At the end of the 4-hour meeting, ACIP members decided to call a meeting in 1 or 2 weeks and evaluate more safety data, specifically reports of people who have received the J&J vaccine in the past 2 weeks.

Some, however, pointed out that delaying a decision could have substantial consequences as well in terms of unused vaccine doses and public confidence.

Committee member Camiile Kotton, MD, described the pause as “devastating.”

“Putting this vaccine on pause for those of us that are frontline health care workers has really been devastating,” she said. “I agree in general that we don’t have enough data to make a decision at this time but we were planning on using this vaccine in the state of Massachusetts for people who were homebound and otherwise not able to get a vaccine. We were planning on using it for our vulnerable inpatient population often with many comorbidities and at high risk for disease but haven’t been able to get vaccinated otherwise.”

Pausing the one-and-done vaccine that doesn’t have the significant refrigeration requirements of the others “is a significant loss,” she said.
 

What is known, not known

Sara Oliver, MD, who leads the COVID-19 Vaccines ACIP Work Group, summarized what is known and unknown about the blood clots.

Among the six cases of cerebral venous sinus thrombosis reported to the Vaccine Adverse Event Reporting System after the J&J shot, all were women aged 18-48 years and all developed the clots 6-13 days after receiving the vaccine.

No cases of these clots have been reported from either the Pfizer or Moderna shots, she noted.

In the United States, the two mRNA vaccine alternatives – the Moderna and Pfizer vaccines – are available “and based on current projections supply of both vaccines are expected to be relatively stable in the near future,” she said.

She said 14 million doses of Pfizer and Moderna are expected each week in the United States and J&J vaccines makes up less than 5% of vaccines administered in the country.

Approximately 13 million J&J doses are available to order or are already at administration sites, she said.

But much more is unknown, she said.

“There may be more cases identified in the coming days to weeks,” Dr. Oliver said, referring back to the average time from vaccination to symptom onset.

Scott Ratzan, MD, editor-in-chief of the Journal of Health Communication: International Perspectives and executive director of Business Partners to CONVINCE (BP2C), a global network of employers that promotes COVID-19 vaccination among employees, suppliers, and customers, applauded ACIP’s delay on making a decision.

Dr. Ratzan, who watched the deliberations online, said in an interview the decision “shows an admirable abundance of caution in the distribution of COVID-19 vaccines.”

“Unfortunately,” he said, “the pause also worsens the existing and pervasive vaccine hesitancy issue.

“We need a rational strategy regarding who should or should not get the J&J/Janssen vaccine since these rare adverse events appear to affect a particular group of people, females aged 18-48. It is essential that we build vaccine confidence and retain the option of using this vaccine for people who are not in this risk group.”

He pointed out there are safety red flags with the Pfizer and Moderna COVID-19 vaccines.

“We should feel reassured about the process of ensuring vaccine safety as the FDA and CDC have quickly addressed risk and shared the data transparently of the J&J vaccine and taken appropriate action,” he said.

ACIP’s executive secretary, Amanda Cohn, MD, said the date for the next meeting would be set by April 16.

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

The recommended pause in use of the Johnson & Johnson COVID-19 vaccine will last at least another week after a Centers for Disease Control and Prevention advisory committee on April 14 decided not to take action.

Johnson &amp; Johnson

The Advisory Committee on Immunization Practices decided there was not adequate information to change again recommend use of the Johnson & Johnson vaccine.

The committee’s decision comes the day after the CDC and Food and Drug Administration recommended that J&J injections be paused after reports of rare, but serious types of blood clots in six patients among the 6.8 million people who had received the J&J vaccine in the United States.

A member of the committee, Beth Bell, MD, said: “I do not want to be sending a message that there is some huge concern here on a different order of magnitude than any other vaccine safety signals that we evaluate. And I don’t want to send a message that there is something fundamentally wrong with the vaccine because that also I don’t agree with.”

At the end of the 4-hour meeting, ACIP members decided to call a meeting in 1 or 2 weeks and evaluate more safety data, specifically reports of people who have received the J&J vaccine in the past 2 weeks.

Some, however, pointed out that delaying a decision could have substantial consequences as well in terms of unused vaccine doses and public confidence.

Committee member Camiile Kotton, MD, described the pause as “devastating.”

“Putting this vaccine on pause for those of us that are frontline health care workers has really been devastating,” she said. “I agree in general that we don’t have enough data to make a decision at this time but we were planning on using this vaccine in the state of Massachusetts for people who were homebound and otherwise not able to get a vaccine. We were planning on using it for our vulnerable inpatient population often with many comorbidities and at high risk for disease but haven’t been able to get vaccinated otherwise.”

Pausing the one-and-done vaccine that doesn’t have the significant refrigeration requirements of the others “is a significant loss,” she said.
 

What is known, not known

Sara Oliver, MD, who leads the COVID-19 Vaccines ACIP Work Group, summarized what is known and unknown about the blood clots.

Among the six cases of cerebral venous sinus thrombosis reported to the Vaccine Adverse Event Reporting System after the J&J shot, all were women aged 18-48 years and all developed the clots 6-13 days after receiving the vaccine.

No cases of these clots have been reported from either the Pfizer or Moderna shots, she noted.

In the United States, the two mRNA vaccine alternatives – the Moderna and Pfizer vaccines – are available “and based on current projections supply of both vaccines are expected to be relatively stable in the near future,” she said.

She said 14 million doses of Pfizer and Moderna are expected each week in the United States and J&J vaccines makes up less than 5% of vaccines administered in the country.

Approximately 13 million J&J doses are available to order or are already at administration sites, she said.

But much more is unknown, she said.

“There may be more cases identified in the coming days to weeks,” Dr. Oliver said, referring back to the average time from vaccination to symptom onset.

Scott Ratzan, MD, editor-in-chief of the Journal of Health Communication: International Perspectives and executive director of Business Partners to CONVINCE (BP2C), a global network of employers that promotes COVID-19 vaccination among employees, suppliers, and customers, applauded ACIP’s delay on making a decision.

Dr. Ratzan, who watched the deliberations online, said in an interview the decision “shows an admirable abundance of caution in the distribution of COVID-19 vaccines.”

“Unfortunately,” he said, “the pause also worsens the existing and pervasive vaccine hesitancy issue.

“We need a rational strategy regarding who should or should not get the J&J/Janssen vaccine since these rare adverse events appear to affect a particular group of people, females aged 18-48. It is essential that we build vaccine confidence and retain the option of using this vaccine for people who are not in this risk group.”

He pointed out there are safety red flags with the Pfizer and Moderna COVID-19 vaccines.

“We should feel reassured about the process of ensuring vaccine safety as the FDA and CDC have quickly addressed risk and shared the data transparently of the J&J vaccine and taken appropriate action,” he said.

ACIP’s executive secretary, Amanda Cohn, MD, said the date for the next meeting would be set by April 16.

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

True Blood casting call!

Lauren Bates/Moments/via Getty Images

If you’ve seen the show True Blood on HBO, you’re probably familiar with blood coming out instead of tears when any of the vampires start crying. Apparently, this interesting phenomenon isn’t unique to vampires on TV.

If you know about female anatomy, you know that the eyes aren’t usually involved in the menstrual cycle. However, a 25-year-old woman went to the ED when she experienced haemolacria, the term for blood tears, for the second time in 2 months during her cycle. She did not appear to have any injuries or illnesses that caused the eye bleeding, but physicians noted that both times she had eye bleeding, she also had her period.

Menstrual bleeding outside of the uterus, called vicarious menstruation, can occur, and it seems that the patient may have had that condition.

Since there are rumors of a True Blood remake circling, perhaps the show’s writers could blend in a little medical fact with vampire fiction.
 

What does skinny smell like? Lemons apparently

anilakkus/E+/via Getty Images

When you smell a lemon, what comes to your mind? How does it make you feel? Now think of the scent of vanilla. How does that one make you feel? Current research suggests certain smells may have an effect on how you perceive your body image.

Researchers from the University of Sussex (England) have found that certain olfactory stimuli (such as lemons and vanilla) and audio stimuli (light steps vs. heavy steps), have a moderate effect on self-image.

During their study, participants were put through a series of auditory and olfactory tests, from listening to stilettos and boots walking across the floor, to being exposed to certain essential oils with different sound pitches.

Exposure to lemon and higher-pitched sounds (like stilettos) made participants feel lighter and was associated with thin, spiky shapes. Exposure to vanilla and lower-pitched sounds was more associated with thicker, rounded shapes. This made researchers believe that multisensory stimuli, such as scents and sounds, can have a bigger role in treating eating disorders.

Our brain functions with multiple “mental models” of ourselves. Based on sensory stimuli from our day-to-day lives, those images and perceptions of ourselves change. Someone complimenting your snazzy new sweater provokes one self-perception, while someone letting you know that your fly is down provokes another.

Well, the researchers believe that, through a sense of smell, we can alter that perception of ourselves when paired with positive influence. Doing this through wearable “interactive clothes” could help boost the confidence and self-esteem of patients struggling with body image. Light smells equals light feelings. Of course, this won’t help the nearly 5% of the world who have some kind of smell disorder.

The researchers said that more research needs to be done, but you can do your own little experiment at home. Think about yourself and how you react to certain smells. How do they make you feel? If it makes you feel good, stop and smell more often.
 

Pregnancy with a side of pregnancy

It was a great day when Rebecca Roberts and her partner went to the obstetrician to confirm their positive pregnancy test. They’d been trying for more than a year without success, and now they would be having a baby. Note the usage of the singular there. That will become important in a moment.

When Ms. Roberts went back for her 12-week ultrasound appointment, there was an unexpected complication: Baby had become babies. The original fetus was there and doing fine, but there was now a second, less-developed fetus who’d invited herself in unannounced. While they were technically twins, the second fetus did not form at the same time, like normal fraternal twins, instead forming from an egg that was released weeks after the first egg was fertilized.

