Immunology

When 23 frail elderly patients in Norway died in early 2021 shortly after they had received an mRNA-based vaccine against COVID-19, Norwegian health authorities cautioned physicians to conduct more thorough assessments of patients prior to immunization, and launched an investigation into the safety of the BNT162b2 vaccine (Comirnaty; Pfizer-BioNTech).

Now, the results of that investigation and of a subsequent larger study of nursing home residents in Norway have shown no increased risk for short-term mortality following COVID-19 vaccination in the overall population of elderly patients. The new research also showed clear evidence of a survival benefit compared with the unvaccinated population, Anette Hylen Ranhoff, MD, PhD, said at the annual meeting of the European Geriatric Medicine Society, held in a hybrid format in Athens, Greece, and online.

“We found no evidence of increased short-term mortality among vaccinated older individuals, and particularly not among the nursing home patients,” said Dr. Ranhoff, a senior researcher at the Norwegian Institute of Public Health and professor at University of Bergen, Norway. “But we think that this [lower] mortality risk was most likely a sort of ‘healthy-vaccinee’ effect, which means that people who were a bit more healthy were vaccinated, and not those who were the very, very most frail.”

“We have more or less the same data in France about events, with very high rates of vaccination,” said session moderator Athanase Benetos MD, PhD, professor and chairman of geriatric medicine at the University Hospital of Nancy in France, who was not involved in the study.

“In my department, a month after the end of the vaccination and at the same time while the pandemic in the city was going up, we had a 90% decrease in mortality from COVID in the nursing homes,” he told Dr. Ranhoff.
 

Potential risks

Frail elderly patients were not included in clinical trials of COVID-19 vaccines, and although previous studies have shown a low incidence of local or systemic reactions to vaccination among older people, “we think that quite mild adverse events following vaccination could trigger and destabilize a frail person,” Dr. Ranhoff said.

As reported Jan. 15, 2021, in BMJ, investigation by the Norwegian Medicines Agency (NOMA) into 13 of the 23 reported cases concluded that common adverse reactions associated with mRNA vaccines could have contributed to the deaths of some of the frail elderly patients

Steinar Madsen, MD, NOMA medical director, told BMJ “we are not alarmed or worried about this, because these are very rare occurrences and they occurred in very frail patients with very serious disease.”
 

Health authorities investigate

In response to the report and at the request of the Norwegian Public Health Institute and NOMA, Dr. Ranhoff and colleagues investigated the first 100 deaths among nursing-home residents who received the vaccine. The team consisted of three geriatricians and an infectious disease specialist who sees patients in nursing homes.

They looked at each patient’s clinical course before and after vaccination, their health trajectory and life expectancy at the time of vaccination, new symptoms following vaccination, and the time from vaccination to new symptoms and to death.

In addition, the investigators evaluated Clinical Frailty Scale (CFS) scores for each patient. CFS scores range from 1 (very fit) to 9 (terminally ill, with a life expectancy of less than 6 months who are otherwise evidently frail).

The initial investigation found that among 95 evaluable patients, the association between vaccination and death was “probable” in 10, “possible” in 26, and “unlikely” in 59.

The mean time from vaccination to symptoms was 1.4 days in the probable cases, 2.5 days in the possible cases, and 4.7 days in the unlikely cases.

The mean time from vaccination to death was 3.1, 8.3, and 8.2 days, respectively.

In all three categories, the patients had mean CFS scores ranging from 7.6 to 7.9, putting them in the “severely frail” category, defined as people who are completely dependent for personal care but seem stable and not at high risk for dying.

“We have quite many nursing home residents in Norway, 35,000; more than 80% have dementia, and the mean age is 85 years. We know that approximately 45 people die every day in these nursing homes, and their mean age of death is 87.5 years,” Dr. Ranhoff said.
 

Population-wide study

Dr. Ranhoff and colleagues also looked more broadly into the question of potential vaccine-related mortality in the total population of older people in Norway from the day of vaccination to follow-up at 3 weeks.

They conducted a matched cohort study to investigate the relationship between the mRNA SARS-CoV-2 vaccine and overall death among persons aged 65 and older in the general population, and across four groups: patients receiving home-based care, long-term nursing home patients, short-term nursing home patients, and those not receiving health services.

The researchers identified a total of 967,786 residents of Norway aged 65 and over at the start of the country’s vaccination campaign at the end of December, 2020, and they matched vaccinated individuals with unvaccinated persons based on demographic, geographic, and clinical risk group factors.

Dr. Ranhoff showed Kaplan-Meier survival curves for the total population and for each of the health-service states. In all cases there was a clear survival benefit for vaccinated vs. unvaccinated patients. She did not, however, provide specific numbers or hazard ratios for the differences between vaccinated and unvaccinated individuals in each of the comparisons.

The study was supported by the Norwegian Institute of Public Health. Dr. Ranhoff and Dr. Benetos reported no conflicts of interest.

When 23 frail elderly patients in Norway died in early 2021 shortly after they had received an mRNA-based vaccine against COVID-19, Norwegian health authorities cautioned physicians to conduct more thorough assessments of patients prior to immunization, and launched an investigation into the safety of the BNT162b2 vaccine (Comirnaty; Pfizer-BioNTech).

Now, the results of that investigation and of a subsequent larger study of nursing home residents in Norway have shown no increased risk for short-term mortality following COVID-19 vaccination in the overall population of elderly patients. The new research also showed clear evidence of a survival benefit compared with the unvaccinated population, Anette Hylen Ranhoff, MD, PhD, said at the annual meeting of the European Geriatric Medicine Society, held in a hybrid format in Athens, Greece, and online.

“We found no evidence of increased short-term mortality among vaccinated older individuals, and particularly not among the nursing home patients,” said Dr. Ranhoff, a senior researcher at the Norwegian Institute of Public Health and professor at University of Bergen, Norway. “But we think that this [lower] mortality risk was most likely a sort of ‘healthy-vaccinee’ effect, which means that people who were a bit more healthy were vaccinated, and not those who were the very, very most frail.”

“We have more or less the same data in France about events, with very high rates of vaccination,” said session moderator Athanase Benetos MD, PhD, professor and chairman of geriatric medicine at the University Hospital of Nancy in France, who was not involved in the study.

“In my department, a month after the end of the vaccination and at the same time while the pandemic in the city was going up, we had a 90% decrease in mortality from COVID in the nursing homes,” he told Dr. Ranhoff.
 

Potential risks

Frail elderly patients were not included in clinical trials of COVID-19 vaccines, and although previous studies have shown a low incidence of local or systemic reactions to vaccination among older people, “we think that quite mild adverse events following vaccination could trigger and destabilize a frail person,” Dr. Ranhoff said.

As reported Jan. 15, 2021, in BMJ, investigation by the Norwegian Medicines Agency (NOMA) into 13 of the 23 reported cases concluded that common adverse reactions associated with mRNA vaccines could have contributed to the deaths of some of the frail elderly patients

Steinar Madsen, MD, NOMA medical director, told BMJ “we are not alarmed or worried about this, because these are very rare occurrences and they occurred in very frail patients with very serious disease.”
 

Health authorities investigate

In response to the report and at the request of the Norwegian Public Health Institute and NOMA, Dr. Ranhoff and colleagues investigated the first 100 deaths among nursing-home residents who received the vaccine. The team consisted of three geriatricians and an infectious disease specialist who sees patients in nursing homes.

They looked at each patient’s clinical course before and after vaccination, their health trajectory and life expectancy at the time of vaccination, new symptoms following vaccination, and the time from vaccination to new symptoms and to death.

In addition, the investigators evaluated Clinical Frailty Scale (CFS) scores for each patient. CFS scores range from 1 (very fit) to 9 (terminally ill, with a life expectancy of less than 6 months who are otherwise evidently frail).

The initial investigation found that among 95 evaluable patients, the association between vaccination and death was “probable” in 10, “possible” in 26, and “unlikely” in 59.

The mean time from vaccination to symptoms was 1.4 days in the probable cases, 2.5 days in the possible cases, and 4.7 days in the unlikely cases.

The mean time from vaccination to death was 3.1, 8.3, and 8.2 days, respectively.

In all three categories, the patients had mean CFS scores ranging from 7.6 to 7.9, putting them in the “severely frail” category, defined as people who are completely dependent for personal care but seem stable and not at high risk for dying.

“We have quite many nursing home residents in Norway, 35,000; more than 80% have dementia, and the mean age is 85 years. We know that approximately 45 people die every day in these nursing homes, and their mean age of death is 87.5 years,” Dr. Ranhoff said.
 

Population-wide study

Dr. Ranhoff and colleagues also looked more broadly into the question of potential vaccine-related mortality in the total population of older people in Norway from the day of vaccination to follow-up at 3 weeks.

They conducted a matched cohort study to investigate the relationship between the mRNA SARS-CoV-2 vaccine and overall death among persons aged 65 and older in the general population, and across four groups: patients receiving home-based care, long-term nursing home patients, short-term nursing home patients, and those not receiving health services.

The researchers identified a total of 967,786 residents of Norway aged 65 and over at the start of the country’s vaccination campaign at the end of December, 2020, and they matched vaccinated individuals with unvaccinated persons based on demographic, geographic, and clinical risk group factors.

Dr. Ranhoff showed Kaplan-Meier survival curves for the total population and for each of the health-service states. In all cases there was a clear survival benefit for vaccinated vs. unvaccinated patients. She did not, however, provide specific numbers or hazard ratios for the differences between vaccinated and unvaccinated individuals in each of the comparisons.

The study was supported by the Norwegian Institute of Public Health. Dr. Ranhoff and Dr. Benetos reported no conflicts of interest.

When 23 frail elderly patients in Norway died in early 2021 shortly after they had received an mRNA-based vaccine against COVID-19, Norwegian health authorities cautioned physicians to conduct more thorough assessments of patients prior to immunization, and launched an investigation into the safety of the BNT162b2 vaccine (Comirnaty; Pfizer-BioNTech).

Now, the results of that investigation and of a subsequent larger study of nursing home residents in Norway have shown no increased risk for short-term mortality following COVID-19 vaccination in the overall population of elderly patients. The new research also showed clear evidence of a survival benefit compared with the unvaccinated population, Anette Hylen Ranhoff, MD, PhD, said at the annual meeting of the European Geriatric Medicine Society, held in a hybrid format in Athens, Greece, and online.

“We found no evidence of increased short-term mortality among vaccinated older individuals, and particularly not among the nursing home patients,” said Dr. Ranhoff, a senior researcher at the Norwegian Institute of Public Health and professor at University of Bergen, Norway. “But we think that this [lower] mortality risk was most likely a sort of ‘healthy-vaccinee’ effect, which means that people who were a bit more healthy were vaccinated, and not those who were the very, very most frail.”

“We have more or less the same data in France about events, with very high rates of vaccination,” said session moderator Athanase Benetos MD, PhD, professor and chairman of geriatric medicine at the University Hospital of Nancy in France, who was not involved in the study.

“In my department, a month after the end of the vaccination and at the same time while the pandemic in the city was going up, we had a 90% decrease in mortality from COVID in the nursing homes,” he told Dr. Ranhoff.
 

Potential risks

Frail elderly patients were not included in clinical trials of COVID-19 vaccines, and although previous studies have shown a low incidence of local or systemic reactions to vaccination among older people, “we think that quite mild adverse events following vaccination could trigger and destabilize a frail person,” Dr. Ranhoff said.

As reported Jan. 15, 2021, in BMJ, investigation by the Norwegian Medicines Agency (NOMA) into 13 of the 23 reported cases concluded that common adverse reactions associated with mRNA vaccines could have contributed to the deaths of some of the frail elderly patients

Steinar Madsen, MD, NOMA medical director, told BMJ “we are not alarmed or worried about this, because these are very rare occurrences and they occurred in very frail patients with very serious disease.”
 

Health authorities investigate

In response to the report and at the request of the Norwegian Public Health Institute and NOMA, Dr. Ranhoff and colleagues investigated the first 100 deaths among nursing-home residents who received the vaccine. The team consisted of three geriatricians and an infectious disease specialist who sees patients in nursing homes.

They looked at each patient’s clinical course before and after vaccination, their health trajectory and life expectancy at the time of vaccination, new symptoms following vaccination, and the time from vaccination to new symptoms and to death.

In addition, the investigators evaluated Clinical Frailty Scale (CFS) scores for each patient. CFS scores range from 1 (very fit) to 9 (terminally ill, with a life expectancy of less than 6 months who are otherwise evidently frail).

The initial investigation found that among 95 evaluable patients, the association between vaccination and death was “probable” in 10, “possible” in 26, and “unlikely” in 59.

The mean time from vaccination to symptoms was 1.4 days in the probable cases, 2.5 days in the possible cases, and 4.7 days in the unlikely cases.

The mean time from vaccination to death was 3.1, 8.3, and 8.2 days, respectively.

In all three categories, the patients had mean CFS scores ranging from 7.6 to 7.9, putting them in the “severely frail” category, defined as people who are completely dependent for personal care but seem stable and not at high risk for dying.

“We have quite many nursing home residents in Norway, 35,000; more than 80% have dementia, and the mean age is 85 years. We know that approximately 45 people die every day in these nursing homes, and their mean age of death is 87.5 years,” Dr. Ranhoff said.
 

Population-wide study

Dr. Ranhoff and colleagues also looked more broadly into the question of potential vaccine-related mortality in the total population of older people in Norway from the day of vaccination to follow-up at 3 weeks.

They conducted a matched cohort study to investigate the relationship between the mRNA SARS-CoV-2 vaccine and overall death among persons aged 65 and older in the general population, and across four groups: patients receiving home-based care, long-term nursing home patients, short-term nursing home patients, and those not receiving health services.

The researchers identified a total of 967,786 residents of Norway aged 65 and over at the start of the country’s vaccination campaign at the end of December, 2020, and they matched vaccinated individuals with unvaccinated persons based on demographic, geographic, and clinical risk group factors.

Dr. Ranhoff showed Kaplan-Meier survival curves for the total population and for each of the health-service states. In all cases there was a clear survival benefit for vaccinated vs. unvaccinated patients. She did not, however, provide specific numbers or hazard ratios for the differences between vaccinated and unvaccinated individuals in each of the comparisons.

The study was supported by the Norwegian Institute of Public Health. Dr. Ranhoff and Dr. Benetos reported no conflicts of interest.

For many children in the process of outgrowing egg allergy, the step-wise reintroduction of foods that contain eggs can be achieved at home using a nine-rung laddered approach, according to updated guidelines from the British Society for Allergy and Clinical Immunology (BSACI).

Attempts to reintroduce egg into the child’s diet can start at the age of 12 months or 6 months from the last reaction, as long as past reactions have been mild to moderate and the child does not have asthma, according to guidelines from the BSACI, which represents allergists, pediatricians, and other health care practitioners.

According to the guidelines, the reintroduction needs to be guided by a specialist allergy service for children who have had severe reactions to egg or who have asthma.

Susan C. Leech, MB BChir, DCH, first author of the guidelines and a consultant in pediatric allergy with the Department of Child Health at Kings College Hospital, London, told this news organization that home reintroduction should begin slowly with small amounts of baked egg, starting with a pea-sized piece of cake, and should proceed gradually.

“Parents can be reassured that it’s a relatively safe thing to do as long as it’s done with caution,” said Dr. Leech.

The expanded guidelines include a new nine-step reintroduction ladder. It builds on a three-stage classification of egg-containing foods that was first introduced in BSACI guidelines in 2010.

On the bottom four rungs, children work their way through small but increasing amounts of fairy cakes (cupcakes), biscuits (cookies), and other foods containing baked eggs.

The next three rungs involve hard-boiled eggs, quiche, and other well-cooked egg products.

At the eighth rung, children can have small mouthfuls of runny scrambled eggs, mayonnaise, and other less-cooked or raw egg-containing products. At the top rung, children can have increasing amounts of those products as well as licks of cake batter.

The guidelines were published online September 29 in Clinical and Experimental Allergy along with a supplement that includes a series of examples showing how the guidelines apply to specific patient cases.

“These are examples only,” the guideline authors caution in the appendix. “Clinical judgment of severity is important as risk assessment is not always easy.”

Anna Nowak-Wegrzyn, MD, PhD, a professor of pediatrics at NYU Grossman School of Medicine and chief of pediatric allergy and immunology for Hassenfeld Children’s Hospital at NYU Langone, who was not involved in the BSACI guidelines, described the egg ladder as a “proactive” strategy that deserves further study and consideration.

“I think that this may be a valid approach,” said Dr. Nowak-Wegrzyn in an interview. “Eggs have good nutritional value, and they are present in a lot of foods, so avoidance creates logistical challenges.”

Using the egg ladder for home-based reintroduction may be especially suited in resource-poor areas where access to an allergist may be difficult, she said. It may also be suited for families that can’t visit the office because of pandemic-related restrictions.

“If the child had a severe reaction or if they have asthma, then it’s a no-go,” she added, “but if you have a patient who has a really mild reaction and you think that overall the risk of a significant reaction or bad symptoms is low, then it may be worth doing.”

Dr. Leech and Dr. Nowak-Wegrzyn have disclosed no relevant financial relationships.

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

For many children in the process of outgrowing egg allergy, the step-wise reintroduction of foods that contain eggs can be achieved at home using a nine-rung laddered approach, according to updated guidelines from the British Society for Allergy and Clinical Immunology (BSACI).

Attempts to reintroduce egg into the child’s diet can start at the age of 12 months or 6 months from the last reaction, as long as past reactions have been mild to moderate and the child does not have asthma, according to guidelines from the BSACI, which represents allergists, pediatricians, and other health care practitioners.

