Immunology

In a large, blinded study of peanut-allergic toddlers published in The Lancet, 71% of treated participants could safely consume 5,000 mg of peanut protein – equivalent to nearly 17 peanuts – after 2½ years on oral immunotherapy. Even after stopping maintenance dosing for the next 6 months, more than 1 in 5 maintained that level of protection, and nearly 3 in 5 still met the 600-mg benchmark (about 2 peanuts) set by the phase 3 PALISADE trial of the FDA-approved peanut-flour product, Palforzia.

About 2% of children in the United States are allergic to peanuts, and most will not outgrow this allergy. In addition, other research suggests that the immune system is more malleable during early childhood.

Consistent with this idea, prior research showed that toddlers can succeed with peanut oral immunotherapy (OIT) – a regimen that builds tolerance through small amounts of the allergen consumed daily for months. However, that trial (DEVIL) was small, was conducted at a single site, and had no placebo group.

In contrast, the Peanut Oral Immunotherapy in Children Trial (IMPACT) enrolled 146 children aged 1-3 years at five academic medical centers in the United States – the first placebo-controlled study of OIT in this younger age group.

“This is a well done study,” Jaclyn Bjelac, MD, associate director of the Food Allergy Center of Excellence at the Cleveland Clinic, told this news organization. “We have seen improved outcomes in OIT, both in our own experience and other published studies, so while this is no surprise, the outcomes and large number of participants contribute to this being a really exciting publication.”

The trial was long and demanding for families. Toddlers who reacted to 500 mg or less of peanut protein in an entry food challenge were randomized in a 2:1 ratio to receive daily peanut flour or oat flour placebo. After initial dose escalation (from 0.1 mg to 6 mg) and biweekly buildup to a 2,000-mg target dose by week 30, participants continued with 20,00-mg daily maintenance dosing through week 134 – at which point they underwent a food challenge. They then went off treatment for 26 weeks and had another food challenge (week 160). In addition, participants came in for skin-prick and blood tests at baseline and at weeks 30, 82, 134, and 160.

In the placebo group, only 23 of 50 participants (46%) completed the study. “If you did 2½ years of this and then bombed the food challenge, you probably can guess that you were not on the real thing. And they were still asked to come back in 6 months and do it again. So, sure enough, a big chunk of those people chose not to continue, and you can’t blame them,” said Lancet co-author Edwin Kim, MD, in an interview. Dr. Kim directs the UNC Food Allergy Initiative at the University of North Carolina School of Medicine, Chapel Hill.

There was attrition in the treatment group as well. Among 96 children initially assigned to this arm, 68 (71%) passed the 5,000-mg peanut challenge at week 134 – but 11 withdrew in the study’s off-treatment phase. “It was a very tough decision. How much do you give toward science?” said Dr. Kim. “When push came to shove, some of the families couldn’t pull the trigger to potentially give up what they worked so hard for.”

In the intention-to-treat analysis, 20 of 96 treated participants (21%) could still tolerate 5,000 mg of peanut protein after going off therapy for 6 months. That translates to a 29% remission rate in the per-protocol subset (n = 70) who completed the study. Forty (57%) of these completers safely consumed at least 1,755 mg of peanut (cumulative dose). By comparison, the PALISADE trial of Palforzia used a 10,430-mg cumulative peanut dose to measure treatment efficacy.

On safety, 98% of treated participants – but also 80% of the placebo group – reported reactions, of which 35 were treated with epinephrine in 21 children receiving peanut OIT.

While some have noted that epinephrine use seemed high, Dr. Kim said, “we’re actually OK with that, because we’d much rather they overtreat and make sure that 1-year-old is safe than take any chances.” Overall, the safety profile looks similar to prior OIT studies of older children. “I think it suggests that, yeah, side effects will happen, [but] they’re all manageable, and people are not anaphylaxing left and right.”

On remission and immunologic parameters, benefits seemed stronger in the youngest subset (12 to 24 months), particularly those with lower peanut-specific IgE at baseline. These trends require further analyses, though, given the limited number of participants under 24 months.

Another noteworthy observation from longitudinal peanut-specific IgE trends in the placebo group: “Avoidance may not be benign,” Dr. Kim said. “If you look at their labs, they don’t stay flat. They actually go up.” The results jibe with the long-held idea of an early window of opportunity while a child’s immune system is maturing. “If you can grab this kid when his IgE is 10, versus next year when it might be 50, maybe you’ll get a different treatment effect,” Dr. Kim said. “We don’t know that for sure, but the placebo labs kind of point toward that.”

Beyond the science, there are practical advantages to starting OIT early. “Trying to convince a 9-year-old who’s been petrified of peanuts for their whole life to start doing this every day is not an easy task,” whereas with a 1- or 2-year-old, “you build it into their routine,” Dr. Kim said.

Plus, some say there’s no need for families to wait for regulatory approval of additional commercial products for very young children. Though some have advocated against the use of “grocery store” products, most peanut OIT research “has used the same 12% light roast defatted peanut flour used in IMPACT,” noted Marcus S. Shaker, MD, professor of pediatrics and of medicine at the Dartmouth Geisel School of Medicine and a physician at the Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. The commercial product (Palforzia) and grocery-store products “come from the exact same source in the U.S.,” he said in an interview. “Both are an option for parents to consider, but a commercial product is not, nor has [it] ever been, a necessity.”

Dr. Bjelac reports no relevant financial relationships. Dr. Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; and grant support from the NIH’s National Institute of Allergy and Infectious Diseases, National Center for Complementary and Integrative Health and Immune Tolerance Network, Food Allergy Research and Education, and the Wallace Research Foundation. Dr. Shaker has participated in research funded by DBV, is cochair of the AAAAI/ACAAI Joint Task Force on Practice Parameters, is an associate editor at the Annals of Allergy, Asthma, and Immunology, and is an editorial board member of the Journal of Allergy and Clinical Immunology in Practice.

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

In a large, blinded study of peanut-allergic toddlers published in The Lancet, 71% of treated participants could safely consume 5,000 mg of peanut protein – equivalent to nearly 17 peanuts – after 2½ years on oral immunotherapy. Even after stopping maintenance dosing for the next 6 months, more than 1 in 5 maintained that level of protection, and nearly 3 in 5 still met the 600-mg benchmark (about 2 peanuts) set by the phase 3 PALISADE trial of the FDA-approved peanut-flour product, Palforzia.

About 2% of children in the United States are allergic to peanuts, and most will not outgrow this allergy. In addition, other research suggests that the immune system is more malleable during early childhood.

Consistent with this idea, prior research showed that toddlers can succeed with peanut oral immunotherapy (OIT) – a regimen that builds tolerance through small amounts of the allergen consumed daily for months. However, that trial (DEVIL) was small, was conducted at a single site, and had no placebo group.

In contrast, the Peanut Oral Immunotherapy in Children Trial (IMPACT) enrolled 146 children aged 1-3 years at five academic medical centers in the United States – the first placebo-controlled study of OIT in this younger age group.

“This is a well done study,” Jaclyn Bjelac, MD, associate director of the Food Allergy Center of Excellence at the Cleveland Clinic, told this news organization. “We have seen improved outcomes in OIT, both in our own experience and other published studies, so while this is no surprise, the outcomes and large number of participants contribute to this being a really exciting publication.”

The trial was long and demanding for families. Toddlers who reacted to 500 mg or less of peanut protein in an entry food challenge were randomized in a 2:1 ratio to receive daily peanut flour or oat flour placebo. After initial dose escalation (from 0.1 mg to 6 mg) and biweekly buildup to a 2,000-mg target dose by week 30, participants continued with 20,00-mg daily maintenance dosing through week 134 – at which point they underwent a food challenge. They then went off treatment for 26 weeks and had another food challenge (week 160). In addition, participants came in for skin-prick and blood tests at baseline and at weeks 30, 82, 134, and 160.

In the placebo group, only 23 of 50 participants (46%) completed the study. “If you did 2½ years of this and then bombed the food challenge, you probably can guess that you were not on the real thing. And they were still asked to come back in 6 months and do it again. So, sure enough, a big chunk of those people chose not to continue, and you can’t blame them,” said Lancet co-author Edwin Kim, MD, in an interview. Dr. Kim directs the UNC Food Allergy Initiative at the University of North Carolina School of Medicine, Chapel Hill.

There was attrition in the treatment group as well. Among 96 children initially assigned to this arm, 68 (71%) passed the 5,000-mg peanut challenge at week 134 – but 11 withdrew in the study’s off-treatment phase. “It was a very tough decision. How much do you give toward science?” said Dr. Kim. “When push came to shove, some of the families couldn’t pull the trigger to potentially give up what they worked so hard for.”

In the intention-to-treat analysis, 20 of 96 treated participants (21%) could still tolerate 5,000 mg of peanut protein after going off therapy for 6 months. That translates to a 29% remission rate in the per-protocol subset (n = 70) who completed the study. Forty (57%) of these completers safely consumed at least 1,755 mg of peanut (cumulative dose). By comparison, the PALISADE trial of Palforzia used a 10,430-mg cumulative peanut dose to measure treatment efficacy.

On safety, 98% of treated participants – but also 80% of the placebo group – reported reactions, of which 35 were treated with epinephrine in 21 children receiving peanut OIT.

While some have noted that epinephrine use seemed high, Dr. Kim said, “we’re actually OK with that, because we’d much rather they overtreat and make sure that 1-year-old is safe than take any chances.” Overall, the safety profile looks similar to prior OIT studies of older children. “I think it suggests that, yeah, side effects will happen, [but] they’re all manageable, and people are not anaphylaxing left and right.”

On remission and immunologic parameters, benefits seemed stronger in the youngest subset (12 to 24 months), particularly those with lower peanut-specific IgE at baseline. These trends require further analyses, though, given the limited number of participants under 24 months.

Another noteworthy observation from longitudinal peanut-specific IgE trends in the placebo group: “Avoidance may not be benign,” Dr. Kim said. “If you look at their labs, they don’t stay flat. They actually go up.” The results jibe with the long-held idea of an early window of opportunity while a child’s immune system is maturing. “If you can grab this kid when his IgE is 10, versus next year when it might be 50, maybe you’ll get a different treatment effect,” Dr. Kim said. “We don’t know that for sure, but the placebo labs kind of point toward that.”

Beyond the science, there are practical advantages to starting OIT early. “Trying to convince a 9-year-old who’s been petrified of peanuts for their whole life to start doing this every day is not an easy task,” whereas with a 1- or 2-year-old, “you build it into their routine,” Dr. Kim said.

Plus, some say there’s no need for families to wait for regulatory approval of additional commercial products for very young children. Though some have advocated against the use of “grocery store” products, most peanut OIT research “has used the same 12% light roast defatted peanut flour used in IMPACT,” noted Marcus S. Shaker, MD, professor of pediatrics and of medicine at the Dartmouth Geisel School of Medicine and a physician at the Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. The commercial product (Palforzia) and grocery-store products “come from the exact same source in the U.S.,” he said in an interview. “Both are an option for parents to consider, but a commercial product is not, nor has [it] ever been, a necessity.”

Dr. Bjelac reports no relevant financial relationships. Dr. Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; and grant support from the NIH’s National Institute of Allergy and Infectious Diseases, National Center for Complementary and Integrative Health and Immune Tolerance Network, Food Allergy Research and Education, and the Wallace Research Foundation. Dr. Shaker has participated in research funded by DBV, is cochair of the AAAAI/ACAAI Joint Task Force on Practice Parameters, is an associate editor at the Annals of Allergy, Asthma, and Immunology, and is an editorial board member of the Journal of Allergy and Clinical Immunology in Practice.

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

In a large, blinded study of peanut-allergic toddlers published in The Lancet, 71% of treated participants could safely consume 5,000 mg of peanut protein – equivalent to nearly 17 peanuts – after 2½ years on oral immunotherapy. Even after stopping maintenance dosing for the next 6 months, more than 1 in 5 maintained that level of protection, and nearly 3 in 5 still met the 600-mg benchmark (about 2 peanuts) set by the phase 3 PALISADE trial of the FDA-approved peanut-flour product, Palforzia.

About 2% of children in the United States are allergic to peanuts, and most will not outgrow this allergy. In addition, other research suggests that the immune system is more malleable during early childhood.

Consistent with this idea, prior research showed that toddlers can succeed with peanut oral immunotherapy (OIT) – a regimen that builds tolerance through small amounts of the allergen consumed daily for months. However, that trial (DEVIL) was small, was conducted at a single site, and had no placebo group.

In contrast, the Peanut Oral Immunotherapy in Children Trial (IMPACT) enrolled 146 children aged 1-3 years at five academic medical centers in the United States – the first placebo-controlled study of OIT in this younger age group.

“This is a well done study,” Jaclyn Bjelac, MD, associate director of the Food Allergy Center of Excellence at the Cleveland Clinic, told this news organization. “We have seen improved outcomes in OIT, both in our own experience and other published studies, so while this is no surprise, the outcomes and large number of participants contribute to this being a really exciting publication.”

The trial was long and demanding for families. Toddlers who reacted to 500 mg or less of peanut protein in an entry food challenge were randomized in a 2:1 ratio to receive daily peanut flour or oat flour placebo. After initial dose escalation (from 0.1 mg to 6 mg) and biweekly buildup to a 2,000-mg target dose by week 30, participants continued with 20,00-mg daily maintenance dosing through week 134 – at which point they underwent a food challenge. They then went off treatment for 26 weeks and had another food challenge (week 160). In addition, participants came in for skin-prick and blood tests at baseline and at weeks 30, 82, 134, and 160.

In the placebo group, only 23 of 50 participants (46%) completed the study. “If you did 2½ years of this and then bombed the food challenge, you probably can guess that you were not on the real thing. And they were still asked to come back in 6 months and do it again. So, sure enough, a big chunk of those people chose not to continue, and you can’t blame them,” said Lancet co-author Edwin Kim, MD, in an interview. Dr. Kim directs the UNC Food Allergy Initiative at the University of North Carolina School of Medicine, Chapel Hill.

There was attrition in the treatment group as well. Among 96 children initially assigned to this arm, 68 (71%) passed the 5,000-mg peanut challenge at week 134 – but 11 withdrew in the study’s off-treatment phase. “It was a very tough decision. How much do you give toward science?” said Dr. Kim. “When push came to shove, some of the families couldn’t pull the trigger to potentially give up what they worked so hard for.”

In the intention-to-treat analysis, 20 of 96 treated participants (21%) could still tolerate 5,000 mg of peanut protein after going off therapy for 6 months. That translates to a 29% remission rate in the per-protocol subset (n = 70) who completed the study. Forty (57%) of these completers safely consumed at least 1,755 mg of peanut (cumulative dose). By comparison, the PALISADE trial of Palforzia used a 10,430-mg cumulative peanut dose to measure treatment efficacy.

On safety, 98% of treated participants – but also 80% of the placebo group – reported reactions, of which 35 were treated with epinephrine in 21 children receiving peanut OIT.

While some have noted that epinephrine use seemed high, Dr. Kim said, “we’re actually OK with that, because we’d much rather they overtreat and make sure that 1-year-old is safe than take any chances.” Overall, the safety profile looks similar to prior OIT studies of older children. “I think it suggests that, yeah, side effects will happen, [but] they’re all manageable, and people are not anaphylaxing left and right.”

On remission and immunologic parameters, benefits seemed stronger in the youngest subset (12 to 24 months), particularly those with lower peanut-specific IgE at baseline. These trends require further analyses, though, given the limited number of participants under 24 months.

Another noteworthy observation from longitudinal peanut-specific IgE trends in the placebo group: “Avoidance may not be benign,” Dr. Kim said. “If you look at their labs, they don’t stay flat. They actually go up.” The results jibe with the long-held idea of an early window of opportunity while a child’s immune system is maturing. “If you can grab this kid when his IgE is 10, versus next year when it might be 50, maybe you’ll get a different treatment effect,” Dr. Kim said. “We don’t know that for sure, but the placebo labs kind of point toward that.”

Beyond the science, there are practical advantages to starting OIT early. “Trying to convince a 9-year-old who’s been petrified of peanuts for their whole life to start doing this every day is not an easy task,” whereas with a 1- or 2-year-old, “you build it into their routine,” Dr. Kim said.

Plus, some say there’s no need for families to wait for regulatory approval of additional commercial products for very young children. Though some have advocated against the use of “grocery store” products, most peanut OIT research “has used the same 12% light roast defatted peanut flour used in IMPACT,” noted Marcus S. Shaker, MD, professor of pediatrics and of medicine at the Dartmouth Geisel School of Medicine and a physician at the Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. The commercial product (Palforzia) and grocery-store products “come from the exact same source in the U.S.,” he said in an interview. “Both are an option for parents to consider, but a commercial product is not, nor has [it] ever been, a necessity.”

Dr. Bjelac reports no relevant financial relationships. Dr. Kim reports consultancy with Aimmune Therapeutics, Allako, AllerGenis, Belhaven Pharma, DBV Technologies, Duke Clinical Research Institute, and Nutricia; advisory board membership with ALK, DBV Technologies, Kenota Health, and Ukko; and grant support from the NIH’s National Institute of Allergy and Infectious Diseases, National Center for Complementary and Integrative Health and Immune Tolerance Network, Food Allergy Research and Education, and the Wallace Research Foundation. Dr. Shaker has participated in research funded by DBV, is cochair of the AAAAI/ACAAI Joint Task Force on Practice Parameters, is an associate editor at the Annals of Allergy, Asthma, and Immunology, and is an editorial board member of the Journal of Allergy and Clinical Immunology in Practice.

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

Epstein-Barr virus (EBV) is the likely cause of multiple sclerosis (MS), new research confirms. Investigators found the risk of MS increased 32-fold following EBV infection.

This study is the first to provide compelling evidence of a causal link between EBV and MS, principal investigator Alberto Ascherio, MD, DrPH, professor of epidemiology, Harvard T. H. Chan School of Public Health, and professor of medicine, Harvard Medical School, Boston, told this news organization.

The “prevailing” view has been that MS is “an autoimmune disease of unknown etiology,” said Dr. Ascherio. “Now we know MS is a complication of a viral infection.” With this knowledge, he added, “we can redirect research” to find antiviral drugs to treat the disease.

The study was published online Jan. 13 in Science.
 

Unique dataset

A chronic disease of the central nervous system, MS involves an inflammatory attack on the myelin sheath and the axons it insulates. The disease affects 2.8 million people worldwide.

EBV is a human herpesvirus that can cause infectious mononucleosis. After infection, it persists in latent form in B-lymphocytes.

EBV is common and infects about 95% of adults. Most individuals are already infected with the virus by age 18 or 20 years, making it difficult to study uninfected populations, said Dr. Ascherio.

However, access to a “huge” database of more than 10 million active-duty U.S. service personnel made this possible, he said.

Service members are screened for HIV at the start of their service care and biennially thereafter. The investigators used stored blood samples to determine the relation between EBV infection and MS over a 20-year period from 1993 to 2013.

Researchers examined 801 MS case patients and 1,566 matched controls without MS. Most individuals were under 20 at the time of their first blood collection. Symptom onset for those who developed MS was a median of 10 years after the first sample was obtained.

Only one of the 801 MS case patients had no serologic evidence of EBV. This individual may have been infected with the virus after the last blood collection, failed to seroconvert in response to infection, or was misdiagnosed, the investigators note.

The hazard ratio for MS between EBV seroconversion versus persistent EBV seronegative was 32.4 (95% CI, 4.3-245.3; P < .001).
 

An MS vaccine?

MS risk was not increased after infection with cytomegalovirus, a herpesvirus that is transmitted through saliva, as is EBV.

Researchers measured serum concentrations of neurofilament light chain (sNflL), a biomarker of neuroaxonal degeneration, in samples from EBV-negative individuals at baseline. There were no signs of neuroaxonal degeneration before EBV seroconversion in subjects who later developed MS.

This indicates that “EBV infection preceded not only symptom onset but also the time of the first detectable pathological mechanisms underlying MS,” the investigators note.

The very magnitude of increased MS risk of MS observed EBV almost completely rules out confounding by known risk factors. Smoking and vitamin D deficiency double the risk, and genetic predisposition and childhood obesity also only raise the risks of MS to a “moderate” degree, said Dr. Ascherio.

It’s not clear why only some people infected with EBV go on to develop MS, he said.

The idea that reverse causation – that immune dysregulation during the preclinical phase of MS increases susceptibility to EBV infection – is unlikely, the investigators note. For instance, EBV seroconversion occurs before elevation of sNfL levels, an early marker of preclinical MS.