The phenomenon, called superfetation, is incredibly rare. Prior to 2008, there were fewer than 10 reported cases in the world, according to the European Journal of Obstetrics & Gynecology and Reproductive Biology. The odds of an egg being released during pregnancy, something that’s not supposed to happen, and then having that egg also become fertilized and successfully implanted in the uterus, is astronomically small.

It was not an easy pregnancy for Ms. Roberts, and at 33 weeks into the first pregnancy, the younger fetus’s umbilical cord began to malfunction, so delivery for both was induced in September 2020. Both infants spent time in the neonatal ICU, with the younger baby being in for 3 months, but after 6 months both are doing well and developing quickly. It’s always nice to have a happy ending to one of these weird medical phenomena, especially one with such an unpleasant-sounding name. If we didn’t know better, we’d think superfetation was something really, really smelly.
 

What’s a little misinformation among neighbors?

Frank Schiefelbein/EyeEm/via Getty Images

Vaccination will, hopefully, get the COVID-19 pandemic under control at some point, but the related misinformation floating around the Internet is another story. Already rampant in the United States, it’s now spreading … to Canada.

Investigators from that northern land took a look at the Twitter accounts of the platform’s 187,000 most active Canadian users and eventually ended up with a database of 147 million tweets, of which 154,000 contained terms associated with misinformation.

The Canadian social media users had more exposure to information from the United States than from Canada, and the exposure to U.S. outlets was more likely to involve misperceptions about COVID-19. “Most of the misinformation circulating on Twitter shared by Canadians was retweeted from U.S. sources,” the researchers said, and “Canadians who followed more American users were more likely to post misinformation.”

The study’s lead investigator, Aengus Bridgman of McGill University in Montreal, put it this way: “It’s hard for Canadian journalists, scientists, and public health experts to be heard by the average Canadian, given all the noise generated by American sources.”

People generally don’t take the time to read the fine print on contracts, and it looks like the Canadians have fallen into that trap. Not entirely their fault, of course, because most people coming from Canada to America don’t pass the Statue of Liberty, but she’s got some fine print of her own.

That poem written on the pedestal, the one that says, “Give me your tired, your poor, your huddled masses yearning to breathe free”? It’s actually a contract, and at the bottom, in very small print, it says, “In return for acceptance of the aforementioned ‘huddled masses,’ countries of origin agree to accept all of the social media noise generated by American sources.”

Sorry, Canada, but we gotcha.
 

True Blood casting call!

Lauren Bates/Moments/via Getty Images

If you’ve seen the show True Blood on HBO, you’re probably familiar with blood coming out instead of tears when any of the vampires start crying. Apparently, this interesting phenomenon isn’t unique to vampires on TV.

If you know about female anatomy, you know that the eyes aren’t usually involved in the menstrual cycle. However, a 25-year-old woman went to the ED when she experienced haemolacria, the term for blood tears, for the second time in 2 months during her cycle. She did not appear to have any injuries or illnesses that caused the eye bleeding, but physicians noted that both times she had eye bleeding, she also had her period.

Menstrual bleeding outside of the uterus, called vicarious menstruation, can occur, and it seems that the patient may have had that condition.

Since there are rumors of a True Blood remake circling, perhaps the show’s writers could blend in a little medical fact with vampire fiction.
 

What does skinny smell like? Lemons apparently

anilakkus/E+/via Getty Images

When you smell a lemon, what comes to your mind? How does it make you feel? Now think of the scent of vanilla. How does that one make you feel? Current research suggests certain smells may have an effect on how you perceive your body image.

Researchers from the University of Sussex (England) have found that certain olfactory stimuli (such as lemons and vanilla) and audio stimuli (light steps vs. heavy steps), have a moderate effect on self-image.

During their study, participants were put through a series of auditory and olfactory tests, from listening to stilettos and boots walking across the floor, to being exposed to certain essential oils with different sound pitches.

Exposure to lemon and higher-pitched sounds (like stilettos) made participants feel lighter and was associated with thin, spiky shapes. Exposure to vanilla and lower-pitched sounds was more associated with thicker, rounded shapes. This made researchers believe that multisensory stimuli, such as scents and sounds, can have a bigger role in treating eating disorders.

Our brain functions with multiple “mental models” of ourselves. Based on sensory stimuli from our day-to-day lives, those images and perceptions of ourselves change. Someone complimenting your snazzy new sweater provokes one self-perception, while someone letting you know that your fly is down provokes another.

Well, the researchers believe that, through a sense of smell, we can alter that perception of ourselves when paired with positive influence. Doing this through wearable “interactive clothes” could help boost the confidence and self-esteem of patients struggling with body image. Light smells equals light feelings. Of course, this won’t help the nearly 5% of the world who have some kind of smell disorder.

The researchers said that more research needs to be done, but you can do your own little experiment at home. Think about yourself and how you react to certain smells. How do they make you feel? If it makes you feel good, stop and smell more often.
 

Pregnancy with a side of pregnancy

It was a great day when Rebecca Roberts and her partner went to the obstetrician to confirm their positive pregnancy test. They’d been trying for more than a year without success, and now they would be having a baby. Note the usage of the singular there. That will become important in a moment.

When Ms. Roberts went back for her 12-week ultrasound appointment, there was an unexpected complication: Baby had become babies. The original fetus was there and doing fine, but there was now a second, less-developed fetus who’d invited herself in unannounced. While they were technically twins, the second fetus did not form at the same time, like normal fraternal twins, instead forming from an egg that was released weeks after the first egg was fertilized.

The phenomenon, called superfetation, is incredibly rare. Prior to 2008, there were fewer than 10 reported cases in the world, according to the European Journal of Obstetrics & Gynecology and Reproductive Biology. The odds of an egg being released during pregnancy, something that’s not supposed to happen, and then having that egg also become fertilized and successfully implanted in the uterus, is astronomically small.

It was not an easy pregnancy for Ms. Roberts, and at 33 weeks into the first pregnancy, the younger fetus’s umbilical cord began to malfunction, so delivery for both was induced in September 2020. Both infants spent time in the neonatal ICU, with the younger baby being in for 3 months, but after 6 months both are doing well and developing quickly. It’s always nice to have a happy ending to one of these weird medical phenomena, especially one with such an unpleasant-sounding name. If we didn’t know better, we’d think superfetation was something really, really smelly.
 

What’s a little misinformation among neighbors?

Frank Schiefelbein/EyeEm/via Getty Images

Vaccination will, hopefully, get the COVID-19 pandemic under control at some point, but the related misinformation floating around the Internet is another story. Already rampant in the United States, it’s now spreading … to Canada.

Investigators from that northern land took a look at the Twitter accounts of the platform’s 187,000 most active Canadian users and eventually ended up with a database of 147 million tweets, of which 154,000 contained terms associated with misinformation.

The Canadian social media users had more exposure to information from the United States than from Canada, and the exposure to U.S. outlets was more likely to involve misperceptions about COVID-19. “Most of the misinformation circulating on Twitter shared by Canadians was retweeted from U.S. sources,” the researchers said, and “Canadians who followed more American users were more likely to post misinformation.”

The study’s lead investigator, Aengus Bridgman of McGill University in Montreal, put it this way: “It’s hard for Canadian journalists, scientists, and public health experts to be heard by the average Canadian, given all the noise generated by American sources.”

People generally don’t take the time to read the fine print on contracts, and it looks like the Canadians have fallen into that trap. Not entirely their fault, of course, because most people coming from Canada to America don’t pass the Statue of Liberty, but she’s got some fine print of her own.

That poem written on the pedestal, the one that says, “Give me your tired, your poor, your huddled masses yearning to breathe free”? It’s actually a contract, and at the bottom, in very small print, it says, “In return for acceptance of the aforementioned ‘huddled masses,’ countries of origin agree to accept all of the social media noise generated by American sources.”

Sorry, Canada, but we gotcha.
 

True Blood casting call!

Lauren Bates/Moments/via Getty Images

If you’ve seen the show True Blood on HBO, you’re probably familiar with blood coming out instead of tears when any of the vampires start crying. Apparently, this interesting phenomenon isn’t unique to vampires on TV.

If you know about female anatomy, you know that the eyes aren’t usually involved in the menstrual cycle. However, a 25-year-old woman went to the ED when she experienced haemolacria, the term for blood tears, for the second time in 2 months during her cycle. She did not appear to have any injuries or illnesses that caused the eye bleeding, but physicians noted that both times she had eye bleeding, she also had her period.

Menstrual bleeding outside of the uterus, called vicarious menstruation, can occur, and it seems that the patient may have had that condition.

Since there are rumors of a True Blood remake circling, perhaps the show’s writers could blend in a little medical fact with vampire fiction.
 

What does skinny smell like? Lemons apparently

anilakkus/E+/via Getty Images

When you smell a lemon, what comes to your mind? How does it make you feel? Now think of the scent of vanilla. How does that one make you feel? Current research suggests certain smells may have an effect on how you perceive your body image.

Researchers from the University of Sussex (England) have found that certain olfactory stimuli (such as lemons and vanilla) and audio stimuli (light steps vs. heavy steps), have a moderate effect on self-image.

During their study, participants were put through a series of auditory and olfactory tests, from listening to stilettos and boots walking across the floor, to being exposed to certain essential oils with different sound pitches.

Exposure to lemon and higher-pitched sounds (like stilettos) made participants feel lighter and was associated with thin, spiky shapes. Exposure to vanilla and lower-pitched sounds was more associated with thicker, rounded shapes. This made researchers believe that multisensory stimuli, such as scents and sounds, can have a bigger role in treating eating disorders.

Our brain functions with multiple “mental models” of ourselves. Based on sensory stimuli from our day-to-day lives, those images and perceptions of ourselves change. Someone complimenting your snazzy new sweater provokes one self-perception, while someone letting you know that your fly is down provokes another.

Well, the researchers believe that, through a sense of smell, we can alter that perception of ourselves when paired with positive influence. Doing this through wearable “interactive clothes” could help boost the confidence and self-esteem of patients struggling with body image. Light smells equals light feelings. Of course, this won’t help the nearly 5% of the world who have some kind of smell disorder.