According to the guidelines, the reintroduction needs to be guided by a specialist allergy service for children who have had severe reactions to egg or who have asthma.

Susan C. Leech, MB BChir, DCH, first author of the guidelines and a consultant in pediatric allergy with the Department of Child Health at Kings College Hospital, London, told this news organization that home reintroduction should begin slowly with small amounts of baked egg, starting with a pea-sized piece of cake, and should proceed gradually.

“Parents can be reassured that it’s a relatively safe thing to do as long as it’s done with caution,” said Dr. Leech.

The expanded guidelines include a new nine-step reintroduction ladder. It builds on a three-stage classification of egg-containing foods that was first introduced in BSACI guidelines in 2010.

On the bottom four rungs, children work their way through small but increasing amounts of fairy cakes (cupcakes), biscuits (cookies), and other foods containing baked eggs.

The next three rungs involve hard-boiled eggs, quiche, and other well-cooked egg products.

At the eighth rung, children can have small mouthfuls of runny scrambled eggs, mayonnaise, and other less-cooked or raw egg-containing products. At the top rung, children can have increasing amounts of those products as well as licks of cake batter.

The guidelines were published online September 29 in Clinical and Experimental Allergy along with a supplement that includes a series of examples showing how the guidelines apply to specific patient cases.

“These are examples only,” the guideline authors caution in the appendix. “Clinical judgment of severity is important as risk assessment is not always easy.”

Anna Nowak-Wegrzyn, MD, PhD, a professor of pediatrics at NYU Grossman School of Medicine and chief of pediatric allergy and immunology for Hassenfeld Children’s Hospital at NYU Langone, who was not involved in the BSACI guidelines, described the egg ladder as a “proactive” strategy that deserves further study and consideration.

“I think that this may be a valid approach,” said Dr. Nowak-Wegrzyn in an interview. “Eggs have good nutritional value, and they are present in a lot of foods, so avoidance creates logistical challenges.”

Using the egg ladder for home-based reintroduction may be especially suited in resource-poor areas where access to an allergist may be difficult, she said. It may also be suited for families that can’t visit the office because of pandemic-related restrictions.

“If the child had a severe reaction or if they have asthma, then it’s a no-go,” she added, “but if you have a patient who has a really mild reaction and you think that overall the risk of a significant reaction or bad symptoms is low, then it may be worth doing.”

Dr. Leech and Dr. Nowak-Wegrzyn have disclosed no relevant financial relationships.

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

For many children in the process of outgrowing egg allergy, the step-wise reintroduction of foods that contain eggs can be achieved at home using a nine-rung laddered approach, according to updated guidelines from the British Society for Allergy and Clinical Immunology (BSACI).

Attempts to reintroduce egg into the child’s diet can start at the age of 12 months or 6 months from the last reaction, as long as past reactions have been mild to moderate and the child does not have asthma, according to guidelines from the BSACI, which represents allergists, pediatricians, and other health care practitioners.

According to the guidelines, the reintroduction needs to be guided by a specialist allergy service for children who have had severe reactions to egg or who have asthma.

Susan C. Leech, MB BChir, DCH, first author of the guidelines and a consultant in pediatric allergy with the Department of Child Health at Kings College Hospital, London, told this news organization that home reintroduction should begin slowly with small amounts of baked egg, starting with a pea-sized piece of cake, and should proceed gradually.

“Parents can be reassured that it’s a relatively safe thing to do as long as it’s done with caution,” said Dr. Leech.

The expanded guidelines include a new nine-step reintroduction ladder. It builds on a three-stage classification of egg-containing foods that was first introduced in BSACI guidelines in 2010.

On the bottom four rungs, children work their way through small but increasing amounts of fairy cakes (cupcakes), biscuits (cookies), and other foods containing baked eggs.

The next three rungs involve hard-boiled eggs, quiche, and other well-cooked egg products.

At the eighth rung, children can have small mouthfuls of runny scrambled eggs, mayonnaise, and other less-cooked or raw egg-containing products. At the top rung, children can have increasing amounts of those products as well as licks of cake batter.

The guidelines were published online September 29 in Clinical and Experimental Allergy along with a supplement that includes a series of examples showing how the guidelines apply to specific patient cases.

“These are examples only,” the guideline authors caution in the appendix. “Clinical judgment of severity is important as risk assessment is not always easy.”

Anna Nowak-Wegrzyn, MD, PhD, a professor of pediatrics at NYU Grossman School of Medicine and chief of pediatric allergy and immunology for Hassenfeld Children’s Hospital at NYU Langone, who was not involved in the BSACI guidelines, described the egg ladder as a “proactive” strategy that deserves further study and consideration.

“I think that this may be a valid approach,” said Dr. Nowak-Wegrzyn in an interview. “Eggs have good nutritional value, and they are present in a lot of foods, so avoidance creates logistical challenges.”

Using the egg ladder for home-based reintroduction may be especially suited in resource-poor areas where access to an allergist may be difficult, she said. It may also be suited for families that can’t visit the office because of pandemic-related restrictions.

“If the child had a severe reaction or if they have asthma, then it’s a no-go,” she added, “but if you have a patient who has a really mild reaction and you think that overall the risk of a significant reaction or bad symptoms is low, then it may be worth doing.”

Dr. Leech and Dr. Nowak-Wegrzyn have disclosed no relevant financial relationships.

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

One week after reporting promising results from the trial of their COVID-19 vaccine in children ages 5-11, Pfizer and BioNTech announced they’d submitted the data to the Food and Drug Administration. But that hasn’t stopped some parents from discreetly getting their children under age 12 vaccinated.

“The FDA, you never want to get ahead of their judgment,” Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, told MSNBC on Sept. 28. “But I would imagine in the next few weeks, they will examine that data and hopefully they’ll give the okay so that we can start vaccinating children, hopefully before the end of October.”
 

Lying to vaccinate now

More than half of all parents with children under 12 say they plan to get their kids vaccinated, according to a Gallup poll. Among those who say they’re “very worried” or “somewhat worried” about their children catching COVID, that number goes up to 90% and 72%, respectively.

And although the FDA and the American Academy of Pediatrics have warned against it, some parents whose children can pass for 12 have lied to get them vaccinated already.

Dawn G. is a mom of two in southwest Missouri, where less than 45% of the population has been fully vaccinated. Her son turns 12 in early October, but in-person school started in mid-August.

“It was scary, thinking of him going to school for even 2 months,” she said. “Some parents thought their kid had a low chance of getting COVID, and their kid died. Nobody expects it to be them.”

In July, she and her husband took their son to a walk-in clinic and lied about his age.

“So many things can happen, from bullying to school shootings, and now this added pandemic risk,” she said. “I’ll do anything I can to protect my child, and a birthdate seems so arbitrary. He’ll be 12 in a matter of weeks. It seems ridiculous that that date would stop me from protecting him.”

In northern California, Carrie S. had a similar thought. When the vaccine was authorized for children ages 12-15 in May, the older of her two children got the shot right away. But her youngest doesn’t turn 12 until November.

“We were tempted to get the younger one vaccinated in May, but it didn’t seem like a rush. We were willing to wait to get the dosage right,” she ssaid. “But as Delta came through, there were no options for online school, the CDC was dropping mask expectations –it seemed like the world was ready to forget the pandemic was happening. It seemed like the least-bad option to get her vaccinated so she could go back to school, and we could find some balance of risk in our lives.”
 

Adult vs. pediatric doses

For now, experts advise against getting younger children vaccinated, even those who are the size of an adult, because of the way the human immune system develops.

“It’s not really about size,” said Anne Liu, MD, an immunologist and pediatrics professor at Stanford (Calif.) University. “The immune system behaves differently at different ages. Younger kids tend to have a more exuberant innate immune system, which is the part of the immune system that senses danger, even before it has developed a memory response.”

The adult Pfizer-BioNTech vaccine contains 30 mcg of mRNA, while the pediatric dose is just 10 mcg. That smaller dose produces an immune response similar to what’s seen in adults who receive 30 mcg, according to Pfizer.

“We were one of the sites that was involved in the phase 1 trial, a lot of times that’s called a dose-finding trial,” said Michael Smith, MD, a coinvestigator for the COVID vaccine trials done at Duke University. “And basically, if younger kids got a higher dose, they had more of a reaction, so it hurt more. They had fever, they had more redness and swelling at the site of the injection, and they just felt lousy, more than at the lower doses.”

At this point, with Pfizer’s data showing that younger children need a smaller dose, it doesn’t make sense to lie about your child’s age, said Dr. Smith.

“If my two options were having my child get the infection versus getting the vaccine, I’d get the vaccine. But we’re a few weeks away from getting the lower dose approved in kids,” he said. “It’s certainly safer. I don’t expect major, lifelong side effects from the higher dose, but it’s going to hurt, your kid’s going to have a fever, they’re going to feel lousy for a couple days, and they just don’t need that much antigen.”

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

One week after reporting promising results from the trial of their COVID-19 vaccine in children ages 5-11, Pfizer and BioNTech announced they’d submitted the data to the Food and Drug Administration. But that hasn’t stopped some parents from discreetly getting their children under age 12 vaccinated.

“The FDA, you never want to get ahead of their judgment,” Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, told MSNBC on Sept. 28. “But I would imagine in the next few weeks, they will examine that data and hopefully they’ll give the okay so that we can start vaccinating children, hopefully before the end of October.”
 

Lying to vaccinate now

More than half of all parents with children under 12 say they plan to get their kids vaccinated, according to a Gallup poll. Among those who say they’re “very worried” or “somewhat worried” about their children catching COVID, that number goes up to 90% and 72%, respectively.

And although the FDA and the American Academy of Pediatrics have warned against it, some parents whose children can pass for 12 have lied to get them vaccinated already.

Dawn G. is a mom of two in southwest Missouri, where less than 45% of the population has been fully vaccinated. Her son turns 12 in early October, but in-person school started in mid-August.

“It was scary, thinking of him going to school for even 2 months,” she said. “Some parents thought their kid had a low chance of getting COVID, and their kid died. Nobody expects it to be them.”

In July, she and her husband took their son to a walk-in clinic and lied about his age.

“So many things can happen, from bullying to school shootings, and now this added pandemic risk,” she said. “I’ll do anything I can to protect my child, and a birthdate seems so arbitrary. He’ll be 12 in a matter of weeks. It seems ridiculous that that date would stop me from protecting him.”

In northern California, Carrie S. had a similar thought. When the vaccine was authorized for children ages 12-15 in May, the older of her two children got the shot right away. But her youngest doesn’t turn 12 until November.

“We were tempted to get the younger one vaccinated in May, but it didn’t seem like a rush. We were willing to wait to get the dosage right,” she ssaid. “But as Delta came through, there were no options for online school, the CDC was dropping mask expectations –it seemed like the world was ready to forget the pandemic was happening. It seemed like the least-bad option to get her vaccinated so she could go back to school, and we could find some balance of risk in our lives.”
 

Adult vs. pediatric doses

For now, experts advise against getting younger children vaccinated, even those who are the size of an adult, because of the way the human immune system develops.

“It’s not really about size,” said Anne Liu, MD, an immunologist and pediatrics professor at Stanford (Calif.) University. “The immune system behaves differently at different ages. Younger kids tend to have a more exuberant innate immune system, which is the part of the immune system that senses danger, even before it has developed a memory response.”

The adult Pfizer-BioNTech vaccine contains 30 mcg of mRNA, while the pediatric dose is just 10 mcg. That smaller dose produces an immune response similar to what’s seen in adults who receive 30 mcg, according to Pfizer.

“We were one of the sites that was involved in the phase 1 trial, a lot of times that’s called a dose-finding trial,” said Michael Smith, MD, a coinvestigator for the COVID vaccine trials done at Duke University. “And basically, if younger kids got a higher dose, they had more of a reaction, so it hurt more. They had fever, they had more redness and swelling at the site of the injection, and they just felt lousy, more than at the lower doses.”

At this point, with Pfizer’s data showing that younger children need a smaller dose, it doesn’t make sense to lie about your child’s age, said Dr. Smith.

“If my two options were having my child get the infection versus getting the vaccine, I’d get the vaccine. But we’re a few weeks away from getting the lower dose approved in kids,” he said. “It’s certainly safer. I don’t expect major, lifelong side effects from the higher dose, but it’s going to hurt, your kid’s going to have a fever, they’re going to feel lousy for a couple days, and they just don’t need that much antigen.”

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

One week after reporting promising results from the trial of their COVID-19 vaccine in children ages 5-11, Pfizer and BioNTech announced they’d submitted the data to the Food and Drug Administration. But that hasn’t stopped some parents from discreetly getting their children under age 12 vaccinated.

“The FDA, you never want to get ahead of their judgment,” Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, told MSNBC on Sept. 28. “But I would imagine in the next few weeks, they will examine that data and hopefully they’ll give the okay so that we can start vaccinating children, hopefully before the end of October.”
 

Lying to vaccinate now

More than half of all parents with children under 12 say they plan to get their kids vaccinated, according to a Gallup poll. Among those who say they’re “very worried” or “somewhat worried” about their children catching COVID, that number goes up to 90% and 72%, respectively.

And although the FDA and the American Academy of Pediatrics have warned against it, some parents whose children can pass for 12 have lied to get them vaccinated already.

Dawn G. is a mom of two in southwest Missouri, where less than 45% of the population has been fully vaccinated. Her son turns 12 in early October, but in-person school started in mid-August.

“It was scary, thinking of him going to school for even 2 months,” she said. “Some parents thought their kid had a low chance of getting COVID, and their kid died. Nobody expects it to be them.”

In July, she and her husband took their son to a walk-in clinic and lied about his age.

“So many things can happen, from bullying to school shootings, and now this added pandemic risk,” she said. “I’ll do anything I can to protect my child, and a birthdate seems so arbitrary. He’ll be 12 in a matter of weeks. It seems ridiculous that that date would stop me from protecting him.”

In northern California, Carrie S. had a similar thought. When the vaccine was authorized for children ages 12-15 in May, the older of her two children got the shot right away. But her youngest doesn’t turn 12 until November.

“We were tempted to get the younger one vaccinated in May, but it didn’t seem like a rush. We were willing to wait to get the dosage right,” she ssaid. “But as Delta came through, there were no options for online school, the CDC was dropping mask expectations –it seemed like the world was ready to forget the pandemic was happening. It seemed like the least-bad option to get her vaccinated so she could go back to school, and we could find some balance of risk in our lives.”
 

Adult vs. pediatric doses

For now, experts advise against getting younger children vaccinated, even those who are the size of an adult, because of the way the human immune system develops.

“It’s not really about size,” said Anne Liu, MD, an immunologist and pediatrics professor at Stanford (Calif.) University. “The immune system behaves differently at different ages. Younger kids tend to have a more exuberant innate immune system, which is the part of the immune system that senses danger, even before it has developed a memory response.”

The adult Pfizer-BioNTech vaccine contains 30 mcg of mRNA, while the pediatric dose is just 10 mcg. That smaller dose produces an immune response similar to what’s seen in adults who receive 30 mcg, according to Pfizer.

“We were one of the sites that was involved in the phase 1 trial, a lot of times that’s called a dose-finding trial,” said Michael Smith, MD, a coinvestigator for the COVID vaccine trials done at Duke University. “And basically, if younger kids got a higher dose, they had more of a reaction, so it hurt more. They had fever, they had more redness and swelling at the site of the injection, and they just felt lousy, more than at the lower doses.”

At this point, with Pfizer’s data showing that younger children need a smaller dose, it doesn’t make sense to lie about your child’s age, said Dr. Smith.

“If my two options were having my child get the infection versus getting the vaccine, I’d get the vaccine. But we’re a few weeks away from getting the lower dose approved in kids,” he said. “It’s certainly safer. I don’t expect major, lifelong side effects from the higher dose, but it’s going to hurt, your kid’s going to have a fever, they’re going to feel lousy for a couple days, and they just don’t need that much antigen.”

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

A 2-YEAR-OLD BOY presented to the emergency room with a 1-day history of a diffuse, mildly pruritic rash and swelling of his knees, ankles, and feet following treatment of acute otitis media with amoxicillin for the previous 8 days. He was mildly febrile and consolable, but he was refusing to walk. His medical history was unremarkable.

Physical examination revealed erythematous annular wheals on his chest, face, back, and extremities. Lymphadenopathy and mucous membrane involvement were not present. A complete blood count (CBC) with differential, inflammatory marker tests, and a comprehensive metabolic panel were ordered. Given the joint swelling and rash, the patient was admitted for observation.

During his second day in the hospital, his skin lesions enlarged and several formed dusky blue centers (FIGURE 1A). He also developed swelling of his hands (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s lab work came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Children with urticaria multiforme may have significant edema of the feet and may find walking difficult; this should not be confused with arthritis or arthralgias.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. The incidence and prevalence are not known. Urticaria multiforme is considered common, but it is frequently misdiagnosed.¹ It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 Individual lesions last less than 24 hours, but new ones may appear. The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Dermatographism due to mast cell–mediated cutaneous hypersensitivity at sites of minor skin trauma is common (44%).¹ Patients often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias. Generally, patients are nontoxic in appearance, and systemic symptoms are limited to a low-grade fever.^1-3

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing.When performed, laboratory studies, including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis are routinely normal.

Erythema multiforme and urticarial vasculitis are part of the differential

The differential diagnosis in this case includes erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis (TABLE^1,2,4).