Since most MS cases appear to be caused by EBV, a suitable vaccine might thwart the disease. “A vaccine could, in theory, prevent infection and prevent MS,” said Dr. Ascherio, adding that there’s ongoing work to develop such a vaccine.

Another approach is to target the virus driving MS disease progression. Developing appropriate antivirals might treat and even cure MS, said Dr. Ascherio.
 

‘Compelling data’

In an accompanying commentary, William H. Robinson, MD, PhD, professor, Division of Immunology and Rheumatology, department of medicine, Stanford (Calif.) University, and a colleague said the study findings “provide compelling data that implicate EBV as the trigger for the development of MS.”

The mechanism or mechanisms by which EBV leads to MS “remain elusive,” the commentary authors write.

“Possibilities include molecular mimicry, through which EBV viral protein sequences mimic human myelin proteins and other CNS proteins and thereby induce autoimmunity against myelin and CNS antigens,” they note.

As other factors, including genetic susceptibility, are important to MS, EBV infection is likely necessary but not sufficient to trigger MS, said the commentary. “Infection with EBV is the initial pathogenic step in MS, but additional fuses must be ignited for the full pathophysiology.”

The commentary authors query whether there may be “new opportunities” for therapy with vaccines or antivirals. “Now that the initial trigger for MS has been identified, perhaps MS could be eradicated.”

In a statement from the Science Media Center, an independent venture promoting views from the scientific community, two other experts offered their take on the study.

Paul Farrell, PhD, professor of tumor virology, Imperial College London, said the paper “provides very clear confirmation of a causal role for EBV in most cases of MS.”

While there’s evidence that a vaccine can prevent the EBV disease infectious mononucleosis, no vaccine candidate has yet prevented the virus from infecting and establishing long-term persistence in people, noted Dr. Farrell.

“So, at this stage it is not clear whether a vaccine of the types currently being developed would be able to prevent the long-term effects of EBV in MS,” he said.

Daniel Davis, PhD, professor of immunology, University of Manchester, United Kingdom, commented that the value of this new discovery is not an immediate medical cure or treatment but is “a major step forward” in understanding MS.

The study “sets up new research working out the precise details of how this virus can sometimes lead to an autoimmune disease,” said Dr. Davis. “There is no shortage of ideas in how this might happen in principle and hopefully the correct details will emerge soon.”

The study received funding from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, National Multiple Sclerosis Society, the German Research Foundation, the National Institutes of Health, and the Howard Hughes Medical Institute. Dr. Ascherio reports no relevant financial relaitonships. Dr. Robinson is a coinventor on a patent application filed by Stanford University that includes antibodies to EBV. Dr. Farrell reports serving on an ad hoc review panel for GSK on EBV vaccines in 2019 as a one off. He has a current grant from MRC on EBV biology, including some EBV sequence variation, but the grant is not about MS. Dr. Davis reports no relevant financial relationships.

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

Epstein-Barr virus (EBV) is the likely cause of multiple sclerosis (MS), new research confirms. Investigators found the risk of MS increased 32-fold following EBV infection.

This study is the first to provide compelling evidence of a causal link between EBV and MS, principal investigator Alberto Ascherio, MD, DrPH, professor of epidemiology, Harvard T. H. Chan School of Public Health, and professor of medicine, Harvard Medical School, Boston, told this news organization.

The “prevailing” view has been that MS is “an autoimmune disease of unknown etiology,” said Dr. Ascherio. “Now we know MS is a complication of a viral infection.” With this knowledge, he added, “we can redirect research” to find antiviral drugs to treat the disease.

The study was published online Jan. 13 in Science.
 

Unique dataset

A chronic disease of the central nervous system, MS involves an inflammatory attack on the myelin sheath and the axons it insulates. The disease affects 2.8 million people worldwide.

EBV is a human herpesvirus that can cause infectious mononucleosis. After infection, it persists in latent form in B-lymphocytes.

EBV is common and infects about 95% of adults. Most individuals are already infected with the virus by age 18 or 20 years, making it difficult to study uninfected populations, said Dr. Ascherio.

However, access to a “huge” database of more than 10 million active-duty U.S. service personnel made this possible, he said.

Service members are screened for HIV at the start of their service care and biennially thereafter. The investigators used stored blood samples to determine the relation between EBV infection and MS over a 20-year period from 1993 to 2013.

Researchers examined 801 MS case patients and 1,566 matched controls without MS. Most individuals were under 20 at the time of their first blood collection. Symptom onset for those who developed MS was a median of 10 years after the first sample was obtained.

Only one of the 801 MS case patients had no serologic evidence of EBV. This individual may have been infected with the virus after the last blood collection, failed to seroconvert in response to infection, or was misdiagnosed, the investigators note.

The hazard ratio for MS between EBV seroconversion versus persistent EBV seronegative was 32.4 (95% CI, 4.3-245.3; P < .001).
 

An MS vaccine?

MS risk was not increased after infection with cytomegalovirus, a herpesvirus that is transmitted through saliva, as is EBV.

Researchers measured serum concentrations of neurofilament light chain (sNflL), a biomarker of neuroaxonal degeneration, in samples from EBV-negative individuals at baseline. There were no signs of neuroaxonal degeneration before EBV seroconversion in subjects who later developed MS.

This indicates that “EBV infection preceded not only symptom onset but also the time of the first detectable pathological mechanisms underlying MS,” the investigators note.

The very magnitude of increased MS risk of MS observed EBV almost completely rules out confounding by known risk factors. Smoking and vitamin D deficiency double the risk, and genetic predisposition and childhood obesity also only raise the risks of MS to a “moderate” degree, said Dr. Ascherio.

It’s not clear why only some people infected with EBV go on to develop MS, he said.

The idea that reverse causation – that immune dysregulation during the preclinical phase of MS increases susceptibility to EBV infection – is unlikely, the investigators note. For instance, EBV seroconversion occurs before elevation of sNfL levels, an early marker of preclinical MS.

Since most MS cases appear to be caused by EBV, a suitable vaccine might thwart the disease. “A vaccine could, in theory, prevent infection and prevent MS,” said Dr. Ascherio, adding that there’s ongoing work to develop such a vaccine.

Another approach is to target the virus driving MS disease progression. Developing appropriate antivirals might treat and even cure MS, said Dr. Ascherio.
 

‘Compelling data’

In an accompanying commentary, William H. Robinson, MD, PhD, professor, Division of Immunology and Rheumatology, department of medicine, Stanford (Calif.) University, and a colleague said the study findings “provide compelling data that implicate EBV as the trigger for the development of MS.”

The mechanism or mechanisms by which EBV leads to MS “remain elusive,” the commentary authors write.

“Possibilities include molecular mimicry, through which EBV viral protein sequences mimic human myelin proteins and other CNS proteins and thereby induce autoimmunity against myelin and CNS antigens,” they note.

As other factors, including genetic susceptibility, are important to MS, EBV infection is likely necessary but not sufficient to trigger MS, said the commentary. “Infection with EBV is the initial pathogenic step in MS, but additional fuses must be ignited for the full pathophysiology.”

The commentary authors query whether there may be “new opportunities” for therapy with vaccines or antivirals. “Now that the initial trigger for MS has been identified, perhaps MS could be eradicated.”

In a statement from the Science Media Center, an independent venture promoting views from the scientific community, two other experts offered their take on the study.

Paul Farrell, PhD, professor of tumor virology, Imperial College London, said the paper “provides very clear confirmation of a causal role for EBV in most cases of MS.”

While there’s evidence that a vaccine can prevent the EBV disease infectious mononucleosis, no vaccine candidate has yet prevented the virus from infecting and establishing long-term persistence in people, noted Dr. Farrell.

“So, at this stage it is not clear whether a vaccine of the types currently being developed would be able to prevent the long-term effects of EBV in MS,” he said.

Daniel Davis, PhD, professor of immunology, University of Manchester, United Kingdom, commented that the value of this new discovery is not an immediate medical cure or treatment but is “a major step forward” in understanding MS.

The study “sets up new research working out the precise details of how this virus can sometimes lead to an autoimmune disease,” said Dr. Davis. “There is no shortage of ideas in how this might happen in principle and hopefully the correct details will emerge soon.”

The study received funding from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, National Multiple Sclerosis Society, the German Research Foundation, the National Institutes of Health, and the Howard Hughes Medical Institute. Dr. Ascherio reports no relevant financial relaitonships. Dr. Robinson is a coinventor on a patent application filed by Stanford University that includes antibodies to EBV. Dr. Farrell reports serving on an ad hoc review panel for GSK on EBV vaccines in 2019 as a one off. He has a current grant from MRC on EBV biology, including some EBV sequence variation, but the grant is not about MS. Dr. Davis reports no relevant financial relationships.

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

Epstein-Barr virus (EBV) is the likely cause of multiple sclerosis (MS), new research confirms. Investigators found the risk of MS increased 32-fold following EBV infection.

This study is the first to provide compelling evidence of a causal link between EBV and MS, principal investigator Alberto Ascherio, MD, DrPH, professor of epidemiology, Harvard T. H. Chan School of Public Health, and professor of medicine, Harvard Medical School, Boston, told this news organization.

The “prevailing” view has been that MS is “an autoimmune disease of unknown etiology,” said Dr. Ascherio. “Now we know MS is a complication of a viral infection.” With this knowledge, he added, “we can redirect research” to find antiviral drugs to treat the disease.

The study was published online Jan. 13 in Science.
 

Unique dataset

A chronic disease of the central nervous system, MS involves an inflammatory attack on the myelin sheath and the axons it insulates. The disease affects 2.8 million people worldwide.

EBV is a human herpesvirus that can cause infectious mononucleosis. After infection, it persists in latent form in B-lymphocytes.

EBV is common and infects about 95% of adults. Most individuals are already infected with the virus by age 18 or 20 years, making it difficult to study uninfected populations, said Dr. Ascherio.

However, access to a “huge” database of more than 10 million active-duty U.S. service personnel made this possible, he said.

Service members are screened for HIV at the start of their service care and biennially thereafter. The investigators used stored blood samples to determine the relation between EBV infection and MS over a 20-year period from 1993 to 2013.

Researchers examined 801 MS case patients and 1,566 matched controls without MS. Most individuals were under 20 at the time of their first blood collection. Symptom onset for those who developed MS was a median of 10 years after the first sample was obtained.

Only one of the 801 MS case patients had no serologic evidence of EBV. This individual may have been infected with the virus after the last blood collection, failed to seroconvert in response to infection, or was misdiagnosed, the investigators note.

The hazard ratio for MS between EBV seroconversion versus persistent EBV seronegative was 32.4 (95% CI, 4.3-245.3; P < .001).
 

An MS vaccine?

MS risk was not increased after infection with cytomegalovirus, a herpesvirus that is transmitted through saliva, as is EBV.

Researchers measured serum concentrations of neurofilament light chain (sNflL), a biomarker of neuroaxonal degeneration, in samples from EBV-negative individuals at baseline. There were no signs of neuroaxonal degeneration before EBV seroconversion in subjects who later developed MS.

This indicates that “EBV infection preceded not only symptom onset but also the time of the first detectable pathological mechanisms underlying MS,” the investigators note.

The very magnitude of increased MS risk of MS observed EBV almost completely rules out confounding by known risk factors. Smoking and vitamin D deficiency double the risk, and genetic predisposition and childhood obesity also only raise the risks of MS to a “moderate” degree, said Dr. Ascherio.

It’s not clear why only some people infected with EBV go on to develop MS, he said.

The idea that reverse causation – that immune dysregulation during the preclinical phase of MS increases susceptibility to EBV infection – is unlikely, the investigators note. For instance, EBV seroconversion occurs before elevation of sNfL levels, an early marker of preclinical MS.

Since most MS cases appear to be caused by EBV, a suitable vaccine might thwart the disease. “A vaccine could, in theory, prevent infection and prevent MS,” said Dr. Ascherio, adding that there’s ongoing work to develop such a vaccine.

Another approach is to target the virus driving MS disease progression. Developing appropriate antivirals might treat and even cure MS, said Dr. Ascherio.
 

‘Compelling data’

In an accompanying commentary, William H. Robinson, MD, PhD, professor, Division of Immunology and Rheumatology, department of medicine, Stanford (Calif.) University, and a colleague said the study findings “provide compelling data that implicate EBV as the trigger for the development of MS.”

The mechanism or mechanisms by which EBV leads to MS “remain elusive,” the commentary authors write.

“Possibilities include molecular mimicry, through which EBV viral protein sequences mimic human myelin proteins and other CNS proteins and thereby induce autoimmunity against myelin and CNS antigens,” they note.

As other factors, including genetic susceptibility, are important to MS, EBV infection is likely necessary but not sufficient to trigger MS, said the commentary. “Infection with EBV is the initial pathogenic step in MS, but additional fuses must be ignited for the full pathophysiology.”

The commentary authors query whether there may be “new opportunities” for therapy with vaccines or antivirals. “Now that the initial trigger for MS has been identified, perhaps MS could be eradicated.”

In a statement from the Science Media Center, an independent venture promoting views from the scientific community, two other experts offered their take on the study.

Paul Farrell, PhD, professor of tumor virology, Imperial College London, said the paper “provides very clear confirmation of a causal role for EBV in most cases of MS.”

While there’s evidence that a vaccine can prevent the EBV disease infectious mononucleosis, no vaccine candidate has yet prevented the virus from infecting and establishing long-term persistence in people, noted Dr. Farrell.

“So, at this stage it is not clear whether a vaccine of the types currently being developed would be able to prevent the long-term effects of EBV in MS,” he said.

Daniel Davis, PhD, professor of immunology, University of Manchester, United Kingdom, commented that the value of this new discovery is not an immediate medical cure or treatment but is “a major step forward” in understanding MS.

The study “sets up new research working out the precise details of how this virus can sometimes lead to an autoimmune disease,” said Dr. Davis. “There is no shortage of ideas in how this might happen in principle and hopefully the correct details will emerge soon.”

The study received funding from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, National Multiple Sclerosis Society, the German Research Foundation, the National Institutes of Health, and the Howard Hughes Medical Institute. Dr. Ascherio reports no relevant financial relaitonships. Dr. Robinson is a coinventor on a patent application filed by Stanford University that includes antibodies to EBV. Dr. Farrell reports serving on an ad hoc review panel for GSK on EBV vaccines in 2019 as a one off. He has a current grant from MRC on EBV biology, including some EBV sequence variation, but the grant is not about MS. Dr. Davis reports no relevant financial relationships.

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

FROM FRONTIERS IN PHYSIOLOGY

Researchers have identified a potential cause of molar hypomineralization (MH), or “chalky teeth,” an underrecognized condition affecting one in five children worldwide. The discovery could lead to preventive medical therapies to reduce dental caries and extractions, they said.

According to a team led by biochemist Michael J. Hubbard, BDS, PhD, professor in the department of medicine, dentistry, and health sciences at the University of Melbourne, the “groundbreaking” research found that the failure of enamel to adequately harden is associated with exposure to serum albumin while teeth are developing. The blood protein “poisons” the growth of mineral crystals rather than injure the cells that deposit enamel, they reported.

The investigators, including researchers from Chile, said their findings hold promise for better clinical management of MH and open a new door into research on the broader pathogenesis and causes of the condition.

“We hope this breakthrough will eventually lead to medical prevention of MH, prompting global health benefits including major reductions in childhood tooth decay,” they wrote in an article published online Dec. 21 in Frontiers in Physiology.
 

More than cosmetic

Chalky teeth, characterized by discolored enamel spots, are not merely a cosmetic problem. The condition can lead to severe toothache, painful eating, tooth decay, and even abscesses and extractions. Although its triggers have eluded dental research for a century, Dr. Hubbard’s group said fossilized blood proteins such as albumin in the tooth appear to be at least one cause.

Biochemical evidence indicates that serum albumin surrounding developing teeth is normally excluded from enamel, Dr. Hubbard said in an interview. “Given that albumin binds strongly to hydroxyapatite-based mineral and blocks its growth, we infer that the epithelial barrier – the enamel-forming cells termed ameloblasts and normally responsible for excluding albumin – must break down in places in response to medical triggers.”

This breach enables localized infiltration of albumin, which then blocks further hardening of soft, immature enamel, leading to residual spots or patches of chalky enamel once the tooth eventually erupts into the mouth. “In other words, we infer that chalky enamel spots coincide with localized breaches of an epithelial barrier that are triggered by yet-to-be determined systemic insults,” he said.

Joseph Brofsky, DMD, section head of pediatric dentistry at North Shore LIJ Cohen Children’s Medical Center of New York, in Queens, agreed that that the definitive cause of MH has evaded identification for a hundred years. However, he expressed skepticism about the fossilized blood protein hypothesis.

“That’s a long shot. It’s a possibility, and I’m not ruling it out, but we’re not 100% sure,” said Dr. Brofsky, who was not involved in the research.

In his experience, MH is somewhat less prevalent in the United States, affecting about 1 in 10 children here, which is about half the global rate. “But it’s a problem, and we wish it would go away, but before we know beyond a reasonable doubt what causes this condition, it’s going to be hard to stop it.”

Most cases of MH involve hypomineralization of the 6-year molars, the first adult molars to erupt, but the process starts at birth. “For 6-year molars, normal hardening of dental enamel takes place from the early postnatal period through infancy,” Dr. Hubbard said.

The 2-year and 12-year molars are affected about half as frequently as their 6-year counterparts, “so this extends the medical-risk window out to early school days, and slightly back to the perinatal period for the 12-year and 2-year molars, respectively,” he said.

A critical question is which childhood illnesses are most likely to set the stage for MH, he added. “Forty-plus years of epidemiology have failed to nail a specific cause or causal association. But given the high prevalence of MH – 20% in otherwise healthy kids – naturally we suspect some common illnesses are the culprits,” he said. “But which diseases, which medications, and which combinations?”

Dr. Hubbard’s advice to pediatricians is to be alert to MH: “If you’re inspecting a child’s throat, then why not look at their back teeth, too – particularly when they’re getting their new molars at 2, 6, and 12 years?”

The study was supported by the Melbourne Research Unit for Facial Disorders Department of Pharmacology & Therapeutics, Department of Paediatrics, and Faculty of Medicine, Dentistry, and Health Sciences at the University of Melbourne. The authors and Dr. Brofsky have disclosed no relevant financial relationships.

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

FROM FRONTIERS IN PHYSIOLOGY

Researchers have identified a potential cause of molar hypomineralization (MH), or “chalky teeth,” an underrecognized condition affecting one in five children worldwide. The discovery could lead to preventive medical therapies to reduce dental caries and extractions, they said.

According to a team led by biochemist Michael J. Hubbard, BDS, PhD, professor in the department of medicine, dentistry, and health sciences at the University of Melbourne, the “groundbreaking” research found that the failure of enamel to adequately harden is associated with exposure to serum albumin while teeth are developing. The blood protein “poisons” the growth of mineral crystals rather than injure the cells that deposit enamel, they reported.

The investigators, including researchers from Chile, said their findings hold promise for better clinical management of MH and open a new door into research on the broader pathogenesis and causes of the condition.

“We hope this breakthrough will eventually lead to medical prevention of MH, prompting global health benefits including major reductions in childhood tooth decay,” they wrote in an article published online Dec. 21 in Frontiers in Physiology.
 

More than cosmetic

Chalky teeth, characterized by discolored enamel spots, are not merely a cosmetic problem. The condition can lead to severe toothache, painful eating, tooth decay, and even abscesses and extractions. Although its triggers have eluded dental research for a century, Dr. Hubbard’s group said fossilized blood proteins such as albumin in the tooth appear to be at least one cause.

Biochemical evidence indicates that serum albumin surrounding developing teeth is normally excluded from enamel, Dr. Hubbard said in an interview. “Given that albumin binds strongly to hydroxyapatite-based mineral and blocks its growth, we infer that the epithelial barrier – the enamel-forming cells termed ameloblasts and normally responsible for excluding albumin – must break down in places in response to medical triggers.”

This breach enables localized infiltration of albumin, which then blocks further hardening of soft, immature enamel, leading to residual spots or patches of chalky enamel once the tooth eventually erupts into the mouth. “In other words, we infer that chalky enamel spots coincide with localized breaches of an epithelial barrier that are triggered by yet-to-be determined systemic insults,” he said.

Joseph Brofsky, DMD, section head of pediatric dentistry at North Shore LIJ Cohen Children’s Medical Center of New York, in Queens, agreed that that the definitive cause of MH has evaded identification for a hundred years. However, he expressed skepticism about the fossilized blood protein hypothesis.