The researchers said that more research needs to be done, but you can do your own little experiment at home. Think about yourself and how you react to certain smells. How do they make you feel? If it makes you feel good, stop and smell more often.
 

Pregnancy with a side of pregnancy

It was a great day when Rebecca Roberts and her partner went to the obstetrician to confirm their positive pregnancy test. They’d been trying for more than a year without success, and now they would be having a baby. Note the usage of the singular there. That will become important in a moment.

When Ms. Roberts went back for her 12-week ultrasound appointment, there was an unexpected complication: Baby had become babies. The original fetus was there and doing fine, but there was now a second, less-developed fetus who’d invited herself in unannounced. While they were technically twins, the second fetus did not form at the same time, like normal fraternal twins, instead forming from an egg that was released weeks after the first egg was fertilized.

The phenomenon, called superfetation, is incredibly rare. Prior to 2008, there were fewer than 10 reported cases in the world, according to the European Journal of Obstetrics & Gynecology and Reproductive Biology. The odds of an egg being released during pregnancy, something that’s not supposed to happen, and then having that egg also become fertilized and successfully implanted in the uterus, is astronomically small.

It was not an easy pregnancy for Ms. Roberts, and at 33 weeks into the first pregnancy, the younger fetus’s umbilical cord began to malfunction, so delivery for both was induced in September 2020. Both infants spent time in the neonatal ICU, with the younger baby being in for 3 months, but after 6 months both are doing well and developing quickly. It’s always nice to have a happy ending to one of these weird medical phenomena, especially one with such an unpleasant-sounding name. If we didn’t know better, we’d think superfetation was something really, really smelly.
 

What’s a little misinformation among neighbors?

Frank Schiefelbein/EyeEm/via Getty Images

Vaccination will, hopefully, get the COVID-19 pandemic under control at some point, but the related misinformation floating around the Internet is another story. Already rampant in the United States, it’s now spreading … to Canada.

Investigators from that northern land took a look at the Twitter accounts of the platform’s 187,000 most active Canadian users and eventually ended up with a database of 147 million tweets, of which 154,000 contained terms associated with misinformation.

The Canadian social media users had more exposure to information from the United States than from Canada, and the exposure to U.S. outlets was more likely to involve misperceptions about COVID-19. “Most of the misinformation circulating on Twitter shared by Canadians was retweeted from U.S. sources,” the researchers said, and “Canadians who followed more American users were more likely to post misinformation.”

The study’s lead investigator, Aengus Bridgman of McGill University in Montreal, put it this way: “It’s hard for Canadian journalists, scientists, and public health experts to be heard by the average Canadian, given all the noise generated by American sources.”

People generally don’t take the time to read the fine print on contracts, and it looks like the Canadians have fallen into that trap. Not entirely their fault, of course, because most people coming from Canada to America don’t pass the Statue of Liberty, but she’s got some fine print of her own.

That poem written on the pedestal, the one that says, “Give me your tired, your poor, your huddled masses yearning to breathe free”? It’s actually a contract, and at the bottom, in very small print, it says, “In return for acceptance of the aforementioned ‘huddled masses,’ countries of origin agree to accept all of the social media noise generated by American sources.”

Sorry, Canada, but we gotcha.
 

An advisory committee to the Centers for Disease Control and Prevention is addressing the safety of the Johnson & Johnson COVID-19 vaccine on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.

This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.

According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.

On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.

In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.

“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness. 

“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.

Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.

Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria. 

This has experts questioning whether all vaccines of this type may cause these rare clots.

“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
 

Adenovirus vaccines scrutinized

Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.

Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses. 

Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system. 

The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.

There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.

The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.

Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans. 

Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.

There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.

Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport. 

But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.

The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1. 

Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.

On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.

The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.

The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.

So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.

A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.

The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.

“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
 

Studies suggest possible mechanism

On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.

The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.

These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.

It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.

The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).

It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.

“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”

No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.

Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising. 
 

Grappling with evidence

The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.

Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.

With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.

They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.

Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.

“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.

“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.

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

An advisory committee to the Centers for Disease Control and Prevention is addressing the safety of the Johnson & Johnson COVID-19 vaccine on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.

This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.

According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.

On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.

In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.

“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness. 

“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.

Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.

Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria. 

This has experts questioning whether all vaccines of this type may cause these rare clots.

“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
 

Adenovirus vaccines scrutinized

Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.

Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses. 

Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system. 

The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.

There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.

The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.

Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans. 

Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.

There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.

Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport. 

But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.

The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1. 

Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.

On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.

The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.

The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.

So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.

A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.

The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.

“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
 

Studies suggest possible mechanism

On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.

The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.

These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.

It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.

The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).

It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.

“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”

No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.

Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising. 
 

Grappling with evidence

The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.

Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.

With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.

They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.

Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.

“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.

“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.

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

An advisory committee to the Centers for Disease Control and Prevention is addressing the safety of the Johnson & Johnson COVID-19 vaccine on April 14, 2021, after the CDC and Food and Drug Administration recommended that states hold off on using it pending a detailed review of six cases of the same kind of rare but serious event – a blood clot in the vessels that drain blood from the brain combined with a large drop in platelets, which increases the risk for bleeding.

This combination can lead to severe strokes that can lead to brain damage or death. Among the six cases reported, which came to light over the past 3 weeks, one person died, according to the CDC. All six were women and ranged in age from 18 to 48 years.

According to a report from the Vaccine Adverse Event Reporting System (VAERS), which is maintained by the Department of Health & Human Services, the woman who died was 45. She developed a gradually worsening headache about a week after receiving the Johnson & Johnson vaccine.

On March 17, the day she came to the hospital, she was dry heaving. Her headache had suddenly gotten much worse, and the left side of her body was weak, which are signs of a stroke. A CT scan revealed both bleeding in her brain and a clot in her cortical vein. She died the following day.

In addition to VAERS, which accepts reports from anyone, the CDC and FDA are monitoring at least eight other safety systems maintained by hospitals, research centers, long-term care facilities, and insurance companies for signs of trouble with the vaccines. VAERS data is searchable and open to the public. Most of these systems are not publicly available to protect patient privacy. It’s unclear which systems detected the six cases cited by federal regulators.

“These are very serious and potentially fatal problems occurring in a healthy young adult. It’s serious and we need to get to the bottom of it,” said Ed Belongia, MD, director of the Center for Clinical Epidemiology and Population Health at the Marshfield (Wis.) Clinic Research Institute. Dr. Belongia leads a research team that helps the CDC monitor vaccine safety and effectiveness. 

“Safety is always the highest priority, and I think what we’ve seen here in the past 24 hours is our vaccine safety monitoring system is working,” he said.

Others agree. “I think what CDC and FDA have detected is a rare, but likely real adverse event associated with this vaccine,” said Paul Offit, MD, director of vaccine education at Children’s Hospital of Philadelphia.

Although much is still unknown about these events, they follow a similar pattern of blood clots reported with the AstraZeneca vaccine in Europe. That vaccine is now sold under the brand name Vaxzevria. 

This has experts questioning whether all vaccines of this type may cause these rare clots.

“I think it’s likely a class effect,” said Dr. Offit, who was a member of the FDA advisory committee that reviewed clinical trial data on the J&J vaccine before it was authorized for use.
 

Adenovirus vaccines scrutinized

Both the Johnson & Johnson and Vaxzevria vaccines use an adenovirus to ferry genetic instructions for making the coronaviruses spike protein into our cells.

Adenoviruses are common, relatively simple viruses that normally cause mild cold or flu symptoms. The ones used in the vaccine are disabled so they can’t make us sick. They’re more like Trojan horses. 

Once inside our cells, they release the DNA instructions they carry to make the spike protein of the new coronavirus. Those cells then crank out copies of the spike protein, which then get displayed on the outer surface of the cell membrane where they are recognized by the immune system. 

The immune system then makes antibodies and other defenses against the spike so that, when the real coronavirus comes along, our bodies are ready to fight the infection.

There’s no question the vaccine works. In clinical trials, the Johnson & Johnson vaccine was 66% percent effective at preventing against moderate to severe COVID-19 infection, and none of the patients who got COVID-19 after vaccination had to be admitted to the hospital or died.

The idea behind using adenoviruses in vaccines isn’t a new one. In a kind of fight-fire-with-fire approach, the idea is to use a virus, which is good at infecting us, to fight a different kind of virus.

Researchers have been working on the concept for about 10 years, but the COVID-19 vaccines that use this technology are some of the first adenovirus-vector vaccines deployed in humans. 

Only one other adenovirus vaccine, for Ebola, has been approved for use in humans. It was approved in Europe last year. Before the Johnson & Johnson vaccine, no other adenovirus vector has been available for use in humans in the United States.

There are six adenovirus-vector vaccines for COVID-19. In addition to AstraZeneca and Johnson & Johnson, there’s the Russian-developed vaccine Sputnik V, along with CanSino from China, and the Covishield vaccine in India.

Adenovirus vaccines are more stable than the mRNA vaccines. That makes them easier to store and transport. 

But they have a significant downside, too. Because adenoviruses infect humans out in the world, we already make antibodies against them. So there’s always a danger that our immune systems might recognize and react to the vaccine, rendering it ineffective. For that reason, scientists try to carefully select the adenovirus vectors, or carriers, they use.

The two vaccines under investigation for blood clots are slightly different. The Johnson & Johnson vaccine uses the vector AD26, because most of the population lacks preexisting immunity to it. Vaxzevria uses an adenovirus that infects chimpanzees, called ChAdOx1. 

Vaxzevria has been widely used in Europe but has not yet been authorized in the United States.

On April 7, the European Medicines Agency, Europe’s counterpart to the FDA, ruled that unusual blood clots with low blood platelets should be listed as rare side effects on the Vaxzevria vaccine.

The decision came after reviewing 62 cases of cerebral venous sinus thrombosis (CVST) linked to the vaccine and 25 cases of another rare type of clot, called a splanchnic vein thrombosis. Splanchnic veins drain blood from the major organs in the digestive system, including the stomach, liver, and intestines; 18 of those events were fatal.