Continue to: Erythema multiforme

Erythema multiforme is a common misdiagnosis in patients with urticaria multiforme.^1,2 The erythema multiforme rash has a “target” lesion with outer erythema and central ecchymosis, which may develop blisters or necrosis. Lesions are fixed and last 2 to 3 weeks. Unlike urticaria multiforme, patients with erythema multiforme commonly have mucous membrane erosions and occasionally ulcerations. Facial and acral edema is rare. Treatment is largely symptomatic and can include glucocorticoids. Antiviral medications may be used to treat recurrences.^1,2

Henoch-Schönlein purpura is an immunoglobulin A–mediated vasculitis that affects the skin, gastrointestinal tract, and joints.^4,5 Patients often present with arthralgias, gastrointestinal symptoms such as abdominal pain and bleeding, and a nonpruritic, erythematous rash that progresses to palpable purpura in dependent areas of the body. Treatment is generally symptomatic, but steroids may be used in severe cases.^4,5

Serum sickness-like reaction can manifest with angioedema and a similar urticarial rash (with central clearing) that lasts 1 to 6 weeks.^1,2,6,7 However, patients tend to have a high-grade fever, arthralgias, myalgias, and lymphadenopathy while dermatographism is absent. Treatment includes discontinuing the offending agent and the use of H1 and H2 antihistamines and steroids, in severe cases.

Urticarial vasculitis manifests as plaques or wheals lasting 1 to 7 days that may cause burning and pain but not pruritis.^2,5 Purpura or hypopigmentation may develop as the hives resolve. Angioedema and arthralgias are common, but dermatographism is not present. Triggers include infections, autoimmune disease, malignancy, and the use of certain medications. H1 and H2 blockers and nonsteroidal anti-inflammatory agents are first-line therapy.²

Step 1: Discontinue offending agents; Step 2: Recommend antihistamines

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Continue to: Our patient's amoxicillin

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

A 2-YEAR-OLD BOY presented to the emergency room with a 1-day history of a diffuse, mildly pruritic rash and swelling of his knees, ankles, and feet following treatment of acute otitis media with amoxicillin for the previous 8 days. He was mildly febrile and consolable, but he was refusing to walk. His medical history was unremarkable.

Physical examination revealed erythematous annular wheals on his chest, face, back, and extremities. Lymphadenopathy and mucous membrane involvement were not present. A complete blood count (CBC) with differential, inflammatory marker tests, and a comprehensive metabolic panel were ordered. Given the joint swelling and rash, the patient was admitted for observation.

During his second day in the hospital, his skin lesions enlarged and several formed dusky blue centers (FIGURE 1A). He also developed swelling of his hands (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s lab work came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Children with urticaria multiforme may have significant edema of the feet and may find walking difficult; this should not be confused with arthritis or arthralgias.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. The incidence and prevalence are not known. Urticaria multiforme is considered common, but it is frequently misdiagnosed.¹ It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 Individual lesions last less than 24 hours, but new ones may appear. The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Dermatographism due to mast cell–mediated cutaneous hypersensitivity at sites of minor skin trauma is common (44%).¹ Patients often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias. Generally, patients are nontoxic in appearance, and systemic symptoms are limited to a low-grade fever.^1-3

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing.When performed, laboratory studies, including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis are routinely normal.

Erythema multiforme and urticarial vasculitis are part of the differential

The differential diagnosis in this case includes erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis (TABLE^1,2,4).

Continue to: Erythema multiforme

Erythema multiforme is a common misdiagnosis in patients with urticaria multiforme.^1,2 The erythema multiforme rash has a “target” lesion with outer erythema and central ecchymosis, which may develop blisters or necrosis. Lesions are fixed and last 2 to 3 weeks. Unlike urticaria multiforme, patients with erythema multiforme commonly have mucous membrane erosions and occasionally ulcerations. Facial and acral edema is rare. Treatment is largely symptomatic and can include glucocorticoids. Antiviral medications may be used to treat recurrences.^1,2

Henoch-Schönlein purpura is an immunoglobulin A–mediated vasculitis that affects the skin, gastrointestinal tract, and joints.^4,5 Patients often present with arthralgias, gastrointestinal symptoms such as abdominal pain and bleeding, and a nonpruritic, erythematous rash that progresses to palpable purpura in dependent areas of the body. Treatment is generally symptomatic, but steroids may be used in severe cases.^4,5

Serum sickness-like reaction can manifest with angioedema and a similar urticarial rash (with central clearing) that lasts 1 to 6 weeks.^1,2,6,7 However, patients tend to have a high-grade fever, arthralgias, myalgias, and lymphadenopathy while dermatographism is absent. Treatment includes discontinuing the offending agent and the use of H1 and H2 antihistamines and steroids, in severe cases.

Urticarial vasculitis manifests as plaques or wheals lasting 1 to 7 days that may cause burning and pain but not pruritis.^2,5 Purpura or hypopigmentation may develop as the hives resolve. Angioedema and arthralgias are common, but dermatographism is not present. Triggers include infections, autoimmune disease, malignancy, and the use of certain medications. H1 and H2 blockers and nonsteroidal anti-inflammatory agents are first-line therapy.²

Step 1: Discontinue offending agents; Step 2: Recommend antihistamines

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Continue to: Our patient's amoxicillin

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

A 2-YEAR-OLD BOY presented to the emergency room with a 1-day history of a diffuse, mildly pruritic rash and swelling of his knees, ankles, and feet following treatment of acute otitis media with amoxicillin for the previous 8 days. He was mildly febrile and consolable, but he was refusing to walk. His medical history was unremarkable.

Physical examination revealed erythematous annular wheals on his chest, face, back, and extremities. Lymphadenopathy and mucous membrane involvement were not present. A complete blood count (CBC) with differential, inflammatory marker tests, and a comprehensive metabolic panel were ordered. Given the joint swelling and rash, the patient was admitted for observation.

During his second day in the hospital, his skin lesions enlarged and several formed dusky blue centers (FIGURE 1A). He also developed swelling of his hands (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s lab work came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Children with urticaria multiforme may have significant edema of the feet and may find walking difficult; this should not be confused with arthritis or arthralgias.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. The incidence and prevalence are not known. Urticaria multiforme is considered common, but it is frequently misdiagnosed.¹ It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 Individual lesions last less than 24 hours, but new ones may appear. The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Dermatographism due to mast cell–mediated cutaneous hypersensitivity at sites of minor skin trauma is common (44%).¹ Patients often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias. Generally, patients are nontoxic in appearance, and systemic symptoms are limited to a low-grade fever.^1-3

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing.When performed, laboratory studies, including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis are routinely normal.

Erythema multiforme and urticarial vasculitis are part of the differential

The differential diagnosis in this case includes erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis (TABLE^1,2,4).

Continue to: Erythema multiforme

Erythema multiforme is a common misdiagnosis in patients with urticaria multiforme.^1,2 The erythema multiforme rash has a “target” lesion with outer erythema and central ecchymosis, which may develop blisters or necrosis. Lesions are fixed and last 2 to 3 weeks. Unlike urticaria multiforme, patients with erythema multiforme commonly have mucous membrane erosions and occasionally ulcerations. Facial and acral edema is rare. Treatment is largely symptomatic and can include glucocorticoids. Antiviral medications may be used to treat recurrences.^1,2

Henoch-Schönlein purpura is an immunoglobulin A–mediated vasculitis that affects the skin, gastrointestinal tract, and joints.^4,5 Patients often present with arthralgias, gastrointestinal symptoms such as abdominal pain and bleeding, and a nonpruritic, erythematous rash that progresses to palpable purpura in dependent areas of the body. Treatment is generally symptomatic, but steroids may be used in severe cases.^4,5

Serum sickness-like reaction can manifest with angioedema and a similar urticarial rash (with central clearing) that lasts 1 to 6 weeks.^1,2,6,7 However, patients tend to have a high-grade fever, arthralgias, myalgias, and lymphadenopathy while dermatographism is absent. Treatment includes discontinuing the offending agent and the use of H1 and H2 antihistamines and steroids, in severe cases.

Urticarial vasculitis manifests as plaques or wheals lasting 1 to 7 days that may cause burning and pain but not pruritis.^2,5 Purpura or hypopigmentation may develop as the hives resolve. Angioedema and arthralgias are common, but dermatographism is not present. Triggers include infections, autoimmune disease, malignancy, and the use of certain medications. H1 and H2 blockers and nonsteroidal anti-inflammatory agents are first-line therapy.²

Step 1: Discontinue offending agents; Step 2: Recommend antihistamines

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Continue to: Our patient's amoxicillin

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

In North America and Europe, penicillin allergy is the most common drug-allergy label.¹ Carrying a penicillin-allergy label, which has recently gained more attention in health care systems, leads to suboptimal outcomes, increased use of broad-spectrum antibiotics, increased risk of adverse reactions, and increased cost of care.^2,3 Despite the high rate of reported reactions, clinically significant immunoglobulin E (IgE)-mediated and T cell–mediated hypersensitivity reactions to penicillins are uncommon.²

Through the Choosing Wisely initiative of the American Board of Internal Medicine Foundation, the American Academy of Allergy, Asthma, and Immunology has issued a recommendation: “Don’t overuse non-beta lactam antibiotics in patients with a history of penicillin allergy without an appropriate evaluation.”⁴ The primary care physician (PCP) plays a critical role in the appropriate evaluation and accurate initial labeling of penicillin allergy. Furthermore, the PCP plays an integral part, in conjunction with the allergist, in removing the “penicillin allergy” label from a patient’s chart when feasible.

The history of penicillin and prevalence of allergy

History. Penicillin, the first antibiotic, was discovered in 1928 by physician and microbiologist Alexander Fleming when he observed that a mold of the Penicillium genus inhibited growth of gram-positive pathogens.⁵ Along with pharmacologist Howard Florey and chemist Ernst Chain, both of whom assisted in the large-scale isolation and production of the antibiotic, Fleming won the Nobel Prize in Physiology or Medicine in 1945 for this discovery.⁵

Studies have confirmed that as many as 90% of patients who report penicillin allergy are, in fact, able to tolerate penicillins.

Antibiotics transformed the practice of medicine across a spectrum, including safer childbirth, surgical procedures, and transplantation.⁶ Penicillin remains first-line therapy for many infections, such as streptococcal pharyngitis,⁷ and is the only recommended medication for treating syphilis during pregnancy.⁸ Continued effectiveness of penicillin in these cases allows broad-spectrum antibiotics to be reserved for more severe infections. Regrettably, incorrect antibiotic allergy labeling poses a significant risk to the patient and health care system.

Epidemiology. As with all medications, the potential for anaphylaxis exists after administration of penicillin. Because its use is widespread, penicillin is the most common cause of drug-induced anaphylaxis. However, the incidence of penicillin-induced anaphylaxis is low⁹: A 1968 World Health Organization report stated that the rate of penicillin anaphylaxis was between 0.015% and 0.04%.¹⁰ A more recent study reported an incidence of 1 in 207,191 patients after an oral dose and 1 in 95,298 after a parenteral dose.¹¹ The most common reactions to penicillins are urticaria and delayed maculopapular rash.⁸

In the United States, the prevalence of reported penicillin allergy is approximately 10% (estimated range, 8% to 12%)^3,12-15; among hospitalized patients, that prevalence is estimated to be as high as 15%.^13,15 However, the prevalence of confirmed penicillin allergy is low and has decreased over time—demonstrated in a longitudinal study in which the rate of a positive skin test fell from 15% in 1995 to 0.8% in 2013.^16,17

Studies have confirmed that as many as 90% of patients who report penicillin allergy are, in fact, able to tolerate penicillins.^14,18-20 This finding might be a consequence of initial mislabeling of penicillin allergy; often, adverse reactions are documented as “allergy” when no risk of anaphylaxis exists. Furthermore, patients can outgrow IgE-mediated penicillin allergy because the presence of penicillin IgE antibodies wanes over time.^14,15

Continue to: Consequences of mislabeling

Consequences of mislabeling

Clinical consequences. A multitude of clinical consequences result from carrying a “penicillin allergy” label.

Use of broad-spectrum antibiotics leads to increased risk of Clostridium difficile infection and to development of resistant bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus.^2,15

Alternative antibiotics used in the setting of a “penicillin allergy” label might be less efficacious and result in suboptimal outcomes.

Alternative antibiotics used in the setting of a “penicillin allergy” label might be less efficacious and result in suboptimal outcomes. For example, vancomycin is less effective against methicillin-sensitive S aureus bacteremia than nafcillin or cefazolin.^2,21 Beta-­lactam antibiotics—in particular, cefazolin—are often first-line for perioperative prophylaxis; patients with reported penicillin allergy often receive a less-optimal alternative, such as clindamycin, vancomycin, or gentamicin.²² These patients are at increased risk of surgical site infection.^2,22

In addition, using penicillin alternatives can result in greater risk of drug reactions and adverse effects.²

Increased health care costs. Primarily through observational studies, penicillin allergy has been associated with higher health care costs.²³ Patients with reported penicillin allergy had, on average, a longer inpatient stay than patients without penicillin allergy, at a 3-year total estimated additional cost of $64.6 million.²⁴ Inpatients with a listed penicillin allergy had direct drug costs ranging from “no difference” to $609 per patient more than patients without a listed penicillin allergy. Outpatient prescription costs were $14 to $193 higher per patient for patients with a listed penicillin allergy.²³

Continue to: Considerations in special populations

Considerations in special populations. Evaluating penicillin allergy during routine care is key to decreasing the necessity for urgent penicillin evaluation and possible desensitization at the time of serious infection. Certain patient populations pose specific challenges:

• Pregnant patients. Unverified penicillin allergy during pregnancy is associated with an increased rate of cesarean section and longer postpartum hospitalization.²⁵ Additionally, group B streptococcus-positive women have increased exposure to alternative antibiotics and an increased incidence of adverse drug reactions.²⁵
• Elderly patients. Drug allergy increases with aging.¹ Elderly patients in a long-term care facility are more likely to experience adverse drug effects or drug–drug interactions from the use of penicillin alternatives, such as clindamycin, vancomycin, and fluoroquinolones.²
• Oncology patients often require antibiotic prophylaxis as well as treatment for illnesses, such as neutropenic fever, for which beta-lactam antibiotics are often used as initial treatment.^2,26
• Other important populations that present specific challenges include hospitalized patients, pediatric patients, and patients with a sexually transmitted infection.²

Active management of a penicillin-allergy label

Greater recognition of the consequences of penicillin allergy in recent years has led to efforts by hospitals and other health care organizations to develop processes by which patients can be successfully de-labeled as part of antibiotic stewardship programs⁹ and other initiatives. Ideally, every patient who has a “penicillin allergy” label would be referred to an allergist for evaluation; however, the number of allergy specialists is limited, and access to such specialists might be restricted in some areas, making this approach impracticable. Active management of penicillin allergy requires strategies to both test and de-label patients, as well as proactive approaches to prevent incorrect labeling. These proactive approaches require involvement of all members of the health care team—especially PCPs.

Preventing incorrect labeling. PCPs are the most likely to initially label a patient as allergic to penicillin.²⁷ Most physicians rely on a reported history of allergy alone when selecting medication¹²; once a patient has been labeled “penicillin allergic,” they often retain that mislabel through adulthood.^27,28 A qualitative study of PCPs’ views on prescribing penicillin found that many were aware that documented allergies were incorrect but were uncomfortable using their clinical judgment to prescribe a penicillin or change the record, for fear of a future anaphylactic reaction.²⁹ The first step in the case of any reported reaction should be for you to elicit an accurate drug allergy history (TABLE 1).

As with other drug reactions, you should consider the context surrounding the reaction to a penicillin. Take care to review signs and symptoms of the reaction to look for clues that make a true allergic reaction more, or less, likely.

Symptoms can generally be divided into low-risk and high-risk categories²⁷ (TABLE 2). An example of a commonly reported low-risk symptom is diarrhea that develops after several doses of a penicillin. In the absence of other symptoms, this finding is most likely due to elimination of normal gut flora,³⁰ not to an allergic reaction to the medication. Symptoms of intolerance to the medication, such as headache and nausea, are also low risk.^27,31 In contrast, immediate onset of abdominal pain after a dose of penicillin and lip or throat swelling are considered high risk.

Continue to: Patients presenting with urticaria...

Patients presenting with urticaria or maculopapular rash after taking penicillin are particularly challenging.³⁰ A study of patients in a primary care pediatrics practice found that 7.4% of children receiving a prescription for a penicillin reported a rash.³² Here, timing of onset of symptoms provides some clarity about the likelihood of true allergy. Rashes that manifest during the first hours after exposure are more likely to be IgE mediated, particularly when accompanied by other systemic symptoms; they should be considered high risk. Delayed-onset rashes (> 72 hours after exposure) are usually non-IgE mediated and therefore are generally lower risk,^8,30,33 except when associated with certain features, such as mucosal involvement and skin peeling.

Despite acknowledging viral exanthems in the differential, many physicians still label patients presenting with any rash as “allergic.”²⁸ Take care to look for other potential causes of a rash; for example, patients taking amoxicillin who have concurrent Epstein-Barr virus infection frequently develop a maculopapular rash.³⁴ Caubet and colleagues found that 56% of pediatric patients with a history of nonimmediate rash and a negative oral challenge to amoxicillin tested positive for viral infection.²⁸

A family history of penicillin allergy alone should not preclude the use of penicillin.^8,27,31 Similarly, if a patient has already received and tolerated a subsequent course of the same penicillin derivative after the initial reaction, the “penicillin allergy” label can be removed. If the reaction history is unknown, refer the patient to an allergist for further evaluation.