“That’s a long shot. It’s a possibility, and I’m not ruling it out, but we’re not 100% sure,” said Dr. Brofsky, who was not involved in the research.

In his experience, MH is somewhat less prevalent in the United States, affecting about 1 in 10 children here, which is about half the global rate. “But it’s a problem, and we wish it would go away, but before we know beyond a reasonable doubt what causes this condition, it’s going to be hard to stop it.”

Most cases of MH involve hypomineralization of the 6-year molars, the first adult molars to erupt, but the process starts at birth. “For 6-year molars, normal hardening of dental enamel takes place from the early postnatal period through infancy,” Dr. Hubbard said.

The 2-year and 12-year molars are affected about half as frequently as their 6-year counterparts, “so this extends the medical-risk window out to early school days, and slightly back to the perinatal period for the 12-year and 2-year molars, respectively,” he said.

A critical question is which childhood illnesses are most likely to set the stage for MH, he added. “Forty-plus years of epidemiology have failed to nail a specific cause or causal association. But given the high prevalence of MH – 20% in otherwise healthy kids – naturally we suspect some common illnesses are the culprits,” he said. “But which diseases, which medications, and which combinations?”

Dr. Hubbard’s advice to pediatricians is to be alert to MH: “If you’re inspecting a child’s throat, then why not look at their back teeth, too – particularly when they’re getting their new molars at 2, 6, and 12 years?”

The study was supported by the Melbourne Research Unit for Facial Disorders Department of Pharmacology & Therapeutics, Department of Paediatrics, and Faculty of Medicine, Dentistry, and Health Sciences at the University of Melbourne. The authors and Dr. Brofsky have disclosed no relevant financial relationships.

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

FROM FRONTIERS IN PHYSIOLOGY

Researchers have identified a potential cause of molar hypomineralization (MH), or “chalky teeth,” an underrecognized condition affecting one in five children worldwide. The discovery could lead to preventive medical therapies to reduce dental caries and extractions, they said.

According to a team led by biochemist Michael J. Hubbard, BDS, PhD, professor in the department of medicine, dentistry, and health sciences at the University of Melbourne, the “groundbreaking” research found that the failure of enamel to adequately harden is associated with exposure to serum albumin while teeth are developing. The blood protein “poisons” the growth of mineral crystals rather than injure the cells that deposit enamel, they reported.

The investigators, including researchers from Chile, said their findings hold promise for better clinical management of MH and open a new door into research on the broader pathogenesis and causes of the condition.

“We hope this breakthrough will eventually lead to medical prevention of MH, prompting global health benefits including major reductions in childhood tooth decay,” they wrote in an article published online Dec. 21 in Frontiers in Physiology.
 

More than cosmetic

Chalky teeth, characterized by discolored enamel spots, are not merely a cosmetic problem. The condition can lead to severe toothache, painful eating, tooth decay, and even abscesses and extractions. Although its triggers have eluded dental research for a century, Dr. Hubbard’s group said fossilized blood proteins such as albumin in the tooth appear to be at least one cause.

Biochemical evidence indicates that serum albumin surrounding developing teeth is normally excluded from enamel, Dr. Hubbard said in an interview. “Given that albumin binds strongly to hydroxyapatite-based mineral and blocks its growth, we infer that the epithelial barrier – the enamel-forming cells termed ameloblasts and normally responsible for excluding albumin – must break down in places in response to medical triggers.”

This breach enables localized infiltration of albumin, which then blocks further hardening of soft, immature enamel, leading to residual spots or patches of chalky enamel once the tooth eventually erupts into the mouth. “In other words, we infer that chalky enamel spots coincide with localized breaches of an epithelial barrier that are triggered by yet-to-be determined systemic insults,” he said.

Joseph Brofsky, DMD, section head of pediatric dentistry at North Shore LIJ Cohen Children’s Medical Center of New York, in Queens, agreed that that the definitive cause of MH has evaded identification for a hundred years. However, he expressed skepticism about the fossilized blood protein hypothesis.

“That’s a long shot. It’s a possibility, and I’m not ruling it out, but we’re not 100% sure,” said Dr. Brofsky, who was not involved in the research.

In his experience, MH is somewhat less prevalent in the United States, affecting about 1 in 10 children here, which is about half the global rate. “But it’s a problem, and we wish it would go away, but before we know beyond a reasonable doubt what causes this condition, it’s going to be hard to stop it.”

Most cases of MH involve hypomineralization of the 6-year molars, the first adult molars to erupt, but the process starts at birth. “For 6-year molars, normal hardening of dental enamel takes place from the early postnatal period through infancy,” Dr. Hubbard said.

The 2-year and 12-year molars are affected about half as frequently as their 6-year counterparts, “so this extends the medical-risk window out to early school days, and slightly back to the perinatal period for the 12-year and 2-year molars, respectively,” he said.

A critical question is which childhood illnesses are most likely to set the stage for MH, he added. “Forty-plus years of epidemiology have failed to nail a specific cause or causal association. But given the high prevalence of MH – 20% in otherwise healthy kids – naturally we suspect some common illnesses are the culprits,” he said. “But which diseases, which medications, and which combinations?”

Dr. Hubbard’s advice to pediatricians is to be alert to MH: “If you’re inspecting a child’s throat, then why not look at their back teeth, too – particularly when they’re getting their new molars at 2, 6, and 12 years?”

The study was supported by the Melbourne Research Unit for Facial Disorders Department of Pharmacology & Therapeutics, Department of Paediatrics, and Faculty of Medicine, Dentistry, and Health Sciences at the University of Melbourne. The authors and Dr. Brofsky have disclosed no relevant financial relationships.

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

Children with peanut allergies treated with peanut oral immunotherapy for 3 years can tolerate increasingly higher exposures to peanuts. But avoidance of peanut-protein exposure for just a single month after the treatment leads to rapid and substantial decreases in tolerance, findings from a small study show.

The findings “underscore the fact that the desensitization achieved with peanut oral immunotherapy is a transient immune state,” report the authors of the study, published in December in The Journal of Allergy and Clinical Immunology: In Practice.

Therefore, “adherence to dosing [in peanut immunotherapy] is very important, and clinicians should expect a decline in tolerance with lapse in dosing,” first author Carla M. Davis, MD, director of the Texas Children’s Hospital Food Allergy Program at Baylor College of Medicine, Houston, told this news organization.

Oral immunotherapy, involving small exposures to peanut protein to build up desensitization, has been shown to mitigate allergic reactions, and, as reported by this news organization, the first peanut oral immunotherapy drug recently received approval from the U.S. Food and Drug Administration.

However, current approaches involve very low daily exposure of about 300 mg of peanut protein, equivalent to only about one to two peanuts, and research is lacking regarding the maximum tolerated doses, as well as on how long the tolerance is sustained if maintenance therapy is discontinued. “For the peanut-allergic population that would like to eat more than 1-2 peanuts, an achievable dose is currently unknown,” the study authors write. “The critical question, of the maximum tolerated dose achieved after POIT, has not been answered.”

To evaluate those issues in their phase 2 study, Dr. Davis and her colleagues enrolled 28 subjects between the ages of 5 and 13 with a diagnosis of eosinophilic esophagitis and peanut allergy.

The treatment protocol included a 1-year buildup phase of oral immunotherapy, followed by a 2-year daily maintenance phase with a dose of 3,900 mg of peanut protein.

After consenting, 11 patients dropped out of the study due to a lack of interest, and two more withdrew after failing to tolerate their first dose, leaving 15 who started treatment in the study, with a mean age of 8.7 years (range, 5.2-12.5 years), and 47% female.

Twelve patients reached the maintenance dose of 3,900 mg over a median of 13 months, and double-blind, placebo-controlled peanut challenges showed that, on average, their mean maximum cumulative tolerated dose after 12 months increased by 12,063 mg (P < .001), and the mean dose triggering a reaction increased by 15,667 mg.

Of the 12 patients, 11 (91.7%) were able to successfully tolerate at least 10,725 mg after 12 months of treatment, and six patients (50.0%) successfully tolerated at least 15,225 mg.

Two patients were able to tolerate up to the maximum cumulative target dose of 26,225 mg, equivalent to more than 105 peanuts.

“The ability to tolerate [greater than] 100 peanuts following peanut oral immunotherapy has never before been demonstrated and gives insight into the potential for food oral immunotherapy to be utilized in a subset of patients who have an immunologic phenotype accepting of this therapy,” the authors write.

“Understanding the risk of ingestion of peanut protein higher than the prescribed peanut oral immunotherapy maintenance dose will improve the safe, practical use of [the therapy],” they add.
 

Tolerance plummets with avoidance

In the protocol’s third phase, after the 3-year buildup and maintenance therapy, daily peanut exposure was avoided for 30 days, and among the six patients who participated, the mean maximum cumulative tolerated dose declined to just 2,783 mg, and the reaction dose dropped to 4,614 mg (P = .03).

“This was a disappointing finding, because we thought the desensitization would last longer after such a long period of treatment,” Dr. Davis said.

While the avoidance period was only a month, Dr. Davis said she expects the rebound in sensitivity would continue if avoidance was prolonged. “Other studies indicate the decline in tolerance would continue over time, [and] we believe it would continue to decline,” she said.

Further analysis of peanut allergy biomarkers showed significant decreases in skin prick test wheal size and cytokine expression within the first 6 weeks of initiation of the peanut oral immunotherapy. The patterns were reversed during the 1-month avoidance, with both measures increasing.

Of note, the changes in biomarkers varied significantly among the participants.

In terms of adverse events, eight patients (53%) required one or two doses of epinephrine during the study, with all but two patients receiving the epinephrine during the 12-month buildup phase, consistent with previous studies.

In commenting on the study, Richard L. Wasserman, MD, PhD, medical director of pediatric allergy and immunology at Medical City Children’s Hospital, Dallas, noted that the findings pertain to the subset of peanut oral immunotherapy patients (about 30%) who want to be able to eat peanuts.

“Most families just want protection against accidental ingestion, and these observations don’t relate to those patients,” he said in an interview.

Dr. Wasserman noted that his approach with patients is to wait until 3 years of daily maintenance after buildup (as opposed to 2 years in the study) before considering an avoidance challenge.

“When our patients pass a sustained unresponsiveness challenge, we recommend continued exposure of 2,000 mg at least weekly,” he explained.

Dr. Wasserman added that the study’s findings on biomarker changes were notable.

“The eventual reduction in peanut serum IgE in all of their patients is very interesting,” he said. “Many of our patients’ peanut serum IgE plateaus after 2 or 3 years.”

And he added, “This report suggests that we should be making patients aware that they may further decrease their peanut serum IgE by increasing their maintenance dose.”

The study was funded by the Scurlock Foundation/Waring Family Foundation and the Texas Children’s Hospital food allergy program. Dr. Davis is a consultant for Aimmune, DBV, and Moonlight Therapeutics. Dr. Wasserman is a consultant for Aimmune and DBV.

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

Children with peanut allergies treated with peanut oral immunotherapy for 3 years can tolerate increasingly higher exposures to peanuts. But avoidance of peanut-protein exposure for just a single month after the treatment leads to rapid and substantial decreases in tolerance, findings from a small study show.

The findings “underscore the fact that the desensitization achieved with peanut oral immunotherapy is a transient immune state,” report the authors of the study, published in December in The Journal of Allergy and Clinical Immunology: In Practice.

Therefore, “adherence to dosing [in peanut immunotherapy] is very important, and clinicians should expect a decline in tolerance with lapse in dosing,” first author Carla M. Davis, MD, director of the Texas Children’s Hospital Food Allergy Program at Baylor College of Medicine, Houston, told this news organization.

Oral immunotherapy, involving small exposures to peanut protein to build up desensitization, has been shown to mitigate allergic reactions, and, as reported by this news organization, the first peanut oral immunotherapy drug recently received approval from the U.S. Food and Drug Administration.

However, current approaches involve very low daily exposure of about 300 mg of peanut protein, equivalent to only about one to two peanuts, and research is lacking regarding the maximum tolerated doses, as well as on how long the tolerance is sustained if maintenance therapy is discontinued. “For the peanut-allergic population that would like to eat more than 1-2 peanuts, an achievable dose is currently unknown,” the study authors write. “The critical question, of the maximum tolerated dose achieved after POIT, has not been answered.”

To evaluate those issues in their phase 2 study, Dr. Davis and her colleagues enrolled 28 subjects between the ages of 5 and 13 with a diagnosis of eosinophilic esophagitis and peanut allergy.

The treatment protocol included a 1-year buildup phase of oral immunotherapy, followed by a 2-year daily maintenance phase with a dose of 3,900 mg of peanut protein.

After consenting, 11 patients dropped out of the study due to a lack of interest, and two more withdrew after failing to tolerate their first dose, leaving 15 who started treatment in the study, with a mean age of 8.7 years (range, 5.2-12.5 years), and 47% female.

Twelve patients reached the maintenance dose of 3,900 mg over a median of 13 months, and double-blind, placebo-controlled peanut challenges showed that, on average, their mean maximum cumulative tolerated dose after 12 months increased by 12,063 mg (P < .001), and the mean dose triggering a reaction increased by 15,667 mg.

Of the 12 patients, 11 (91.7%) were able to successfully tolerate at least 10,725 mg after 12 months of treatment, and six patients (50.0%) successfully tolerated at least 15,225 mg.

Two patients were able to tolerate up to the maximum cumulative target dose of 26,225 mg, equivalent to more than 105 peanuts.

“The ability to tolerate [greater than] 100 peanuts following peanut oral immunotherapy has never before been demonstrated and gives insight into the potential for food oral immunotherapy to be utilized in a subset of patients who have an immunologic phenotype accepting of this therapy,” the authors write.

“Understanding the risk of ingestion of peanut protein higher than the prescribed peanut oral immunotherapy maintenance dose will improve the safe, practical use of [the therapy],” they add.
 

Tolerance plummets with avoidance

In the protocol’s third phase, after the 3-year buildup and maintenance therapy, daily peanut exposure was avoided for 30 days, and among the six patients who participated, the mean maximum cumulative tolerated dose declined to just 2,783 mg, and the reaction dose dropped to 4,614 mg (P = .03).

“This was a disappointing finding, because we thought the desensitization would last longer after such a long period of treatment,” Dr. Davis said.

While the avoidance period was only a month, Dr. Davis said she expects the rebound in sensitivity would continue if avoidance was prolonged. “Other studies indicate the decline in tolerance would continue over time, [and] we believe it would continue to decline,” she said.

Further analysis of peanut allergy biomarkers showed significant decreases in skin prick test wheal size and cytokine expression within the first 6 weeks of initiation of the peanut oral immunotherapy. The patterns were reversed during the 1-month avoidance, with both measures increasing.

Of note, the changes in biomarkers varied significantly among the participants.

In terms of adverse events, eight patients (53%) required one or two doses of epinephrine during the study, with all but two patients receiving the epinephrine during the 12-month buildup phase, consistent with previous studies.

In commenting on the study, Richard L. Wasserman, MD, PhD, medical director of pediatric allergy and immunology at Medical City Children’s Hospital, Dallas, noted that the findings pertain to the subset of peanut oral immunotherapy patients (about 30%) who want to be able to eat peanuts.

“Most families just want protection against accidental ingestion, and these observations don’t relate to those patients,” he said in an interview.

Dr. Wasserman noted that his approach with patients is to wait until 3 years of daily maintenance after buildup (as opposed to 2 years in the study) before considering an avoidance challenge.

“When our patients pass a sustained unresponsiveness challenge, we recommend continued exposure of 2,000 mg at least weekly,” he explained.

Dr. Wasserman added that the study’s findings on biomarker changes were notable.

“The eventual reduction in peanut serum IgE in all of their patients is very interesting,” he said. “Many of our patients’ peanut serum IgE plateaus after 2 or 3 years.”

And he added, “This report suggests that we should be making patients aware that they may further decrease their peanut serum IgE by increasing their maintenance dose.”

The study was funded by the Scurlock Foundation/Waring Family Foundation and the Texas Children’s Hospital food allergy program. Dr. Davis is a consultant for Aimmune, DBV, and Moonlight Therapeutics. Dr. Wasserman is a consultant for Aimmune and DBV.

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

Children with peanut allergies treated with peanut oral immunotherapy for 3 years can tolerate increasingly higher exposures to peanuts. But avoidance of peanut-protein exposure for just a single month after the treatment leads to rapid and substantial decreases in tolerance, findings from a small study show.

The findings “underscore the fact that the desensitization achieved with peanut oral immunotherapy is a transient immune state,” report the authors of the study, published in December in The Journal of Allergy and Clinical Immunology: In Practice.

Therefore, “adherence to dosing [in peanut immunotherapy] is very important, and clinicians should expect a decline in tolerance with lapse in dosing,” first author Carla M. Davis, MD, director of the Texas Children’s Hospital Food Allergy Program at Baylor College of Medicine, Houston, told this news organization.

Oral immunotherapy, involving small exposures to peanut protein to build up desensitization, has been shown to mitigate allergic reactions, and, as reported by this news organization, the first peanut oral immunotherapy drug recently received approval from the U.S. Food and Drug Administration.

However, current approaches involve very low daily exposure of about 300 mg of peanut protein, equivalent to only about one to two peanuts, and research is lacking regarding the maximum tolerated doses, as well as on how long the tolerance is sustained if maintenance therapy is discontinued. “For the peanut-allergic population that would like to eat more than 1-2 peanuts, an achievable dose is currently unknown,” the study authors write. “The critical question, of the maximum tolerated dose achieved after POIT, has not been answered.”

To evaluate those issues in their phase 2 study, Dr. Davis and her colleagues enrolled 28 subjects between the ages of 5 and 13 with a diagnosis of eosinophilic esophagitis and peanut allergy.

The treatment protocol included a 1-year buildup phase of oral immunotherapy, followed by a 2-year daily maintenance phase with a dose of 3,900 mg of peanut protein.

After consenting, 11 patients dropped out of the study due to a lack of interest, and two more withdrew after failing to tolerate their first dose, leaving 15 who started treatment in the study, with a mean age of 8.7 years (range, 5.2-12.5 years), and 47% female.

Twelve patients reached the maintenance dose of 3,900 mg over a median of 13 months, and double-blind, placebo-controlled peanut challenges showed that, on average, their mean maximum cumulative tolerated dose after 12 months increased by 12,063 mg (P < .001), and the mean dose triggering a reaction increased by 15,667 mg.

Of the 12 patients, 11 (91.7%) were able to successfully tolerate at least 10,725 mg after 12 months of treatment, and six patients (50.0%) successfully tolerated at least 15,225 mg.

Two patients were able to tolerate up to the maximum cumulative target dose of 26,225 mg, equivalent to more than 105 peanuts.

“The ability to tolerate [greater than] 100 peanuts following peanut oral immunotherapy has never before been demonstrated and gives insight into the potential for food oral immunotherapy to be utilized in a subset of patients who have an immunologic phenotype accepting of this therapy,” the authors write.

“Understanding the risk of ingestion of peanut protein higher than the prescribed peanut oral immunotherapy maintenance dose will improve the safe, practical use of [the therapy],” they add.
 

Tolerance plummets with avoidance

In the protocol’s third phase, after the 3-year buildup and maintenance therapy, daily peanut exposure was avoided for 30 days, and among the six patients who participated, the mean maximum cumulative tolerated dose declined to just 2,783 mg, and the reaction dose dropped to 4,614 mg (P = .03).

“This was a disappointing finding, because we thought the desensitization would last longer after such a long period of treatment,” Dr. Davis said.

While the avoidance period was only a month, Dr. Davis said she expects the rebound in sensitivity would continue if avoidance was prolonged. “Other studies indicate the decline in tolerance would continue over time, [and] we believe it would continue to decline,” she said.

Further analysis of peanut allergy biomarkers showed significant decreases in skin prick test wheal size and cytokine expression within the first 6 weeks of initiation of the peanut oral immunotherapy. The patterns were reversed during the 1-month avoidance, with both measures increasing.

Of note, the changes in biomarkers varied significantly among the participants.

In terms of adverse events, eight patients (53%) required one or two doses of epinephrine during the study, with all but two patients receiving the epinephrine during the 12-month buildup phase, consistent with previous studies.

In commenting on the study, Richard L. Wasserman, MD, PhD, medical director of pediatric allergy and immunology at Medical City Children’s Hospital, Dallas, noted that the findings pertain to the subset of peanut oral immunotherapy patients (about 30%) who want to be able to eat peanuts.