The reports were culled from reporting in Europe and the United Kingdom, where around 25 million people have received the Vaxzevria vaccine, making these clots exceptionally rare, but serious.

So far, six cases of CVST have been reported in the United States, after more than 7 million doses of the Johnson & Johnson vaccines have been administered.

A key question for U.S. regulators will be the background rate for these types of rare combinations of clots and deplenished platelets. The background rate is the number of events that would be expected to occur naturally in a population of unvaccinated people. On a press call on April 13, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, was asked about the frequency of this dangerous combination. He said the combination of low platelets and clots was so rare that it was hard to pinpoint, but might be somewhere between 2 and 14 cases per million people over the course of a year.

The first Johnson & Johnson doses were given in early March. That means the six cases came to light within the first few weeks of use of the vaccine in the United States, a very short amount of time.

“These were six cases per million people for 2 weeks, which is the same thing as 25 million per year, so it’s clearly above the background rate,” Dr. Offit said.
 

Studies suggest possible mechanism

On April 9, the New England Journal of Medicine published a detailed evaluation of the 11 patients in Germany and Austria who developed the rare clots after their Vaxzevria vaccines.

The study detected rare antibodies to a signaling protein called platelet factor 4, which helps to coordinate clot formation.

These same type of antibodies form in some people given the blood thinning drug heparin. In those reactions, which are also exceptionally rare, the same type of syndrome develops, leading to large, devastating clots that consume circulating platelets.

It’s not yet clear whether people who develop reactions to the vaccines already have some platelet factor 4 antibodies before they are vaccinated, or whether the vaccines somehow spur the body to make these antibodies, which then launch a kind of autoimmune attack.

The researchers on the paper gave the syndrome a name, vaccine-induced thrombotic thrombocytopenia (VITT).

It’s also not clear why more cases seem to be in women than in men. Andrew Eisenberger, MD, an associate professor of hematology and oncology at Columbia University, New York, said the most common causes of cerebral venous sinus thrombosis have to do with conditions that raise estrogen levels, like pregnancy and hormonal contraception.

“Estrogen naturally leads to changes in several clotting proteins in the blood that may predispose to abnormal blood clotting in a few different sites in the body,” he said. “The clotting changes we are encountering with some of COVID-19 vaccines are likely to be synergistic with the effects of estrogen on the blood.”

No matter the cause, the CDC on April 13 alerted doctors to keep a high index of suspicion for VITT in patients who have received the Johnson & Johnson vaccination within the last 2 weeks. In those patients, the usual course of treatment with blood thinning drugs like heparin may be harmful.

Symptoms to watch for include severe headache or backache, new neurologic symptoms, severe abdominal pain, shortness of breath, leg swelling, tiny red spots on the skin, or easy bruising. 
 

Grappling with evidence

The CDC’s Advisory Committee on Immunization Practices will meet today in an emergency session to review the cases and see if any changes are needed to use of the J&J vaccine in the United States.

Last week, for example, the United Kingdom restricted the use of the AstraZeneca vaccine in people aged younger than 30 years, saying the risks and benefits of vaccination are “more finely balanced” for this age group.

With cases of COVID-19 rising again in the United States, and the Johnson & Johnson vaccine currently the most convenient form of protection against the virus, the committee will have to weigh the risks of that infection against the risk of rare clots caused by vaccination.

They will also likely have to rule out whether any of the cases had COVID. At least one study has reported CVST clots in three patients with confirmed COVID infections. In Europe, COVID infection did not seem to play a role in the formation of the clots with low platelets.

Hilda Bastian, PhD, a clinical trials expert who cofounded the Cochrane Collaboration, said it won’t be an easy task. Much will depend on how certain the committee members feel they know about all the events linked to the vaccine.

“That’s the really, really hard issue from my point of view for them right this moment. Have we missed any? Or how many are we likely to have missed?” asked Dr. Bastian, who lives in Australia.

“In a country that size with that fragmented [of] a health care system, how sure can you be that you know them all? That’s going to be a really difficult situation for them to grapple with, the quality of information that they’ve got,” she said.

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

On April 13, the Centers for Disease Control and Prevention and the Food and Drug Administration issued a joint statement recommending a pause in Johnson & Johnson vaccine administration, pending review of six reported U.S. cases of a rare and severe type of blood clot occurring after receiving the Johnson & Johnson vaccine. To date, more than 6.8 million doses of that vaccine have been given in the United States, so at this point the rate of detected cases of this problem is less than one in a million.

The six cases occurred in women aged 18-48 years, and symptoms occurred 6-13 days after vaccination. In these cases, cerebral venous sinus thrombosis was seen in addition to thrombocytopenia.

Physicians may receive calls from concerned patients who have received a COVID vaccine. However, more than 95% of the vaccine administrations in the United States to date have been the Pfizer and Moderna messenger RNA vaccines. No association between these vaccines and blood clots has been detected. Also, these six cases occurred within 2 weeks of Johnson & Johnson vaccination, so even among those receiving the Johnson & Johnson vaccine, those who are more than 3 weeks out from their vaccination have no need for concern regarding this rare complication.

Physicians should counsel those who have received the Johnson & Johnson vaccine less than 3 weeks ago to watch for easy bruising, gum bleeding, nose bleeds, leg or arm pain or swelling, severe headache or abdominal pain, shortness of breath, or chest pain. If they notice one or more of those symptoms, they should seek medical attention.

The Centers for Disease Control and Prevention will convene a meeting of the Advisory Committee on Immunization Practices on April 14 to review the six U.S. cases of the Johnson & Johnson vaccine and determine their significance.

Several cases of unusual thromboses and thrombocytopenia have been detected after the Oxford AstraZeneca vaccine, which uses the same adenovirus vector technology as the Johnson & Johnson vaccine, but which is not authorized for use in the United States. The Oxford AstraZeneca vaccine uses a recombinant deficient chimpanzee adenovirus to deliver the message to cells to produce antibody against the SARS-CoV-2 spike protein. The Johnson & Johnson vaccine uses a recombinant deficient human adenovirus to deliver this same message.  

Two recent reports in the New England Journal of Medicine have reported on thrombosis and thrombocytopenia after the Oxford AstraZeneca vaccine in Europe. Both of these reports identified high levels of IgG antibodies to platelet factor 4–polyanion complexes, similar to the mechanism of heparin-induced thrombocytopenia. The term vaccine-induced immune thrombocytopenia was proposed for this phenomenon. Treatment of this condition involves administration of intravenous immunoglobulin and nonheparin anticoagulants. Recent updates from the World Health Organization report that 169 cases of cerebral venous sinus thrombosis and 53 of splanchnic venous thrombosis occurred after 34 million doses of the Oxford AstraZeneca vaccine was administered in the European Union and United Kingdom.

While this pause in Johnson & Johnson vaccination is disappointing news amid increased cases in parts of the country, the Johnson & Johnson vaccines make up less than 5% of the U.S. vaccine doses administered to date. According to the CDC, more than 122 million Americans have received at least one dose and more than 75 million are fully vaccinated.

Dr. Patterson has received an honorarium from Pfizer for an antifungal symposium and is a subinvestigator for the Novavax vaccine. Her spouse served as a consultant for SCYNEXIS, as a speaker for Gilead Sciences and Basilea, and has received a research grant from the National Institutes of Health for the ACTT remdesivir trial.

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

On April 13, the Centers for Disease Control and Prevention and the Food and Drug Administration issued a joint statement recommending a pause in Johnson & Johnson vaccine administration, pending review of six reported U.S. cases of a rare and severe type of blood clot occurring after receiving the Johnson & Johnson vaccine. To date, more than 6.8 million doses of that vaccine have been given in the United States, so at this point the rate of detected cases of this problem is less than one in a million.

The six cases occurred in women aged 18-48 years, and symptoms occurred 6-13 days after vaccination. In these cases, cerebral venous sinus thrombosis was seen in addition to thrombocytopenia.

Physicians may receive calls from concerned patients who have received a COVID vaccine. However, more than 95% of the vaccine administrations in the United States to date have been the Pfizer and Moderna messenger RNA vaccines. No association between these vaccines and blood clots has been detected. Also, these six cases occurred within 2 weeks of Johnson & Johnson vaccination, so even among those receiving the Johnson & Johnson vaccine, those who are more than 3 weeks out from their vaccination have no need for concern regarding this rare complication.

Physicians should counsel those who have received the Johnson & Johnson vaccine less than 3 weeks ago to watch for easy bruising, gum bleeding, nose bleeds, leg or arm pain or swelling, severe headache or abdominal pain, shortness of breath, or chest pain. If they notice one or more of those symptoms, they should seek medical attention.

The Centers for Disease Control and Prevention will convene a meeting of the Advisory Committee on Immunization Practices on April 14 to review the six U.S. cases of the Johnson & Johnson vaccine and determine their significance.

Several cases of unusual thromboses and thrombocytopenia have been detected after the Oxford AstraZeneca vaccine, which uses the same adenovirus vector technology as the Johnson & Johnson vaccine, but which is not authorized for use in the United States. The Oxford AstraZeneca vaccine uses a recombinant deficient chimpanzee adenovirus to deliver the message to cells to produce antibody against the SARS-CoV-2 spike protein. The Johnson & Johnson vaccine uses a recombinant deficient human adenovirus to deliver this same message.  

Two recent reports in the New England Journal of Medicine have reported on thrombosis and thrombocytopenia after the Oxford AstraZeneca vaccine in Europe. Both of these reports identified high levels of IgG antibodies to platelet factor 4–polyanion complexes, similar to the mechanism of heparin-induced thrombocytopenia. The term vaccine-induced immune thrombocytopenia was proposed for this phenomenon. Treatment of this condition involves administration of intravenous immunoglobulin and nonheparin anticoagulants. Recent updates from the World Health Organization report that 169 cases of cerebral venous sinus thrombosis and 53 of splanchnic venous thrombosis occurred after 34 million doses of the Oxford AstraZeneca vaccine was administered in the European Union and United Kingdom.

