COVID-19 has now killed at least 675,000 Americans, a death toll that has surpassed the estimates of the number of Americans who died during the 1918 influenza pandemic, according to data collected by Johns Hopkins University.

Although the raw numbers match, epidemiologists point out that 675,000 deaths in 1918 was a much greater proportion of the population. In 1918, the U.S. population was 105 million, less than one third of what it is today.

The AIDS pandemic of the 1980s remains the deadliest of the 20th Century, claiming the lives of 700,000 Americans. But at our current pace of 2,000 COVID deaths a day, we could quickly eclipse that death toll, too.

Even though the 1918 epidemic is often called the “Spanish Flu,” there is no universal consensus regarding where the virus originated, according to the Centers for Disease Control and Prevention.

Still, the almost incomprehensible loss harkens back to a time when medicine and technology were far less advanced than they are today.

In 1918, the United States didn’t have access to a vaccine, or near real-time tools to trace the spread and communicate the threat.

In some ways, the United States has failed to learn from the mistakes of the past.

There are many similarities between the two pandemics. In the spring of 1918, when the first wave of influenza hit, the United States and its allies were nearing victory in Europe in World War I. Just this summer the United States has ended its longest war, the conflict in Afghanistan, as COVID cases surge.

In both pandemics, hospitals and funeral homes were overrun and makeshift clinics were opened where space was available. Mask mandates were installed; schools, churches, and theaters closed; and social distancing was encouraged.

As is the case today, different jurisdictions took different steps to fight the pandemic and some were more successful than others.

According to History.com, in 1918, Philadelphia’s mayor said a popular annual parade could be held, and an estimated 200,000 people attended. In less than 2 weeks, more than 1,000 local residents were dead. But in St. Louis, public gatherings were banned, schools and theaters closed, and the death toll there was one eighth of Philadelphia’s.

Just as in 1918, America has at times continued to fan the flames of the epidemic by relaxing restrictions too quickly and relying on unproven treatments. Poor communication allowed younger people to feel that they wouldn’t necessarily face the worst consequences of the virus, contributing to a false sense of security in the age group that was fueling the spread.

“A lot of the mistakes that we definitely fell into in 1918, we hoped we wouldn’t fall into in 2020,” epidemiologist Stephen Kissler, PhD, of the Harvard T.H. Chan School of Public Health, told CNN. “We did.”

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

COVID-19 has now killed at least 675,000 Americans, a death toll that has surpassed the estimates of the number of Americans who died during the 1918 influenza pandemic, according to data collected by Johns Hopkins University.

Although the raw numbers match, epidemiologists point out that 675,000 deaths in 1918 was a much greater proportion of the population. In 1918, the U.S. population was 105 million, less than one third of what it is today.

The AIDS pandemic of the 1980s remains the deadliest of the 20th Century, claiming the lives of 700,000 Americans. But at our current pace of 2,000 COVID deaths a day, we could quickly eclipse that death toll, too.

Even though the 1918 epidemic is often called the “Spanish Flu,” there is no universal consensus regarding where the virus originated, according to the Centers for Disease Control and Prevention.

Still, the almost incomprehensible loss harkens back to a time when medicine and technology were far less advanced than they are today.

In 1918, the United States didn’t have access to a vaccine, or near real-time tools to trace the spread and communicate the threat.

In some ways, the United States has failed to learn from the mistakes of the past.

There are many similarities between the two pandemics. In the spring of 1918, when the first wave of influenza hit, the United States and its allies were nearing victory in Europe in World War I. Just this summer the United States has ended its longest war, the conflict in Afghanistan, as COVID cases surge.

In both pandemics, hospitals and funeral homes were overrun and makeshift clinics were opened where space was available. Mask mandates were installed; schools, churches, and theaters closed; and social distancing was encouraged.

As is the case today, different jurisdictions took different steps to fight the pandemic and some were more successful than others.

According to History.com, in 1918, Philadelphia’s mayor said a popular annual parade could be held, and an estimated 200,000 people attended. In less than 2 weeks, more than 1,000 local residents were dead. But in St. Louis, public gatherings were banned, schools and theaters closed, and the death toll there was one eighth of Philadelphia’s.