“Most families just want protection against accidental ingestion, and these observations don’t relate to those patients,” he said in an interview.

Dr. Wasserman noted that his approach with patients is to wait until 3 years of daily maintenance after buildup (as opposed to 2 years in the study) before considering an avoidance challenge.

“When our patients pass a sustained unresponsiveness challenge, we recommend continued exposure of 2,000 mg at least weekly,” he explained.

Dr. Wasserman added that the study’s findings on biomarker changes were notable.

“The eventual reduction in peanut serum IgE in all of their patients is very interesting,” he said. “Many of our patients’ peanut serum IgE plateaus after 2 or 3 years.”

And he added, “This report suggests that we should be making patients aware that they may further decrease their peanut serum IgE by increasing their maintenance dose.”

The study was funded by the Scurlock Foundation/Waring Family Foundation and the Texas Children’s Hospital food allergy program. Dr. Davis is a consultant for Aimmune, DBV, and Moonlight Therapeutics. Dr. Wasserman is a consultant for Aimmune and DBV.

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

International guidelines developed to help nonspecialists diagnose cow’s milk allergy (CMA) lead providers to attribute normal infant symptoms to CMA and result in overdiagnosis, say authors of a study published online in Clinical & Experimental Allergy.

Lead author Rosie Vincent, MBChB, with Population Health Sciences at University of Bristol, United Kingdom, told this news organization their study shows that symptoms listed in the international Milk Allergy in Primary Care (iMAP) guidelines as indicative of non-immunoglobulin E (IgE)-mediated milk allergy are very common in a baby’s first year. Examples include vomiting, regurgitating milk, loose or more frequent stools, colic, and irritability.

Findings come from performing a secondary analysis of data from 1,303 infants from the EAT study, a population-based, randomized controlled trial in the U.K. that looked at whether introducing allergenic foods into an infant’s diet reduced the risk of developing an allergy to that food.

In an indication of how common the symptoms in the guidelines (published in 2017 and 2019) are found in all infants, nearly three-fourths (74%) of participants reported at least two mild-to-moderate symptoms, and 9% reported at least two severe symptoms in at least one month between 3 and 12 months of age. Data were not available for younger infants.

However, the prevalence of non–IgE-mediated CMA is thought to be less than 1% in infants in European countries, the study states.

In the study, two or more non-IgE CMA mild-to-moderate symptoms were reported by 25% of families, and 1.4% reported severe symptoms each month between ages 3 and 12 months.

“These symptoms peaked at 38%, with at least two mild-to-moderate symptoms and 4.3% with at least two severe symptoms at 3 months, when participants were not directly consuming cow’s milk,” Ms. Vincent said.

Researchers write that at 6 months there was no significant difference in the proportion of children with at least two symptoms between those consuming and not consuming cow’s milk.
 

Consequences of misdiagnosis

Overdiagnosing milk allergy can lead to additional costs, unnecessary tests, and less breastfeeding, she said.

Cow’s milk protein is commonly found in standard infant formula or in milk-containing foods.

The authors note that “small levels of lactoglobulin are found in breastmilk; however, the quantities are below the threshold likely to trigger a reaction in more than 99% of infants with IgE-mediated cow’s milk allergy.”

Misdiagnosis is likely to result in increasing prescriptions of unwarranted specialized formula, with increased cost to patients and health care systems, and use of unvalidated allergy tests, Ms. Vincent said.

Ms. Vincent added that even the suggestion that cow’s milk protein delivered through breast milk might be inducing symptoms could lead a mother to stop breastfeeding.

The authors also note that in reviewing recent CMA guidelines, “three of nine CMA guidelines were directly supported by formula manufacturers or marketing consultants, and 81% of all guideline authors reported a conflict of interest with formula manufacturers.”

Heather Cassell, MD, a pediatric allergy and immunology specialist with Banner Health and a clinical associate professor of pediatrics at the University of Arizona College of Medicine in Tucson, told this news organization the conflicts of interest in milk allergy research and guidelines have been a long-standing problem.

She said historically there has been a big push “that people who can afford formula should be paying for formula. That was 100% marketed by the formula companies.”

“We have formula companies bringing us samples to encourage pediatricians to use the formula early if we’re concerned about a milk protein allergy,” Dr. Cassell said.

As for the overdiagnosis of milk allergy, she said reintroduction of cow’s milk later is one way to improve diagnosis to see if the child no longer has a reaction. However, she points out that in this study, only 21% of parents reintroduced cow’s milk.

“Really, it should be closer to 100%, with the exception of the babies who are having severe symptoms,” Dr. Cassell said. “You don’t want to keep a baby from progressing with their diet.”

She said families and providers need to look at several contextual clues before they land on a milk allergy label.

“It’s not just about reflux, it’s not just about a baby spitting up. Happy babies spit up and there’s nothing that needs to be done because they will eventually grow out of it,” Dr. Cassell stressed.

She said significant irritability with blood in the stool might warrant more concern. “I think the [emphasis] needs to be on retrying the food another time,” she suggested.

Ms. Vincent pointed out that there is no quick or easy test to diagnose non–IgE-mediated cow’s milk allergy.

“We need further research to identify what symptoms are much more likely to point to a diagnosis,” she said.

Although the researchers used iMAP guidelines, they write that results are likely to apply to other CMA guidelines, because they list similar symptoms and signs.

The study was funded by the International Society of Atopic Dermatitis. Ms. Vincent reports receiving a 3-month research fellowship award from Pfizer and support from the NIHR School for Primary Care Research. Other authors’ financial disclosures are available with the full text. Dr. Cassell reports that the University of Arizona School of Medicine is a trial site for testing a patch to help with diagnosing milk protein allergy in infants.

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

International guidelines developed to help nonspecialists diagnose cow’s milk allergy (CMA) lead providers to attribute normal infant symptoms to CMA and result in overdiagnosis, say authors of a study published online in Clinical & Experimental Allergy.

Lead author Rosie Vincent, MBChB, with Population Health Sciences at University of Bristol, United Kingdom, told this news organization their study shows that symptoms listed in the international Milk Allergy in Primary Care (iMAP) guidelines as indicative of non-immunoglobulin E (IgE)-mediated milk allergy are very common in a baby’s first year. Examples include vomiting, regurgitating milk, loose or more frequent stools, colic, and irritability.

Findings come from performing a secondary analysis of data from 1,303 infants from the EAT study, a population-based, randomized controlled trial in the U.K. that looked at whether introducing allergenic foods into an infant’s diet reduced the risk of developing an allergy to that food.

In an indication of how common the symptoms in the guidelines (published in 2017 and 2019) are found in all infants, nearly three-fourths (74%) of participants reported at least two mild-to-moderate symptoms, and 9% reported at least two severe symptoms in at least one month between 3 and 12 months of age. Data were not available for younger infants.

However, the prevalence of non–IgE-mediated CMA is thought to be less than 1% in infants in European countries, the study states.

In the study, two or more non-IgE CMA mild-to-moderate symptoms were reported by 25% of families, and 1.4% reported severe symptoms each month between ages 3 and 12 months.

“These symptoms peaked at 38%, with at least two mild-to-moderate symptoms and 4.3% with at least two severe symptoms at 3 months, when participants were not directly consuming cow’s milk,” Ms. Vincent said.

Researchers write that at 6 months there was no significant difference in the proportion of children with at least two symptoms between those consuming and not consuming cow’s milk.
 

Consequences of misdiagnosis

Overdiagnosing milk allergy can lead to additional costs, unnecessary tests, and less breastfeeding, she said.

Cow’s milk protein is commonly found in standard infant formula or in milk-containing foods.

The authors note that “small levels of lactoglobulin are found in breastmilk; however, the quantities are below the threshold likely to trigger a reaction in more than 99% of infants with IgE-mediated cow’s milk allergy.”

Misdiagnosis is likely to result in increasing prescriptions of unwarranted specialized formula, with increased cost to patients and health care systems, and use of unvalidated allergy tests, Ms. Vincent said.

Ms. Vincent added that even the suggestion that cow’s milk protein delivered through breast milk might be inducing symptoms could lead a mother to stop breastfeeding.

The authors also note that in reviewing recent CMA guidelines, “three of nine CMA guidelines were directly supported by formula manufacturers or marketing consultants, and 81% of all guideline authors reported a conflict of interest with formula manufacturers.”

Heather Cassell, MD, a pediatric allergy and immunology specialist with Banner Health and a clinical associate professor of pediatrics at the University of Arizona College of Medicine in Tucson, told this news organization the conflicts of interest in milk allergy research and guidelines have been a long-standing problem.

She said historically there has been a big push “that people who can afford formula should be paying for formula. That was 100% marketed by the formula companies.”

“We have formula companies bringing us samples to encourage pediatricians to use the formula early if we’re concerned about a milk protein allergy,” Dr. Cassell said.

As for the overdiagnosis of milk allergy, she said reintroduction of cow’s milk later is one way to improve diagnosis to see if the child no longer has a reaction. However, she points out that in this study, only 21% of parents reintroduced cow’s milk.

“Really, it should be closer to 100%, with the exception of the babies who are having severe symptoms,” Dr. Cassell said. “You don’t want to keep a baby from progressing with their diet.”

She said families and providers need to look at several contextual clues before they land on a milk allergy label.

“It’s not just about reflux, it’s not just about a baby spitting up. Happy babies spit up and there’s nothing that needs to be done because they will eventually grow out of it,” Dr. Cassell stressed.

She said significant irritability with blood in the stool might warrant more concern. “I think the [emphasis] needs to be on retrying the food another time,” she suggested.

Ms. Vincent pointed out that there is no quick or easy test to diagnose non–IgE-mediated cow’s milk allergy.

“We need further research to identify what symptoms are much more likely to point to a diagnosis,” she said.

Although the researchers used iMAP guidelines, they write that results are likely to apply to other CMA guidelines, because they list similar symptoms and signs.

The study was funded by the International Society of Atopic Dermatitis. Ms. Vincent reports receiving a 3-month research fellowship award from Pfizer and support from the NIHR School for Primary Care Research. Other authors’ financial disclosures are available with the full text. Dr. Cassell reports that the University of Arizona School of Medicine is a trial site for testing a patch to help with diagnosing milk protein allergy in infants.

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

International guidelines developed to help nonspecialists diagnose cow’s milk allergy (CMA) lead providers to attribute normal infant symptoms to CMA and result in overdiagnosis, say authors of a study published online in Clinical & Experimental Allergy.

Lead author Rosie Vincent, MBChB, with Population Health Sciences at University of Bristol, United Kingdom, told this news organization their study shows that symptoms listed in the international Milk Allergy in Primary Care (iMAP) guidelines as indicative of non-immunoglobulin E (IgE)-mediated milk allergy are very common in a baby’s first year. Examples include vomiting, regurgitating milk, loose or more frequent stools, colic, and irritability.

Findings come from performing a secondary analysis of data from 1,303 infants from the EAT study, a population-based, randomized controlled trial in the U.K. that looked at whether introducing allergenic foods into an infant’s diet reduced the risk of developing an allergy to that food.

In an indication of how common the symptoms in the guidelines (published in 2017 and 2019) are found in all infants, nearly three-fourths (74%) of participants reported at least two mild-to-moderate symptoms, and 9% reported at least two severe symptoms in at least one month between 3 and 12 months of age. Data were not available for younger infants.

However, the prevalence of non–IgE-mediated CMA is thought to be less than 1% in infants in European countries, the study states.

In the study, two or more non-IgE CMA mild-to-moderate symptoms were reported by 25% of families, and 1.4% reported severe symptoms each month between ages 3 and 12 months.

“These symptoms peaked at 38%, with at least two mild-to-moderate symptoms and 4.3% with at least two severe symptoms at 3 months, when participants were not directly consuming cow’s milk,” Ms. Vincent said.

Researchers write that at 6 months there was no significant difference in the proportion of children with at least two symptoms between those consuming and not consuming cow’s milk.
 

Consequences of misdiagnosis

Overdiagnosing milk allergy can lead to additional costs, unnecessary tests, and less breastfeeding, she said.

Cow’s milk protein is commonly found in standard infant formula or in milk-containing foods.

The authors note that “small levels of lactoglobulin are found in breastmilk; however, the quantities are below the threshold likely to trigger a reaction in more than 99% of infants with IgE-mediated cow’s milk allergy.”

Misdiagnosis is likely to result in increasing prescriptions of unwarranted specialized formula, with increased cost to patients and health care systems, and use of unvalidated allergy tests, Ms. Vincent said.

Ms. Vincent added that even the suggestion that cow’s milk protein delivered through breast milk might be inducing symptoms could lead a mother to stop breastfeeding.

The authors also note that in reviewing recent CMA guidelines, “three of nine CMA guidelines were directly supported by formula manufacturers or marketing consultants, and 81% of all guideline authors reported a conflict of interest with formula manufacturers.”

Heather Cassell, MD, a pediatric allergy and immunology specialist with Banner Health and a clinical associate professor of pediatrics at the University of Arizona College of Medicine in Tucson, told this news organization the conflicts of interest in milk allergy research and guidelines have been a long-standing problem.

She said historically there has been a big push “that people who can afford formula should be paying for formula. That was 100% marketed by the formula companies.”

“We have formula companies bringing us samples to encourage pediatricians to use the formula early if we’re concerned about a milk protein allergy,” Dr. Cassell said.

As for the overdiagnosis of milk allergy, she said reintroduction of cow’s milk later is one way to improve diagnosis to see if the child no longer has a reaction. However, she points out that in this study, only 21% of parents reintroduced cow’s milk.

“Really, it should be closer to 100%, with the exception of the babies who are having severe symptoms,” Dr. Cassell said. “You don’t want to keep a baby from progressing with their diet.”

She said families and providers need to look at several contextual clues before they land on a milk allergy label.

“It’s not just about reflux, it’s not just about a baby spitting up. Happy babies spit up and there’s nothing that needs to be done because they will eventually grow out of it,” Dr. Cassell stressed.

She said significant irritability with blood in the stool might warrant more concern. “I think the [emphasis] needs to be on retrying the food another time,” she suggested.

Ms. Vincent pointed out that there is no quick or easy test to diagnose non–IgE-mediated cow’s milk allergy.

“We need further research to identify what symptoms are much more likely to point to a diagnosis,” she said.

Although the researchers used iMAP guidelines, they write that results are likely to apply to other CMA guidelines, because they list similar symptoms and signs.

The study was funded by the International Society of Atopic Dermatitis. Ms. Vincent reports receiving a 3-month research fellowship award from Pfizer and support from the NIHR School for Primary Care Research. Other authors’ financial disclosures are available with the full text. Dr. Cassell reports that the University of Arizona School of Medicine is a trial site for testing a patch to help with diagnosing milk protein allergy in infants.

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

The World Health Organization estimates that, in 2020, worldwide, there were 604,000 new cases of uterine cervical cancer and approximately 342,000 deaths, 84% of which occurred in developing countries.¹ In the United States, as of 2018, the lifetime risk of death from cervical cancer was 2.2 for every 100,000, with a mean age of 50 years at diagnosis.²

In this article, we summarize recent updates in the epidemiology, prevention, and treatment of cervical cancer. We emphasize recent information of value to family physicians, including updates in clinical guidelines and other pertinent national recommendations.

Spotlight continues to shine on HPV

It has been known for several decades that cervical cancer is caused by human papillomavirus (HPV). Of more than 100 known HPV types, 14 or 15 are classified as carcinogenic. HPV 16 is the most common oncogenic type, causing more than 60% of cases of cervical cancer^3,4; HPV 18 is second, causing 16.5% of cases—taken together, the 2 types account for more than 75% of cervical cancers.

HPV is the most common sexually transmitted infection, with as many as 80% of sexually active people becoming infected during their lifetime, generally before 50 years of age.⁵ HPV also causes other anogenital and oropharyngeal cancers; however, worldwide, more than 80% of HPV-associated cancers are cervical.⁶ Risk factors for cervical cancer are listed in TABLE 1.⁷ Cervical cancer is less common when partners are circumcised.⁷

Most cases of HPV infection clear in 1 or 2 years. In approximately 1% of untreated cases, cancer develops. Once infection progresses to high-grade dysplasia (ie, cervical intraepithelial neoplasia [CIN] 3), further progression to invasive cervical cancer occurs in approximately 30% of untreated cases.⁸ Patients who develop cervical cancer generally test positive for a high-risk HPV genotype for at least 3 to 5 years before infection progresses to cancer.⁹

At least 70% of cervical cancers are squamous cell carcinoma (SCC); 20% to 25% are adenocarcinoma (ADC); and < 3% to 5% are adenosquamous carcinoma.¹⁰ Almost 100% of cervical SCCs are HPV+, as are 86% of cervical ADCs. The most common reason for HPV-negative status in patients with cervical cancer is false-negative testing because of inadequate methods.

Primary prevention through vaccination

HPV vaccination was introduced in 2006 in the United States for girls,^a and for boys^a in 2011. The primary reason for vaccinating boys is to reduce the rates of HPV-related anal and oropharyngeal cancer. The only available HPV vaccine in the United States is Gardasil 9 (9-valent vaccine, recombinant; Merck), which provides coverage for 7 high-risk HPV types that account for approximately 90% of cervical cancers and 2 types (6 and 11) that are the principal causes of condylomata acuminata (genital warts). Future generations of prophylactic vaccines are expected to cover additional strains.

Continue to: Vaccine studies...

Vaccine studies have been summarized in a Cochrane review,¹¹ showing that vaccination is highly effective for prevention of cervical dysplasia, especially when given to young girls and women^a previously unexposed to the virus. It has not been fully established how long protection lasts, but vaccination appears to be 70% to 90% effective for ≥ 10 years.

Dosing schedule. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommends a 2-dose schedule 6 to 15 months apart, for both girls and boys between 9 and 14 years of age.¹² A third dose is indicated if the first and second doses were given less than 5 months apart, or the person is older than 15 years or is immunocompromised. No recommendation has been made for revaccination after the primary series.

In 2018, the US Food and Drug Administration approved Gardasil 9 for adults 27 to 45 years of age. In June 2019, ACIP recommended vaccination for men^a as old as 26 years, and adopted a recommendation that unvaccinated men and women between 27 and 45 years discuss HPV vaccination with their physician.¹³

The adolescent HPV vaccination rate varies by state; however, all states lag behind the CDC’s Healthy People 2020 goal of 80%.¹⁴ Barriers to vaccination include cost, infrastructure limitations, and social stigma.

Secondary prevention: Screening and Tx of precancerous lesions

Cervical cancer screening identifies patients at increased risk of cervical cancer and reassures the great majority of them that their risk of cervical cancer is very low. There are 3 general approaches to cervical cancer screening:

• cytology-based screening, which has been implemented for decades in many countries
• primary testing for DNA or RNA markers of high-risk HPV types
• co-testing with cytology-based screening plus HPV testing.

Continue to: USPSTF guidance

USPSTF guidance. Recommendations of the US Preventive Services Task Force (USPSTF) for cervical cancer screening were updated in 2018 (TABLE 2¹⁵). The recommendations state that high-risk HPV screening alone is a strategy that is amenable to patient self-sampling and self-mailing for processing—a protocol that has the potential to improve access to testing for patients who are inadequately screened.

ASCCP guidance. The American Society of Colposcopy and Cervical Pathology (ASCCP) makes nearly the same recommendations for cervical cancer screening. An exception is that ASCCP guidelines allow for the possibility of screening using primary high-risk HPV testing for patients starting at 25 years of age.¹⁶

Screening programs that can be initiated at a later age and longer intervals should be possible once the adolescent vaccination rate is optimized and vaccination registries are widely implemented.

Cervical cytology protocol

Cervical cytologic abnormalities are reported using the Bethesda system. Specimen adequacy is the most important component of quality assurance,¹⁷ and is determined primarily by sufficient cellularity. However, any specimen containing abnormal squamous cells of undetermined significance (ASCUS) or atypical glandular cells (AGCs) is considered satisfactory, regardless of the number of cells. Obscuring factors that impair quality include excessive blood; inflammation; air-drying artifact; and an interfering substance, such as lubricant. The presence of reactive changes resulting from inflammation does not require further evaluation unless the patient is immunosuppressed.

Abnormalities are most often of squamous cells, of 2 categories: low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs). HSILs are more likely to be associated with persistent HPV infection and higher risk of progression to cervical cancer.

Continue to: Cytologic findings...