While this pause in Johnson & Johnson vaccination is disappointing news amid increased cases in parts of the country, the Johnson & Johnson vaccines make up less than 5% of the U.S. vaccine doses administered to date. According to the CDC, more than 122 million Americans have received at least one dose and more than 75 million are fully vaccinated.

Dr. Patterson has received an honorarium from Pfizer for an antifungal symposium and is a subinvestigator for the Novavax vaccine. Her spouse served as a consultant for SCYNEXIS, as a speaker for Gilead Sciences and Basilea, and has received a research grant from the National Institutes of Health for the ACTT remdesivir trial.

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

On April 13, the Centers for Disease Control and Prevention and the Food and Drug Administration issued a joint statement recommending a pause in Johnson & Johnson vaccine administration, pending review of six reported U.S. cases of a rare and severe type of blood clot occurring after receiving the Johnson & Johnson vaccine. To date, more than 6.8 million doses of that vaccine have been given in the United States, so at this point the rate of detected cases of this problem is less than one in a million.

The six cases occurred in women aged 18-48 years, and symptoms occurred 6-13 days after vaccination. In these cases, cerebral venous sinus thrombosis was seen in addition to thrombocytopenia.

Physicians may receive calls from concerned patients who have received a COVID vaccine. However, more than 95% of the vaccine administrations in the United States to date have been the Pfizer and Moderna messenger RNA vaccines. No association between these vaccines and blood clots has been detected. Also, these six cases occurred within 2 weeks of Johnson & Johnson vaccination, so even among those receiving the Johnson & Johnson vaccine, those who are more than 3 weeks out from their vaccination have no need for concern regarding this rare complication.

Physicians should counsel those who have received the Johnson & Johnson vaccine less than 3 weeks ago to watch for easy bruising, gum bleeding, nose bleeds, leg or arm pain or swelling, severe headache or abdominal pain, shortness of breath, or chest pain. If they notice one or more of those symptoms, they should seek medical attention.

The Centers for Disease Control and Prevention will convene a meeting of the Advisory Committee on Immunization Practices on April 14 to review the six U.S. cases of the Johnson & Johnson vaccine and determine their significance.

Several cases of unusual thromboses and thrombocytopenia have been detected after the Oxford AstraZeneca vaccine, which uses the same adenovirus vector technology as the Johnson & Johnson vaccine, but which is not authorized for use in the United States. The Oxford AstraZeneca vaccine uses a recombinant deficient chimpanzee adenovirus to deliver the message to cells to produce antibody against the SARS-CoV-2 spike protein. The Johnson & Johnson vaccine uses a recombinant deficient human adenovirus to deliver this same message.  

Two recent reports in the New England Journal of Medicine have reported on thrombosis and thrombocytopenia after the Oxford AstraZeneca vaccine in Europe. Both of these reports identified high levels of IgG antibodies to platelet factor 4–polyanion complexes, similar to the mechanism of heparin-induced thrombocytopenia. The term vaccine-induced immune thrombocytopenia was proposed for this phenomenon. Treatment of this condition involves administration of intravenous immunoglobulin and nonheparin anticoagulants. Recent updates from the World Health Organization report that 169 cases of cerebral venous sinus thrombosis and 53 of splanchnic venous thrombosis occurred after 34 million doses of the Oxford AstraZeneca vaccine was administered in the European Union and United Kingdom.

While this pause in Johnson & Johnson vaccination is disappointing news amid increased cases in parts of the country, the Johnson & Johnson vaccines make up less than 5% of the U.S. vaccine doses administered to date. According to the CDC, more than 122 million Americans have received at least one dose and more than 75 million are fully vaccinated.

Dr. Patterson has received an honorarium from Pfizer for an antifungal symposium and is a subinvestigator for the Novavax vaccine. Her spouse served as a consultant for SCYNEXIS, as a speaker for Gilead Sciences and Basilea, and has received a research grant from the National Institutes of Health for the ACTT remdesivir trial.

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

Two recent articles in the medical literature provide new information on mucocutaneous manifestations of COVID-19 in children, which may help guide dermatologists in making accurate diagnoses and stratifying children at risk for serious, systemic illness due to the virus.

In a single-center descriptive study carried out over a 9-month period, researchers in Madrid found that of 50 hospitalized children infected with COVID-19, 21 (42%) had mucocutaneous symptoms, most commonly exanthem, followed by conjunctival hyperemia without secretion and red cracked lips or strawberry tongue. In addition, 18 (36%) fulfilled criteria for Multisystem Inflammatory Syndrome in Children (MIS-C).

“Based on findings in adult patients, the skin manifestations of COVID-19 have been classified under five categories: acral pseudo-chilblain, vesicular eruptions, urticarial lesions, maculopapular eruptions, and livedo or necrosis,” David Andina-Martinez, MD, of Hospital Infantil Universitario Niño Jesús, Madrid, and colleagues wrote in the study, which was published online on April 2 in the Journal of the American Academy of Dermatology.

“Chilblain lesions in healthy children and adolescents have received much attention; these lesions resolve without complications after a few weeks,” they added. “Besides, other cutaneous manifestations of COVID-19 in children have been the matter of case reports or small case series. Nevertheless, the mucocutaneous manifestations in hospitalized children infected with SARS-CoV-2 and their implications on the clinical course have not yet been extensively described.”

In an effort to describe the mucocutaneous manifestations in children hospitalized for COVID-19, the researchers evaluated 50 children up to 18 years of age who were admitted between March 1 and Nov. 30, 2020, to Hospital Infantil Universitario Niño Jesús, which was designated as a pediatric reference center during the peak of the pandemic. The main reasons for admission were respiratory illness (40%) and MIS-C (40%).

Of the 50 patients, 44 (88%) had a positive RT-PCR for SARS-CoV-2 and 6 (12%) met clinical suspicion criteria and had a negative RT-PCR with a positive IgG serology. In 34 patients (68%), a close contact with a suspected or confirmed case of COVID-19 was referred, while the source of the infection remained unknown in the remaining 16 patients (32%).

The researchers reported that 21 patients (42%) had mucocutaneous symptoms, most commonly maculopapular exanthem (86%), conjunctival hyperemia (81%), and red cracked lips or strawberry tongue (43%). In addition, 18 of the 21 patients (86%) fulfilled criteria for MIS-C.

“A tricky thing about MIS-C is that it often manifests 4-5 weeks after a child had COVID-19,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study. “MIS-C is associated with characteristic bright red lips and a red tongue that might resemble a strawberry. Such oral findings should prompt rapid evaluation for other signs and symptoms. There can be redness of the eyes or other more nonspecific skin findings (large or small areas of redness on the trunk or limbs, sometimes with surface change), but more importantly, fever, a rapid heartbeat, diarrhea, or breathing issues. The risk with MIS-C is a rapid decline in a child’s health, with admission to an intensive care unit.”

Dr. Andina-Martinez and his colleagues also contrast the skin findings of MIS-C, which are not generally on the hands or feet, with the so-called “COVID toe” or finger phenomenon, which has also been associated with SARS-CoV-2, particularly in children. “Only one of the patients in this series had skin involvement of a finger, and it only appeared after recovery from MIS-C,” Dr. Ko noted. “Distinguishing COVID toes from MIS-C is important, as COVID toes has a very good outcome, while MIS-C can have severe consequences, including protracted heart disease.”

In other findings, patients who presented with mucocutaneous signs tended to be older than those without skin signs and they presented at the emergency department with poor general status and extreme tachycardia. They also had higher C-reactive protein and D-dimer levels and lower lymphocyte counts and faced a more than a 10-fold increased risk of being admitted to the PICU, compared with patients who did not have skin signs (OR, 10.24; P = .003).

In a separate study published online on April 7 in JAMA Dermatology, Zachary E. Holcomb, MD, of the combined dermatology residency program at Massachusetts General Hospital, Boston, and colleagues presented what is believed to be the first case report of reactive infectious mucocutaneous eruption (RIME) triggered by SARS-CoV-2. RIME is the preferred term for pediatric patients who present with mucositis and rash (often a scant or even absent skin eruption) triggered by various infectious agents.

The patient, a 17-year-old male, presented to the emergency department with 3 days of mouth pain and nonpainful penile erosions. “One week prior, he experienced transient anosmia and ageusia that had since spontaneously resolved,” the researchers wrote. “At that time, he was tested for SARS-CoV-2 infection via nasopharyngeal polymerase chain reaction (PCR), the results of which were positive.”

At presentation, the patient had no fever, his vital signs were normal, and the physical exam revealed shallow erosions of the vermilion lips and hard palate, circumferential erythematous erosions of the periurethral glans penis, and five small vesicles on the trunk and upper extremities. Serum analysis revealed a normal white blood cell count with mild absolute lymphopenia, slightly elevated creatinine level, normal liver function, slightly elevated C-reactive protein level, and normal ferritin level.

Dr. Holcomb and colleagues made a diagnosis of SARS-CoV-2–associated RIME based on microbiological results, which revealed positive repeated SARS-CoV-2 nasopharyngeal PCR and negative nasopharyngeal PCR testing for Mycoplasma pneumoniae, adenovirus, Chlamydophila pneumoniae, human metapneumovirus, influenza A/B, parainfluenza 1 to 4, rhinovirus, and respiratory syncytial virus. In addition, titers of Mycoplasma pneumoniae IgM levels were negative, but Mycoplasma pneumoniae IgG levels were elevated.

The lesions resolved with 60 mg of oral prednisone taken daily for 4 days. A recurrence of oral mucositis 3 months later responded to 80 mg oral prednisone taken daily for 6 days.

“It’s not surprising that SARS-CoV-2 is yet another trigger for RIME,” said Anna Yasmine Kirkorian, MD, chief of the division of dermatology at Children’s National Hospital, Washington, who was asked to comment about the case report.

“The take-home message is for clinicians to be aware of this association and distinguish these patients from those with MIS-C, because patients with MIS-C require monitoring and urgent systemic treatment. RIME and MIS-C may potentially be distinguished clinically based on the nature of the mucositis (hemorrhagic and erosive in RIME, dry, cracked lips with ‘strawberry tongue’ in MIS-C) but more importantly patients with RIME lack laboratory evidence of severe systemic inflammation,” such as ESR, CRP, or ferritin, she said.