Accurate charting is key. With most hospital systems and physician practices now documenting in an electronic health record, there exists the ability to document, in great detail, patients’ reactions to medications. Previous studies have found, however, that such documentation is often done poorly, or not done at all. One such study found that (1) > 20% of patients with a “penicillin allergy” label did not have reaction details listed and (2) when reactions were listed, many were incorrectly labeled as “allergy,” not “intolerance.”³⁵

Many electronic health record systems lump drug allergies, adverse effects, and food and environmental allergies into a single section, leading to a lack of distinction between adverse reactions and true allergy.³¹ Although many PCPs report that it is easy to change a patient’s allergy label in the record,²⁹ more often, a nurse, resident, or consultant actually documents the reaction.³⁵

Continue to: Documentation at the time of the reaction...

Documentation at the time of the reaction, within the encounter note and the allergy tab, is essential, so that other physicians caring for the patient, in the future, will be knowledgeable about the details of the reaction. Make it your responsibility to accurately document penicillin allergy in patients’ charts, including removing the “penicillin allergy” label from the chart of patients whose history is inconsistent with allergy, who have tolerated subsequent courses of the same penicillin derivative, or who have passed testing in an allergist’s office. In a study of 639 patients who tested negative for penicillin allergy, 51% still had a “penicillin allergy” label in their chart more than 4 years later.³⁶

Penicillin allergy evaluation. When a patient cannot be cleared of a “penicillin allergy” label by history alone, and in the absence of severe features such as mucous membrane involvement, they should be further evaluated through objective testing for potential IgE-mediated allergy. This assessment includes penicillin skin testing or an oral challenge, or both.

Skin testing involves skin-prick testing of major and minor determinants of penicillin; when skin-prick testing is negative, intradermal testing of major and minor determinants should follow. The negative predictive value of penicillin skin testing is high: In a prospective, multicenter investigation, researchers demonstrated that, when both the major penicillin determinant and a minor determinant mixture were used, negative predictive value was 97.9%.³⁷

Rashes manifesting during the first hours after exposure are more likely to be IgE mediated, particularly when accompanied by other systemic symptoms; consider them a high-risk sign.

However, a minor determinant mixture is not commercially available in the United States; therefore, penicillin G is often used alone as the minor determinant. Typically, if a patient passes skin testing, a challenge dose of penicillin or amoxicillin is administered, followed by an observation period. The risk of re-sensitization after oral penicillin is thought to be low and does not preclude future use.³⁸

Although drug testing is most often performed in an allergist’s office, several groups have developed protocols that allow for limited testing of low-risk patients in a primary care setting.^8,31 For example, several studies have demonstrated that patients presenting with low-risk skin rash can be safely tested with a supervised oral challenge alone.^18,28 The FIGURE^{8,27,30,31,33,34} outlines our proposed workflow for risk stratification and subsequent management of patients with a “penicillin allergy” label.

Continue to: De-labeling requires a systems approach

De-labeling requires a systems approach. Given the mismatch between the large number of patients labeled “penicillin allergic” and the few allergy specialists, referral alone is not enough to solve the problem of mislabeling. Targeting specific populations for testing, such as patients presenting to an inner-city sexually transmitted infection clinic¹⁹ or preoperative patients, as is done at the Mayo Clinic,⁹ has been successful. Skin testing in an inpatient setting has also been shown to be safe and effective,¹³ allowing for protocol-driven testing under the supervision of trained pharmacists (and others), to relieve the burden on allergy specialists.⁹

CORRESPONDENCE
Andrew Lutzkanin, MD, 500 University Drive, PO Box 850, Hershey, PA 17033; [email protected]

In North America and Europe, penicillin allergy is the most common drug-allergy label.¹ Carrying a penicillin-allergy label, which has recently gained more attention in health care systems, leads to suboptimal outcomes, increased use of broad-spectrum antibiotics, increased risk of adverse reactions, and increased cost of care.^2,3 Despite the high rate of reported reactions, clinically significant immunoglobulin E (IgE)-mediated and T cell–mediated hypersensitivity reactions to penicillins are uncommon.²

Through the Choosing Wisely initiative of the American Board of Internal Medicine Foundation, the American Academy of Allergy, Asthma, and Immunology has issued a recommendation: “Don’t overuse non-beta lactam antibiotics in patients with a history of penicillin allergy without an appropriate evaluation.”⁴ The primary care physician (PCP) plays a critical role in the appropriate evaluation and accurate initial labeling of penicillin allergy. Furthermore, the PCP plays an integral part, in conjunction with the allergist, in removing the “penicillin allergy” label from a patient’s chart when feasible.

The history of penicillin and prevalence of allergy

History. Penicillin, the first antibiotic, was discovered in 1928 by physician and microbiologist Alexander Fleming when he observed that a mold of the Penicillium genus inhibited growth of gram-positive pathogens.⁵ Along with pharmacologist Howard Florey and chemist Ernst Chain, both of whom assisted in the large-scale isolation and production of the antibiotic, Fleming won the Nobel Prize in Physiology or Medicine in 1945 for this discovery.⁵

Studies have confirmed that as many as 90% of patients who report penicillin allergy are, in fact, able to tolerate penicillins.

Antibiotics transformed the practice of medicine across a spectrum, including safer childbirth, surgical procedures, and transplantation.⁶ Penicillin remains first-line therapy for many infections, such as streptococcal pharyngitis,⁷ and is the only recommended medication for treating syphilis during pregnancy.⁸ Continued effectiveness of penicillin in these cases allows broad-spectrum antibiotics to be reserved for more severe infections. Regrettably, incorrect antibiotic allergy labeling poses a significant risk to the patient and health care system.

Epidemiology. As with all medications, the potential for anaphylaxis exists after administration of penicillin. Because its use is widespread, penicillin is the most common cause of drug-induced anaphylaxis. However, the incidence of penicillin-induced anaphylaxis is low⁹: A 1968 World Health Organization report stated that the rate of penicillin anaphylaxis was between 0.015% and 0.04%.¹⁰ A more recent study reported an incidence of 1 in 207,191 patients after an oral dose and 1 in 95,298 after a parenteral dose.¹¹ The most common reactions to penicillins are urticaria and delayed maculopapular rash.⁸

In the United States, the prevalence of reported penicillin allergy is approximately 10% (estimated range, 8% to 12%)^3,12-15; among hospitalized patients, that prevalence is estimated to be as high as 15%.^13,15 However, the prevalence of confirmed penicillin allergy is low and has decreased over time—demonstrated in a longitudinal study in which the rate of a positive skin test fell from 15% in 1995 to 0.8% in 2013.^16,17

Studies have confirmed that as many as 90% of patients who report penicillin allergy are, in fact, able to tolerate penicillins.^14,18-20 This finding might be a consequence of initial mislabeling of penicillin allergy; often, adverse reactions are documented as “allergy” when no risk of anaphylaxis exists. Furthermore, patients can outgrow IgE-mediated penicillin allergy because the presence of penicillin IgE antibodies wanes over time.^14,15

Continue to: Consequences of mislabeling

Consequences of mislabeling

Clinical consequences. A multitude of clinical consequences result from carrying a “penicillin allergy” label.

Use of broad-spectrum antibiotics leads to increased risk of Clostridium difficile infection and to development of resistant bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus.^2,15

Alternative antibiotics used in the setting of a “penicillin allergy” label might be less efficacious and result in suboptimal outcomes.

Alternative antibiotics used in the setting of a “penicillin allergy” label might be less efficacious and result in suboptimal outcomes. For example, vancomycin is less effective against methicillin-sensitive S aureus bacteremia than nafcillin or cefazolin.^2,21 Beta-­lactam antibiotics—in particular, cefazolin—are often first-line for perioperative prophylaxis; patients with reported penicillin allergy often receive a less-optimal alternative, such as clindamycin, vancomycin, or gentamicin.²² These patients are at increased risk of surgical site infection.^2,22

In addition, using penicillin alternatives can result in greater risk of drug reactions and adverse effects.²

Increased health care costs. Primarily through observational studies, penicillin allergy has been associated with higher health care costs.²³ Patients with reported penicillin allergy had, on average, a longer inpatient stay than patients without penicillin allergy, at a 3-year total estimated additional cost of $64.6 million.²⁴ Inpatients with a listed penicillin allergy had direct drug costs ranging from “no difference” to $609 per patient more than patients without a listed penicillin allergy. Outpatient prescription costs were $14 to $193 higher per patient for patients with a listed penicillin allergy.²³

Continue to: Considerations in special populations

Considerations in special populations. Evaluating penicillin allergy during routine care is key to decreasing the necessity for urgent penicillin evaluation and possible desensitization at the time of serious infection. Certain patient populations pose specific challenges:

• Pregnant patients. Unverified penicillin allergy during pregnancy is associated with an increased rate of cesarean section and longer postpartum hospitalization.²⁵ Additionally, group B streptococcus-positive women have increased exposure to alternative antibiotics and an increased incidence of adverse drug reactions.²⁵
• Elderly patients. Drug allergy increases with aging.¹ Elderly patients in a long-term care facility are more likely to experience adverse drug effects or drug–drug interactions from the use of penicillin alternatives, such as clindamycin, vancomycin, and fluoroquinolones.²
• Oncology patients often require antibiotic prophylaxis as well as treatment for illnesses, such as neutropenic fever, for which beta-lactam antibiotics are often used as initial treatment.^2,26
• Other important populations that present specific challenges include hospitalized patients, pediatric patients, and patients with a sexually transmitted infection.²

Active management of a penicillin-allergy label

Greater recognition of the consequences of penicillin allergy in recent years has led to efforts by hospitals and other health care organizations to develop processes by which patients can be successfully de-labeled as part of antibiotic stewardship programs⁹ and other initiatives. Ideally, every patient who has a “penicillin allergy” label would be referred to an allergist for evaluation; however, the number of allergy specialists is limited, and access to such specialists might be restricted in some areas, making this approach impracticable. Active management of penicillin allergy requires strategies to both test and de-label patients, as well as proactive approaches to prevent incorrect labeling. These proactive approaches require involvement of all members of the health care team—especially PCPs.

Preventing incorrect labeling. PCPs are the most likely to initially label a patient as allergic to penicillin.²⁷ Most physicians rely on a reported history of allergy alone when selecting medication¹²; once a patient has been labeled “penicillin allergic,” they often retain that mislabel through adulthood.^27,28 A qualitative study of PCPs’ views on prescribing penicillin found that many were aware that documented allergies were incorrect but were uncomfortable using their clinical judgment to prescribe a penicillin or change the record, for fear of a future anaphylactic reaction.²⁹ The first step in the case of any reported reaction should be for you to elicit an accurate drug allergy history (TABLE 1).

As with other drug reactions, you should consider the context surrounding the reaction to a penicillin. Take care to review signs and symptoms of the reaction to look for clues that make a true allergic reaction more, or less, likely.

Symptoms can generally be divided into low-risk and high-risk categories²⁷ (TABLE 2). An example of a commonly reported low-risk symptom is diarrhea that develops after several doses of a penicillin. In the absence of other symptoms, this finding is most likely due to elimination of normal gut flora,³⁰ not to an allergic reaction to the medication. Symptoms of intolerance to the medication, such as headache and nausea, are also low risk.^27,31 In contrast, immediate onset of abdominal pain after a dose of penicillin and lip or throat swelling are considered high risk.

Continue to: Patients presenting with urticaria...

Patients presenting with urticaria or maculopapular rash after taking penicillin are particularly challenging.³⁰ A study of patients in a primary care pediatrics practice found that 7.4% of children receiving a prescription for a penicillin reported a rash.³² Here, timing of onset of symptoms provides some clarity about the likelihood of true allergy. Rashes that manifest during the first hours after exposure are more likely to be IgE mediated, particularly when accompanied by other systemic symptoms; they should be considered high risk. Delayed-onset rashes (> 72 hours after exposure) are usually non-IgE mediated and therefore are generally lower risk,^8,30,33 except when associated with certain features, such as mucosal involvement and skin peeling.

Despite acknowledging viral exanthems in the differential, many physicians still label patients presenting with any rash as “allergic.”²⁸ Take care to look for other potential causes of a rash; for example, patients taking amoxicillin who have concurrent Epstein-Barr virus infection frequently develop a maculopapular rash.³⁴ Caubet and colleagues found that 56% of pediatric patients with a history of nonimmediate rash and a negative oral challenge to amoxicillin tested positive for viral infection.²⁸

A family history of penicillin allergy alone should not preclude the use of penicillin.^8,27,31 Similarly, if a patient has already received and tolerated a subsequent course of the same penicillin derivative after the initial reaction, the “penicillin allergy” label can be removed. If the reaction history is unknown, refer the patient to an allergist for further evaluation.

Accurate charting is key. With most hospital systems and physician practices now documenting in an electronic health record, there exists the ability to document, in great detail, patients’ reactions to medications. Previous studies have found, however, that such documentation is often done poorly, or not done at all. One such study found that (1) > 20% of patients with a “penicillin allergy” label did not have reaction details listed and (2) when reactions were listed, many were incorrectly labeled as “allergy,” not “intolerance.”³⁵

Many electronic health record systems lump drug allergies, adverse effects, and food and environmental allergies into a single section, leading to a lack of distinction between adverse reactions and true allergy.³¹ Although many PCPs report that it is easy to change a patient’s allergy label in the record,²⁹ more often, a nurse, resident, or consultant actually documents the reaction.³⁵

Continue to: Documentation at the time of the reaction...

Documentation at the time of the reaction, within the encounter note and the allergy tab, is essential, so that other physicians caring for the patient, in the future, will be knowledgeable about the details of the reaction. Make it your responsibility to accurately document penicillin allergy in patients’ charts, including removing the “penicillin allergy” label from the chart of patients whose history is inconsistent with allergy, who have tolerated subsequent courses of the same penicillin derivative, or who have passed testing in an allergist’s office. In a study of 639 patients who tested negative for penicillin allergy, 51% still had a “penicillin allergy” label in their chart more than 4 years later.³⁶

Penicillin allergy evaluation. When a patient cannot be cleared of a “penicillin allergy” label by history alone, and in the absence of severe features such as mucous membrane involvement, they should be further evaluated through objective testing for potential IgE-mediated allergy. This assessment includes penicillin skin testing or an oral challenge, or both.

Skin testing involves skin-prick testing of major and minor determinants of penicillin; when skin-prick testing is negative, intradermal testing of major and minor determinants should follow. The negative predictive value of penicillin skin testing is high: In a prospective, multicenter investigation, researchers demonstrated that, when both the major penicillin determinant and a minor determinant mixture were used, negative predictive value was 97.9%.³⁷

Rashes manifesting during the first hours after exposure are more likely to be IgE mediated, particularly when accompanied by other systemic symptoms; consider them a high-risk sign.

However, a minor determinant mixture is not commercially available in the United States; therefore, penicillin G is often used alone as the minor determinant. Typically, if a patient passes skin testing, a challenge dose of penicillin or amoxicillin is administered, followed by an observation period. The risk of re-sensitization after oral penicillin is thought to be low and does not preclude future use.³⁸

Although drug testing is most often performed in an allergist’s office, several groups have developed protocols that allow for limited testing of low-risk patients in a primary care setting.^8,31 For example, several studies have demonstrated that patients presenting with low-risk skin rash can be safely tested with a supervised oral challenge alone.^18,28 The FIGURE^{8,27,30,31,33,34} outlines our proposed workflow for risk stratification and subsequent management of patients with a “penicillin allergy” label.

Continue to: De-labeling requires a systems approach

De-labeling requires a systems approach. Given the mismatch between the large number of patients labeled “penicillin allergic” and the few allergy specialists, referral alone is not enough to solve the problem of mislabeling. Targeting specific populations for testing, such as patients presenting to an inner-city sexually transmitted infection clinic¹⁹ or preoperative patients, as is done at the Mayo Clinic,⁹ has been successful. Skin testing in an inpatient setting has also been shown to be safe and effective,¹³ allowing for protocol-driven testing under the supervision of trained pharmacists (and others), to relieve the burden on allergy specialists.⁹

CORRESPONDENCE
Andrew Lutzkanin, MD, 500 University Drive, PO Box 850, Hershey, PA 17033; [email protected]

In North America and Europe, penicillin allergy is the most common drug-allergy label.¹ Carrying a penicillin-allergy label, which has recently gained more attention in health care systems, leads to suboptimal outcomes, increased use of broad-spectrum antibiotics, increased risk of adverse reactions, and increased cost of care.^2,3 Despite the high rate of reported reactions, clinically significant immunoglobulin E (IgE)-mediated and T cell–mediated hypersensitivity reactions to penicillins are uncommon.²

Through the Choosing Wisely initiative of the American Board of Internal Medicine Foundation, the American Academy of Allergy, Asthma, and Immunology has issued a recommendation: “Don’t overuse non-beta lactam antibiotics in patients with a history of penicillin allergy without an appropriate evaluation.”⁴ The primary care physician (PCP) plays a critical role in the appropriate evaluation and accurate initial labeling of penicillin allergy. Furthermore, the PCP plays an integral part, in conjunction with the allergist, in removing the “penicillin allergy” label from a patient’s chart when feasible.

The history of penicillin and prevalence of allergy

History. Penicillin, the first antibiotic, was discovered in 1928 by physician and microbiologist Alexander Fleming when he observed that a mold of the Penicillium genus inhibited growth of gram-positive pathogens.⁵ Along with pharmacologist Howard Florey and chemist Ernst Chain, both of whom assisted in the large-scale isolation and production of the antibiotic, Fleming won the Nobel Prize in Physiology or Medicine in 1945 for this discovery.⁵

Studies have confirmed that as many as 90% of patients who report penicillin allergy are, in fact, able to tolerate penicillins.