Cytologic findings can be associated with histologic findings that are sometimes more, sometimes less, severe. LSIL cytology specimens that contain a few cells that are suspicious for HSIL, but that do not contain enough cells to be diagnostic, are reported as atypical squamous cells, and do not exclude a high-grade intraepithelial lesion.

Glandular-cell abnormalities usually originate from the glandular epithelium of the endocervix or the endometrium—most often, AGCs. Less frequent are AGCs, favor neoplasia; endocervical adenocarcinoma in situ; and ADC. Rarely, AGCs are associated with adenosquamous carcinoma. Endometrial polyps are a typical benign pathology that can be associated with AGCs.

High-risk HPV screening alone is amenable to patient selfsampling and self-mailing for processing—a protocol that has the potential to improve access to testing.

In about 30% of cases, AGCs are associated with premalignant or malignant disease.¹⁸ The risk of malignancy in patients with AGCs increases with age, from < 2% among patients younger than 40 years to approximately 15% among those > 50 years.¹⁹ Endometrial malignancy is more common than cervical malignancy among patients > 40 years.

AGC cytology requires endocervical curettage, plus endometrial sampling for patients ≥ 35 years. Patients with a history of AGCs are at higher risk of cervical cancer for as long as 15 years.

Cytology-based screening has limitations. Sensitivity is relatively low and dependent on the expertise of the cytologist, although regular repeat testing has been used to overcome this limitation. A substantial subset of results are reported as equivocal—ie, ASCUS.

Continue to: Primary HPV screening

Primary HPV screening

Primary HPV testing was approved by the US Food and Drug Administration in 2015 and recommended as an appropriate screening option by professional societies.

In contrast to cytology-based screening, HPV testing has high sensitivity (≥ 90%); the population-based negative likelihood ratio is near zero.²⁰ This degree of sensitivity allows for extended screening intervals. However, primary HPV testing lacks specificity for persistent infection and high-grade or invasive lesions, which approximately doubles the number of patients who screen positive. The potential for excess patients to be referred for colposcopy led to the need for secondary triage.

Instituting secondary triage. Cytology is, currently, the primary method of secondary triage, reducing the number of referrals for colposcopy by nearly one-half, compared to referrals for all high-risk HPV results, and with better overall accuracy over cytology with high-risk HPV triage.²¹ When cytology shows ASCUS, or worse, refer the patient for colposcopy; alternatively, if so-called reflex testing for HPV types 16 and 18 is available and positive, direct referral to colposcopy without cytology is also appropriate.

In the future, secondary triage for cytology is likely to be replaced with improved technologies, such as immunostaining of the specimen for biomarkers associated with cervical precancer or cancer, or for viral genome methylation testing.²²

Management of abnormal cervical cancer screening results

Routine screening applies to asymptomatic patients who do not require surveillance because they have not had prior abnormal screening results. In 2020, ASCCP published risk-based management consensus guidelines that were developed for abnormal cervical cancer screening tests and for cancer precursors.¹⁶ Guiding principles, and screening situations in which the guidelines can be applied, are summarized in TABLE 3.¹⁶

Continue to: ASCCP guidelines...

ASCCP guidelines provide a framework to incorporate new data and technologies without major revision. The web-based ASCCP resource can be obtained at no cost at http://asccp.org; there is also a smartphone app resource ($9.99).

Some noteworthy scenarios in ASCCP risk-based management are:

• For unsatisfactory cytology with a negative HPV test or no HPV test, repeat age-based screening in 2 to 4 months. (Note: A negative HPV test might reflect an inadequate specimen; do not interpret this result as a true negative.)
• An absent transformation zone (ie, between glandular and squamous cervical cells) with an otherwise adequate specimen should be interpreted as satisfactory for screening in patients 21 to 29 years of age. For those ≥ 30 years and with no HPV testing in this circumstance, HPV testing is preferred; repeating cytology, in 3 years, is also acceptable.
• After a finding of LSIL/CIN1 without evidence of a high-grade abnormality, and after 2 negative annual screenings (including HPV testing), a return to 3-year (not 5-year) screening is ­recommended.
• A cytology result of an HSIL carries a risk of 26% for CIN3+, in which case colposcopy is recommended, regardless of HPV test results.
• For long-term management after treatment for CIN2+, continue surveillance testing every 3 years after 3 consecutive negative HPV tests or cytology findings, for at least 25 years. If the 25-year threshold is reached before 65 years of age, continuing surveillance every 3 years is optional, as long as the patient is in good health (ie, life expectancy ≥ 10 years).
• After hysterectomy for a high-grade abnormality, annual vaginal HPV testing is recommended until 3 negative tests are returned; after that, surveillance shifts to a 3-year interval until the 25-year threshold.

Treatment of cancer precursors

Treatment for cervical dysplasia is excisional or ablative.

Excisional therapy. In most cases, excisional therapy (either a loop electrosurgical excision procedure [LEEP; also known as large loop excision of the transformation zone, cold knife conization, and laser conization] or cone biopsy) is required, or preferred. Excisional treatment has the advantage of providing a diagnostic specimen.

In about 30% of cases, atypical glandular cells (AGCs) found on cytology are associated with premalignant or malignant disease. The risk of malignancy with AGCs increases with age.

The World Health Organization recommends LEEP over ablation in settings in which LEEP is available.²³ ASCCP states that, in the relatively few cases in which treatment is needed and it is for CIN1, either excision or ablation is acceptable. TABLE 4¹⁶ lists situations in which excisional treatment is required because a diagnostic specimen is needed.

Continue to: Ablative treatments

Ablative treatments are cryotherapy, CO₂ laser ablation, and thermal ablation. Ablative therapy has the advantage of presenting less risk of adverse obstetric outcomes (eg, preterm birth); it can be used if the indication for therapy is:

• CIN1 or CIN2 and HPV type 16 or 18 positivity
• concordant cytology and histology
• satisfactory colposcopy
• negative endocervical curettage.

The most common ablative treatment is liquid nitrogen applied to a metal tip under local anesthesia.

Hysterectomy can be considered for patients with recurrent CIN2+ who have completed childbearing or for whom repeat excision is infeasible (eg, scarring or a short cervix), or both.

Cost, availability, and convenience might play a role in decision-making with regard to the treatment choice for cancer precursors.

Is care after treatment called for? Patients who continue to be at increased risk of (and thus mortality from) cervical and vaginal cancer require enhanced surveillance. The risk of cancer is more than triple for patients who were given their diagnosis, and treated, when they were > 60 years, compared to patients treated in their 30s.¹ The excess period of risk covers at least 25 years after treatment, even among patients who have had 3 posttreatment screenings.

Continue to: Persistent HPV positivity...

Persistent HPV positivity is more challenging. Patients infected with HPV type 16 have an increased risk of residual disease.

Cancer management

Invasive cancer. Most cervical cancers (60%) occur among patients who have not been screened during the 5 years before their diagnosis.²⁴ For patients who have a diagnosis of cancer, those detected through screening have a much better prognosis than those identified by symptoms (mean cure rate, 92% and 66%, respectively).²⁵ The median 5-year survival for patients who were not screened during the 5 years before their diagnosis of cervical cancer is 66%.²

In unscreened patients, cervical cancer usually manifests as abnormal vaginal bleeding, especially postcoitally. In approximately 45% of cases, the patient has localized disease at diagnosis; in 36%, regional disease; and in 15%, distant metastases.²⁶

For cancers marked by stromal invasion < 3 mm, appropriate treatment is cone biopsy or simple hysterectomy.²⁷

Most patients with early-stage cervical cancer undergo modified radical hysterectomy. The ovaries are usually conserved, unless the cancer is adenocarcinoma. Sentinel-node dissection has become standard practice. Primary radiation therapy is most often used for patients who are a poor surgical candidate because of medical comorbidity or poor functional status. Antiangiogenic agents (eg, bevacizumab) can be used as adjuvant palliative therapy for advanced and recurrent disease.²⁸

Continue to: After treatment for...

After treatment for invasive cervical cancer, the goal is early detection of recurrence, although there is no consensus on a protocol. Most recurrences are detected within the first 2 years.

After treatment for invasive cervical cancer, the goal is early detection of recurrence. Most recurrences are detected within the first 2 years.

Long-term sequelae after treatment for advanced cancer are considerable. Patients report significantly lower quality of life, comparatively, across multiple dimensions, including mental health, physical health, and sexual function.²⁹

Hormone replacement therapy is generally considered acceptable after treatment of cervical cancer because it does not increase replication of HPV.

Recurrent or metastatic cancer. Recurrence or metastases will develop in 15% to 60% of patients,³⁰ usually within the first 2 years after treatment.

Management depends on location and extent of disease, using mainly radiation therapy or surgical resection. Recurrence or metastasis is usually incurable.

Continue to: Last, there are promising...

Last, there are promising areas of research for more effective treatment for cervical cancer precursors and cancers, including gene editing tools³¹ and therapeutic vaccination,³² which is intended to target and kill infected cells.

Prospects for better cervical cancer care

Prevention. HPV vaccination is likely to have a large impact on population-based risk of both cancer and cancer precursors in the next generation.

Screening in the foreseeable future will gravitate toward reliance on primary HPV screening, with a self-sampling option.

Surveillance after dysplastic disease. The 2019 ASCCP guidelines for surveillance and intervention decisions after abnormal cancer screening results will evolve to incorporate introduction of new technology into computerized algorithms.

Treatment. New biologic therapies, including monoclonal antibodies and therapeutic vaccines against HPV, will likely be introduced for treating cancer precursors and invasive cancer.

A NOTE FROM THE EDITORS The Editors of The Journal of Family Practice recognize the importance of addressing the reproductive health of gender-diverse individuals. In this article, we use the words “women,” “men,” “girls,” and “boys” in limited circumstances (1) for ease of reading and (2) to reflect the official language of the US Food and Drug Administration and the Advisory Committee on Immunization Practices. The reader should consider the information and guidance offered in this discussion of cervical cancer and other human papillomavirus-related cancers to speak to the care of people with a uterine cervix and people with a penis.

CORRESPONDENCE
Linda Speer, MD, 3000 Arlington Avenue, MS 1179, Toledo, OH 43614; [email protected]

The World Health Organization estimates that, in 2020, worldwide, there were 604,000 new cases of uterine cervical cancer and approximately 342,000 deaths, 84% of which occurred in developing countries.¹ In the United States, as of 2018, the lifetime risk of death from cervical cancer was 2.2 for every 100,000, with a mean age of 50 years at diagnosis.²

In this article, we summarize recent updates in the epidemiology, prevention, and treatment of cervical cancer. We emphasize recent information of value to family physicians, including updates in clinical guidelines and other pertinent national recommendations.

Spotlight continues to shine on HPV

It has been known for several decades that cervical cancer is caused by human papillomavirus (HPV). Of more than 100 known HPV types, 14 or 15 are classified as carcinogenic. HPV 16 is the most common oncogenic type, causing more than 60% of cases of cervical cancer^3,4; HPV 18 is second, causing 16.5% of cases—taken together, the 2 types account for more than 75% of cervical cancers.

HPV is the most common sexually transmitted infection, with as many as 80% of sexually active people becoming infected during their lifetime, generally before 50 years of age.⁵ HPV also causes other anogenital and oropharyngeal cancers; however, worldwide, more than 80% of HPV-associated cancers are cervical.⁶ Risk factors for cervical cancer are listed in TABLE 1.⁷ Cervical cancer is less common when partners are circumcised.⁷

Most cases of HPV infection clear in 1 or 2 years. In approximately 1% of untreated cases, cancer develops. Once infection progresses to high-grade dysplasia (ie, cervical intraepithelial neoplasia [CIN] 3), further progression to invasive cervical cancer occurs in approximately 30% of untreated cases.⁸ Patients who develop cervical cancer generally test positive for a high-risk HPV genotype for at least 3 to 5 years before infection progresses to cancer.⁹

At least 70% of cervical cancers are squamous cell carcinoma (SCC); 20% to 25% are adenocarcinoma (ADC); and < 3% to 5% are adenosquamous carcinoma.¹⁰ Almost 100% of cervical SCCs are HPV+, as are 86% of cervical ADCs. The most common reason for HPV-negative status in patients with cervical cancer is false-negative testing because of inadequate methods.

Primary prevention through vaccination

HPV vaccination was introduced in 2006 in the United States for girls,^a and for boys^a in 2011. The primary reason for vaccinating boys is to reduce the rates of HPV-related anal and oropharyngeal cancer. The only available HPV vaccine in the United States is Gardasil 9 (9-valent vaccine, recombinant; Merck), which provides coverage for 7 high-risk HPV types that account for approximately 90% of cervical cancers and 2 types (6 and 11) that are the principal causes of condylomata acuminata (genital warts). Future generations of prophylactic vaccines are expected to cover additional strains.

Continue to: Vaccine studies...

Vaccine studies have been summarized in a Cochrane review,¹¹ showing that vaccination is highly effective for prevention of cervical dysplasia, especially when given to young girls and women^a previously unexposed to the virus. It has not been fully established how long protection lasts, but vaccination appears to be 70% to 90% effective for ≥ 10 years.

Dosing schedule. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommends a 2-dose schedule 6 to 15 months apart, for both girls and boys between 9 and 14 years of age.¹² A third dose is indicated if the first and second doses were given less than 5 months apart, or the person is older than 15 years or is immunocompromised. No recommendation has been made for revaccination after the primary series.

In 2018, the US Food and Drug Administration approved Gardasil 9 for adults 27 to 45 years of age. In June 2019, ACIP recommended vaccination for men^a as old as 26 years, and adopted a recommendation that unvaccinated men and women between 27 and 45 years discuss HPV vaccination with their physician.¹³

The adolescent HPV vaccination rate varies by state; however, all states lag behind the CDC’s Healthy People 2020 goal of 80%.¹⁴ Barriers to vaccination include cost, infrastructure limitations, and social stigma.

Secondary prevention: Screening and Tx of precancerous lesions

Cervical cancer screening identifies patients at increased risk of cervical cancer and reassures the great majority of them that their risk of cervical cancer is very low. There are 3 general approaches to cervical cancer screening:

• cytology-based screening, which has been implemented for decades in many countries
• primary testing for DNA or RNA markers of high-risk HPV types
• co-testing with cytology-based screening plus HPV testing.

Continue to: USPSTF guidance

USPSTF guidance. Recommendations of the US Preventive Services Task Force (USPSTF) for cervical cancer screening were updated in 2018 (TABLE 2¹⁵). The recommendations state that high-risk HPV screening alone is a strategy that is amenable to patient self-sampling and self-mailing for processing—a protocol that has the potential to improve access to testing for patients who are inadequately screened.

ASCCP guidance. The American Society of Colposcopy and Cervical Pathology (ASCCP) makes nearly the same recommendations for cervical cancer screening. An exception is that ASCCP guidelines allow for the possibility of screening using primary high-risk HPV testing for patients starting at 25 years of age.¹⁶

Screening programs that can be initiated at a later age and longer intervals should be possible once the adolescent vaccination rate is optimized and vaccination registries are widely implemented.

Cervical cytology protocol

Cervical cytologic abnormalities are reported using the Bethesda system. Specimen adequacy is the most important component of quality assurance,¹⁷ and is determined primarily by sufficient cellularity. However, any specimen containing abnormal squamous cells of undetermined significance (ASCUS) or atypical glandular cells (AGCs) is considered satisfactory, regardless of the number of cells. Obscuring factors that impair quality include excessive blood; inflammation; air-drying artifact; and an interfering substance, such as lubricant. The presence of reactive changes resulting from inflammation does not require further evaluation unless the patient is immunosuppressed.

Abnormalities are most often of squamous cells, of 2 categories: low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs). HSILs are more likely to be associated with persistent HPV infection and higher risk of progression to cervical cancer.

Continue to: Cytologic findings...

Cytologic findings can be associated with histologic findings that are sometimes more, sometimes less, severe. LSIL cytology specimens that contain a few cells that are suspicious for HSIL, but that do not contain enough cells to be diagnostic, are reported as atypical squamous cells, and do not exclude a high-grade intraepithelial lesion.

Glandular-cell abnormalities usually originate from the glandular epithelium of the endocervix or the endometrium—most often, AGCs. Less frequent are AGCs, favor neoplasia; endocervical adenocarcinoma in situ; and ADC. Rarely, AGCs are associated with adenosquamous carcinoma. Endometrial polyps are a typical benign pathology that can be associated with AGCs.

High-risk HPV screening alone is amenable to patient selfsampling and self-mailing for processing—a protocol that has the potential to improve access to testing.

In about 30% of cases, AGCs are associated with premalignant or malignant disease.¹⁸ The risk of malignancy in patients with AGCs increases with age, from < 2% among patients younger than 40 years to approximately 15% among those > 50 years.¹⁹ Endometrial malignancy is more common than cervical malignancy among patients > 40 years.

AGC cytology requires endocervical curettage, plus endometrial sampling for patients ≥ 35 years. Patients with a history of AGCs are at higher risk of cervical cancer for as long as 15 years.

Cytology-based screening has limitations. Sensitivity is relatively low and dependent on the expertise of the cytologist, although regular repeat testing has been used to overcome this limitation. A substantial subset of results are reported as equivocal—ie, ASCUS.

Continue to: Primary HPV screening

Primary HPV screening

Primary HPV testing was approved by the US Food and Drug Administration in 2015 and recommended as an appropriate screening option by professional societies.

In contrast to cytology-based screening, HPV testing has high sensitivity (≥ 90%); the population-based negative likelihood ratio is near zero.²⁰ This degree of sensitivity allows for extended screening intervals. However, primary HPV testing lacks specificity for persistent infection and high-grade or invasive lesions, which approximately doubles the number of patients who screen positive. The potential for excess patients to be referred for colposcopy led to the need for secondary triage.

Instituting secondary triage. Cytology is, currently, the primary method of secondary triage, reducing the number of referrals for colposcopy by nearly one-half, compared to referrals for all high-risk HPV results, and with better overall accuracy over cytology with high-risk HPV triage.²¹ When cytology shows ASCUS, or worse, refer the patient for colposcopy; alternatively, if so-called reflex testing for HPV types 16 and 18 is available and positive, direct referral to colposcopy without cytology is also appropriate.

In the future, secondary triage for cytology is likely to be replaced with improved technologies, such as immunostaining of the specimen for biomarkers associated with cervical precancer or cancer, or for viral genome methylation testing.²²

Management of abnormal cervical cancer screening results

Routine screening applies to asymptomatic patients who do not require surveillance because they have not had prior abnormal screening results. In 2020, ASCCP published risk-based management consensus guidelines that were developed for abnormal cervical cancer screening tests and for cancer precursors.¹⁶ Guiding principles, and screening situations in which the guidelines can be applied, are summarized in TABLE 3.¹⁶

Continue to: ASCCP guidelines...

ASCCP guidelines provide a framework to incorporate new data and technologies without major revision. The web-based ASCCP resource can be obtained at no cost at http://asccp.org; there is also a smartphone app resource ($9.99).

Some noteworthy scenarios in ASCCP risk-based management are:

• For unsatisfactory cytology with a negative HPV test or no HPV test, repeat age-based screening in 2 to 4 months. (Note: A negative HPV test might reflect an inadequate specimen; do not interpret this result as a true negative.)
• An absent transformation zone (ie, between glandular and squamous cervical cells) with an otherwise adequate specimen should be interpreted as satisfactory for screening in patients 21 to 29 years of age. For those ≥ 30 years and with no HPV testing in this circumstance, HPV testing is preferred; repeating cytology, in 3 years, is also acceptable.
• After a finding of LSIL/CIN1 without evidence of a high-grade abnormality, and after 2 negative annual screenings (including HPV testing), a return to 3-year (not 5-year) screening is ­recommended.
• A cytology result of an HSIL carries a risk of 26% for CIN3+, in which case colposcopy is recommended, regardless of HPV test results.
• For long-term management after treatment for CIN2+, continue surveillance testing every 3 years after 3 consecutive negative HPV tests or cytology findings, for at least 25 years. If the 25-year threshold is reached before 65 years of age, continuing surveillance every 3 years is optional, as long as the patient is in good health (ie, life expectancy ≥ 10 years).
• After hysterectomy for a high-grade abnormality, annual vaginal HPV testing is recommended until 3 negative tests are returned; after that, surveillance shifts to a 3-year interval until the 25-year threshold.

Treatment of cancer precursors

Treatment for cervical dysplasia is excisional or ablative.

Excisional therapy. In most cases, excisional therapy (either a loop electrosurgical excision procedure [LEEP; also known as large loop excision of the transformation zone, cold knife conization, and laser conization] or cone biopsy) is required, or preferred. Excisional treatment has the advantage of providing a diagnostic specimen.