Just as in 1918, America has at times continued to fan the flames of the epidemic by relaxing restrictions too quickly and relying on unproven treatments. Poor communication allowed younger people to feel that they wouldn’t necessarily face the worst consequences of the virus, contributing to a false sense of security in the age group that was fueling the spread.

“A lot of the mistakes that we definitely fell into in 1918, we hoped we wouldn’t fall into in 2020,” epidemiologist Stephen Kissler, PhD, of the Harvard T.H. Chan School of Public Health, told CNN. “We did.”

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

COVID-19 has now killed at least 675,000 Americans, a death toll that has surpassed the estimates of the number of Americans who died during the 1918 influenza pandemic, according to data collected by Johns Hopkins University.

Although the raw numbers match, epidemiologists point out that 675,000 deaths in 1918 was a much greater proportion of the population. In 1918, the U.S. population was 105 million, less than one third of what it is today.

The AIDS pandemic of the 1980s remains the deadliest of the 20th Century, claiming the lives of 700,000 Americans. But at our current pace of 2,000 COVID deaths a day, we could quickly eclipse that death toll, too.

Even though the 1918 epidemic is often called the “Spanish Flu,” there is no universal consensus regarding where the virus originated, according to the Centers for Disease Control and Prevention.

Still, the almost incomprehensible loss harkens back to a time when medicine and technology were far less advanced than they are today.

In 1918, the United States didn’t have access to a vaccine, or near real-time tools to trace the spread and communicate the threat.

In some ways, the United States has failed to learn from the mistakes of the past.

There are many similarities between the two pandemics. In the spring of 1918, when the first wave of influenza hit, the United States and its allies were nearing victory in Europe in World War I. Just this summer the United States has ended its longest war, the conflict in Afghanistan, as COVID cases surge.

In both pandemics, hospitals and funeral homes were overrun and makeshift clinics were opened where space was available. Mask mandates were installed; schools, churches, and theaters closed; and social distancing was encouraged.

As is the case today, different jurisdictions took different steps to fight the pandemic and some were more successful than others.

According to History.com, in 1918, Philadelphia’s mayor said a popular annual parade could be held, and an estimated 200,000 people attended. In less than 2 weeks, more than 1,000 local residents were dead. But in St. Louis, public gatherings were banned, schools and theaters closed, and the death toll there was one eighth of Philadelphia’s.

Just as in 1918, America has at times continued to fan the flames of the epidemic by relaxing restrictions too quickly and relying on unproven treatments. Poor communication allowed younger people to feel that they wouldn’t necessarily face the worst consequences of the virus, contributing to a false sense of security in the age group that was fueling the spread.

“A lot of the mistakes that we definitely fell into in 1918, we hoped we wouldn’t fall into in 2020,” epidemiologist Stephen Kissler, PhD, of the Harvard T.H. Chan School of Public Health, told CNN. “We did.”

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

Despite a decrease in reported adverse events after receiving the human papillomavirus (HPV) vaccine, among parents of unvaccinated adolescents, concerns about the vaccine’s safety rose 80% from 2015 to 2018, according to research published September 17 in JAMA Network Open.

Since its approval in 2006 by the U.S. Food and Drug Administration, uptake of the HPV vaccine has consistently lagged behind that of other routine vaccinations. According to the most recent data from the Centers for Disease Control and Prevention, released September 3, 58.6% of adolescents were considered up to date with their HPV vaccinations in 2020.

Trials prior to the vaccine’s FDA approval as well as an abundance of clinical and observational evidence after it hit the market demonstrate the vaccine’s efficacy and safety, said lead author Kalyani Sonawane, PhD, an assistant professor of management, policy, and community health at the UTHealth School of Public Health, in Houston, Texas, in an interview. Still, recent research suggests that safety concerns are a main reason why parents are hesitant to have their children vaccinated, she noted.