“A final interesting point in this article was the recurrence of mucositis in this patient, which could mean that recurrent mucositis/recurrent RIME might be yet another manifestation of ‘long-COVID’ (now called post-Acute Sequelae of SARS-CoV-2 infection) in some patients,” Dr. Kirkorian added. She noted that the American Academy of Dermatology–International League of Dermatologic Societies COVID-19 Dermatology Registry and articles like these “provide invaluable ‘hot off the presses’ information for clinicians who are facing the protean manifestations of a novel viral epidemic.”

The researchers reported having no financial disclosures.
 

[email protected]

Two recent articles in the medical literature provide new information on mucocutaneous manifestations of COVID-19 in children, which may help guide dermatologists in making accurate diagnoses and stratifying children at risk for serious, systemic illness due to the virus.

In a single-center descriptive study carried out over a 9-month period, researchers in Madrid found that of 50 hospitalized children infected with COVID-19, 21 (42%) had mucocutaneous symptoms, most commonly exanthem, followed by conjunctival hyperemia without secretion and red cracked lips or strawberry tongue. In addition, 18 (36%) fulfilled criteria for Multisystem Inflammatory Syndrome in Children (MIS-C).

“Based on findings in adult patients, the skin manifestations of COVID-19 have been classified under five categories: acral pseudo-chilblain, vesicular eruptions, urticarial lesions, maculopapular eruptions, and livedo or necrosis,” David Andina-Martinez, MD, of Hospital Infantil Universitario Niño Jesús, Madrid, and colleagues wrote in the study, which was published online on April 2 in the Journal of the American Academy of Dermatology.

“Chilblain lesions in healthy children and adolescents have received much attention; these lesions resolve without complications after a few weeks,” they added. “Besides, other cutaneous manifestations of COVID-19 in children have been the matter of case reports or small case series. Nevertheless, the mucocutaneous manifestations in hospitalized children infected with SARS-CoV-2 and their implications on the clinical course have not yet been extensively described.”

In an effort to describe the mucocutaneous manifestations in children hospitalized for COVID-19, the researchers evaluated 50 children up to 18 years of age who were admitted between March 1 and Nov. 30, 2020, to Hospital Infantil Universitario Niño Jesús, which was designated as a pediatric reference center during the peak of the pandemic. The main reasons for admission were respiratory illness (40%) and MIS-C (40%).

Of the 50 patients, 44 (88%) had a positive RT-PCR for SARS-CoV-2 and 6 (12%) met clinical suspicion criteria and had a negative RT-PCR with a positive IgG serology. In 34 patients (68%), a close contact with a suspected or confirmed case of COVID-19 was referred, while the source of the infection remained unknown in the remaining 16 patients (32%).

The researchers reported that 21 patients (42%) had mucocutaneous symptoms, most commonly maculopapular exanthem (86%), conjunctival hyperemia (81%), and red cracked lips or strawberry tongue (43%). In addition, 18 of the 21 patients (86%) fulfilled criteria for MIS-C.

“A tricky thing about MIS-C is that it often manifests 4-5 weeks after a child had COVID-19,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study. “MIS-C is associated with characteristic bright red lips and a red tongue that might resemble a strawberry. Such oral findings should prompt rapid evaluation for other signs and symptoms. There can be redness of the eyes or other more nonspecific skin findings (large or small areas of redness on the trunk or limbs, sometimes with surface change), but more importantly, fever, a rapid heartbeat, diarrhea, or breathing issues. The risk with MIS-C is a rapid decline in a child’s health, with admission to an intensive care unit.”

Dr. Andina-Martinez and his colleagues also contrast the skin findings of MIS-C, which are not generally on the hands or feet, with the so-called “COVID toe” or finger phenomenon, which has also been associated with SARS-CoV-2, particularly in children. “Only one of the patients in this series had skin involvement of a finger, and it only appeared after recovery from MIS-C,” Dr. Ko noted. “Distinguishing COVID toes from MIS-C is important, as COVID toes has a very good outcome, while MIS-C can have severe consequences, including protracted heart disease.”

In other findings, patients who presented with mucocutaneous signs tended to be older than those without skin signs and they presented at the emergency department with poor general status and extreme tachycardia. They also had higher C-reactive protein and D-dimer levels and lower lymphocyte counts and faced a more than a 10-fold increased risk of being admitted to the PICU, compared with patients who did not have skin signs (OR, 10.24; P = .003).

In a separate study published online on April 7 in JAMA Dermatology, Zachary E. Holcomb, MD, of the combined dermatology residency program at Massachusetts General Hospital, Boston, and colleagues presented what is believed to be the first case report of reactive infectious mucocutaneous eruption (RIME) triggered by SARS-CoV-2. RIME is the preferred term for pediatric patients who present with mucositis and rash (often a scant or even absent skin eruption) triggered by various infectious agents.

The patient, a 17-year-old male, presented to the emergency department with 3 days of mouth pain and nonpainful penile erosions. “One week prior, he experienced transient anosmia and ageusia that had since spontaneously resolved,” the researchers wrote. “At that time, he was tested for SARS-CoV-2 infection via nasopharyngeal polymerase chain reaction (PCR), the results of which were positive.”

At presentation, the patient had no fever, his vital signs were normal, and the physical exam revealed shallow erosions of the vermilion lips and hard palate, circumferential erythematous erosions of the periurethral glans penis, and five small vesicles on the trunk and upper extremities. Serum analysis revealed a normal white blood cell count with mild absolute lymphopenia, slightly elevated creatinine level, normal liver function, slightly elevated C-reactive protein level, and normal ferritin level.

Dr. Holcomb and colleagues made a diagnosis of SARS-CoV-2–associated RIME based on microbiological results, which revealed positive repeated SARS-CoV-2 nasopharyngeal PCR and negative nasopharyngeal PCR testing for Mycoplasma pneumoniae, adenovirus, Chlamydophila pneumoniae, human metapneumovirus, influenza A/B, parainfluenza 1 to 4, rhinovirus, and respiratory syncytial virus. In addition, titers of Mycoplasma pneumoniae IgM levels were negative, but Mycoplasma pneumoniae IgG levels were elevated.

The lesions resolved with 60 mg of oral prednisone taken daily for 4 days. A recurrence of oral mucositis 3 months later responded to 80 mg oral prednisone taken daily for 6 days.

“It’s not surprising that SARS-CoV-2 is yet another trigger for RIME,” said Anna Yasmine Kirkorian, MD, chief of the division of dermatology at Children’s National Hospital, Washington, who was asked to comment about the case report.

“The take-home message is for clinicians to be aware of this association and distinguish these patients from those with MIS-C, because patients with MIS-C require monitoring and urgent systemic treatment. RIME and MIS-C may potentially be distinguished clinically based on the nature of the mucositis (hemorrhagic and erosive in RIME, dry, cracked lips with ‘strawberry tongue’ in MIS-C) but more importantly patients with RIME lack laboratory evidence of severe systemic inflammation,” such as ESR, CRP, or ferritin, she said.

“A final interesting point in this article was the recurrence of mucositis in this patient, which could mean that recurrent mucositis/recurrent RIME might be yet another manifestation of ‘long-COVID’ (now called post-Acute Sequelae of SARS-CoV-2 infection) in some patients,” Dr. Kirkorian added. She noted that the American Academy of Dermatology–International League of Dermatologic Societies COVID-19 Dermatology Registry and articles like these “provide invaluable ‘hot off the presses’ information for clinicians who are facing the protean manifestations of a novel viral epidemic.”

The researchers reported having no financial disclosures.
 

[email protected]

Two recent articles in the medical literature provide new information on mucocutaneous manifestations of COVID-19 in children, which may help guide dermatologists in making accurate diagnoses and stratifying children at risk for serious, systemic illness due to the virus.

In a single-center descriptive study carried out over a 9-month period, researchers in Madrid found that of 50 hospitalized children infected with COVID-19, 21 (42%) had mucocutaneous symptoms, most commonly exanthem, followed by conjunctival hyperemia without secretion and red cracked lips or strawberry tongue. In addition, 18 (36%) fulfilled criteria for Multisystem Inflammatory Syndrome in Children (MIS-C).

“Based on findings in adult patients, the skin manifestations of COVID-19 have been classified under five categories: acral pseudo-chilblain, vesicular eruptions, urticarial lesions, maculopapular eruptions, and livedo or necrosis,” David Andina-Martinez, MD, of Hospital Infantil Universitario Niño Jesús, Madrid, and colleagues wrote in the study, which was published online on April 2 in the Journal of the American Academy of Dermatology.

“Chilblain lesions in healthy children and adolescents have received much attention; these lesions resolve without complications after a few weeks,” they added. “Besides, other cutaneous manifestations of COVID-19 in children have been the matter of case reports or small case series. Nevertheless, the mucocutaneous manifestations in hospitalized children infected with SARS-CoV-2 and their implications on the clinical course have not yet been extensively described.”

In an effort to describe the mucocutaneous manifestations in children hospitalized for COVID-19, the researchers evaluated 50 children up to 18 years of age who were admitted between March 1 and Nov. 30, 2020, to Hospital Infantil Universitario Niño Jesús, which was designated as a pediatric reference center during the peak of the pandemic. The main reasons for admission were respiratory illness (40%) and MIS-C (40%).

Of the 50 patients, 44 (88%) had a positive RT-PCR for SARS-CoV-2 and 6 (12%) met clinical suspicion criteria and had a negative RT-PCR with a positive IgG serology. In 34 patients (68%), a close contact with a suspected or confirmed case of COVID-19 was referred, while the source of the infection remained unknown in the remaining 16 patients (32%).

The researchers reported that 21 patients (42%) had mucocutaneous symptoms, most commonly maculopapular exanthem (86%), conjunctival hyperemia (81%), and red cracked lips or strawberry tongue (43%). In addition, 18 of the 21 patients (86%) fulfilled criteria for MIS-C.