In about 30% of cases, atypical glandular cells (AGCs) found on cytology are associated with premalignant or malignant disease. The risk of malignancy with AGCs increases with age.

The World Health Organization recommends LEEP over ablation in settings in which LEEP is available.²³ ASCCP states that, in the relatively few cases in which treatment is needed and it is for CIN1, either excision or ablation is acceptable. TABLE 4¹⁶ lists situations in which excisional treatment is required because a diagnostic specimen is needed.

Continue to: Ablative treatments

Ablative treatments are cryotherapy, CO₂ laser ablation, and thermal ablation. Ablative therapy has the advantage of presenting less risk of adverse obstetric outcomes (eg, preterm birth); it can be used if the indication for therapy is:

• CIN1 or CIN2 and HPV type 16 or 18 positivity
• concordant cytology and histology
• satisfactory colposcopy
• negative endocervical curettage.

The most common ablative treatment is liquid nitrogen applied to a metal tip under local anesthesia.

Hysterectomy can be considered for patients with recurrent CIN2+ who have completed childbearing or for whom repeat excision is infeasible (eg, scarring or a short cervix), or both.

Cost, availability, and convenience might play a role in decision-making with regard to the treatment choice for cancer precursors.

Is care after treatment called for? Patients who continue to be at increased risk of (and thus mortality from) cervical and vaginal cancer require enhanced surveillance. The risk of cancer is more than triple for patients who were given their diagnosis, and treated, when they were > 60 years, compared to patients treated in their 30s.¹ The excess period of risk covers at least 25 years after treatment, even among patients who have had 3 posttreatment screenings.

Continue to: Persistent HPV positivity...

Persistent HPV positivity is more challenging. Patients infected with HPV type 16 have an increased risk of residual disease.

Cancer management

Invasive cancer. Most cervical cancers (60%) occur among patients who have not been screened during the 5 years before their diagnosis.²⁴ For patients who have a diagnosis of cancer, those detected through screening have a much better prognosis than those identified by symptoms (mean cure rate, 92% and 66%, respectively).²⁵ The median 5-year survival for patients who were not screened during the 5 years before their diagnosis of cervical cancer is 66%.²

In unscreened patients, cervical cancer usually manifests as abnormal vaginal bleeding, especially postcoitally. In approximately 45% of cases, the patient has localized disease at diagnosis; in 36%, regional disease; and in 15%, distant metastases.²⁶

For cancers marked by stromal invasion < 3 mm, appropriate treatment is cone biopsy or simple hysterectomy.²⁷

Most patients with early-stage cervical cancer undergo modified radical hysterectomy. The ovaries are usually conserved, unless the cancer is adenocarcinoma. Sentinel-node dissection has become standard practice. Primary radiation therapy is most often used for patients who are a poor surgical candidate because of medical comorbidity or poor functional status. Antiangiogenic agents (eg, bevacizumab) can be used as adjuvant palliative therapy for advanced and recurrent disease.²⁸

Continue to: After treatment for...

After treatment for invasive cervical cancer, the goal is early detection of recurrence, although there is no consensus on a protocol. Most recurrences are detected within the first 2 years.

After treatment for invasive cervical cancer, the goal is early detection of recurrence. Most recurrences are detected within the first 2 years.

Long-term sequelae after treatment for advanced cancer are considerable. Patients report significantly lower quality of life, comparatively, across multiple dimensions, including mental health, physical health, and sexual function.²⁹

Hormone replacement therapy is generally considered acceptable after treatment of cervical cancer because it does not increase replication of HPV.

Recurrent or metastatic cancer. Recurrence or metastases will develop in 15% to 60% of patients,³⁰ usually within the first 2 years after treatment.

Management depends on location and extent of disease, using mainly radiation therapy or surgical resection. Recurrence or metastasis is usually incurable.

Continue to: Last, there are promising...

Last, there are promising areas of research for more effective treatment for cervical cancer precursors and cancers, including gene editing tools³¹ and therapeutic vaccination,³² which is intended to target and kill infected cells.

Prospects for better cervical cancer care

Prevention. HPV vaccination is likely to have a large impact on population-based risk of both cancer and cancer precursors in the next generation.

Screening in the foreseeable future will gravitate toward reliance on primary HPV screening, with a self-sampling option.

Surveillance after dysplastic disease. The 2019 ASCCP guidelines for surveillance and intervention decisions after abnormal cancer screening results will evolve to incorporate introduction of new technology into computerized algorithms.

Treatment. New biologic therapies, including monoclonal antibodies and therapeutic vaccines against HPV, will likely be introduced for treating cancer precursors and invasive cancer.

A NOTE FROM THE EDITORS The Editors of The Journal of Family Practice recognize the importance of addressing the reproductive health of gender-diverse individuals. In this article, we use the words “women,” “men,” “girls,” and “boys” in limited circumstances (1) for ease of reading and (2) to reflect the official language of the US Food and Drug Administration and the Advisory Committee on Immunization Practices. The reader should consider the information and guidance offered in this discussion of cervical cancer and other human papillomavirus-related cancers to speak to the care of people with a uterine cervix and people with a penis.

CORRESPONDENCE
Linda Speer, MD, 3000 Arlington Avenue, MS 1179, Toledo, OH 43614; [email protected]

The World Health Organization estimates that, in 2020, worldwide, there were 604,000 new cases of uterine cervical cancer and approximately 342,000 deaths, 84% of which occurred in developing countries.¹ In the United States, as of 2018, the lifetime risk of death from cervical cancer was 2.2 for every 100,000, with a mean age of 50 years at diagnosis.²

In this article, we summarize recent updates in the epidemiology, prevention, and treatment of cervical cancer. We emphasize recent information of value to family physicians, including updates in clinical guidelines and other pertinent national recommendations.

Spotlight continues to shine on HPV

It has been known for several decades that cervical cancer is caused by human papillomavirus (HPV). Of more than 100 known HPV types, 14 or 15 are classified as carcinogenic. HPV 16 is the most common oncogenic type, causing more than 60% of cases of cervical cancer^3,4; HPV 18 is second, causing 16.5% of cases—taken together, the 2 types account for more than 75% of cervical cancers.

HPV is the most common sexually transmitted infection, with as many as 80% of sexually active people becoming infected during their lifetime, generally before 50 years of age.⁵ HPV also causes other anogenital and oropharyngeal cancers; however, worldwide, more than 80% of HPV-associated cancers are cervical.⁶ Risk factors for cervical cancer are listed in TABLE 1.⁷ Cervical cancer is less common when partners are circumcised.⁷

Most cases of HPV infection clear in 1 or 2 years. In approximately 1% of untreated cases, cancer develops. Once infection progresses to high-grade dysplasia (ie, cervical intraepithelial neoplasia [CIN] 3), further progression to invasive cervical cancer occurs in approximately 30% of untreated cases.⁸ Patients who develop cervical cancer generally test positive for a high-risk HPV genotype for at least 3 to 5 years before infection progresses to cancer.⁹

At least 70% of cervical cancers are squamous cell carcinoma (SCC); 20% to 25% are adenocarcinoma (ADC); and < 3% to 5% are adenosquamous carcinoma.¹⁰ Almost 100% of cervical SCCs are HPV+, as are 86% of cervical ADCs. The most common reason for HPV-negative status in patients with cervical cancer is false-negative testing because of inadequate methods.

Primary prevention through vaccination

HPV vaccination was introduced in 2006 in the United States for girls,^a and for boys^a in 2011. The primary reason for vaccinating boys is to reduce the rates of HPV-related anal and oropharyngeal cancer. The only available HPV vaccine in the United States is Gardasil 9 (9-valent vaccine, recombinant; Merck), which provides coverage for 7 high-risk HPV types that account for approximately 90% of cervical cancers and 2 types (6 and 11) that are the principal causes of condylomata acuminata (genital warts). Future generations of prophylactic vaccines are expected to cover additional strains.

Continue to: Vaccine studies...

Vaccine studies have been summarized in a Cochrane review,¹¹ showing that vaccination is highly effective for prevention of cervical dysplasia, especially when given to young girls and women^a previously unexposed to the virus. It has not been fully established how long protection lasts, but vaccination appears to be 70% to 90% effective for ≥ 10 years.

Dosing schedule. The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) recommends a 2-dose schedule 6 to 15 months apart, for both girls and boys between 9 and 14 years of age.¹² A third dose is indicated if the first and second doses were given less than 5 months apart, or the person is older than 15 years or is immunocompromised. No recommendation has been made for revaccination after the primary series.

In 2018, the US Food and Drug Administration approved Gardasil 9 for adults 27 to 45 years of age. In June 2019, ACIP recommended vaccination for men^a as old as 26 years, and adopted a recommendation that unvaccinated men and women between 27 and 45 years discuss HPV vaccination with their physician.¹³

The adolescent HPV vaccination rate varies by state; however, all states lag behind the CDC’s Healthy People 2020 goal of 80%.¹⁴ Barriers to vaccination include cost, infrastructure limitations, and social stigma.

Secondary prevention: Screening and Tx of precancerous lesions

Cervical cancer screening identifies patients at increased risk of cervical cancer and reassures the great majority of them that their risk of cervical cancer is very low. There are 3 general approaches to cervical cancer screening:

• cytology-based screening, which has been implemented for decades in many countries
• primary testing for DNA or RNA markers of high-risk HPV types
• co-testing with cytology-based screening plus HPV testing.

Continue to: USPSTF guidance

USPSTF guidance. Recommendations of the US Preventive Services Task Force (USPSTF) for cervical cancer screening were updated in 2018 (TABLE 2¹⁵). The recommendations state that high-risk HPV screening alone is a strategy that is amenable to patient self-sampling and self-mailing for processing—a protocol that has the potential to improve access to testing for patients who are inadequately screened.

ASCCP guidance. The American Society of Colposcopy and Cervical Pathology (ASCCP) makes nearly the same recommendations for cervical cancer screening. An exception is that ASCCP guidelines allow for the possibility of screening using primary high-risk HPV testing for patients starting at 25 years of age.¹⁶

Screening programs that can be initiated at a later age and longer intervals should be possible once the adolescent vaccination rate is optimized and vaccination registries are widely implemented.

Cervical cytology protocol

Cervical cytologic abnormalities are reported using the Bethesda system. Specimen adequacy is the most important component of quality assurance,¹⁷ and is determined primarily by sufficient cellularity. However, any specimen containing abnormal squamous cells of undetermined significance (ASCUS) or atypical glandular cells (AGCs) is considered satisfactory, regardless of the number of cells. Obscuring factors that impair quality include excessive blood; inflammation; air-drying artifact; and an interfering substance, such as lubricant. The presence of reactive changes resulting from inflammation does not require further evaluation unless the patient is immunosuppressed.

Abnormalities are most often of squamous cells, of 2 categories: low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs). HSILs are more likely to be associated with persistent HPV infection and higher risk of progression to cervical cancer.

Continue to: Cytologic findings...

Cytologic findings can be associated with histologic findings that are sometimes more, sometimes less, severe. LSIL cytology specimens that contain a few cells that are suspicious for HSIL, but that do not contain enough cells to be diagnostic, are reported as atypical squamous cells, and do not exclude a high-grade intraepithelial lesion.

Glandular-cell abnormalities usually originate from the glandular epithelium of the endocervix or the endometrium—most often, AGCs. Less frequent are AGCs, favor neoplasia; endocervical adenocarcinoma in situ; and ADC. Rarely, AGCs are associated with adenosquamous carcinoma. Endometrial polyps are a typical benign pathology that can be associated with AGCs.

High-risk HPV screening alone is amenable to patient selfsampling and self-mailing for processing—a protocol that has the potential to improve access to testing.

In about 30% of cases, AGCs are associated with premalignant or malignant disease.¹⁸ The risk of malignancy in patients with AGCs increases with age, from < 2% among patients younger than 40 years to approximately 15% among those > 50 years.¹⁹ Endometrial malignancy is more common than cervical malignancy among patients > 40 years.

AGC cytology requires endocervical curettage, plus endometrial sampling for patients ≥ 35 years. Patients with a history of AGCs are at higher risk of cervical cancer for as long as 15 years.

Cytology-based screening has limitations. Sensitivity is relatively low and dependent on the expertise of the cytologist, although regular repeat testing has been used to overcome this limitation. A substantial subset of results are reported as equivocal—ie, ASCUS.

Continue to: Primary HPV screening

Primary HPV screening

Primary HPV testing was approved by the US Food and Drug Administration in 2015 and recommended as an appropriate screening option by professional societies.

In contrast to cytology-based screening, HPV testing has high sensitivity (≥ 90%); the population-based negative likelihood ratio is near zero.²⁰ This degree of sensitivity allows for extended screening intervals. However, primary HPV testing lacks specificity for persistent infection and high-grade or invasive lesions, which approximately doubles the number of patients who screen positive. The potential for excess patients to be referred for colposcopy led to the need for secondary triage.

Instituting secondary triage. Cytology is, currently, the primary method of secondary triage, reducing the number of referrals for colposcopy by nearly one-half, compared to referrals for all high-risk HPV results, and with better overall accuracy over cytology with high-risk HPV triage.²¹ When cytology shows ASCUS, or worse, refer the patient for colposcopy; alternatively, if so-called reflex testing for HPV types 16 and 18 is available and positive, direct referral to colposcopy without cytology is also appropriate.

In the future, secondary triage for cytology is likely to be replaced with improved technologies, such as immunostaining of the specimen for biomarkers associated with cervical precancer or cancer, or for viral genome methylation testing.²²

Management of abnormal cervical cancer screening results

Routine screening applies to asymptomatic patients who do not require surveillance because they have not had prior abnormal screening results. In 2020, ASCCP published risk-based management consensus guidelines that were developed for abnormal cervical cancer screening tests and for cancer precursors.¹⁶ Guiding principles, and screening situations in which the guidelines can be applied, are summarized in TABLE 3.¹⁶

Continue to: ASCCP guidelines...

ASCCP guidelines provide a framework to incorporate new data and technologies without major revision. The web-based ASCCP resource can be obtained at no cost at http://asccp.org; there is also a smartphone app resource ($9.99).

Some noteworthy scenarios in ASCCP risk-based management are:

• For unsatisfactory cytology with a negative HPV test or no HPV test, repeat age-based screening in 2 to 4 months. (Note: A negative HPV test might reflect an inadequate specimen; do not interpret this result as a true negative.)
• An absent transformation zone (ie, between glandular and squamous cervical cells) with an otherwise adequate specimen should be interpreted as satisfactory for screening in patients 21 to 29 years of age. For those ≥ 30 years and with no HPV testing in this circumstance, HPV testing is preferred; repeating cytology, in 3 years, is also acceptable.
• After a finding of LSIL/CIN1 without evidence of a high-grade abnormality, and after 2 negative annual screenings (including HPV testing), a return to 3-year (not 5-year) screening is ­recommended.
• A cytology result of an HSIL carries a risk of 26% for CIN3+, in which case colposcopy is recommended, regardless of HPV test results.
• For long-term management after treatment for CIN2+, continue surveillance testing every 3 years after 3 consecutive negative HPV tests or cytology findings, for at least 25 years. If the 25-year threshold is reached before 65 years of age, continuing surveillance every 3 years is optional, as long as the patient is in good health (ie, life expectancy ≥ 10 years).
• After hysterectomy for a high-grade abnormality, annual vaginal HPV testing is recommended until 3 negative tests are returned; after that, surveillance shifts to a 3-year interval until the 25-year threshold.

Treatment of cancer precursors

Treatment for cervical dysplasia is excisional or ablative.

Excisional therapy. In most cases, excisional therapy (either a loop electrosurgical excision procedure [LEEP; also known as large loop excision of the transformation zone, cold knife conization, and laser conization] or cone biopsy) is required, or preferred. Excisional treatment has the advantage of providing a diagnostic specimen.

In about 30% of cases, atypical glandular cells (AGCs) found on cytology are associated with premalignant or malignant disease. The risk of malignancy with AGCs increases with age.

The World Health Organization recommends LEEP over ablation in settings in which LEEP is available.²³ ASCCP states that, in the relatively few cases in which treatment is needed and it is for CIN1, either excision or ablation is acceptable. TABLE 4¹⁶ lists situations in which excisional treatment is required because a diagnostic specimen is needed.

Continue to: Ablative treatments

Ablative treatments are cryotherapy, CO₂ laser ablation, and thermal ablation. Ablative therapy has the advantage of presenting less risk of adverse obstetric outcomes (eg, preterm birth); it can be used if the indication for therapy is:

• CIN1 or CIN2 and HPV type 16 or 18 positivity
• concordant cytology and histology
• satisfactory colposcopy
• negative endocervical curettage.

The most common ablative treatment is liquid nitrogen applied to a metal tip under local anesthesia.

Hysterectomy can be considered for patients with recurrent CIN2+ who have completed childbearing or for whom repeat excision is infeasible (eg, scarring or a short cervix), or both.

Cost, availability, and convenience might play a role in decision-making with regard to the treatment choice for cancer precursors.

Is care after treatment called for? Patients who continue to be at increased risk of (and thus mortality from) cervical and vaginal cancer require enhanced surveillance. The risk of cancer is more than triple for patients who were given their diagnosis, and treated, when they were > 60 years, compared to patients treated in their 30s.¹ The excess period of risk covers at least 25 years after treatment, even among patients who have had 3 posttreatment screenings.

Continue to: Persistent HPV positivity...

Persistent HPV positivity is more challenging. Patients infected with HPV type 16 have an increased risk of residual disease.

Cancer management

Invasive cancer. Most cervical cancers (60%) occur among patients who have not been screened during the 5 years before their diagnosis.²⁴ For patients who have a diagnosis of cancer, those detected through screening have a much better prognosis than those identified by symptoms (mean cure rate, 92% and 66%, respectively).²⁵ The median 5-year survival for patients who were not screened during the 5 years before their diagnosis of cervical cancer is 66%.²

In unscreened patients, cervical cancer usually manifests as abnormal vaginal bleeding, especially postcoitally. In approximately 45% of cases, the patient has localized disease at diagnosis; in 36%, regional disease; and in 15%, distant metastases.²⁶

For cancers marked by stromal invasion < 3 mm, appropriate treatment is cone biopsy or simple hysterectomy.²⁷

Most patients with early-stage cervical cancer undergo modified radical hysterectomy. The ovaries are usually conserved, unless the cancer is adenocarcinoma. Sentinel-node dissection has become standard practice. Primary radiation therapy is most often used for patients who are a poor surgical candidate because of medical comorbidity or poor functional status. Antiangiogenic agents (eg, bevacizumab) can be used as adjuvant palliative therapy for advanced and recurrent disease.²⁸

Continue to: After treatment for...

After treatment for invasive cervical cancer, the goal is early detection of recurrence, although there is no consensus on a protocol. Most recurrences are detected within the first 2 years.

After treatment for invasive cervical cancer, the goal is early detection of recurrence. Most recurrences are detected within the first 2 years.

Long-term sequelae after treatment for advanced cancer are considerable. Patients report significantly lower quality of life, comparatively, across multiple dimensions, including mental health, physical health, and sexual function.²⁹

Hormone replacement therapy is generally considered acceptable after treatment of cervical cancer because it does not increase replication of HPV.

Recurrent or metastatic cancer. Recurrence or metastases will develop in 15% to 60% of patients,³⁰ usually within the first 2 years after treatment.

Management depends on location and extent of disease, using mainly radiation therapy or surgical resection. Recurrence or metastasis is usually incurable.

Continue to: Last, there are promising...

Last, there are promising areas of research for more effective treatment for cervical cancer precursors and cancers, including gene editing tools³¹ and therapeutic vaccination,³² which is intended to target and kill infected cells.

Prospects for better cervical cancer care

Prevention. HPV vaccination is likely to have a large impact on population-based risk of both cancer and cancer precursors in the next generation.

Screening in the foreseeable future will gravitate toward reliance on primary HPV screening, with a self-sampling option.

Surveillance after dysplastic disease. The 2019 ASCCP guidelines for surveillance and intervention decisions after abnormal cancer screening results will evolve to incorporate introduction of new technology into computerized algorithms.

Treatment. New biologic therapies, including monoclonal antibodies and therapeutic vaccines against HPV, will likely be introduced for treating cancer precursors and invasive cancer.