In the study, Dr. Sonawane and colleagues analyzed data from National Immunization Survey-Teen (NIS-Teen) from 2015 through 2018. NIS-Teen is a random-digit-dialed telephone survey conducted annually by the CDC to monitor routine vaccination coverage among adolescents aged 13 to 17. The researchers identified 39,364 adolescents who had not received any HPV shots and reviewed the caregivers’ reasons for vaccine hesitancy. The research team also reviewed the Vaccine Adverse Event Reporting System (VAERS). They identified 16,621 reports that listed the HPV vaccine from 2015 through 2018.

The top five reasons caregivers cited for avoiding the HPV vaccine were the following:

• not needed or necessary
• safety concerns
• not recommended
• lack of knowledge
• not sexually active

Of these, safety concerns were the only factor that increased during the study period. They increased from 13.0% in 2015 to 23.4% in 2018. Concerns over vaccine safety rose in 30 states, with increases of over 200% in California, Hawaii, South Dakota, and Mississippi.

The proportion of unvaccinated adolescents whose caregivers thought the HPV vaccine was not needed or necessary remained steady at around 25%. Those whose caregivers listed “not recommended,” “lack of knowledge,” and “not sexually active” as reasons for avoiding vaccination decreased over the study period.

The reporting rate for adverse events following HPV vaccination decreased from 44.7 per 100,000 doses in 2015 to 29.4 per 100,000 doses in 2018. Of the reported 16,621 adverse events following HPV vaccination that occurred over the study period, 4.6% were serious, resulting in hospitalizations, disability, life-threatening events, or death. From 2015 through 2018, reporting rates for serious adverse events remained level at around 0.3 events per 100,000 doses.

This mismatch between increasing vaccine safety concerns and decreasing adverse events suggests that disinformation may be driving these concerns more than scientific fact, Nosayaba Osazuwa-Peters, PhD, MPH, an assistant professor in head and neck surgery and communication sciences at the Duke University School of Medicine, in Durham, North Carolina, told this news organization. He co-wrote an invited commentary on the study and was not involved with the research. Although there have always been people who are hesitant to receive vaccinations, he said, social media and the internet have undoubtedly played a role in spreading concern.

Dr. Sonawane agreed. Online, “there are a lot of antivaccine groups that are making unwarranted claims about the vaccine’s safety,” such as that the HPV vaccine causes autism or fertility problems in women, she said. “We believe that this growing antivaccine movement in the U.S. and across the globe – which the World Health Organization has declared as one of the biggest threats right now – is also contributing to safety concerns among U.S. parents, particularly HPV vaccine safety.”

Although the study did not address strategies to combat this misinformation, Dr. Osazuwa-Peters said clinicians need to improve their communication with parents and patients. One way to do that, he said, is by bolstering an online presence and by countering vaccine disinformation with evidence-based responses on the internet. Most people get their medical information online. “Many people are just afraid because they don’t trust the messages coming from health care,” he said. “So, we need to a better job of not just providing the facts but providing the facts in a way that the end users can understand and appreciate.”

Dr. Sonawane and Dr. Osazuwa-Peters report no relevant financial relationships.

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

Despite a decrease in reported adverse events after receiving the human papillomavirus (HPV) vaccine, among parents of unvaccinated adolescents, concerns about the vaccine’s safety rose 80% from 2015 to 2018, according to research published September 17 in JAMA Network Open.

Since its approval in 2006 by the U.S. Food and Drug Administration, uptake of the HPV vaccine has consistently lagged behind that of other routine vaccinations. According to the most recent data from the Centers for Disease Control and Prevention, released September 3, 58.6% of adolescents were considered up to date with their HPV vaccinations in 2020.

Trials prior to the vaccine’s FDA approval as well as an abundance of clinical and observational evidence after it hit the market demonstrate the vaccine’s efficacy and safety, said lead author Kalyani Sonawane, PhD, an assistant professor of management, policy, and community health at the UTHealth School of Public Health, in Houston, Texas, in an interview. Still, recent research suggests that safety concerns are a main reason why parents are hesitant to have their children vaccinated, she noted.