“A tricky thing about MIS-C is that it often manifests 4-5 weeks after a child had COVID-19,” said Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study. “MIS-C is associated with characteristic bright red lips and a red tongue that might resemble a strawberry. Such oral findings should prompt rapid evaluation for other signs and symptoms. There can be redness of the eyes or other more nonspecific skin findings (large or small areas of redness on the trunk or limbs, sometimes with surface change), but more importantly, fever, a rapid heartbeat, diarrhea, or breathing issues. The risk with MIS-C is a rapid decline in a child’s health, with admission to an intensive care unit.”

Dr. Andina-Martinez and his colleagues also contrast the skin findings of MIS-C, which are not generally on the hands or feet, with the so-called “COVID toe” or finger phenomenon, which has also been associated with SARS-CoV-2, particularly in children. “Only one of the patients in this series had skin involvement of a finger, and it only appeared after recovery from MIS-C,” Dr. Ko noted. “Distinguishing COVID toes from MIS-C is important, as COVID toes has a very good outcome, while MIS-C can have severe consequences, including protracted heart disease.”

In other findings, patients who presented with mucocutaneous signs tended to be older than those without skin signs and they presented at the emergency department with poor general status and extreme tachycardia. They also had higher C-reactive protein and D-dimer levels and lower lymphocyte counts and faced a more than a 10-fold increased risk of being admitted to the PICU, compared with patients who did not have skin signs (OR, 10.24; P = .003).

In a separate study published online on April 7 in JAMA Dermatology, Zachary E. Holcomb, MD, of the combined dermatology residency program at Massachusetts General Hospital, Boston, and colleagues presented what is believed to be the first case report of reactive infectious mucocutaneous eruption (RIME) triggered by SARS-CoV-2. RIME is the preferred term for pediatric patients who present with mucositis and rash (often a scant or even absent skin eruption) triggered by various infectious agents.

The patient, a 17-year-old male, presented to the emergency department with 3 days of mouth pain and nonpainful penile erosions. “One week prior, he experienced transient anosmia and ageusia that had since spontaneously resolved,” the researchers wrote. “At that time, he was tested for SARS-CoV-2 infection via nasopharyngeal polymerase chain reaction (PCR), the results of which were positive.”

At presentation, the patient had no fever, his vital signs were normal, and the physical exam revealed shallow erosions of the vermilion lips and hard palate, circumferential erythematous erosions of the periurethral glans penis, and five small vesicles on the trunk and upper extremities. Serum analysis revealed a normal white blood cell count with mild absolute lymphopenia, slightly elevated creatinine level, normal liver function, slightly elevated C-reactive protein level, and normal ferritin level.

Dr. Holcomb and colleagues made a diagnosis of SARS-CoV-2–associated RIME based on microbiological results, which revealed positive repeated SARS-CoV-2 nasopharyngeal PCR and negative nasopharyngeal PCR testing for Mycoplasma pneumoniae, adenovirus, Chlamydophila pneumoniae, human metapneumovirus, influenza A/B, parainfluenza 1 to 4, rhinovirus, and respiratory syncytial virus. In addition, titers of Mycoplasma pneumoniae IgM levels were negative, but Mycoplasma pneumoniae IgG levels were elevated.

The lesions resolved with 60 mg of oral prednisone taken daily for 4 days. A recurrence of oral mucositis 3 months later responded to 80 mg oral prednisone taken daily for 6 days.

“It’s not surprising that SARS-CoV-2 is yet another trigger for RIME,” said Anna Yasmine Kirkorian, MD, chief of the division of dermatology at Children’s National Hospital, Washington, who was asked to comment about the case report.

“The take-home message is for clinicians to be aware of this association and distinguish these patients from those with MIS-C, because patients with MIS-C require monitoring and urgent systemic treatment. RIME and MIS-C may potentially be distinguished clinically based on the nature of the mucositis (hemorrhagic and erosive in RIME, dry, cracked lips with ‘strawberry tongue’ in MIS-C) but more importantly patients with RIME lack laboratory evidence of severe systemic inflammation,” such as ESR, CRP, or ferritin, she said.

“A final interesting point in this article was the recurrence of mucositis in this patient, which could mean that recurrent mucositis/recurrent RIME might be yet another manifestation of ‘long-COVID’ (now called post-Acute Sequelae of SARS-CoV-2 infection) in some patients,” Dr. Kirkorian added. She noted that the American Academy of Dermatology–International League of Dermatologic Societies COVID-19 Dermatology Registry and articles like these “provide invaluable ‘hot off the presses’ information for clinicians who are facing the protean manifestations of a novel viral epidemic.”

The researchers reported having no financial disclosures.
 

[email protected]

Seven years after concluding that evidence was insufficient to recommend screening for vitamin D deficiency in the general population, the United States Preventive Services Task Force (USPSTF) has revisited the issue – and come up with the same conclusion.

Overall, “the current evidence is inadequate to determine whether screening for and treatment of asymptomatic low 25(OH)D levels improve clinical outcomes in community dwelling adults,” the task force concluded in its statement, recommending an “I” for insufficient.

The statement was published online April 13 in JAMA.

In the absence of screening recommendations, clinicians may be best advised to instead focus on diet and supplementation for those considered at risk, said Anne R. Cappola, MD, of the University of Pennsylvania, Philadelphia.

“Rather than posing the question of screening the general population for vitamin D deficiency, let’s focus on ensuring that everyone consumes the age-based recommended daily allowance of vitamin D instead,” Dr. Cappola, a coauthor of the accompanying editorial, said in an interview.
 

No studies have directly evaluated benefits of screening

The latest USPSTF recommendation is based on a systematic review of the benefits and harms of screening and early treatment for vitamin D deficiency in asymptomatic, community-dwelling nonpregnant adults aged 18 or older in the primary care setting with no signs or symptoms of deficiency.

The review found no studies that directly evaluated the benefits of screening for vitamin D deficiency.

However, 26 randomized clinical trials and one nested case-control study evaluated the effectiveness of treatment of vitamin D deficiency with supplementation.

And while observational studies have linked lower vitamin D levels with a multitude of conditions and risks, evidence of any benefit was inconsistent, with none identified for most major outcomes in asymptomatic adults – the focus of the Task Force recommendation.

“Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events,” the review authors stress.

“The evidence is inconclusive about the effect of treatment on physical functioning and infection.”
 

One in four are vitamin D deficient

In terms of the further question of the potential harms of vitamin D screening of asymptomatic individuals, a key concern is the potential for misclassification and over- or underdiagnosis due to inconsistent cutoffs and variability of different screening assays, the review concluded.

However, with the rare exception of vitamin D toxicity from supplementation well above sufficient levels, treatment with vitamin D supplementation appears relatively safe.

With a lack of consensus even over the basic cutoff for vitamin D deficiency, the National Academy of Medicine determined in 2011 that hydroxyvitamin D (25[OH]D) levels below 20 ng/mL are deficient for bone health, with no evidence of different thresholds for any other health condition.

Based on that cutoff, the National Health and Nutrition Examination Survey (NHANES), reported in 2014 that 25% of the U.S. population over the age of 1 was vitamin D deficient, with 18% of the population having 25(OH)D levels of 12-19 ng/mL and 5% having very low levels (< 12 ng/mL).
 

More work needed to determine groups at risk

While the task force report did not delve into testing or treatment recommendations for symptomatic adults, key established risk factors that may help clinicians identify those who are vitamin D deficient include obesity, receiving little or no UVB light exposure, and older age.

In general, obesity is associated with a 1.3- to 2-fold risk of being vitamin D deficient based on the criteria used, while non-Hispanic Blacks are 2-10 times more likely to be deficient compared with non-Hispanic White patients, the task force noted.

However, the implications of vitamin D deficiency in certain populations can vary. For instance, non-Hispanic Black people, despite having a higher prevalence of lower vitamin D levels compared with White people, in fact, have lower reported rates of fractures.

To address the various issues and gain a better understanding of the complexities of vitamin D deficiency, the task force calls for further research in key areas.

“More research is needed to determine whether total serum 25(OH)D levels are the best measure of vitamin D deficiency and whether the best measure of vitamin D deficiency varies by subgroups defined by race, ethnicity, or sex,” the authors indicated.

Furthermore, “more research is needed to determine the cutoff that defines vitamin D deficiency and whether that cutoff varies by specific clinical outcome or by subgroups defined by race, ethnicity, or sex.”
 

No support for population-based screening in guidelines

With the lack of conclusive evidence, no organizations currently recommend population-based screening for vitamin D deficiency in asymptomatic patients, and the American Society for Clinical Pathology endorses this stance.

The Endocrine Society and the American Association of Clinical Endocrinologists meanwhile do recommend screening for vitamin D deficiency in patients considered at risk.

Data show there was as much as an 80-fold increase in Medicare reimbursement volumes for vitamin D testing among clinicians from 2000 to 2010; however, that rate may have leveled off after the National Academy of Medicine reported on set deficiency levels, said Sherri-Ann M. Burnett-Bowie, MD, MPH, Dr. Cappola’s editorial coauthor.

Dr. Burnett-Bowie noted that she regularly tests her patients’ vitamin D levels, however most of her patients have osteoporosis or fractures.

“I do screen them for vitamin D deficiency since optimizing their vitamin D will improve calcium absorption, which is important for treating their osteoporosis,” Dr. Burnett-Bowie, of the endocrine division, department of medicine, Massachusetts General Hospital, Boston, said in an interview.

In terms of broader testing of asymptomatic patients in the general population, however, any changes in screening will likely be contingent on developments in the effects of treatment, she said.

“Given the challenge in finding benefits of vitamin D supplementation in those who are deficient, it will likely be more challenging to find benefits from wider screening,” she concluded.

The USPSTF and editorialists reported having no relevant financial relationships.

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

Seven years after concluding that evidence was insufficient to recommend screening for vitamin D deficiency in the general population, the United States Preventive Services Task Force (USPSTF) has revisited the issue – and come up with the same conclusion.

Overall, “the current evidence is inadequate to determine whether screening for and treatment of asymptomatic low 25(OH)D levels improve clinical outcomes in community dwelling adults,” the task force concluded in its statement, recommending an “I” for insufficient.