A NOTE FROM THE EDITORS The Editors of The Journal of Family Practice recognize the importance of addressing the reproductive health of gender-diverse individuals. In this article, we use the words “women,” “men,” “girls,” and “boys” in limited circumstances (1) for ease of reading and (2) to reflect the official language of the US Food and Drug Administration and the Advisory Committee on Immunization Practices. The reader should consider the information and guidance offered in this discussion of cervical cancer and other human papillomavirus-related cancers to speak to the care of people with a uterine cervix and people with a penis.

CORRESPONDENCE
Linda Speer, MD, 3000 Arlington Avenue, MS 1179, Toledo, OH 43614; [email protected]

THE CASE

A 25-year-old woman presented to an infectious diseases (ID) physician with a 4-day history of symptoms following receipt of a quadrivalent influenza vaccine. Two hours after receiving the vaccine, the patient experienced abdominal pain. One hour later, she felt warm and developed diffuse urticaria and rigors. Because of her worsening condition, she presented to the emergency department, where she was given intravenous methylprednisolone 40 mg, ondansetron 8 mg, diphenhydramine 25 mg, and normal saline. Her urticarial rash resolved within 45 minutes, and she was discharged home.

Three days later, she sought additional medical care because of persistent chest tightness, new-onset bronchospasm, pleuritic chest pain, nausea, diarrhea, facial swelling, urticaria, and anorexia. The patient’s vital signs were within normal limits. The oropharynx lacked erythema or obstruction. The lungs were clear to auscultation bilaterally, and heart sounds were regular, with no ectopy or murmurs. Her abdomen was soft, nontender, and nondistended. The patient demonstrated dermatographism on her back.

Historically, the patient had received the influenza vaccine without difficulty. She tolerated latex but had concerns about egg allergy due to vomiting with egg-yolk exposure.

THE DIAGNOSIS

The ID physician, suspecting anaphylaxis and sustained allergic response to the influenza vaccine, arranged for immediate follow-up with an allergist. Multiple tests were done. A negative result on epicutaneous testing to egg was inconsistent with an immunoglobulin (Ig) E-mediated food allergy.

Intradermal testing with the flu vaccine (diluted 1:100) was subsequently performed with appropriate controls. A positive intradermal result is typically a wheal ≥ 5 mm larger than the control. The patient had a 5-mm/15-mm wheal-and-flare response to the flu vaccine, compared to a negative response to saline (FIGURE). (Since the vaccine did not contain gelatin, this was not tested.)

Based on the positive response to flu vaccine and negative response to egg, it was determined that the patient had experienced an anaphylactic reaction to the vaccine itself.

DISCUSSION

In adults, the most common adverse reactions to quadrivalent flu vaccine include pain, headache, and fatigue. IgE-mediated reactions to the influenza vaccine, especially anaphylactic reactions, are rare. A Vaccine Safety Datalink study found 10 cases of anaphylaxis after more than 7.4 million doses of inactivated flu vaccine were given, for a rate of 1.35 per 1 million doses.¹

Continue to: Don't blame eggs

Don’t blame eggs. It was previously believed that reactions to the flu vaccine were due to egg allergies, because the vaccine may contain a tiny amount of ovalbumin, a protein found in egg. However, multiple studies have supported the safety of injectable influenza vaccine in patients with an egg allergy because the amount of ovalbumin contained in each dose is very low and thus not likely to evoke an allergic response.^2,3

How and when to test for allergy. For patients who have a severe allergic reaction or anaphylaxis after immunization, immediate-type allergy skin testing should be performed by an allergist to establish whether the reaction was IgE mediated and to determine the causative agent.

Wait 4 to 6 weeks after an anaphylactic reaction before doing skin testing, as earlier testing can lead to false-negative results.

It’s best to wait 4 to 6 weeks after an anaphylactic reaction before doing skin testing, as earlier testing can lead to false-negative results.⁴ The vaccine should first be tested by using the prick method. If this test is negative, an intradermal test with the vaccine diluted 1:100 should be performed with appropriate controls.⁵

Should the patient receive future vaccinations?

If skin testing is positive, there are several ways to proceed. A vaccine to which the patient has previously had an allergic reaction and positive skin test can still be administered, with caution.⁵ With emergency supplies, medication, and equipment immediately available, medical personnel can administer the influenza vaccine in titrated doses. If the full vaccine dose is normally a volume of 0.5 mL, the patient is first given 0.05 mL of a 1:10 dilution and then, at 15-minute intervals, given full-strength vaccine at doses of 0.05, 0.1, 0.15, and finally 0.2 mL, for a cumulative dose of 0.5 mL.⁵

Alternatively, the patient can forego the vaccination, although this decision has its own risks. In a patient who has previously had an anaphylactic reaction but has negative skin tests—meaning it is unlikely that the patient has IgE antibody to the vaccine—the vaccine can be administered and followed with an observation period of at least 30 minutes.⁵z Our patient was counseled on both options and decided to forego the vaccine.

THE TAKEAWAY

Anaphylaxis is a life-threatening allergic reaction requiring immediate treatment. Anaphylaxis after vaccine receipt is exceedingly rare.⁶ Most IgE-mediated allergic reactions post vaccination are attributed to added or residual substances in the vaccine, rather than the immunizing agent itself.⁶ While common local reactions and fever post vaccination do not contraindicate future vaccination, rare anaphylactic reactions need to be further evaluated, with a referral to an allergist to determine if the patient is, in fact, allergic to additive ingredients within the vaccine vs allergic to the vaccine itself.

CORRESPONDENCE
Kathleen Dass, MD, 24601 Coolidge Highway, Oak Park, MI 48237; [email protected]

THE CASE

A 25-year-old woman presented to an infectious diseases (ID) physician with a 4-day history of symptoms following receipt of a quadrivalent influenza vaccine. Two hours after receiving the vaccine, the patient experienced abdominal pain. One hour later, she felt warm and developed diffuse urticaria and rigors. Because of her worsening condition, she presented to the emergency department, where she was given intravenous methylprednisolone 40 mg, ondansetron 8 mg, diphenhydramine 25 mg, and normal saline. Her urticarial rash resolved within 45 minutes, and she was discharged home.

Three days later, she sought additional medical care because of persistent chest tightness, new-onset bronchospasm, pleuritic chest pain, nausea, diarrhea, facial swelling, urticaria, and anorexia. The patient’s vital signs were within normal limits. The oropharynx lacked erythema or obstruction. The lungs were clear to auscultation bilaterally, and heart sounds were regular, with no ectopy or murmurs. Her abdomen was soft, nontender, and nondistended. The patient demonstrated dermatographism on her back.

Historically, the patient had received the influenza vaccine without difficulty. She tolerated latex but had concerns about egg allergy due to vomiting with egg-yolk exposure.

THE DIAGNOSIS

The ID physician, suspecting anaphylaxis and sustained allergic response to the influenza vaccine, arranged for immediate follow-up with an allergist. Multiple tests were done. A negative result on epicutaneous testing to egg was inconsistent with an immunoglobulin (Ig) E-mediated food allergy.

Intradermal testing with the flu vaccine (diluted 1:100) was subsequently performed with appropriate controls. A positive intradermal result is typically a wheal ≥ 5 mm larger than the control. The patient had a 5-mm/15-mm wheal-and-flare response to the flu vaccine, compared to a negative response to saline (FIGURE). (Since the vaccine did not contain gelatin, this was not tested.)

Based on the positive response to flu vaccine and negative response to egg, it was determined that the patient had experienced an anaphylactic reaction to the vaccine itself.

DISCUSSION

In adults, the most common adverse reactions to quadrivalent flu vaccine include pain, headache, and fatigue. IgE-mediated reactions to the influenza vaccine, especially anaphylactic reactions, are rare. A Vaccine Safety Datalink study found 10 cases of anaphylaxis after more than 7.4 million doses of inactivated flu vaccine were given, for a rate of 1.35 per 1 million doses.¹

Continue to: Don't blame eggs

Don’t blame eggs. It was previously believed that reactions to the flu vaccine were due to egg allergies, because the vaccine may contain a tiny amount of ovalbumin, a protein found in egg. However, multiple studies have supported the safety of injectable influenza vaccine in patients with an egg allergy because the amount of ovalbumin contained in each dose is very low and thus not likely to evoke an allergic response.^2,3

How and when to test for allergy. For patients who have a severe allergic reaction or anaphylaxis after immunization, immediate-type allergy skin testing should be performed by an allergist to establish whether the reaction was IgE mediated and to determine the causative agent.

Wait 4 to 6 weeks after an anaphylactic reaction before doing skin testing, as earlier testing can lead to false-negative results.

It’s best to wait 4 to 6 weeks after an anaphylactic reaction before doing skin testing, as earlier testing can lead to false-negative results.⁴ The vaccine should first be tested by using the prick method. If this test is negative, an intradermal test with the vaccine diluted 1:100 should be performed with appropriate controls.⁵

Should the patient receive future vaccinations?

If skin testing is positive, there are several ways to proceed. A vaccine to which the patient has previously had an allergic reaction and positive skin test can still be administered, with caution.⁵ With emergency supplies, medication, and equipment immediately available, medical personnel can administer the influenza vaccine in titrated doses. If the full vaccine dose is normally a volume of 0.5 mL, the patient is first given 0.05 mL of a 1:10 dilution and then, at 15-minute intervals, given full-strength vaccine at doses of 0.05, 0.1, 0.15, and finally 0.2 mL, for a cumulative dose of 0.5 mL.⁵

Alternatively, the patient can forego the vaccination, although this decision has its own risks. In a patient who has previously had an anaphylactic reaction but has negative skin tests—meaning it is unlikely that the patient has IgE antibody to the vaccine—the vaccine can be administered and followed with an observation period of at least 30 minutes.⁵z Our patient was counseled on both options and decided to forego the vaccine.

THE TAKEAWAY

Anaphylaxis is a life-threatening allergic reaction requiring immediate treatment. Anaphylaxis after vaccine receipt is exceedingly rare.⁶ Most IgE-mediated allergic reactions post vaccination are attributed to added or residual substances in the vaccine, rather than the immunizing agent itself.⁶ While common local reactions and fever post vaccination do not contraindicate future vaccination, rare anaphylactic reactions need to be further evaluated, with a referral to an allergist to determine if the patient is, in fact, allergic to additive ingredients within the vaccine vs allergic to the vaccine itself.

CORRESPONDENCE
Kathleen Dass, MD, 24601 Coolidge Highway, Oak Park, MI 48237; [email protected]

THE CASE

A 25-year-old woman presented to an infectious diseases (ID) physician with a 4-day history of symptoms following receipt of a quadrivalent influenza vaccine. Two hours after receiving the vaccine, the patient experienced abdominal pain. One hour later, she felt warm and developed diffuse urticaria and rigors. Because of her worsening condition, she presented to the emergency department, where she was given intravenous methylprednisolone 40 mg, ondansetron 8 mg, diphenhydramine 25 mg, and normal saline. Her urticarial rash resolved within 45 minutes, and she was discharged home.

Three days later, she sought additional medical care because of persistent chest tightness, new-onset bronchospasm, pleuritic chest pain, nausea, diarrhea, facial swelling, urticaria, and anorexia. The patient’s vital signs were within normal limits. The oropharynx lacked erythema or obstruction. The lungs were clear to auscultation bilaterally, and heart sounds were regular, with no ectopy or murmurs. Her abdomen was soft, nontender, and nondistended. The patient demonstrated dermatographism on her back.

Historically, the patient had received the influenza vaccine without difficulty. She tolerated latex but had concerns about egg allergy due to vomiting with egg-yolk exposure.

THE DIAGNOSIS

The ID physician, suspecting anaphylaxis and sustained allergic response to the influenza vaccine, arranged for immediate follow-up with an allergist. Multiple tests were done. A negative result on epicutaneous testing to egg was inconsistent with an immunoglobulin (Ig) E-mediated food allergy.

Intradermal testing with the flu vaccine (diluted 1:100) was subsequently performed with appropriate controls. A positive intradermal result is typically a wheal ≥ 5 mm larger than the control. The patient had a 5-mm/15-mm wheal-and-flare response to the flu vaccine, compared to a negative response to saline (FIGURE). (Since the vaccine did not contain gelatin, this was not tested.)

Based on the positive response to flu vaccine and negative response to egg, it was determined that the patient had experienced an anaphylactic reaction to the vaccine itself.

DISCUSSION

In adults, the most common adverse reactions to quadrivalent flu vaccine include pain, headache, and fatigue. IgE-mediated reactions to the influenza vaccine, especially anaphylactic reactions, are rare. A Vaccine Safety Datalink study found 10 cases of anaphylaxis after more than 7.4 million doses of inactivated flu vaccine were given, for a rate of 1.35 per 1 million doses.¹

Continue to: Don't blame eggs

Don’t blame eggs. It was previously believed that reactions to the flu vaccine were due to egg allergies, because the vaccine may contain a tiny amount of ovalbumin, a protein found in egg. However, multiple studies have supported the safety of injectable influenza vaccine in patients with an egg allergy because the amount of ovalbumin contained in each dose is very low and thus not likely to evoke an allergic response.^2,3

How and when to test for allergy. For patients who have a severe allergic reaction or anaphylaxis after immunization, immediate-type allergy skin testing should be performed by an allergist to establish whether the reaction was IgE mediated and to determine the causative agent.

Wait 4 to 6 weeks after an anaphylactic reaction before doing skin testing, as earlier testing can lead to false-negative results.

It’s best to wait 4 to 6 weeks after an anaphylactic reaction before doing skin testing, as earlier testing can lead to false-negative results.⁴ The vaccine should first be tested by using the prick method. If this test is negative, an intradermal test with the vaccine diluted 1:100 should be performed with appropriate controls.⁵

Should the patient receive future vaccinations?

If skin testing is positive, there are several ways to proceed. A vaccine to which the patient has previously had an allergic reaction and positive skin test can still be administered, with caution.⁵ With emergency supplies, medication, and equipment immediately available, medical personnel can administer the influenza vaccine in titrated doses. If the full vaccine dose is normally a volume of 0.5 mL, the patient is first given 0.05 mL of a 1:10 dilution and then, at 15-minute intervals, given full-strength vaccine at doses of 0.05, 0.1, 0.15, and finally 0.2 mL, for a cumulative dose of 0.5 mL.⁵

Alternatively, the patient can forego the vaccination, although this decision has its own risks. In a patient who has previously had an anaphylactic reaction but has negative skin tests—meaning it is unlikely that the patient has IgE antibody to the vaccine—the vaccine can be administered and followed with an observation period of at least 30 minutes.⁵z Our patient was counseled on both options and decided to forego the vaccine.

THE TAKEAWAY

Anaphylaxis is a life-threatening allergic reaction requiring immediate treatment. Anaphylaxis after vaccine receipt is exceedingly rare.⁶ Most IgE-mediated allergic reactions post vaccination are attributed to added or residual substances in the vaccine, rather than the immunizing agent itself.⁶ While common local reactions and fever post vaccination do not contraindicate future vaccination, rare anaphylactic reactions need to be further evaluated, with a referral to an allergist to determine if the patient is, in fact, allergic to additive ingredients within the vaccine vs allergic to the vaccine itself.

CORRESPONDENCE
Kathleen Dass, MD, 24601 Coolidge Highway, Oak Park, MI 48237; [email protected]

Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.

• Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
• Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
• Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
• Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
• Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
• Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
• Median time spent in the hospital was 2 days.
• A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
• More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
• Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
• 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.

“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.

“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.

Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”

The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.

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

Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.

• Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
• Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
• Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
• Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
• Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
• Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
• Median time spent in the hospital was 2 days.
• A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
• More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
• Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
• 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.

“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.

“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.

Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”

The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.

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

Adolescents and adults younger than age 21 who develop myocarditis after mRNA COVID-19 vaccination frequently have abnormal findings on cardiac MRI (cMRI) but most have a mild clinical course with rapid resolution of symptoms, a new study concludes.

• Most patients were male (90.6%), White (66.2%) and with a median age of 15.8 years.
• Suspected myocarditis occurred in 136 patients (97.8%) following mRNA vaccine, with 131 (94.2%) following the Pfizer-BioNTech vaccine; 128 cases (91.4%) occurred after the second dose.
• Symptoms started a median of 2 days (range 0 to 22 days) following vaccination administration.
• Chest pain was the most common symptom (99.3%), with fever present in 30.9% of patients and shortness of breath in 27.3%.
• Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%), glucocorticoids (21.6%), colchicine (7.9%) or no anti-inflammatory therapies (8.6%).
• Twenty-six patients (18.7%) were admitted to the intensive care unit; 2 received inotropic/vasoactive support; none required extracorporeal membrane oxygenation or died.
• Median time spent in the hospital was 2 days.
• A total of 111 patients had elevated troponin I (8.12 ng/mL) and 28 had elevated troponin T (0.61 ng/mL).
• More than two-thirds (69.8%) had abnormal electrocardiograms and/or arrhythmias (7 with nonsustained ventricular tachycardia).
• Twenty-six patients (18.7%) had left ventricular ejection fraction (LVEF) less than 55% on echocardiogram; LVEF had returned to normal in the 25 who returned for follow-up.
• 75 of 97 patients (77.3%) who underwent cMRI at a median of 5 days from symptom onset had abnormal findings; 74 (76.3%) had late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria for myocarditis.

“These data suggest that most cases of suspected COVID-19 vaccine–related myocarditis in people younger than 21 are mild and resolve quickly,” corresponding author Dongngan Truong, MD, Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, Salt Lake City, said in a statement.

“We were very happy to see that type of recovery. However, we are awaiting further studies to better understand the long-term outcomes of patients who have had COVID-19 vaccination-related myocarditis. We also need to study the risk factors and mechanisms for this rare complication,” Dr. Truong added.

Dr. Lloyd-Jones said these findings support the AHA’s position that COVID-19 vaccines are “safe, highly effective, and fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic.”

The study received no funding. Dr. Truong consults for Pfizer on vaccine-associated myocarditis. A complete list of author disclosures is available with the original article.

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

An abstract and poster presentation questioning the safety of mRNA-based COVID-19 vaccines, embraced by some and lambasted by others, has drawn an “expression of concern” from the American Heart Association, along with a bid for correction.

The abstract in question concludes that COVID vaccines “dramatically increase” levels of certain inflammatory biomarkers, and therefore, the 5-year risk of acute coronary syndromes (ACS), based on pre- and post-vaccination results of an obscure blood panel called the PULS Cardiac Test (GD Biosciences). The findings were presented at the AHA’s 2021 Scientific Sessionsas, an uncontrolled observational study of 566 patients in a preventive cardiology practice.

Some on social media have seized on the abstract as evidence of serious potential harm from the two available mRNA-based SARS-CoV-2 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). But others contend that the study’s described design and findings are specious and its conclusions overstated.

They also point to the notoriety of its one listed author, Steven R. Gundry, MD, who promotes his diet books and supplements as well as fringe, highly criticized theories about diet and disease on several websites, including drgundry.com. Dr. Gundry has not responded to requests for an interview.

Dr. Gundry’s abstract from the AHA Scientific Sessions 2021, available on the meeting’s program planner, was marked with an “expression of concern” by the AHA that is to stand “until a suitable correction is published, to indicate that the abstract in its current version may not be reliable.”

The expression of concern statement, also published online Nov. 24 in Circulation, says “potential errors in the abstract” were brought to the attention of the meeting planners. “Specifically, there are several typographical errors, there is no data in the abstract regarding myocardial T-cell infiltration, there are no statistical analyses for significance provided, and the author is not clear that only anecdotal data was used.”

The biomarker elevations on which the abstract’s conclusions are based included hepatocyte growth factor, “which serves as a marker for chemotaxis of T-cells into epithelium and cardiac tissue,” it states.

“The expression of concern about the abstract will remain in place until a correction is accepted and published” in Circulation, AHA spokesperson Suzanne Grant told this news organization by email.

“The specific data needed will be up to the abstract author to determine and supply,” she said, noting that Dr. Gundry “has been in communication with the journal throughout this process.”

Submitting researchers “must always attest to the validity of the abstract,” Ms. Grant said. “Abstracts are then curated by independent review panels, blinded to the identities of the abstract authors, and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting.”

Regarding the AHA’s system for vetting abstracts vying for acceptance to the scientific sessions, she said it is not primarily intended to “evaluate scientific validity” and that the organization is “currently reviewing its existing abstract submission processes.”

A recent Reuters report reviews the controversy and provides links to criticisms of the study on social media.

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

An abstract and poster presentation questioning the safety of mRNA-based COVID-19 vaccines, embraced by some and lambasted by others, has drawn an “expression of concern” from the American Heart Association, along with a bid for correction.