In the study, Dr. Sonawane and colleagues analyzed data from National Immunization Survey-Teen (NIS-Teen) from 2015 through 2018. NIS-Teen is a random-digit-dialed telephone survey conducted annually by the CDC to monitor routine vaccination coverage among adolescents aged 13 to 17. The researchers identified 39,364 adolescents who had not received any HPV shots and reviewed the caregivers’ reasons for vaccine hesitancy. The research team also reviewed the Vaccine Adverse Event Reporting System (VAERS). They identified 16,621 reports that listed the HPV vaccine from 2015 through 2018.

The top five reasons caregivers cited for avoiding the HPV vaccine were the following:

• not needed or necessary
• safety concerns
• not recommended
• lack of knowledge
• not sexually active

Of these, safety concerns were the only factor that increased during the study period. They increased from 13.0% in 2015 to 23.4% in 2018. Concerns over vaccine safety rose in 30 states, with increases of over 200% in California, Hawaii, South Dakota, and Mississippi.

The proportion of unvaccinated adolescents whose caregivers thought the HPV vaccine was not needed or necessary remained steady at around 25%. Those whose caregivers listed “not recommended,” “lack of knowledge,” and “not sexually active” as reasons for avoiding vaccination decreased over the study period.

The reporting rate for adverse events following HPV vaccination decreased from 44.7 per 100,000 doses in 2015 to 29.4 per 100,000 doses in 2018. Of the reported 16,621 adverse events following HPV vaccination that occurred over the study period, 4.6% were serious, resulting in hospitalizations, disability, life-threatening events, or death. From 2015 through 2018, reporting rates for serious adverse events remained level at around 0.3 events per 100,000 doses.

This mismatch between increasing vaccine safety concerns and decreasing adverse events suggests that disinformation may be driving these concerns more than scientific fact, Nosayaba Osazuwa-Peters, PhD, MPH, an assistant professor in head and neck surgery and communication sciences at the Duke University School of Medicine, in Durham, North Carolina, told this news organization. He co-wrote an invited commentary on the study and was not involved with the research. Although there have always been people who are hesitant to receive vaccinations, he said, social media and the internet have undoubtedly played a role in spreading concern.

Dr. Sonawane agreed. Online, “there are a lot of antivaccine groups that are making unwarranted claims about the vaccine’s safety,” such as that the HPV vaccine causes autism or fertility problems in women, she said. “We believe that this growing antivaccine movement in the U.S. and across the globe – which the World Health Organization has declared as one of the biggest threats right now – is also contributing to safety concerns among U.S. parents, particularly HPV vaccine safety.”

Although the study did not address strategies to combat this misinformation, Dr. Osazuwa-Peters said clinicians need to improve their communication with parents and patients. One way to do that, he said, is by bolstering an online presence and by countering vaccine disinformation with evidence-based responses on the internet. Most people get their medical information online. “Many people are just afraid because they don’t trust the messages coming from health care,” he said. “So, we need to a better job of not just providing the facts but providing the facts in a way that the end users can understand and appreciate.”

Dr. Sonawane and Dr. Osazuwa-Peters report no relevant financial relationships.

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

Despite a decrease in reported adverse events after receiving the human papillomavirus (HPV) vaccine, among parents of unvaccinated adolescents, concerns about the vaccine’s safety rose 80% from 2015 to 2018, according to research published September 17 in JAMA Network Open.

Since its approval in 2006 by the U.S. Food and Drug Administration, uptake of the HPV vaccine has consistently lagged behind that of other routine vaccinations. According to the most recent data from the Centers for Disease Control and Prevention, released September 3, 58.6% of adolescents were considered up to date with their HPV vaccinations in 2020.

Trials prior to the vaccine’s FDA approval as well as an abundance of clinical and observational evidence after it hit the market demonstrate the vaccine’s efficacy and safety, said lead author Kalyani Sonawane, PhD, an assistant professor of management, policy, and community health at the UTHealth School of Public Health, in Houston, Texas, in an interview. Still, recent research suggests that safety concerns are a main reason why parents are hesitant to have their children vaccinated, she noted.

In the study, Dr. Sonawane and colleagues analyzed data from National Immunization Survey-Teen (NIS-Teen) from 2015 through 2018. NIS-Teen is a random-digit-dialed telephone survey conducted annually by the CDC to monitor routine vaccination coverage among adolescents aged 13 to 17. The researchers identified 39,364 adolescents who had not received any HPV shots and reviewed the caregivers’ reasons for vaccine hesitancy. The research team also reviewed the Vaccine Adverse Event Reporting System (VAERS). They identified 16,621 reports that listed the HPV vaccine from 2015 through 2018.