The statement was published online April 13 in JAMA.

In the absence of screening recommendations, clinicians may be best advised to instead focus on diet and supplementation for those considered at risk, said Anne R. Cappola, MD, of the University of Pennsylvania, Philadelphia.

“Rather than posing the question of screening the general population for vitamin D deficiency, let’s focus on ensuring that everyone consumes the age-based recommended daily allowance of vitamin D instead,” Dr. Cappola, a coauthor of the accompanying editorial, said in an interview.
 

No studies have directly evaluated benefits of screening

The latest USPSTF recommendation is based on a systematic review of the benefits and harms of screening and early treatment for vitamin D deficiency in asymptomatic, community-dwelling nonpregnant adults aged 18 or older in the primary care setting with no signs or symptoms of deficiency.

The review found no studies that directly evaluated the benefits of screening for vitamin D deficiency.

However, 26 randomized clinical trials and one nested case-control study evaluated the effectiveness of treatment of vitamin D deficiency with supplementation.

And while observational studies have linked lower vitamin D levels with a multitude of conditions and risks, evidence of any benefit was inconsistent, with none identified for most major outcomes in asymptomatic adults – the focus of the Task Force recommendation.

“Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events,” the review authors stress.

“The evidence is inconclusive about the effect of treatment on physical functioning and infection.”
 

One in four are vitamin D deficient

In terms of the further question of the potential harms of vitamin D screening of asymptomatic individuals, a key concern is the potential for misclassification and over- or underdiagnosis due to inconsistent cutoffs and variability of different screening assays, the review concluded.

However, with the rare exception of vitamin D toxicity from supplementation well above sufficient levels, treatment with vitamin D supplementation appears relatively safe.

With a lack of consensus even over the basic cutoff for vitamin D deficiency, the National Academy of Medicine determined in 2011 that hydroxyvitamin D (25[OH]D) levels below 20 ng/mL are deficient for bone health, with no evidence of different thresholds for any other health condition.

Based on that cutoff, the National Health and Nutrition Examination Survey (NHANES), reported in 2014 that 25% of the U.S. population over the age of 1 was vitamin D deficient, with 18% of the population having 25(OH)D levels of 12-19 ng/mL and 5% having very low levels (< 12 ng/mL).
 

More work needed to determine groups at risk

While the task force report did not delve into testing or treatment recommendations for symptomatic adults, key established risk factors that may help clinicians identify those who are vitamin D deficient include obesity, receiving little or no UVB light exposure, and older age.

In general, obesity is associated with a 1.3- to 2-fold risk of being vitamin D deficient based on the criteria used, while non-Hispanic Blacks are 2-10 times more likely to be deficient compared with non-Hispanic White patients, the task force noted.

However, the implications of vitamin D deficiency in certain populations can vary. For instance, non-Hispanic Black people, despite having a higher prevalence of lower vitamin D levels compared with White people, in fact, have lower reported rates of fractures.

To address the various issues and gain a better understanding of the complexities of vitamin D deficiency, the task force calls for further research in key areas.

“More research is needed to determine whether total serum 25(OH)D levels are the best measure of vitamin D deficiency and whether the best measure of vitamin D deficiency varies by subgroups defined by race, ethnicity, or sex,” the authors indicated.

Furthermore, “more research is needed to determine the cutoff that defines vitamin D deficiency and whether that cutoff varies by specific clinical outcome or by subgroups defined by race, ethnicity, or sex.”
 

No support for population-based screening in guidelines

With the lack of conclusive evidence, no organizations currently recommend population-based screening for vitamin D deficiency in asymptomatic patients, and the American Society for Clinical Pathology endorses this stance.

The Endocrine Society and the American Association of Clinical Endocrinologists meanwhile do recommend screening for vitamin D deficiency in patients considered at risk.

Data show there was as much as an 80-fold increase in Medicare reimbursement volumes for vitamin D testing among clinicians from 2000 to 2010; however, that rate may have leveled off after the National Academy of Medicine reported on set deficiency levels, said Sherri-Ann M. Burnett-Bowie, MD, MPH, Dr. Cappola’s editorial coauthor.

Dr. Burnett-Bowie noted that she regularly tests her patients’ vitamin D levels, however most of her patients have osteoporosis or fractures.

“I do screen them for vitamin D deficiency since optimizing their vitamin D will improve calcium absorption, which is important for treating their osteoporosis,” Dr. Burnett-Bowie, of the endocrine division, department of medicine, Massachusetts General Hospital, Boston, said in an interview.

In terms of broader testing of asymptomatic patients in the general population, however, any changes in screening will likely be contingent on developments in the effects of treatment, she said.

“Given the challenge in finding benefits of vitamin D supplementation in those who are deficient, it will likely be more challenging to find benefits from wider screening,” she concluded.

The USPSTF and editorialists reported having no relevant financial relationships.

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

Seven years after concluding that evidence was insufficient to recommend screening for vitamin D deficiency in the general population, the United States Preventive Services Task Force (USPSTF) has revisited the issue – and come up with the same conclusion.

Overall, “the current evidence is inadequate to determine whether screening for and treatment of asymptomatic low 25(OH)D levels improve clinical outcomes in community dwelling adults,” the task force concluded in its statement, recommending an “I” for insufficient.

The statement was published online April 13 in JAMA.

In the absence of screening recommendations, clinicians may be best advised to instead focus on diet and supplementation for those considered at risk, said Anne R. Cappola, MD, of the University of Pennsylvania, Philadelphia.

“Rather than posing the question of screening the general population for vitamin D deficiency, let’s focus on ensuring that everyone consumes the age-based recommended daily allowance of vitamin D instead,” Dr. Cappola, a coauthor of the accompanying editorial, said in an interview.
 

No studies have directly evaluated benefits of screening

The latest USPSTF recommendation is based on a systematic review of the benefits and harms of screening and early treatment for vitamin D deficiency in asymptomatic, community-dwelling nonpregnant adults aged 18 or older in the primary care setting with no signs or symptoms of deficiency.

The review found no studies that directly evaluated the benefits of screening for vitamin D deficiency.

However, 26 randomized clinical trials and one nested case-control study evaluated the effectiveness of treatment of vitamin D deficiency with supplementation.

And while observational studies have linked lower vitamin D levels with a multitude of conditions and risks, evidence of any benefit was inconsistent, with none identified for most major outcomes in asymptomatic adults – the focus of the Task Force recommendation.

“Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events,” the review authors stress.

“The evidence is inconclusive about the effect of treatment on physical functioning and infection.”
 

One in four are vitamin D deficient

In terms of the further question of the potential harms of vitamin D screening of asymptomatic individuals, a key concern is the potential for misclassification and over- or underdiagnosis due to inconsistent cutoffs and variability of different screening assays, the review concluded.

However, with the rare exception of vitamin D toxicity from supplementation well above sufficient levels, treatment with vitamin D supplementation appears relatively safe.

With a lack of consensus even over the basic cutoff for vitamin D deficiency, the National Academy of Medicine determined in 2011 that hydroxyvitamin D (25[OH]D) levels below 20 ng/mL are deficient for bone health, with no evidence of different thresholds for any other health condition.

Based on that cutoff, the National Health and Nutrition Examination Survey (NHANES), reported in 2014 that 25% of the U.S. population over the age of 1 was vitamin D deficient, with 18% of the population having 25(OH)D levels of 12-19 ng/mL and 5% having very low levels (< 12 ng/mL).
 

More work needed to determine groups at risk

While the task force report did not delve into testing or treatment recommendations for symptomatic adults, key established risk factors that may help clinicians identify those who are vitamin D deficient include obesity, receiving little or no UVB light exposure, and older age.

In general, obesity is associated with a 1.3- to 2-fold risk of being vitamin D deficient based on the criteria used, while non-Hispanic Blacks are 2-10 times more likely to be deficient compared with non-Hispanic White patients, the task force noted.

However, the implications of vitamin D deficiency in certain populations can vary. For instance, non-Hispanic Black people, despite having a higher prevalence of lower vitamin D levels compared with White people, in fact, have lower reported rates of fractures.

To address the various issues and gain a better understanding of the complexities of vitamin D deficiency, the task force calls for further research in key areas.

“More research is needed to determine whether total serum 25(OH)D levels are the best measure of vitamin D deficiency and whether the best measure of vitamin D deficiency varies by subgroups defined by race, ethnicity, or sex,” the authors indicated.

Furthermore, “more research is needed to determine the cutoff that defines vitamin D deficiency and whether that cutoff varies by specific clinical outcome or by subgroups defined by race, ethnicity, or sex.”
 

No support for population-based screening in guidelines

With the lack of conclusive evidence, no organizations currently recommend population-based screening for vitamin D deficiency in asymptomatic patients, and the American Society for Clinical Pathology endorses this stance.

The Endocrine Society and the American Association of Clinical Endocrinologists meanwhile do recommend screening for vitamin D deficiency in patients considered at risk.

Data show there was as much as an 80-fold increase in Medicare reimbursement volumes for vitamin D testing among clinicians from 2000 to 2010; however, that rate may have leveled off after the National Academy of Medicine reported on set deficiency levels, said Sherri-Ann M. Burnett-Bowie, MD, MPH, Dr. Cappola’s editorial coauthor.

Dr. Burnett-Bowie noted that she regularly tests her patients’ vitamin D levels, however most of her patients have osteoporosis or fractures.

“I do screen them for vitamin D deficiency since optimizing their vitamin D will improve calcium absorption, which is important for treating their osteoporosis,” Dr. Burnett-Bowie, of the endocrine division, department of medicine, Massachusetts General Hospital, Boston, said in an interview.

In terms of broader testing of asymptomatic patients in the general population, however, any changes in screening will likely be contingent on developments in the effects of treatment, she said.

“Given the challenge in finding benefits of vitamin D supplementation in those who are deficient, it will likely be more challenging to find benefits from wider screening,” she concluded.

The USPSTF and editorialists reported having no relevant financial relationships.

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