The abstract in question concludes that COVID vaccines “dramatically increase” levels of certain inflammatory biomarkers, and therefore, the 5-year risk of acute coronary syndromes (ACS), based on pre- and post-vaccination results of an obscure blood panel called the PULS Cardiac Test (GD Biosciences). The findings were presented at the AHA’s 2021 Scientific Sessionsas, an uncontrolled observational study of 566 patients in a preventive cardiology practice.

Some on social media have seized on the abstract as evidence of serious potential harm from the two available mRNA-based SARS-CoV-2 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). But others contend that the study’s described design and findings are specious and its conclusions overstated.

They also point to the notoriety of its one listed author, Steven R. Gundry, MD, who promotes his diet books and supplements as well as fringe, highly criticized theories about diet and disease on several websites, including drgundry.com. Dr. Gundry has not responded to requests for an interview.

Dr. Gundry’s abstract from the AHA Scientific Sessions 2021, available on the meeting’s program planner, was marked with an “expression of concern” by the AHA that is to stand “until a suitable correction is published, to indicate that the abstract in its current version may not be reliable.”

The expression of concern statement, also published online Nov. 24 in Circulation, says “potential errors in the abstract” were brought to the attention of the meeting planners. “Specifically, there are several typographical errors, there is no data in the abstract regarding myocardial T-cell infiltration, there are no statistical analyses for significance provided, and the author is not clear that only anecdotal data was used.”

The biomarker elevations on which the abstract’s conclusions are based included hepatocyte growth factor, “which serves as a marker for chemotaxis of T-cells into epithelium and cardiac tissue,” it states.

“The expression of concern about the abstract will remain in place until a correction is accepted and published” in Circulation, AHA spokesperson Suzanne Grant told this news organization by email.

“The specific data needed will be up to the abstract author to determine and supply,” she said, noting that Dr. Gundry “has been in communication with the journal throughout this process.”

Submitting researchers “must always attest to the validity of the abstract,” Ms. Grant said. “Abstracts are then curated by independent review panels, blinded to the identities of the abstract authors, and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting.”

Regarding the AHA’s system for vetting abstracts vying for acceptance to the scientific sessions, she said it is not primarily intended to “evaluate scientific validity” and that the organization is “currently reviewing its existing abstract submission processes.”

A recent Reuters report reviews the controversy and provides links to criticisms of the study on social media.

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

An abstract and poster presentation questioning the safety of mRNA-based COVID-19 vaccines, embraced by some and lambasted by others, has drawn an “expression of concern” from the American Heart Association, along with a bid for correction.

The abstract in question concludes that COVID vaccines “dramatically increase” levels of certain inflammatory biomarkers, and therefore, the 5-year risk of acute coronary syndromes (ACS), based on pre- and post-vaccination results of an obscure blood panel called the PULS Cardiac Test (GD Biosciences). The findings were presented at the AHA’s 2021 Scientific Sessionsas, an uncontrolled observational study of 566 patients in a preventive cardiology practice.

Some on social media have seized on the abstract as evidence of serious potential harm from the two available mRNA-based SARS-CoV-2 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). But others contend that the study’s described design and findings are specious and its conclusions overstated.

They also point to the notoriety of its one listed author, Steven R. Gundry, MD, who promotes his diet books and supplements as well as fringe, highly criticized theories about diet and disease on several websites, including drgundry.com. Dr. Gundry has not responded to requests for an interview.

Dr. Gundry’s abstract from the AHA Scientific Sessions 2021, available on the meeting’s program planner, was marked with an “expression of concern” by the AHA that is to stand “until a suitable correction is published, to indicate that the abstract in its current version may not be reliable.”

The expression of concern statement, also published online Nov. 24 in Circulation, says “potential errors in the abstract” were brought to the attention of the meeting planners. “Specifically, there are several typographical errors, there is no data in the abstract regarding myocardial T-cell infiltration, there are no statistical analyses for significance provided, and the author is not clear that only anecdotal data was used.”

The biomarker elevations on which the abstract’s conclusions are based included hepatocyte growth factor, “which serves as a marker for chemotaxis of T-cells into epithelium and cardiac tissue,” it states.

“The expression of concern about the abstract will remain in place until a correction is accepted and published” in Circulation, AHA spokesperson Suzanne Grant told this news organization by email.

“The specific data needed will be up to the abstract author to determine and supply,” she said, noting that Dr. Gundry “has been in communication with the journal throughout this process.”

Submitting researchers “must always attest to the validity of the abstract,” Ms. Grant said. “Abstracts are then curated by independent review panels, blinded to the identities of the abstract authors, and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting.”

Regarding the AHA’s system for vetting abstracts vying for acceptance to the scientific sessions, she said it is not primarily intended to “evaluate scientific validity” and that the organization is “currently reviewing its existing abstract submission processes.”

A recent Reuters report reviews the controversy and provides links to criticisms of the study on social media.

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

Children with severe cow’s milk allergy may be able to safely tolerate small amounts of baked milk after 12 months of oral immunotherapy, new research suggests.

The small, ongoing clinical trial has enabled some participants – all of whom reacted to less than a tablespoon of baked milk at baseline – to begin incorporating baked milk products into everyday diets and to eat in restaurants with less fear of allergic reactions, reported study author Jennifer Dantzer, MD, MHS, assistant professor of pediatrics in the division of pediatric allergy, immunology, and rheumatology at Johns Hopkins University in Baltimore.

Cow’s milk is the most common food allergy in young children, and “for many, it’s a constant stressor that’s always there,” Dr. Dantzer said in an interview. “For a lot of families, this impacts where they eat out, if they eat out, and sometimes where they vacation, or a lot of the social activities they do.

“This was a unique group of kids with a very severe milk phenotype who were reactive to teeny doses and may not have qualified or done well with other types of oral immunotherapy,” she added. “Using a modified allergen – baked milk – seems to work. But for now, we think this is something that still needs further research before it’s ready for a clinical setting.”

The study, for which 24-month unblinded results are being tallied, was recently published in the Journal of Allergy and Clinical Immunology .

About 2%-3% of preschool-age children are affected by cow’s milk allergy. Children often outgrow it, but for about 20% of children, it persists into adolescence and adulthood. The only current management approaches are avoidance and emergency medications to treat reactions.

But for those with severe milk allergy who react to even trace amounts of milk in any form, the now-routine clinical practice of introducing baked milk isn’t an option, Dr. Dantzer said. The new trial stood out from prior research by using lower starting doses and a more gradual dose escalation of extensively heated milk to determine if oral immunotherapy could be safer but still effective.

Dr. Dantzer and her team randomly assigned 30 participants (aged 3-18 years) into two blinded groups. For 12 months, one group received baked milk oral immunotherapy (BMOIT), and the other a placebo consisting of tapioca flour. At baseline, for all participants, the milk skin prick test wheal diameter was ≥ 3 mm, and the cow’s milk immunoglobulin E (IgE) level was > 5 kU/L. All the children experienced positive dose-limiting reactions to < 1 tablespoon of baked milk protein but could tolerate at least 3 mg on initial dose escalation.

Measured doses of baked milk and placebo powders were supplied to participants for all doses consumed at home. Participants were given instructions on how to prepare it in cupcake or muffin batter. Over 12 months, doses were gradually increased to a maximum cumulative dose of 4,044 mg baked milk protein, or approximately a half tablespoon.

Researchers collected blood samples for immune studies, and participants or their parents completed quality-of-life questionnaires that asked about food anxiety, social and dietary limitations, emotional impact, risk for accidental ingestion, and allergen avoidance.

Fourteen of 15 participants (93%) in the BMOIT group reached the goal-maintenance dose of 2,000 mg of baked milk protein (about a quarter tablespoon). Of those who completed the 12-month challenge, 11 of 14 (79%) in the BMOIT group tolerated 4,000 mg of baked milk protein, compared to none in the placebo group.

“We anticipated that by starting with really small amounts, we would be able to build up the amount of baked milk these kids could tolerate,” Dr. Dantzer said. “We were very pleased by how many could reach the maximal dose at the end of the first year. Once we get the results of the second year, that will provide a lot of additional detail about how this translates into unheated milk amounts they can tolerate and introduce into their diet at home.”

No significant changes were found in IgE levels over time in either study group. Most in the BMOIT group reported improvement in at least one quality-of-life domain, while more in the placebo group reported improvements in only the emotional impact domain.

Adverse events such as gastrointestinal side effects occurred in both groups of participants, but the vast majority of events were mild, Dr. Dantzer said. Fewer than 1% of dosing-related reactions were severe. Four participants required epinephrine.

“This highlights how this needs to be done by someone comfortable and trained, and not by a family at home on their own,” Dr. Dantzer said. “But potentially in the future, this concept of using a modified allergen could be applied to more kids with milk allergy.”

A Montreal-based pediatric allergy specialist who was not involved in the study said the results weren’t surprising. “We’ve known for a good while that the allergenic proteins found in certain foods, or caused by milk in this context, are influenced by the way in which food is processed,” said Christine McCusker, MD, associate professor of pediatrics and director of the division of pediatric allergy, immunology, and dermatology at Montreal Children’s Hospital at McGill University Health Center.

But “having this relatively definitive data that supports what you’re suggesting to patients is obviously the way to optimize your management,” Dr. McCusker said in an interview. “These types of studies are important steps, especially in this age of increased food allergies where many of these things can be dealt with in very young children before their immune systems are fixed.”

Dr. Dantzer and Dr. McCusker agreed that the small size of the study was a limitation, though “waiting for more participants means you don’t always get information out there in a timely manner,” Dr. McCusker said.

She said additional research should focus on preidentifying which children may be prone to severe, lasting food allergies. “If you have a milk allergy that will stay with you the rest of your life and we could maybe modify that outcome with early, targeted intervention, that would be the nirvana of the field,” Dr. McCusker said.

Dr. Dantzer said her research “showed us that oral immunotherapy is an option, but not a perfect option.

“We still need to keep working on other alternatives that can be even safer and potentially work better,” she added.

The study was supported by the Myra Reinhard Family Foundation. Dr. Dantzer and Dr. McCusker report no relevant financial relationships.

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

Children with severe cow’s milk allergy may be able to safely tolerate small amounts of baked milk after 12 months of oral immunotherapy, new research suggests.

The small, ongoing clinical trial has enabled some participants – all of whom reacted to less than a tablespoon of baked milk at baseline – to begin incorporating baked milk products into everyday diets and to eat in restaurants with less fear of allergic reactions, reported study author Jennifer Dantzer, MD, MHS, assistant professor of pediatrics in the division of pediatric allergy, immunology, and rheumatology at Johns Hopkins University in Baltimore.

Cow’s milk is the most common food allergy in young children, and “for many, it’s a constant stressor that’s always there,” Dr. Dantzer said in an interview. “For a lot of families, this impacts where they eat out, if they eat out, and sometimes where they vacation, or a lot of the social activities they do.

“This was a unique group of kids with a very severe milk phenotype who were reactive to teeny doses and may not have qualified or done well with other types of oral immunotherapy,” she added. “Using a modified allergen – baked milk – seems to work. But for now, we think this is something that still needs further research before it’s ready for a clinical setting.”

The study, for which 24-month unblinded results are being tallied, was recently published in the Journal of Allergy and Clinical Immunology .

About 2%-3% of preschool-age children are affected by cow’s milk allergy. Children often outgrow it, but for about 20% of children, it persists into adolescence and adulthood. The only current management approaches are avoidance and emergency medications to treat reactions.

But for those with severe milk allergy who react to even trace amounts of milk in any form, the now-routine clinical practice of introducing baked milk isn’t an option, Dr. Dantzer said. The new trial stood out from prior research by using lower starting doses and a more gradual dose escalation of extensively heated milk to determine if oral immunotherapy could be safer but still effective.

Dr. Dantzer and her team randomly assigned 30 participants (aged 3-18 years) into two blinded groups. For 12 months, one group received baked milk oral immunotherapy (BMOIT), and the other a placebo consisting of tapioca flour. At baseline, for all participants, the milk skin prick test wheal diameter was ≥ 3 mm, and the cow’s milk immunoglobulin E (IgE) level was > 5 kU/L. All the children experienced positive dose-limiting reactions to < 1 tablespoon of baked milk protein but could tolerate at least 3 mg on initial dose escalation.

Measured doses of baked milk and placebo powders were supplied to participants for all doses consumed at home. Participants were given instructions on how to prepare it in cupcake or muffin batter. Over 12 months, doses were gradually increased to a maximum cumulative dose of 4,044 mg baked milk protein, or approximately a half tablespoon.

Researchers collected blood samples for immune studies, and participants or their parents completed quality-of-life questionnaires that asked about food anxiety, social and dietary limitations, emotional impact, risk for accidental ingestion, and allergen avoidance.

Fourteen of 15 participants (93%) in the BMOIT group reached the goal-maintenance dose of 2,000 mg of baked milk protein (about a quarter tablespoon). Of those who completed the 12-month challenge, 11 of 14 (79%) in the BMOIT group tolerated 4,000 mg of baked milk protein, compared to none in the placebo group.

“We anticipated that by starting with really small amounts, we would be able to build up the amount of baked milk these kids could tolerate,” Dr. Dantzer said. “We were very pleased by how many could reach the maximal dose at the end of the first year. Once we get the results of the second year, that will provide a lot of additional detail about how this translates into unheated milk amounts they can tolerate and introduce into their diet at home.”

No significant changes were found in IgE levels over time in either study group. Most in the BMOIT group reported improvement in at least one quality-of-life domain, while more in the placebo group reported improvements in only the emotional impact domain.

Adverse events such as gastrointestinal side effects occurred in both groups of participants, but the vast majority of events were mild, Dr. Dantzer said. Fewer than 1% of dosing-related reactions were severe. Four participants required epinephrine.

“This highlights how this needs to be done by someone comfortable and trained, and not by a family at home on their own,” Dr. Dantzer said. “But potentially in the future, this concept of using a modified allergen could be applied to more kids with milk allergy.”

A Montreal-based pediatric allergy specialist who was not involved in the study said the results weren’t surprising. “We’ve known for a good while that the allergenic proteins found in certain foods, or caused by milk in this context, are influenced by the way in which food is processed,” said Christine McCusker, MD, associate professor of pediatrics and director of the division of pediatric allergy, immunology, and dermatology at Montreal Children’s Hospital at McGill University Health Center.

But “having this relatively definitive data that supports what you’re suggesting to patients is obviously the way to optimize your management,” Dr. McCusker said in an interview. “These types of studies are important steps, especially in this age of increased food allergies where many of these things can be dealt with in very young children before their immune systems are fixed.”

Dr. Dantzer and Dr. McCusker agreed that the small size of the study was a limitation, though “waiting for more participants means you don’t always get information out there in a timely manner,” Dr. McCusker said.

She said additional research should focus on preidentifying which children may be prone to severe, lasting food allergies. “If you have a milk allergy that will stay with you the rest of your life and we could maybe modify that outcome with early, targeted intervention, that would be the nirvana of the field,” Dr. McCusker said.

Dr. Dantzer said her research “showed us that oral immunotherapy is an option, but not a perfect option.

“We still need to keep working on other alternatives that can be even safer and potentially work better,” she added.

The study was supported by the Myra Reinhard Family Foundation. Dr. Dantzer and Dr. McCusker report no relevant financial relationships.

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

Children with severe cow’s milk allergy may be able to safely tolerate small amounts of baked milk after 12 months of oral immunotherapy, new research suggests.

The small, ongoing clinical trial has enabled some participants – all of whom reacted to less than a tablespoon of baked milk at baseline – to begin incorporating baked milk products into everyday diets and to eat in restaurants with less fear of allergic reactions, reported study author Jennifer Dantzer, MD, MHS, assistant professor of pediatrics in the division of pediatric allergy, immunology, and rheumatology at Johns Hopkins University in Baltimore.

Cow’s milk is the most common food allergy in young children, and “for many, it’s a constant stressor that’s always there,” Dr. Dantzer said in an interview. “For a lot of families, this impacts where they eat out, if they eat out, and sometimes where they vacation, or a lot of the social activities they do.

“This was a unique group of kids with a very severe milk phenotype who were reactive to teeny doses and may not have qualified or done well with other types of oral immunotherapy,” she added. “Using a modified allergen – baked milk – seems to work. But for now, we think this is something that still needs further research before it’s ready for a clinical setting.”

The study, for which 24-month unblinded results are being tallied, was recently published in the Journal of Allergy and Clinical Immunology .

About 2%-3% of preschool-age children are affected by cow’s milk allergy. Children often outgrow it, but for about 20% of children, it persists into adolescence and adulthood. The only current management approaches are avoidance and emergency medications to treat reactions.

But for those with severe milk allergy who react to even trace amounts of milk in any form, the now-routine clinical practice of introducing baked milk isn’t an option, Dr. Dantzer said. The new trial stood out from prior research by using lower starting doses and a more gradual dose escalation of extensively heated milk to determine if oral immunotherapy could be safer but still effective.

Dr. Dantzer and her team randomly assigned 30 participants (aged 3-18 years) into two blinded groups. For 12 months, one group received baked milk oral immunotherapy (BMOIT), and the other a placebo consisting of tapioca flour. At baseline, for all participants, the milk skin prick test wheal diameter was ≥ 3 mm, and the cow’s milk immunoglobulin E (IgE) level was > 5 kU/L. All the children experienced positive dose-limiting reactions to < 1 tablespoon of baked milk protein but could tolerate at least 3 mg on initial dose escalation.

Measured doses of baked milk and placebo powders were supplied to participants for all doses consumed at home. Participants were given instructions on how to prepare it in cupcake or muffin batter. Over 12 months, doses were gradually increased to a maximum cumulative dose of 4,044 mg baked milk protein, or approximately a half tablespoon.

Researchers collected blood samples for immune studies, and participants or their parents completed quality-of-life questionnaires that asked about food anxiety, social and dietary limitations, emotional impact, risk for accidental ingestion, and allergen avoidance.

Fourteen of 15 participants (93%) in the BMOIT group reached the goal-maintenance dose of 2,000 mg of baked milk protein (about a quarter tablespoon). Of those who completed the 12-month challenge, 11 of 14 (79%) in the BMOIT group tolerated 4,000 mg of baked milk protein, compared to none in the placebo group.

“We anticipated that by starting with really small amounts, we would be able to build up the amount of baked milk these kids could tolerate,” Dr. Dantzer said. “We were very pleased by how many could reach the maximal dose at the end of the first year. Once we get the results of the second year, that will provide a lot of additional detail about how this translates into unheated milk amounts they can tolerate and introduce into their diet at home.”

No significant changes were found in IgE levels over time in either study group. Most in the BMOIT group reported improvement in at least one quality-of-life domain, while more in the placebo group reported improvements in only the emotional impact domain.

Adverse events such as gastrointestinal side effects occurred in both groups of participants, but the vast majority of events were mild, Dr. Dantzer said. Fewer than 1% of dosing-related reactions were severe. Four participants required epinephrine.

“This highlights how this needs to be done by someone comfortable and trained, and not by a family at home on their own,” Dr. Dantzer said. “But potentially in the future, this concept of using a modified allergen could be applied to more kids with milk allergy.”

A Montreal-based pediatric allergy specialist who was not involved in the study said the results weren’t surprising. “We’ve known for a good while that the allergenic proteins found in certain foods, or caused by milk in this context, are influenced by the way in which food is processed,” said Christine McCusker, MD, associate professor of pediatrics and director of the division of pediatric allergy, immunology, and dermatology at Montreal Children’s Hospital at McGill University Health Center.

But “having this relatively definitive data that supports what you’re suggesting to patients is obviously the way to optimize your management,” Dr. McCusker said in an interview. “These types of studies are important steps, especially in this age of increased food allergies where many of these things can be dealt with in very young children before their immune systems are fixed.”

Dr. Dantzer and Dr. McCusker agreed that the small size of the study was a limitation, though “waiting for more participants means you don’t always get information out there in a timely manner,” Dr. McCusker said.

She said additional research should focus on preidentifying which children may be prone to severe, lasting food allergies. “If you have a milk allergy that will stay with you the rest of your life and we could maybe modify that outcome with early, targeted intervention, that would be the nirvana of the field,” Dr. McCusker said.

Dr. Dantzer said her research “showed us that oral immunotherapy is an option, but not a perfect option.

“We still need to keep working on other alternatives that can be even safer and potentially work better,” she added.

The study was supported by the Myra Reinhard Family Foundation. Dr. Dantzer and Dr. McCusker report no relevant financial relationships.

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