The top five reasons caregivers cited for avoiding the HPV vaccine were the following:

• not needed or necessary
• safety concerns
• not recommended
• lack of knowledge
• not sexually active

Of these, safety concerns were the only factor that increased during the study period. They increased from 13.0% in 2015 to 23.4% in 2018. Concerns over vaccine safety rose in 30 states, with increases of over 200% in California, Hawaii, South Dakota, and Mississippi.

The proportion of unvaccinated adolescents whose caregivers thought the HPV vaccine was not needed or necessary remained steady at around 25%. Those whose caregivers listed “not recommended,” “lack of knowledge,” and “not sexually active” as reasons for avoiding vaccination decreased over the study period.

The reporting rate for adverse events following HPV vaccination decreased from 44.7 per 100,000 doses in 2015 to 29.4 per 100,000 doses in 2018. Of the reported 16,621 adverse events following HPV vaccination that occurred over the study period, 4.6% were serious, resulting in hospitalizations, disability, life-threatening events, or death. From 2015 through 2018, reporting rates for serious adverse events remained level at around 0.3 events per 100,000 doses.

This mismatch between increasing vaccine safety concerns and decreasing adverse events suggests that disinformation may be driving these concerns more than scientific fact, Nosayaba Osazuwa-Peters, PhD, MPH, an assistant professor in head and neck surgery and communication sciences at the Duke University School of Medicine, in Durham, North Carolina, told this news organization. He co-wrote an invited commentary on the study and was not involved with the research. Although there have always been people who are hesitant to receive vaccinations, he said, social media and the internet have undoubtedly played a role in spreading concern.

Dr. Sonawane agreed. Online, “there are a lot of antivaccine groups that are making unwarranted claims about the vaccine’s safety,” such as that the HPV vaccine causes autism or fertility problems in women, she said. “We believe that this growing antivaccine movement in the U.S. and across the globe – which the World Health Organization has declared as one of the biggest threats right now – is also contributing to safety concerns among U.S. parents, particularly HPV vaccine safety.”

Although the study did not address strategies to combat this misinformation, Dr. Osazuwa-Peters said clinicians need to improve their communication with parents and patients. One way to do that, he said, is by bolstering an online presence and by countering vaccine disinformation with evidence-based responses on the internet. Most people get their medical information online. “Many people are just afraid because they don’t trust the messages coming from health care,” he said. “So, we need to a better job of not just providing the facts but providing the facts in a way that the end users can understand and appreciate.”

Dr. Sonawane and Dr. Osazuwa-Peters report no relevant financial relationships.

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

A majority of patients with Parkinson’s disease experiencing “off” episodes successfully tolerated titration to an effective and tolerable dose of sublingual apomorphine film (SL-apo; Kynmobi, Sunovion Pharmaceuticals) without the use of antiemetic medication, new research shows.

“The bottom line was that the majority of patients did not have dose-limiting nausea or vomiting,” said coinvestigator William Ondo, MD, from Houston Methodist Neurological Institute. “And although it really did not compare in a prospective, placebo-controlled manner use of [trimethobenzamide antiemetic] ... versus not using [it], anecdotally and based on historic data, nausea really seemed to be about the same even without the antinausea medication.”

The findings were presented at the International Congress of Parkinson’s Disease and Movement Disorders.

This study was the dose-titration phase to determine the effective and tolerable dose of the drug as part of a longer study looking at safety and efficacy.

Only 13% of patients experienced nausea and/or vomiting, and of those, 74% cases were of mild severity and 26% were of moderate severity. These rates of nausea/vomiting were lower than those seen when trimethobenzamide (Tigan, Pfizer) was needed to be administered during the titration period, at the discretion of the investigator.

This multicenter, ongoing, open-label, phase 3 study enrolled 176 patients (mean age, 64.4 years) who had idiopathic Parkinson’s disease for a mean of 8.0 years and had no prior exposure to SL-apo, with modified Hoehn and Yahr stage 1-3 disease (83% stage 2 or 2.5 during “on” time).