Antibiotics transformed the practice of medicine across a spectrum, including safer childbirth, surgical procedures, and transplantation.⁶ Penicillin remains first-line therapy for many infections, such as streptococcal pharyngitis,⁷ and is the only recommended medication for treating syphilis during pregnancy.⁸ Continued effectiveness of penicillin in these cases allows broad-spectrum antibiotics to be reserved for more severe infections. Regrettably, incorrect antibiotic allergy labeling poses a significant risk to the patient and health care system.

Epidemiology. As with all medications, the potential for anaphylaxis exists after administration of penicillin. Because its use is widespread, penicillin is the most common cause of drug-induced anaphylaxis. However, the incidence of penicillin-induced anaphylaxis is low⁹: A 1968 World Health Organization report stated that the rate of penicillin anaphylaxis was between 0.015% and 0.04%.¹⁰ A more recent study reported an incidence of 1 in 207,191 patients after an oral dose and 1 in 95,298 after a parenteral dose.¹¹ The most common reactions to penicillins are urticaria and delayed maculopapular rash.⁸

In the United States, the prevalence of reported penicillin allergy is approximately 10% (estimated range, 8% to 12%)^3,12-15; among hospitalized patients, that prevalence is estimated to be as high as 15%.^13,15 However, the prevalence of confirmed penicillin allergy is low and has decreased over time—demonstrated in a longitudinal study in which the rate of a positive skin test fell from 15% in 1995 to 0.8% in 2013.^16,17

Studies have confirmed that as many as 90% of patients who report penicillin allergy are, in fact, able to tolerate penicillins.^14,18-20 This finding might be a consequence of initial mislabeling of penicillin allergy; often, adverse reactions are documented as “allergy” when no risk of anaphylaxis exists. Furthermore, patients can outgrow IgE-mediated penicillin allergy because the presence of penicillin IgE antibodies wanes over time.^14,15

Continue to: Consequences of mislabeling

Consequences of mislabeling

Clinical consequences. A multitude of clinical consequences result from carrying a “penicillin allergy” label.

Use of broad-spectrum antibiotics leads to increased risk of Clostridium difficile infection and to development of resistant bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus.^2,15

Alternative antibiotics used in the setting of a “penicillin allergy” label might be less efficacious and result in suboptimal outcomes.

Alternative antibiotics used in the setting of a “penicillin allergy” label might be less efficacious and result in suboptimal outcomes. For example, vancomycin is less effective against methicillin-sensitive S aureus bacteremia than nafcillin or cefazolin.^2,21 Beta-­lactam antibiotics—in particular, cefazolin—are often first-line for perioperative prophylaxis; patients with reported penicillin allergy often receive a less-optimal alternative, such as clindamycin, vancomycin, or gentamicin.²² These patients are at increased risk of surgical site infection.^2,22

In addition, using penicillin alternatives can result in greater risk of drug reactions and adverse effects.²

Increased health care costs. Primarily through observational studies, penicillin allergy has been associated with higher health care costs.²³ Patients with reported penicillin allergy had, on average, a longer inpatient stay than patients without penicillin allergy, at a 3-year total estimated additional cost of $64.6 million.²⁴ Inpatients with a listed penicillin allergy had direct drug costs ranging from “no difference” to $609 per patient more than patients without a listed penicillin allergy. Outpatient prescription costs were $14 to $193 higher per patient for patients with a listed penicillin allergy.²³

Continue to: Considerations in special populations

Considerations in special populations. Evaluating penicillin allergy during routine care is key to decreasing the necessity for urgent penicillin evaluation and possible desensitization at the time of serious infection. Certain patient populations pose specific challenges:

• Pregnant patients. Unverified penicillin allergy during pregnancy is associated with an increased rate of cesarean section and longer postpartum hospitalization.²⁵ Additionally, group B streptococcus-positive women have increased exposure to alternative antibiotics and an increased incidence of adverse drug reactions.²⁵
• Elderly patients. Drug allergy increases with aging.¹ Elderly patients in a long-term care facility are more likely to experience adverse drug effects or drug–drug interactions from the use of penicillin alternatives, such as clindamycin, vancomycin, and fluoroquinolones.²
• Oncology patients often require antibiotic prophylaxis as well as treatment for illnesses, such as neutropenic fever, for which beta-lactam antibiotics are often used as initial treatment.^2,26
• Other important populations that present specific challenges include hospitalized patients, pediatric patients, and patients with a sexually transmitted infection.²

Active management of a penicillin-allergy label

Greater recognition of the consequences of penicillin allergy in recent years has led to efforts by hospitals and other health care organizations to develop processes by which patients can be successfully de-labeled as part of antibiotic stewardship programs⁹ and other initiatives. Ideally, every patient who has a “penicillin allergy” label would be referred to an allergist for evaluation; however, the number of allergy specialists is limited, and access to such specialists might be restricted in some areas, making this approach impracticable. Active management of penicillin allergy requires strategies to both test and de-label patients, as well as proactive approaches to prevent incorrect labeling. These proactive approaches require involvement of all members of the health care team—especially PCPs.

Preventing incorrect labeling. PCPs are the most likely to initially label a patient as allergic to penicillin.²⁷ Most physicians rely on a reported history of allergy alone when selecting medication¹²; once a patient has been labeled “penicillin allergic,” they often retain that mislabel through adulthood.^27,28 A qualitative study of PCPs’ views on prescribing penicillin found that many were aware that documented allergies were incorrect but were uncomfortable using their clinical judgment to prescribe a penicillin or change the record, for fear of a future anaphylactic reaction.²⁹ The first step in the case of any reported reaction should be for you to elicit an accurate drug allergy history (TABLE 1).

As with other drug reactions, you should consider the context surrounding the reaction to a penicillin. Take care to review signs and symptoms of the reaction to look for clues that make a true allergic reaction more, or less, likely.

Symptoms can generally be divided into low-risk and high-risk categories²⁷ (TABLE 2). An example of a commonly reported low-risk symptom is diarrhea that develops after several doses of a penicillin. In the absence of other symptoms, this finding is most likely due to elimination of normal gut flora,³⁰ not to an allergic reaction to the medication. Symptoms of intolerance to the medication, such as headache and nausea, are also low risk.^27,31 In contrast, immediate onset of abdominal pain after a dose of penicillin and lip or throat swelling are considered high risk.

Continue to: Patients presenting with urticaria...

Patients presenting with urticaria or maculopapular rash after taking penicillin are particularly challenging.³⁰ A study of patients in a primary care pediatrics practice found that 7.4% of children receiving a prescription for a penicillin reported a rash.³² Here, timing of onset of symptoms provides some clarity about the likelihood of true allergy. Rashes that manifest during the first hours after exposure are more likely to be IgE mediated, particularly when accompanied by other systemic symptoms; they should be considered high risk. Delayed-onset rashes (> 72 hours after exposure) are usually non-IgE mediated and therefore are generally lower risk,^8,30,33 except when associated with certain features, such as mucosal involvement and skin peeling.

Despite acknowledging viral exanthems in the differential, many physicians still label patients presenting with any rash as “allergic.”²⁸ Take care to look for other potential causes of a rash; for example, patients taking amoxicillin who have concurrent Epstein-Barr virus infection frequently develop a maculopapular rash.³⁴ Caubet and colleagues found that 56% of pediatric patients with a history of nonimmediate rash and a negative oral challenge to amoxicillin tested positive for viral infection.²⁸

A family history of penicillin allergy alone should not preclude the use of penicillin.^8,27,31 Similarly, if a patient has already received and tolerated a subsequent course of the same penicillin derivative after the initial reaction, the “penicillin allergy” label can be removed. If the reaction history is unknown, refer the patient to an allergist for further evaluation.

Accurate charting is key. With most hospital systems and physician practices now documenting in an electronic health record, there exists the ability to document, in great detail, patients’ reactions to medications. Previous studies have found, however, that such documentation is often done poorly, or not done at all. One such study found that (1) > 20% of patients with a “penicillin allergy” label did not have reaction details listed and (2) when reactions were listed, many were incorrectly labeled as “allergy,” not “intolerance.”³⁵

Many electronic health record systems lump drug allergies, adverse effects, and food and environmental allergies into a single section, leading to a lack of distinction between adverse reactions and true allergy.³¹ Although many PCPs report that it is easy to change a patient’s allergy label in the record,²⁹ more often, a nurse, resident, or consultant actually documents the reaction.³⁵

Continue to: Documentation at the time of the reaction...

Documentation at the time of the reaction, within the encounter note and the allergy tab, is essential, so that other physicians caring for the patient, in the future, will be knowledgeable about the details of the reaction. Make it your responsibility to accurately document penicillin allergy in patients’ charts, including removing the “penicillin allergy” label from the chart of patients whose history is inconsistent with allergy, who have tolerated subsequent courses of the same penicillin derivative, or who have passed testing in an allergist’s office. In a study of 639 patients who tested negative for penicillin allergy, 51% still had a “penicillin allergy” label in their chart more than 4 years later.³⁶

Penicillin allergy evaluation. When a patient cannot be cleared of a “penicillin allergy” label by history alone, and in the absence of severe features such as mucous membrane involvement, they should be further evaluated through objective testing for potential IgE-mediated allergy. This assessment includes penicillin skin testing or an oral challenge, or both.

Skin testing involves skin-prick testing of major and minor determinants of penicillin; when skin-prick testing is negative, intradermal testing of major and minor determinants should follow. The negative predictive value of penicillin skin testing is high: In a prospective, multicenter investigation, researchers demonstrated that, when both the major penicillin determinant and a minor determinant mixture were used, negative predictive value was 97.9%.³⁷

Rashes manifesting during the first hours after exposure are more likely to be IgE mediated, particularly when accompanied by other systemic symptoms; consider them a high-risk sign.

However, a minor determinant mixture is not commercially available in the United States; therefore, penicillin G is often used alone as the minor determinant. Typically, if a patient passes skin testing, a challenge dose of penicillin or amoxicillin is administered, followed by an observation period. The risk of re-sensitization after oral penicillin is thought to be low and does not preclude future use.³⁸

Although drug testing is most often performed in an allergist’s office, several groups have developed protocols that allow for limited testing of low-risk patients in a primary care setting.^8,31 For example, several studies have demonstrated that patients presenting with low-risk skin rash can be safely tested with a supervised oral challenge alone.^18,28 The FIGURE^{8,27,30,31,33,34} outlines our proposed workflow for risk stratification and subsequent management of patients with a “penicillin allergy” label.

Continue to: De-labeling requires a systems approach

De-labeling requires a systems approach. Given the mismatch between the large number of patients labeled “penicillin allergic” and the few allergy specialists, referral alone is not enough to solve the problem of mislabeling. Targeting specific populations for testing, such as patients presenting to an inner-city sexually transmitted infection clinic¹⁹ or preoperative patients, as is done at the Mayo Clinic,⁹ has been successful. Skin testing in an inpatient setting has also been shown to be safe and effective,¹³ allowing for protocol-driven testing under the supervision of trained pharmacists (and others), to relieve the burden on allergy specialists.⁹

CORRESPONDENCE
Andrew Lutzkanin, MD, 500 University Drive, PO Box 850, Hershey, PA 17033; [email protected]

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

A recent analysis of 142 peanut-allergic children treated for 1.5 to 2 years with a licensed oral immunotherapy (OIT) product confirms what various smaller studies have shown: Maintaining treatment for longer periods improves protection and reduces adverse effects. The findings offer some reassurance regarding the controversial approach, which has become available at a small number of clinics yet faces an uncertain future.

The new study, published July 28 in Allergy, included a subset of patients who chose to complete an extension of the phase 3 PALISADE trial of Palforzia, a proprietary set of premeasured peanut flour capsules developed by Aimmune Therapeutics.

Palforzia was approved last year for children aged 4 to 17 years with peanut allergy – one of the most common food allergies, affecting around 2% of children in the United States and Europe. The treatment is not a cure – patients must still watch what they eat and carry epinephrine for emergency reactions – but it helps build protection through daily ingestion of gradually increasing amounts of the allergen over a period of months.

In the 1-year PALISADE trial, which enrolled 496 peanut-allergic children at 66 sites in North America and Europe, participants received daily doses of study drug or placebo. The dose of the drug was escalated from 3 mg to 300 mg over 6 months; the 300-mg dose was then maintained for another 6 months. By the end of the study, about two-thirds of the children who underwent treatment could safely consume at least 600 mg of peanut protein, about the equivalent of two peanuts.

Could protection be increased with further treatment, and what would be required to sustain it? To address these questions, PALISADE patients who successfully reached the 600-mg threshold, along with those from the placebo group, were invited to participate in Aimmune’s open-label follow-on study. The extension study also explored whether protection could be maintained with less frequent dosing.

Among the 358 eligible participants who opted into the 1-year extension study, 256 came from the PALISADE treatment arm. These children were assigned to five cohorts to continue for 6 months or 12 months with daily or less frequent doses. Within the 6-month group, all started with the 300-mg daily dose. A subset received two doses a week. Within the 12-month group, some patients maintained daily dosing throughout; others received doses every other day, twice weekly, or once every 2 weeks.

The children who continued daily maintenance dosing the longest gained the most protection. Those in less-frequent dosing groups experienced more adverse events than those who received doses every day, the company reported last December in The Journal of Allergy and Clinical Immunology: In Practice.

More than a quarter (97 of 358, or 27.1%) of participants failed to complete the extension. Families could withdraw any time for any reason. Participating in an OIT trial is demanding – it requires office visits for dosing adjustments and blood tests, rest periods, keeping symptom logs in which daily doses are recorded, and possible allergic reactions from the treatment itself. “A common reason for ‘withdrawal of consent’ in clinical studies is the inconvenience of remaining in a long-term study,” Mohamed Yassine, MD, Aimmune’s senior vice present of medical affairs, said via email.

Attrition was concentrated within certain subgroups. Most participants in (88.7%; 102 of 115) PALISADE who received placebo elected to enter the open-label extension; nearly half did not finish. Dropout rates were also high (29.2%) for non-daily dosing participants who had come from the PALISADE treatment arm.

The authors did not report on those high-dropout groups. Instead, they focused their analysis on the 142 treated PALISADE participants who continued daily dosing through the extension – 110 patients for a total of about 1.5 years and 32 patients for about 2 years. In a subgroup analysis, 48.1% of children in the 1.5-year group upped their tolerance to 2,000 mg peanut protein, and even more (80.8%) in the 2-year group reached that threshold – all while taking a 300-mg maintenance dose.

Those who remained on treatment longer also had fewer adverse events. At the exit food challenge, 24% of the 1.5-year participants had reactions that required epinephrine, but among 2-year participants, only 3.8% needed the rescue medication.

Continuing therapy past the first year seemed to have additional benefits, Sandra Hong, MD, director of the Cleveland Clinic Food Allergy Center of Excellence, said in an interview. Dr. Hong was not involved in the new research and has no financial ties with Aimmune or other food allergy companies. “Not only can you ingest more, but your reaction when you do react is going to be less,” she says.

Palforzia is only available through a risk evaluation and mitigation strategy (REMS) program, which educates patients, health care professionals, and pharmacies about immunotherapy risks and precautionary measures. As of last summer, before Aimmune was acquired by Nestlé Health Science, about 100 allergists in the United States had enrolled patients in the REMS program. Families can find allergists who are certified to prescribe Palforzia using the website’s Certified Participant Locator.

Although the field at large remains apprehensive about OIT and other forms of immunotherapy, an estimated 200 or more U.S. clinics are administering home-grown OIT using commercial food products, says Richard Wasserman, an OIT pioneer whose clinic in Dallas has treated allergies to about 20 foods since the practice started offering the therapy in 2008. OIT practitioners have treated more than 15,000 food allergy patients nationwide, Dr. Wasserman said via email, yet they make up just a tiny fraction of the more than 6,000 board-certified allergists in the United States.

Whether using Palforzia or nonproprietary food products, oral immunotherapy requires a lot of time and effort – not just for patients but also practitioners. “You need more space. You need more staffing. Patients doing oral challenges stay in your office for 4 to 5 hours, and we have one-to-one nursing care for them,” said Dr. Hong. “So it’s a lot of resources.”

Her team has treated about 20 children with Palforzia since the Cleveland Clinic began offering the therapy last summer. Dr. Hong and coworkers have administered OIT using commercial peanut flour and peanut butter to some 80 peanut-allergic toddlers younger than 4 years who are too young to receive for the U.S. Food and Drug Administration–approved treatment. Their early data, which were presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in February, suggest that toddlers get complete OIT more quickly with fewer side effects than older children, Dr. Hong says. A recent study of preschoolers in Canada also found that nonproprietary OIT is very safe and effective in this younger set and could be cost-saving in the long run.

By comparison, Palforzia, which has a list price of $890 per month, was judged to be less cost-effective in analyses by academic allergists and by the Institute for Clinical and Economic Review. But through a copay savings program, depending on their insurance coverage, some eligible families can pay as little as $20 per month for the FDA-approved treatment.

Because the therapy is time consuming for families and is resource intensive for practices, questions remain as to how long and how frequently patients need to remain on treatment to sustain protection. Do they need to keep taking Palforzia, or “can we switch them to an equivalent amount of food and not bother with the study drug?” said Edwin Kim, director of the UNC Food Allergy Initiative, Chapel Hill, North Carolina, and study investigator for several Palforzia trials, in an interview.