Study participants had Mini-Mental State Examination scores greater than 25, were receiving stable doses of levodopa/carbidopa, and had 1 or more (mean, 4.2) “off” episodes per day with a total daily “off” time of 2 hours or more. Patients with mouth cankers or sores within 30 days of screening were excluded.

Open-label dose titration occurred during sequential office visits while patients were “off,” with escalating doses of 10-35 mg in 5-mg increments to determine a tolerable dose leading to a full “on” period within 45 minutes. Patients self-administered this achieved dose of SL-apo for up to five “off” episodes per day with a minimum of 2 hours between doses for the full 48-week study period.

The study protocol prohibited antiemetic use except when clinically warranted at the investigator’s discretion. Of the 176 patients, 31 (18%) received the antiemetic trimethobenzamide and 145 (82%) did not.

Of the 176 patients, 76% received their effective and tolerated dose within the first three doses. Just over half (55%) received 10 mg or 15 mg. Only 24% received the highest doses of 25 mg or 30 mg.

About 52%of patients who received trimethobenzamide experienced treatment-related nausea and 13% experienced vomiting; in comparison, 13% not receiving trimethobenzamide had nausea and 1% had vomiting. About 10%of patients in the former group and none in the latter discontinued the study because of nausea and/or vomiting.

Good news

Commenting on the study, Ludy Shih, MD, MMSc, from Boston University, noted that the drug label reports that “13%-15% had oropharyngeal soft tissue swelling or pain ... and 7% had oral ulcers and stomatitis.”

In addition, oral trimethobenzamide has been discontinued, although an injectable form is still available. This situation may present a problem, she said. “Most antinausea drugs block dopamine, so ... I would say they’re contraindicated for treating people with Parkinson’s disease. But trimethobenzamide in particular is one that we often reach for. ... But that appears to be constrained and may, in fact, be expensive for patients.”

Turning to the study findings, she said they suggest that “not everyone needs prophylactic use of trimethobenzamide before they take the apomorphine sublingual film, which is good news that helps doctors try to decide whether or not it’s reasonable to recommend people trying it without the trimethobenzamide.”

Although some patients did experience mild nausea, she said the fact that no needle is involved may attract some patients. Moreover, taking this medication may be easier than administering an injection during an “off” episode.

Dr. Ondo is a consultant for Sunovion Pharmaceuticals, which sponsored the study. Dr. Shih had no relevant disclosures.

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

A majority of patients with Parkinson’s disease experiencing “off” episodes successfully tolerated titration to an effective and tolerable dose of sublingual apomorphine film (SL-apo; Kynmobi, Sunovion Pharmaceuticals) without the use of antiemetic medication, new research shows.

“The bottom line was that the majority of patients did not have dose-limiting nausea or vomiting,” said coinvestigator William Ondo, MD, from Houston Methodist Neurological Institute. “And although it really did not compare in a prospective, placebo-controlled manner use of [trimethobenzamide antiemetic] ... versus not using [it], anecdotally and based on historic data, nausea really seemed to be about the same even without the antinausea medication.”

The findings were presented at the International Congress of Parkinson’s Disease and Movement Disorders.

This study was the dose-titration phase to determine the effective and tolerable dose of the drug as part of a longer study looking at safety and efficacy.

Only 13% of patients experienced nausea and/or vomiting, and of those, 74% cases were of mild severity and 26% were of moderate severity. These rates of nausea/vomiting were lower than those seen when trimethobenzamide (Tigan, Pfizer) was needed to be administered during the titration period, at the discretion of the investigator.

This multicenter, ongoing, open-label, phase 3 study enrolled 176 patients (mean age, 64.4 years) who had idiopathic Parkinson’s disease for a mean of 8.0 years and had no prior exposure to SL-apo, with modified Hoehn and Yahr stage 1-3 disease (83% stage 2 or 2.5 during “on” time).