The Food Allergy Support Team, a nonprofit group started by Dr. Wasserman and colleagues, publishes best practices and meets annually to discuss research and protocols. However, the best maintenance dose, the best dosing frequency, and the duration of daily dosing that yields the best outcomes are not known, Dr. Wasserman says.

“We think the best way to answer that question is with a regulated, pharmaceutical-grade form of peanut protein,” Dr. Yassine said.

The field’s experience with Palforzia raises a dilemma: Does its approval legitimize oral immunotherapy in general, or will rigorous, multi-million dollar trials be needed to approve products for each food or combination of foods? About 32 million people in the United States have food allergies – about 1 in 10 adults and 1 in 13 children.

“I think the field has always grappled with that, honestly,” said Stacie Jones, MD, professor of pediatrics and chief of allergy and immunology at the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, in an interview. Home-grown OIT is “easier to do when you have high control of your small patient volumes or you’re in a clinical trial,” said Dr. Jones, who has served as an investigator on Palforzia trials and last year received more than $30,000 in consulting fees from Aimmune. “It becomes a very different situation when it becomes a national or an international recommended therapy.”

The Canadian Society of Allergy and Clinical Immunology has published clinical practice guidelines and provides practical information on its website on how to implement OIT – including protocols for dozens of foods and diary sheets for patients to log doses and symptoms.

However, U.S. professional societies still consider OIT investigational and suggest that it will not be approved by the FDA. “As a field, are we willing to wait 4 to 5 more years for an egg product? Should we? Are we willing?” said Dr. Kim. “These are tough questions.”

Stacie M. Jones reports advisory board fees, Aimmune Therapeutics, FARE; personal fees, DBV Technologies; clinical trials grants, Aimmune Therapeutics, DBV Technologies, Astellas, Sanofi, Regeneron, FARE, Genentech, and NIH-NIAID. Edwin 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; 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. Richard Wasserman receives consulting fees from Aimmune Therapeutics and DBV Technologies. Mohamed Yassine is employed by Aimmune Therapeutics. Sandra Hong has disclosed no relevant financial relationships.

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

A recent analysis of 142 peanut-allergic children treated for 1.5 to 2 years with a licensed oral immunotherapy (OIT) product confirms what various smaller studies have shown: Maintaining treatment for longer periods improves protection and reduces adverse effects. The findings offer some reassurance regarding the controversial approach, which has become available at a small number of clinics yet faces an uncertain future.

The new study, published July 28 in Allergy, included a subset of patients who chose to complete an extension of the phase 3 PALISADE trial of Palforzia, a proprietary set of premeasured peanut flour capsules developed by Aimmune Therapeutics.

Palforzia was approved last year for children aged 4 to 17 years with peanut allergy – one of the most common food allergies, affecting around 2% of children in the United States and Europe. The treatment is not a cure – patients must still watch what they eat and carry epinephrine for emergency reactions – but it helps build protection through daily ingestion of gradually increasing amounts of the allergen over a period of months.

In the 1-year PALISADE trial, which enrolled 496 peanut-allergic children at 66 sites in North America and Europe, participants received daily doses of study drug or placebo. The dose of the drug was escalated from 3 mg to 300 mg over 6 months; the 300-mg dose was then maintained for another 6 months. By the end of the study, about two-thirds of the children who underwent treatment could safely consume at least 600 mg of peanut protein, about the equivalent of two peanuts.

Could protection be increased with further treatment, and what would be required to sustain it? To address these questions, PALISADE patients who successfully reached the 600-mg threshold, along with those from the placebo group, were invited to participate in Aimmune’s open-label follow-on study. The extension study also explored whether protection could be maintained with less frequent dosing.

Among the 358 eligible participants who opted into the 1-year extension study, 256 came from the PALISADE treatment arm. These children were assigned to five cohorts to continue for 6 months or 12 months with daily or less frequent doses. Within the 6-month group, all started with the 300-mg daily dose. A subset received two doses a week. Within the 12-month group, some patients maintained daily dosing throughout; others received doses every other day, twice weekly, or once every 2 weeks.

The children who continued daily maintenance dosing the longest gained the most protection. Those in less-frequent dosing groups experienced more adverse events than those who received doses every day, the company reported last December in The Journal of Allergy and Clinical Immunology: In Practice.

More than a quarter (97 of 358, or 27.1%) of participants failed to complete the extension. Families could withdraw any time for any reason. Participating in an OIT trial is demanding – it requires office visits for dosing adjustments and blood tests, rest periods, keeping symptom logs in which daily doses are recorded, and possible allergic reactions from the treatment itself. “A common reason for ‘withdrawal of consent’ in clinical studies is the inconvenience of remaining in a long-term study,” Mohamed Yassine, MD, Aimmune’s senior vice present of medical affairs, said via email.

Attrition was concentrated within certain subgroups. Most participants in (88.7%; 102 of 115) PALISADE who received placebo elected to enter the open-label extension; nearly half did not finish. Dropout rates were also high (29.2%) for non-daily dosing participants who had come from the PALISADE treatment arm.

The authors did not report on those high-dropout groups. Instead, they focused their analysis on the 142 treated PALISADE participants who continued daily dosing through the extension – 110 patients for a total of about 1.5 years and 32 patients for about 2 years. In a subgroup analysis, 48.1% of children in the 1.5-year group upped their tolerance to 2,000 mg peanut protein, and even more (80.8%) in the 2-year group reached that threshold – all while taking a 300-mg maintenance dose.

Those who remained on treatment longer also had fewer adverse events. At the exit food challenge, 24% of the 1.5-year participants had reactions that required epinephrine, but among 2-year participants, only 3.8% needed the rescue medication.

Continuing therapy past the first year seemed to have additional benefits, Sandra Hong, MD, director of the Cleveland Clinic Food Allergy Center of Excellence, said in an interview. Dr. Hong was not involved in the new research and has no financial ties with Aimmune or other food allergy companies. “Not only can you ingest more, but your reaction when you do react is going to be less,” she says.

Palforzia is only available through a risk evaluation and mitigation strategy (REMS) program, which educates patients, health care professionals, and pharmacies about immunotherapy risks and precautionary measures. As of last summer, before Aimmune was acquired by Nestlé Health Science, about 100 allergists in the United States had enrolled patients in the REMS program. Families can find allergists who are certified to prescribe Palforzia using the website’s Certified Participant Locator.

Although the field at large remains apprehensive about OIT and other forms of immunotherapy, an estimated 200 or more U.S. clinics are administering home-grown OIT using commercial food products, says Richard Wasserman, an OIT pioneer whose clinic in Dallas has treated allergies to about 20 foods since the practice started offering the therapy in 2008. OIT practitioners have treated more than 15,000 food allergy patients nationwide, Dr. Wasserman said via email, yet they make up just a tiny fraction of the more than 6,000 board-certified allergists in the United States.

Whether using Palforzia or nonproprietary food products, oral immunotherapy requires a lot of time and effort – not just for patients but also practitioners. “You need more space. You need more staffing. Patients doing oral challenges stay in your office for 4 to 5 hours, and we have one-to-one nursing care for them,” said Dr. Hong. “So it’s a lot of resources.”

Her team has treated about 20 children with Palforzia since the Cleveland Clinic began offering the therapy last summer. Dr. Hong and coworkers have administered OIT using commercial peanut flour and peanut butter to some 80 peanut-allergic toddlers younger than 4 years who are too young to receive for the U.S. Food and Drug Administration–approved treatment. Their early data, which were presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in February, suggest that toddlers get complete OIT more quickly with fewer side effects than older children, Dr. Hong says. A recent study of preschoolers in Canada also found that nonproprietary OIT is very safe and effective in this younger set and could be cost-saving in the long run.

By comparison, Palforzia, which has a list price of $890 per month, was judged to be less cost-effective in analyses by academic allergists and by the Institute for Clinical and Economic Review. But through a copay savings program, depending on their insurance coverage, some eligible families can pay as little as $20 per month for the FDA-approved treatment.

Because the therapy is time consuming for families and is resource intensive for practices, questions remain as to how long and how frequently patients need to remain on treatment to sustain protection. Do they need to keep taking Palforzia, or “can we switch them to an equivalent amount of food and not bother with the study drug?” said Edwin Kim, director of the UNC Food Allergy Initiative, Chapel Hill, North Carolina, and study investigator for several Palforzia trials, in an interview.

The Food Allergy Support Team, a nonprofit group started by Dr. Wasserman and colleagues, publishes best practices and meets annually to discuss research and protocols. However, the best maintenance dose, the best dosing frequency, and the duration of daily dosing that yields the best outcomes are not known, Dr. Wasserman says.

“We think the best way to answer that question is with a regulated, pharmaceutical-grade form of peanut protein,” Dr. Yassine said.

The field’s experience with Palforzia raises a dilemma: Does its approval legitimize oral immunotherapy in general, or will rigorous, multi-million dollar trials be needed to approve products for each food or combination of foods? About 32 million people in the United States have food allergies – about 1 in 10 adults and 1 in 13 children.

“I think the field has always grappled with that, honestly,” said Stacie Jones, MD, professor of pediatrics and chief of allergy and immunology at the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, in an interview. Home-grown OIT is “easier to do when you have high control of your small patient volumes or you’re in a clinical trial,” said Dr. Jones, who has served as an investigator on Palforzia trials and last year received more than $30,000 in consulting fees from Aimmune. “It becomes a very different situation when it becomes a national or an international recommended therapy.”

The Canadian Society of Allergy and Clinical Immunology has published clinical practice guidelines and provides practical information on its website on how to implement OIT – including protocols for dozens of foods and diary sheets for patients to log doses and symptoms.

However, U.S. professional societies still consider OIT investigational and suggest that it will not be approved by the FDA. “As a field, are we willing to wait 4 to 5 more years for an egg product? Should we? Are we willing?” said Dr. Kim. “These are tough questions.”

Stacie M. Jones reports advisory board fees, Aimmune Therapeutics, FARE; personal fees, DBV Technologies; clinical trials grants, Aimmune Therapeutics, DBV Technologies, Astellas, Sanofi, Regeneron, FARE, Genentech, and NIH-NIAID. Edwin 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; 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. Richard Wasserman receives consulting fees from Aimmune Therapeutics and DBV Technologies. Mohamed Yassine is employed by Aimmune Therapeutics. Sandra Hong has disclosed no relevant financial relationships.

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

A recent analysis of 142 peanut-allergic children treated for 1.5 to 2 years with a licensed oral immunotherapy (OIT) product confirms what various smaller studies have shown: Maintaining treatment for longer periods improves protection and reduces adverse effects. The findings offer some reassurance regarding the controversial approach, which has become available at a small number of clinics yet faces an uncertain future.

The new study, published July 28 in Allergy, included a subset of patients who chose to complete an extension of the phase 3 PALISADE trial of Palforzia, a proprietary set of premeasured peanut flour capsules developed by Aimmune Therapeutics.

Palforzia was approved last year for children aged 4 to 17 years with peanut allergy – one of the most common food allergies, affecting around 2% of children in the United States and Europe. The treatment is not a cure – patients must still watch what they eat and carry epinephrine for emergency reactions – but it helps build protection through daily ingestion of gradually increasing amounts of the allergen over a period of months.

In the 1-year PALISADE trial, which enrolled 496 peanut-allergic children at 66 sites in North America and Europe, participants received daily doses of study drug or placebo. The dose of the drug was escalated from 3 mg to 300 mg over 6 months; the 300-mg dose was then maintained for another 6 months. By the end of the study, about two-thirds of the children who underwent treatment could safely consume at least 600 mg of peanut protein, about the equivalent of two peanuts.

Could protection be increased with further treatment, and what would be required to sustain it? To address these questions, PALISADE patients who successfully reached the 600-mg threshold, along with those from the placebo group, were invited to participate in Aimmune’s open-label follow-on study. The extension study also explored whether protection could be maintained with less frequent dosing.

Among the 358 eligible participants who opted into the 1-year extension study, 256 came from the PALISADE treatment arm. These children were assigned to five cohorts to continue for 6 months or 12 months with daily or less frequent doses. Within the 6-month group, all started with the 300-mg daily dose. A subset received two doses a week. Within the 12-month group, some patients maintained daily dosing throughout; others received doses every other day, twice weekly, or once every 2 weeks.

The children who continued daily maintenance dosing the longest gained the most protection. Those in less-frequent dosing groups experienced more adverse events than those who received doses every day, the company reported last December in The Journal of Allergy and Clinical Immunology: In Practice.

More than a quarter (97 of 358, or 27.1%) of participants failed to complete the extension. Families could withdraw any time for any reason. Participating in an OIT trial is demanding – it requires office visits for dosing adjustments and blood tests, rest periods, keeping symptom logs in which daily doses are recorded, and possible allergic reactions from the treatment itself. “A common reason for ‘withdrawal of consent’ in clinical studies is the inconvenience of remaining in a long-term study,” Mohamed Yassine, MD, Aimmune’s senior vice present of medical affairs, said via email.

Attrition was concentrated within certain subgroups. Most participants in (88.7%; 102 of 115) PALISADE who received placebo elected to enter the open-label extension; nearly half did not finish. Dropout rates were also high (29.2%) for non-daily dosing participants who had come from the PALISADE treatment arm.

The authors did not report on those high-dropout groups. Instead, they focused their analysis on the 142 treated PALISADE participants who continued daily dosing through the extension – 110 patients for a total of about 1.5 years and 32 patients for about 2 years. In a subgroup analysis, 48.1% of children in the 1.5-year group upped their tolerance to 2,000 mg peanut protein, and even more (80.8%) in the 2-year group reached that threshold – all while taking a 300-mg maintenance dose.

Those who remained on treatment longer also had fewer adverse events. At the exit food challenge, 24% of the 1.5-year participants had reactions that required epinephrine, but among 2-year participants, only 3.8% needed the rescue medication.

Continuing therapy past the first year seemed to have additional benefits, Sandra Hong, MD, director of the Cleveland Clinic Food Allergy Center of Excellence, said in an interview. Dr. Hong was not involved in the new research and has no financial ties with Aimmune or other food allergy companies. “Not only can you ingest more, but your reaction when you do react is going to be less,” she says.

Palforzia is only available through a risk evaluation and mitigation strategy (REMS) program, which educates patients, health care professionals, and pharmacies about immunotherapy risks and precautionary measures. As of last summer, before Aimmune was acquired by Nestlé Health Science, about 100 allergists in the United States had enrolled patients in the REMS program. Families can find allergists who are certified to prescribe Palforzia using the website’s Certified Participant Locator.

Although the field at large remains apprehensive about OIT and other forms of immunotherapy, an estimated 200 or more U.S. clinics are administering home-grown OIT using commercial food products, says Richard Wasserman, an OIT pioneer whose clinic in Dallas has treated allergies to about 20 foods since the practice started offering the therapy in 2008. OIT practitioners have treated more than 15,000 food allergy patients nationwide, Dr. Wasserman said via email, yet they make up just a tiny fraction of the more than 6,000 board-certified allergists in the United States.

Whether using Palforzia or nonproprietary food products, oral immunotherapy requires a lot of time and effort – not just for patients but also practitioners. “You need more space. You need more staffing. Patients doing oral challenges stay in your office for 4 to 5 hours, and we have one-to-one nursing care for them,” said Dr. Hong. “So it’s a lot of resources.”

Her team has treated about 20 children with Palforzia since the Cleveland Clinic began offering the therapy last summer. Dr. Hong and coworkers have administered OIT using commercial peanut flour and peanut butter to some 80 peanut-allergic toddlers younger than 4 years who are too young to receive for the U.S. Food and Drug Administration–approved treatment. Their early data, which were presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in February, suggest that toddlers get complete OIT more quickly with fewer side effects than older children, Dr. Hong says. A recent study of preschoolers in Canada also found that nonproprietary OIT is very safe and effective in this younger set and could be cost-saving in the long run.

By comparison, Palforzia, which has a list price of $890 per month, was judged to be less cost-effective in analyses by academic allergists and by the Institute for Clinical and Economic Review. But through a copay savings program, depending on their insurance coverage, some eligible families can pay as little as $20 per month for the FDA-approved treatment.

Because the therapy is time consuming for families and is resource intensive for practices, questions remain as to how long and how frequently patients need to remain on treatment to sustain protection. Do they need to keep taking Palforzia, or “can we switch them to an equivalent amount of food and not bother with the study drug?” said Edwin Kim, director of the UNC Food Allergy Initiative, Chapel Hill, North Carolina, and study investigator for several Palforzia trials, in an interview.

The Food Allergy Support Team, a nonprofit group started by Dr. Wasserman and colleagues, publishes best practices and meets annually to discuss research and protocols. However, the best maintenance dose, the best dosing frequency, and the duration of daily dosing that yields the best outcomes are not known, Dr. Wasserman says.

“We think the best way to answer that question is with a regulated, pharmaceutical-grade form of peanut protein,” Dr. Yassine said.

The field’s experience with Palforzia raises a dilemma: Does its approval legitimize oral immunotherapy in general, or will rigorous, multi-million dollar trials be needed to approve products for each food or combination of foods? About 32 million people in the United States have food allergies – about 1 in 10 adults and 1 in 13 children.

“I think the field has always grappled with that, honestly,” said Stacie Jones, MD, professor of pediatrics and chief of allergy and immunology at the University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, in an interview. Home-grown OIT is “easier to do when you have high control of your small patient volumes or you’re in a clinical trial,” said Dr. Jones, who has served as an investigator on Palforzia trials and last year received more than $30,000 in consulting fees from Aimmune. “It becomes a very different situation when it becomes a national or an international recommended therapy.”

The Canadian Society of Allergy and Clinical Immunology has published clinical practice guidelines and provides practical information on its website on how to implement OIT – including protocols for dozens of foods and diary sheets for patients to log doses and symptoms.

However, U.S. professional societies still consider OIT investigational and suggest that it will not be approved by the FDA. “As a field, are we willing to wait 4 to 5 more years for an egg product? Should we? Are we willing?” said Dr. Kim. “These are tough questions.”

Stacie M. Jones reports advisory board fees, Aimmune Therapeutics, FARE; personal fees, DBV Technologies; clinical trials grants, Aimmune Therapeutics, DBV Technologies, Astellas, Sanofi, Regeneron, FARE, Genentech, and NIH-NIAID. Edwin 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; 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. Richard Wasserman receives consulting fees from Aimmune Therapeutics and DBV Technologies. Mohamed Yassine is employed by Aimmune Therapeutics. Sandra Hong has disclosed no relevant financial relationships.

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

Exposure to secondhand marijuana smoke is more strongly associated with viral respiratory infections in children, compared with children who were exposed to tobacco smoke and those with no smoke exposure, new research shows.

“The findings of this study are interesting and pleasantly raise further questions,” said Kristen Miller, MD, attending physician in the division of pulmonary and sleep medicine at Children’s Hospital of Philadelphia, who was not involved in the study. “Given the robust literature regarding secondhand smoke exposure and the current landscape surrounding marijuana, this is a timely study to evaluate the prevalence of marijuana use and the associated effects of marijuana exposure among children.”

Prior research has linked primary marijuana use with respiratory effects. A 2020 study associated cannabis use with an increased risk of severe bronchitis, lung hyperinflation, and increased central airway resistance. However, according to the Centers for Disease Control and Prevention, there are still a lot of unanswered questions surrounding secondhand marijuana smoke exposure and its effects.

“If kids are exposed to enough secondhand smoke, regardless of what the substance is, they’re going to have some negative health outcomes with it,” study author Adam Johnson, MD, of Wake Forest University, Winston-Salem, N.C., said in an interview.

The study, published in Pediatric Research, looked at rates of reported ED and urgent care visits and specific illnesses – such as otitis media, viral respiratory infections, and asthma exacerbations – among children with marijuana exposure and tobacco exposure.

For the study, Dr. Johnson and colleagues surveyed 1,500 parents and caregivers who went to an academic children’s hospital between Dec. 1, 2015, and July 30, 2017. Researchers found that children exposed to marijuana smoke had higher rates of ED visits at 2.21 within the past 12 months, compared with those exposed to tobacco smoke (2.14 within the past 12 months) and those with no smoke exposure (1.94 within the past 12 months). However, the difference in these visits were not statistically significant.

Researchers saw that children exposed to secondhand marijuana smoke saw a 30% increase in viral respiratory infections, compared with those who were not exposed to tobacco or marijuana smoke, Dr. Johnson said. Caregivers who smoked marijuana reported a rate of 1.31 viral infections in their children within the last year. Meanwhile those who smoked tobacco reported a rate of 1.00 infections within the last 12 months and caregivers who did not smoke reported 1.04 infections within the year.

“It suggests that components in marijuana smoke may depress the body’s immune responses to viral infections in children,” Dr. Miller said in an interview.

When it came to otitis media episodes, children exposed to marijuana had a rate of 0.96 episodes within the past 12 months. Children experiencing secondhand tobacco smoke had a rate of 0.83 episodes and those with no smoke exposure had 0.75 episodes within the past 12 months. Researchers did not note this difference as statistically significant.

When it came to asthma exacerbations, children exposed to marijuana smoke also had statistically insignificantly higher rates of exacerbations, compared with those exposed to tobacco smoke and those not exposed to smoke.

“I think it was surprising that the survey results found that marijuana seemed to be more strongly associated with the viral respiratory infections than tobacco,” Dr. Johnson said. “We know that secondhand tobacco smoke exposure in kids does lead to things like otitis media or ear infections, asthma attacks, and other processes, including colds. It was interesting that we didn’t find that association [in the new study], but we found that with marijuana.”

Dr. Johnson said the findings are especially concerning with increases in the acceptance and accessibility of marijuana as it becomes legalized in many states.

A 2015 study examined the effect of secondhand marijuana smoke exposure. Researchers found that exposure to secondhand marijuana smoke can increase heart rate, have mild to moderate sedative effects and can produce detectable cannabinoid levels in blood and urine. However, another study published in 2012 found that low to moderate primary marijuana use is less harmful to users’ lungs than tobacco exposure.

Dr. Miller added that little is known about how exposure to marijuana smoke can affect the innate responses to pathogens and there is a need to “study this in more detail” to figure out if secondhand marijuana smoke is a risk factor for either an increase in respiratory virus infections or their severity.

“These questions could have considerable implications for the health of our children and public health measures regarding marijuana use,” she explained. “As documented marijuana use increases, health care providers need to be aware of the effects of marijuana use and exposure.”

Neither Dr. Johnson nor Dr. Miller has any relevant financial disclosures.

Exposure to secondhand marijuana smoke is more strongly associated with viral respiratory infections in children, compared with children who were exposed to tobacco smoke and those with no smoke exposure, new research shows.

“The findings of this study are interesting and pleasantly raise further questions,” said Kristen Miller, MD, attending physician in the division of pulmonary and sleep medicine at Children’s Hospital of Philadelphia, who was not involved in the study. “Given the robust literature regarding secondhand smoke exposure and the current landscape surrounding marijuana, this is a timely study to evaluate the prevalence of marijuana use and the associated effects of marijuana exposure among children.”

Prior research has linked primary marijuana use with respiratory effects. A 2020 study associated cannabis use with an increased risk of severe bronchitis, lung hyperinflation, and increased central airway resistance. However, according to the Centers for Disease Control and Prevention, there are still a lot of unanswered questions surrounding secondhand marijuana smoke exposure and its effects.

“If kids are exposed to enough secondhand smoke, regardless of what the substance is, they’re going to have some negative health outcomes with it,” study author Adam Johnson, MD, of Wake Forest University, Winston-Salem, N.C., said in an interview.

The study, published in Pediatric Research, looked at rates of reported ED and urgent care visits and specific illnesses – such as otitis media, viral respiratory infections, and asthma exacerbations – among children with marijuana exposure and tobacco exposure.

For the study, Dr. Johnson and colleagues surveyed 1,500 parents and caregivers who went to an academic children’s hospital between Dec. 1, 2015, and July 30, 2017. Researchers found that children exposed to marijuana smoke had higher rates of ED visits at 2.21 within the past 12 months, compared with those exposed to tobacco smoke (2.14 within the past 12 months) and those with no smoke exposure (1.94 within the past 12 months). However, the difference in these visits were not statistically significant.

Researchers saw that children exposed to secondhand marijuana smoke saw a 30% increase in viral respiratory infections, compared with those who were not exposed to tobacco or marijuana smoke, Dr. Johnson said. Caregivers who smoked marijuana reported a rate of 1.31 viral infections in their children within the last year. Meanwhile those who smoked tobacco reported a rate of 1.00 infections within the last 12 months and caregivers who did not smoke reported 1.04 infections within the year.

“It suggests that components in marijuana smoke may depress the body’s immune responses to viral infections in children,” Dr. Miller said in an interview.

When it came to otitis media episodes, children exposed to marijuana had a rate of 0.96 episodes within the past 12 months. Children experiencing secondhand tobacco smoke had a rate of 0.83 episodes and those with no smoke exposure had 0.75 episodes within the past 12 months. Researchers did not note this difference as statistically significant.

When it came to asthma exacerbations, children exposed to marijuana smoke also had statistically insignificantly higher rates of exacerbations, compared with those exposed to tobacco smoke and those not exposed to smoke.

“I think it was surprising that the survey results found that marijuana seemed to be more strongly associated with the viral respiratory infections than tobacco,” Dr. Johnson said. “We know that secondhand tobacco smoke exposure in kids does lead to things like otitis media or ear infections, asthma attacks, and other processes, including colds. It was interesting that we didn’t find that association [in the new study], but we found that with marijuana.”

Dr. Johnson said the findings are especially concerning with increases in the acceptance and accessibility of marijuana as it becomes legalized in many states.

A 2015 study examined the effect of secondhand marijuana smoke exposure. Researchers found that exposure to secondhand marijuana smoke can increase heart rate, have mild to moderate sedative effects and can produce detectable cannabinoid levels in blood and urine. However, another study published in 2012 found that low to moderate primary marijuana use is less harmful to users’ lungs than tobacco exposure.

Dr. Miller added that little is known about how exposure to marijuana smoke can affect the innate responses to pathogens and there is a need to “study this in more detail” to figure out if secondhand marijuana smoke is a risk factor for either an increase in respiratory virus infections or their severity.

“These questions could have considerable implications for the health of our children and public health measures regarding marijuana use,” she explained. “As documented marijuana use increases, health care providers need to be aware of the effects of marijuana use and exposure.”

Neither Dr. Johnson nor Dr. Miller has any relevant financial disclosures.

Exposure to secondhand marijuana smoke is more strongly associated with viral respiratory infections in children, compared with children who were exposed to tobacco smoke and those with no smoke exposure, new research shows.

“The findings of this study are interesting and pleasantly raise further questions,” said Kristen Miller, MD, attending physician in the division of pulmonary and sleep medicine at Children’s Hospital of Philadelphia, who was not involved in the study. “Given the robust literature regarding secondhand smoke exposure and the current landscape surrounding marijuana, this is a timely study to evaluate the prevalence of marijuana use and the associated effects of marijuana exposure among children.”

Prior research has linked primary marijuana use with respiratory effects. A 2020 study associated cannabis use with an increased risk of severe bronchitis, lung hyperinflation, and increased central airway resistance. However, according to the Centers for Disease Control and Prevention, there are still a lot of unanswered questions surrounding secondhand marijuana smoke exposure and its effects.

“If kids are exposed to enough secondhand smoke, regardless of what the substance is, they’re going to have some negative health outcomes with it,” study author Adam Johnson, MD, of Wake Forest University, Winston-Salem, N.C., said in an interview.

The study, published in Pediatric Research, looked at rates of reported ED and urgent care visits and specific illnesses – such as otitis media, viral respiratory infections, and asthma exacerbations – among children with marijuana exposure and tobacco exposure.

For the study, Dr. Johnson and colleagues surveyed 1,500 parents and caregivers who went to an academic children’s hospital between Dec. 1, 2015, and July 30, 2017. Researchers found that children exposed to marijuana smoke had higher rates of ED visits at 2.21 within the past 12 months, compared with those exposed to tobacco smoke (2.14 within the past 12 months) and those with no smoke exposure (1.94 within the past 12 months). However, the difference in these visits were not statistically significant.

Researchers saw that children exposed to secondhand marijuana smoke saw a 30% increase in viral respiratory infections, compared with those who were not exposed to tobacco or marijuana smoke, Dr. Johnson said. Caregivers who smoked marijuana reported a rate of 1.31 viral infections in their children within the last year. Meanwhile those who smoked tobacco reported a rate of 1.00 infections within the last 12 months and caregivers who did not smoke reported 1.04 infections within the year.

“It suggests that components in marijuana smoke may depress the body’s immune responses to viral infections in children,” Dr. Miller said in an interview.

When it came to otitis media episodes, children exposed to marijuana had a rate of 0.96 episodes within the past 12 months. Children experiencing secondhand tobacco smoke had a rate of 0.83 episodes and those with no smoke exposure had 0.75 episodes within the past 12 months. Researchers did not note this difference as statistically significant.

When it came to asthma exacerbations, children exposed to marijuana smoke also had statistically insignificantly higher rates of exacerbations, compared with those exposed to tobacco smoke and those not exposed to smoke.

“I think it was surprising that the survey results found that marijuana seemed to be more strongly associated with the viral respiratory infections than tobacco,” Dr. Johnson said. “We know that secondhand tobacco smoke exposure in kids does lead to things like otitis media or ear infections, asthma attacks, and other processes, including colds. It was interesting that we didn’t find that association [in the new study], but we found that with marijuana.”

Dr. Johnson said the findings are especially concerning with increases in the acceptance and accessibility of marijuana as it becomes legalized in many states.

A 2015 study examined the effect of secondhand marijuana smoke exposure. Researchers found that exposure to secondhand marijuana smoke can increase heart rate, have mild to moderate sedative effects and can produce detectable cannabinoid levels in blood and urine. However, another study published in 2012 found that low to moderate primary marijuana use is less harmful to users’ lungs than tobacco exposure.

Dr. Miller added that little is known about how exposure to marijuana smoke can affect the innate responses to pathogens and there is a need to “study this in more detail” to figure out if secondhand marijuana smoke is a risk factor for either an increase in respiratory virus infections or their severity.

“These questions could have considerable implications for the health of our children and public health measures regarding marijuana use,” she explained. “As documented marijuana use increases, health care providers need to be aware of the effects of marijuana use and exposure.”

Neither Dr. Johnson nor Dr. Miller has any relevant financial disclosures.

After SARS-CoV-2 spread at a sleepaway camp in Georgia last summer, researchers described the efficient spread and high attack rates at camp.

In a report published online in The New England Journal of Medicine, researchers found that campers spread COVID to household members after returning home – but transmission was more likely from some than others. Distancing and masking helped reduce the risk.

Victoria T. Chu, MD, MPH, with the Centers for Disease Control and Prevention, Atlanta, and colleagues with the agency and the Georgia Department of Health followed up with 224 camp attendees, aged 7 to 19 years, who had evidence of SARS-CoV-2 infection on laboratory testing.

These index patients – 88% of whom had symptoms – had 526 household contacts, mainly parents and siblings. Of 377 household contacts who underwent testing, 46 (12%) tested positive. Another two cases in household contacts were identified using clinical and epidemiologic criteria.
 

Family members hospitalized

Of the 41 adult household contacts who were infected, four (about 10%) were hospitalized. Their hospital stays ranged from 5 to 11 days. Of the seven infected household contacts who were younger than 18 years, none were hospitalized.

The four hospitalized adults were parents and grandparents aged 45 to 80 years, Dr. Chu said. Two of the four had underlying conditions. None of the household contacts died.

In an adjusted analysis, campers who had practiced physical distancing were less likely to transmit the virus at home, compared with those who had not practiced physical distancing (adjusted odds ratio, 0.4). Household members who had had close or direct contact with the index patients were more than 5 times more likely to become infected, compared with family members with minimal or no contact, analyses showed.

“This retrospective study showed that the efficient transmission of SARS-CoV-2 from school-age children and adolescents to household members led to the hospitalization of adults with secondary cases of COVID-19,” the researchers write. “In households in which transmission occurred, half the household contacts were infected.”

The secondary attack rates in this report may be an underestimate because testing was voluntary and participants reported the results themselves, the authors note. It is possible that infected household contacts spread the virus further, but this study did not address that question, Dr. Chu said.

For the study, investigators interviewed all camp attendees and their parents or guardians by phone between July 17, 2020 and Aug. 24, 2020, to collect information about demographic and clinical characteristics, SARS-CoV-2 testing, and preventive measures. The researchers’ analysis excluded households in which illness onset in a household contact occurred before or less than 2 days after a camper became sick.

About a third of the index patients began to have symptoms while still at camp. These campers may have been less infectious by the time they got home, compared with those whose symptoms started after they returned.

Two-thirds of the index patients adopted physical distancing at home, which “probably reduced the transmission of SARS-CoV-2 in the household,” Dr. Chu and colleagues wrote.

“Children who have had a known COVID-19 exposure should quarantine and obtain testing if they develop symptoms within the 14 days of returning home,” Dr. Chu advised. “If a child develops COVID-19, the child should be cared for and monitored using the proper combination of physical distancing, isolation when feasible, and mask use to prevent household transmission as much as possible. In addition, any person over the age of 12 is now eligible for vaccination in the United States. If eligible, children attending camp and their family members should get vaccinated to protect themselves and others, as vaccinations are our most effective public health prevention strategy.”
 

Mitigation can help

Another report regarding four overnight camps in Maine – in which three campers tested positive after they arrived last summer – shows that “aggressive mitigation strategies can be effective” in limiting transmission of the virus, William T. Basco Jr., MD, writes in a commentary for this news organization.

This summer, a range of factors, including vaccination rates at the camp, may influence transmission dynamics, Dr. Chu said in an interview. In July, the Associated Press reported outbreaks tied to summer camps in several states.

“Transmission dynamics will probably vary from summer camp to summer camp depending on many factors, such as vaccination rates of camp attendees, the mitigation measures in place, and the number of individual introductions during camp,” Dr. Chu said. “We would expect that a camp with a low vaccination rate among attendees and no enforcement of mitigation measures” still may experience a large outbreak.

“On the other hand, a large proportion of vaccinated individuals and appropriate implementation of multiple mitigation measures, such as wearing masks, may be quite effective at keeping their transmission rates low,” Dr. Chu added. “For camps with younger children who are not currently eligible for vaccination, implementing layered prevention strategies (e.g., mask use, physical distancing, and encouraging outdoor activities when feasible) is important to prevent transmission.”

Although COVID-19 transmission from children to adults, potentially leading to hospitalization, is not a new phenomenon, “data on the extent of transmission driven by children and adolescents in different settings are still quite sparse,” Dr. Chu said. “A better understanding of their impact on household and community transmission to help guide public health recommendations is particularly important, as most children are still not eligible for vaccination, and in-person schools will be reopening this fall.”

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

After SARS-CoV-2 spread at a sleepaway camp in Georgia last summer, researchers described the efficient spread and high attack rates at camp.

In a report published online in The New England Journal of Medicine, researchers found that campers spread COVID to household members after returning home – but transmission was more likely from some than others. Distancing and masking helped reduce the risk.

Victoria T. Chu, MD, MPH, with the Centers for Disease Control and Prevention, Atlanta, and colleagues with the agency and the Georgia Department of Health followed up with 224 camp attendees, aged 7 to 19 years, who had evidence of SARS-CoV-2 infection on laboratory testing.

These index patients – 88% of whom had symptoms – had 526 household contacts, mainly parents and siblings. Of 377 household contacts who underwent testing, 46 (12%) tested positive. Another two cases in household contacts were identified using clinical and epidemiologic criteria.
 

Family members hospitalized

Of the 41 adult household contacts who were infected, four (about 10%) were hospitalized. Their hospital stays ranged from 5 to 11 days. Of the seven infected household contacts who were younger than 18 years, none were hospitalized.

The four hospitalized adults were parents and grandparents aged 45 to 80 years, Dr. Chu said. Two of the four had underlying conditions. None of the household contacts died.

In an adjusted analysis, campers who had practiced physical distancing were less likely to transmit the virus at home, compared with those who had not practiced physical distancing (adjusted odds ratio, 0.4). Household members who had had close or direct contact with the index patients were more than 5 times more likely to become infected, compared with family members with minimal or no contact, analyses showed.

“This retrospective study showed that the efficient transmission of SARS-CoV-2 from school-age children and adolescents to household members led to the hospitalization of adults with secondary cases of COVID-19,” the researchers write. “In households in which transmission occurred, half the household contacts were infected.”

The secondary attack rates in this report may be an underestimate because testing was voluntary and participants reported the results themselves, the authors note. It is possible that infected household contacts spread the virus further, but this study did not address that question, Dr. Chu said.

For the study, investigators interviewed all camp attendees and their parents or guardians by phone between July 17, 2020 and Aug. 24, 2020, to collect information about demographic and clinical characteristics, SARS-CoV-2 testing, and preventive measures. The researchers’ analysis excluded households in which illness onset in a household contact occurred before or less than 2 days after a camper became sick.

About a third of the index patients began to have symptoms while still at camp. These campers may have been less infectious by the time they got home, compared with those whose symptoms started after they returned.

Two-thirds of the index patients adopted physical distancing at home, which “probably reduced the transmission of SARS-CoV-2 in the household,” Dr. Chu and colleagues wrote.

“Children who have had a known COVID-19 exposure should quarantine and obtain testing if they develop symptoms within the 14 days of returning home,” Dr. Chu advised. “If a child develops COVID-19, the child should be cared for and monitored using the proper combination of physical distancing, isolation when feasible, and mask use to prevent household transmission as much as possible. In addition, any person over the age of 12 is now eligible for vaccination in the United States. If eligible, children attending camp and their family members should get vaccinated to protect themselves and others, as vaccinations are our most effective public health prevention strategy.”
 

Mitigation can help

Another report regarding four overnight camps in Maine – in which three campers tested positive after they arrived last summer – shows that “aggressive mitigation strategies can be effective” in limiting transmission of the virus, William T. Basco Jr., MD, writes in a commentary for this news organization.

This summer, a range of factors, including vaccination rates at the camp, may influence transmission dynamics, Dr. Chu said in an interview. In July, the Associated Press reported outbreaks tied to summer camps in several states.

“Transmission dynamics will probably vary from summer camp to summer camp depending on many factors, such as vaccination rates of camp attendees, the mitigation measures in place, and the number of individual introductions during camp,” Dr. Chu said. “We would expect that a camp with a low vaccination rate among attendees and no enforcement of mitigation measures” still may experience a large outbreak.

“On the other hand, a large proportion of vaccinated individuals and appropriate implementation of multiple mitigation measures, such as wearing masks, may be quite effective at keeping their transmission rates low,” Dr. Chu added. “For camps with younger children who are not currently eligible for vaccination, implementing layered prevention strategies (e.g., mask use, physical distancing, and encouraging outdoor activities when feasible) is important to prevent transmission.”

Although COVID-19 transmission from children to adults, potentially leading to hospitalization, is not a new phenomenon, “data on the extent of transmission driven by children and adolescents in different settings are still quite sparse,” Dr. Chu said. “A better understanding of their impact on household and community transmission to help guide public health recommendations is particularly important, as most children are still not eligible for vaccination, and in-person schools will be reopening this fall.”

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

After SARS-CoV-2 spread at a sleepaway camp in Georgia last summer, researchers described the efficient spread and high attack rates at camp.

In a report published online in The New England Journal of Medicine, researchers found that campers spread COVID to household members after returning home – but transmission was more likely from some than others. Distancing and masking helped reduce the risk.

Victoria T. Chu, MD, MPH, with the Centers for Disease Control and Prevention, Atlanta, and colleagues with the agency and the Georgia Department of Health followed up with 224 camp attendees, aged 7 to 19 years, who had evidence of SARS-CoV-2 infection on laboratory testing.

These index patients – 88% of whom had symptoms – had 526 household contacts, mainly parents and siblings. Of 377 household contacts who underwent testing, 46 (12%) tested positive. Another two cases in household contacts were identified using clinical and epidemiologic criteria.
 

Family members hospitalized

Of the 41 adult household contacts who were infected, four (about 10%) were hospitalized. Their hospital stays ranged from 5 to 11 days. Of the seven infected household contacts who were younger than 18 years, none were hospitalized.

The four hospitalized adults were parents and grandparents aged 45 to 80 years, Dr. Chu said. Two of the four had underlying conditions. None of the household contacts died.

In an adjusted analysis, campers who had practiced physical distancing were less likely to transmit the virus at home, compared with those who had not practiced physical distancing (adjusted odds ratio, 0.4). Household members who had had close or direct contact with the index patients were more than 5 times more likely to become infected, compared with family members with minimal or no contact, analyses showed.

“This retrospective study showed that the efficient transmission of SARS-CoV-2 from school-age children and adolescents to household members led to the hospitalization of adults with secondary cases of COVID-19,” the researchers write. “In households in which transmission occurred, half the household contacts were infected.”

The secondary attack rates in this report may be an underestimate because testing was voluntary and participants reported the results themselves, the authors note. It is possible that infected household contacts spread the virus further, but this study did not address that question, Dr. Chu said.

For the study, investigators interviewed all camp attendees and their parents or guardians by phone between July 17, 2020 and Aug. 24, 2020, to collect information about demographic and clinical characteristics, SARS-CoV-2 testing, and preventive measures. The researchers’ analysis excluded households in which illness onset in a household contact occurred before or less than 2 days after a camper became sick.

About a third of the index patients began to have symptoms while still at camp. These campers may have been less infectious by the time they got home, compared with those whose symptoms started after they returned.

Two-thirds of the index patients adopted physical distancing at home, which “probably reduced the transmission of SARS-CoV-2 in the household,” Dr. Chu and colleagues wrote.

“Children who have had a known COVID-19 exposure should quarantine and obtain testing if they develop symptoms within the 14 days of returning home,” Dr. Chu advised. “If a child develops COVID-19, the child should be cared for and monitored using the proper combination of physical distancing, isolation when feasible, and mask use to prevent household transmission as much as possible. In addition, any person over the age of 12 is now eligible for vaccination in the United States. If eligible, children attending camp and their family members should get vaccinated to protect themselves and others, as vaccinations are our most effective public health prevention strategy.”
 

Mitigation can help

Another report regarding four overnight camps in Maine – in which three campers tested positive after they arrived last summer – shows that “aggressive mitigation strategies can be effective” in limiting transmission of the virus, William T. Basco Jr., MD, writes in a commentary for this news organization.

This summer, a range of factors, including vaccination rates at the camp, may influence transmission dynamics, Dr. Chu said in an interview. In July, the Associated Press reported outbreaks tied to summer camps in several states.

“Transmission dynamics will probably vary from summer camp to summer camp depending on many factors, such as vaccination rates of camp attendees, the mitigation measures in place, and the number of individual introductions during camp,” Dr. Chu said. “We would expect that a camp with a low vaccination rate among attendees and no enforcement of mitigation measures” still may experience a large outbreak.

“On the other hand, a large proportion of vaccinated individuals and appropriate implementation of multiple mitigation measures, such as wearing masks, may be quite effective at keeping their transmission rates low,” Dr. Chu added. “For camps with younger children who are not currently eligible for vaccination, implementing layered prevention strategies (e.g., mask use, physical distancing, and encouraging outdoor activities when feasible) is important to prevent transmission.”

Although COVID-19 transmission from children to adults, potentially leading to hospitalization, is not a new phenomenon, “data on the extent of transmission driven by children and adolescents in different settings are still quite sparse,” Dr. Chu said. “A better understanding of their impact on household and community transmission to help guide public health recommendations is particularly important, as most children are still not eligible for vaccination, and in-person schools will be reopening this fall.”

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

A meta-analysis by Australian researchers found no link between childhood vaccinations and an increase in allergies and asthma. In fact, children who received the BCG vaccine actually had a lesser incidence of eczema than other children, but there was no difference shown in any of the allergies or asthma.

The researchers, in a report published in the journal Allergy, write, “We found no evidence that childhood vaccination with commonly administered vaccines was associated with increased risk of later allergic disease.”

“Allergies have increased worldwide in the last 50 years, and in developed countries, earlier,” said study author Caroline J. Lodge, PhD, principal research fellow at the University of Melbourne, in an interview. “In developing countries, it is still a crisis.” No one knows why, she said. That was the reason for the recent study.

Allergic diseases such as allergic rhinitis (hay fever) and food allergies have a serious influence on quality of life, and the incidence is growing. According to the Global Asthma Network, there are 334 million people living with asthma. Between 2%-10% of adults have atopic eczema, and more than a 250,000 people have food allergies. This coincides temporally with an increase in mass vaccination of children.

Unlike the controversy surrounding vaccinations and autism, which has long been debunked as baseless, a hygiene hypothesis postulates that when children acquire immunity from many diseases, they become vulnerable to allergic reactions. Thanks to vaccinations, children in the developed world now are routinely immune to dozens of diseases.

That immunity leads to suppression of a major antibody response, increasing sensitivity to allergens and allergic disease. Suspicion of a link with childhood vaccinations has been used by opponents of vaccines in lobbying campaigns jeopardizing the sustainability of vaccine programs. In recent days, for example, the state of Tennessee has halted a program to encourage vaccination for COVID-19 as well as all other vaccinations, the result of pressure on the state by anti-vaccination lobbying.

But the Melbourne researchers reported that the meta-analysis of 42 published research studies doesn’t support the vaccine–allergy hypothesis. Using PubMed and EMBASE records between January 1946 and January 2018, researchers selected studies to be included in the analysis, looking for allergic outcomes in children given BCG or vaccines for measles or pertussis. Thirty-five publications reported cohort studies, and seven were based on randomized controlled trials.

The Australian study is not the only one showing the same lack of linkage between vaccination and allergy. The International Study of Asthma and Allergies in Childhood (ISAAC) found no association between mass vaccination and atopic disease. A 1998 Swedish study of 669 children found no differences in the incidence of allergic diseases between those who received pertussis vaccine and those who did not.

“The bottom line is that vaccines prevent infectious diseases,” said Matthew B. Laurens, associate professor of pediatrics at the University of Maryland, Baltimore, in an interview. Dr. Laurens was not part of the Australian study.

“Large-scale epidemiological studies do not support the theory that vaccines are associated with an increased risk of allergy or asthma,” he stressed. “Parents should not be deterred from vaccinating their children because of fears that this would increase risks of allergy and/or asthma.”

Dr. Lodge and Dr. Laurens have disclosed no relevant financial relationships.

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

A meta-analysis by Australian researchers found no link between childhood vaccinations and an increase in allergies and asthma. In fact, children who received the BCG vaccine actually had a lesser incidence of eczema than other children, but there was no difference shown in any of the allergies or asthma.

The researchers, in a report published in the journal Allergy, write, “We found no evidence that childhood vaccination with commonly administered vaccines was associated with increased risk of later allergic disease.”

“Allergies have increased worldwide in the last 50 years, and in developed countries, earlier,” said study author Caroline J. Lodge, PhD, principal research fellow at the University of Melbourne, in an interview. “In developing countries, it is still a crisis.” No one knows why, she said. That was the reason for the recent study.

Allergic diseases such as allergic rhinitis (hay fever) and food allergies have a serious influence on quality of life, and the incidence is growing. According to the Global Asthma Network, there are 334 million people living with asthma. Between 2%-10% of adults have atopic eczema, and more than a 250,000 people have food allergies. This coincides temporally with an increase in mass vaccination of children.

Unlike the controversy surrounding vaccinations and autism, which has long been debunked as baseless, a hygiene hypothesis postulates that when children acquire immunity from many diseases, they become vulnerable to allergic reactions. Thanks to vaccinations, children in the developed world now are routinely immune to dozens of diseases.

That immunity leads to suppression of a major antibody response, increasing sensitivity to allergens and allergic disease. Suspicion of a link with childhood vaccinations has been used by opponents of vaccines in lobbying campaigns jeopardizing the sustainability of vaccine programs. In recent days, for example, the state of Tennessee has halted a program to encourage vaccination for COVID-19 as well as all other vaccinations, the result of pressure on the state by anti-vaccination lobbying.

But the Melbourne researchers reported that the meta-analysis of 42 published research studies doesn’t support the vaccine–allergy hypothesis. Using PubMed and EMBASE records between January 1946 and January 2018, researchers selected studies to be included in the analysis, looking for allergic outcomes in children given BCG or vaccines for measles or pertussis. Thirty-five publications reported cohort studies, and seven were based on randomized controlled trials.

The Australian study is not the only one showing the same lack of linkage between vaccination and allergy. The International Study of Asthma and Allergies in Childhood (ISAAC) found no association between mass vaccination and atopic disease. A 1998 Swedish study of 669 children found no differences in the incidence of allergic diseases between those who received pertussis vaccine and those who did not.

“The bottom line is that vaccines prevent infectious diseases,” said Matthew B. Laurens, associate professor of pediatrics at the University of Maryland, Baltimore, in an interview. Dr. Laurens was not part of the Australian study.

“Large-scale epidemiological studies do not support the theory that vaccines are associated with an increased risk of allergy or asthma,” he stressed. “Parents should not be deterred from vaccinating their children because of fears that this would increase risks of allergy and/or asthma.”

Dr. Lodge and Dr. Laurens have disclosed no relevant financial relationships.

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

A meta-analysis by Australian researchers found no link between childhood vaccinations and an increase in allergies and asthma. In fact, children who received the BCG vaccine actually had a lesser incidence of eczema than other children, but there was no difference shown in any of the allergies or asthma.

The researchers, in a report published in the journal Allergy, write, “We found no evidence that childhood vaccination with commonly administered vaccines was associated with increased risk of later allergic disease.”

“Allergies have increased worldwide in the last 50 years, and in developed countries, earlier,” said study author Caroline J. Lodge, PhD, principal research fellow at the University of Melbourne, in an interview. “In developing countries, it is still a crisis.” No one knows why, she said. That was the reason for the recent study.

Allergic diseases such as allergic rhinitis (hay fever) and food allergies have a serious influence on quality of life, and the incidence is growing. According to the Global Asthma Network, there are 334 million people living with asthma. Between 2%-10% of adults have atopic eczema, and more than a 250,000 people have food allergies. This coincides temporally with an increase in mass vaccination of children.

Unlike the controversy surrounding vaccinations and autism, which has long been debunked as baseless, a hygiene hypothesis postulates that when children acquire immunity from many diseases, they become vulnerable to allergic reactions. Thanks to vaccinations, children in the developed world now are routinely immune to dozens of diseases.

That immunity leads to suppression of a major antibody response, increasing sensitivity to allergens and allergic disease. Suspicion of a link with childhood vaccinations has been used by opponents of vaccines in lobbying campaigns jeopardizing the sustainability of vaccine programs. In recent days, for example, the state of Tennessee has halted a program to encourage vaccination for COVID-19 as well as all other vaccinations, the result of pressure on the state by anti-vaccination lobbying.

But the Melbourne researchers reported that the meta-analysis of 42 published research studies doesn’t support the vaccine–allergy hypothesis. Using PubMed and EMBASE records between January 1946 and January 2018, researchers selected studies to be included in the analysis, looking for allergic outcomes in children given BCG or vaccines for measles or pertussis. Thirty-five publications reported cohort studies, and seven were based on randomized controlled trials.

The Australian study is not the only one showing the same lack of linkage between vaccination and allergy. The International Study of Asthma and Allergies in Childhood (ISAAC) found no association between mass vaccination and atopic disease. A 1998 Swedish study of 669 children found no differences in the incidence of allergic diseases between those who received pertussis vaccine and those who did not.

“The bottom line is that vaccines prevent infectious diseases,” said Matthew B. Laurens, associate professor of pediatrics at the University of Maryland, Baltimore, in an interview. Dr. Laurens was not part of the Australian study.

“Large-scale epidemiological studies do not support the theory that vaccines are associated with an increased risk of allergy or asthma,” he stressed. “Parents should not be deterred from vaccinating their children because of fears that this would increase risks of allergy and/or asthma.”

Dr. Lodge and Dr. Laurens have disclosed no relevant financial relationships.

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