Study participants had Mini-Mental State Examination scores greater than 25, were receiving stable doses of levodopa/carbidopa, and had 1 or more (mean, 4.2) “off” episodes per day with a total daily “off” time of 2 hours or more. Patients with mouth cankers or sores within 30 days of screening were excluded.

Open-label dose titration occurred during sequential office visits while patients were “off,” with escalating doses of 10-35 mg in 5-mg increments to determine a tolerable dose leading to a full “on” period within 45 minutes. Patients self-administered this achieved dose of SL-apo for up to five “off” episodes per day with a minimum of 2 hours between doses for the full 48-week study period.

The study protocol prohibited antiemetic use except when clinically warranted at the investigator’s discretion. Of the 176 patients, 31 (18%) received the antiemetic trimethobenzamide and 145 (82%) did not.

Of the 176 patients, 76% received their effective and tolerated dose within the first three doses. Just over half (55%) received 10 mg or 15 mg. Only 24% received the highest doses of 25 mg or 30 mg.

About 52%of patients who received trimethobenzamide experienced treatment-related nausea and 13% experienced vomiting; in comparison, 13% not receiving trimethobenzamide had nausea and 1% had vomiting. About 10%of patients in the former group and none in the latter discontinued the study because of nausea and/or vomiting.

Good news

Commenting on the study, Ludy Shih, MD, MMSc, from Boston University, noted that the drug label reports that “13%-15% had oropharyngeal soft tissue swelling or pain ... and 7% had oral ulcers and stomatitis.”

In addition, oral trimethobenzamide has been discontinued, although an injectable form is still available. This situation may present a problem, she said. “Most antinausea drugs block dopamine, so ... I would say they’re contraindicated for treating people with Parkinson’s disease. But trimethobenzamide in particular is one that we often reach for. ... But that appears to be constrained and may, in fact, be expensive for patients.”

Turning to the study findings, she said they suggest that “not everyone needs prophylactic use of trimethobenzamide before they take the apomorphine sublingual film, which is good news that helps doctors try to decide whether or not it’s reasonable to recommend people trying it without the trimethobenzamide.”

Although some patients did experience mild nausea, she said the fact that no needle is involved may attract some patients. Moreover, taking this medication may be easier than administering an injection during an “off” episode.

Dr. Ondo is a consultant for Sunovion Pharmaceuticals, which sponsored the study. Dr. Shih had no relevant disclosures.

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

A majority of patients with Parkinson’s disease experiencing “off” episodes successfully tolerated titration to an effective and tolerable dose of sublingual apomorphine film (SL-apo; Kynmobi, Sunovion Pharmaceuticals) without the use of antiemetic medication, new research shows.

“The bottom line was that the majority of patients did not have dose-limiting nausea or vomiting,” said coinvestigator William Ondo, MD, from Houston Methodist Neurological Institute. “And although it really did not compare in a prospective, placebo-controlled manner use of [trimethobenzamide antiemetic] ... versus not using [it], anecdotally and based on historic data, nausea really seemed to be about the same even without the antinausea medication.”

The findings were presented at the International Congress of Parkinson’s Disease and Movement Disorders.

This study was the dose-titration phase to determine the effective and tolerable dose of the drug as part of a longer study looking at safety and efficacy.

Only 13% of patients experienced nausea and/or vomiting, and of those, 74% cases were of mild severity and 26% were of moderate severity. These rates of nausea/vomiting were lower than those seen when trimethobenzamide (Tigan, Pfizer) was needed to be administered during the titration period, at the discretion of the investigator.

This multicenter, ongoing, open-label, phase 3 study enrolled 176 patients (mean age, 64.4 years) who had idiopathic Parkinson’s disease for a mean of 8.0 years and had no prior exposure to SL-apo, with modified Hoehn and Yahr stage 1-3 disease (83% stage 2 or 2.5 during “on” time).

Study participants had Mini-Mental State Examination scores greater than 25, were receiving stable doses of levodopa/carbidopa, and had 1 or more (mean, 4.2) “off” episodes per day with a total daily “off” time of 2 hours or more. Patients with mouth cankers or sores within 30 days of screening were excluded.

Open-label dose titration occurred during sequential office visits while patients were “off,” with escalating doses of 10-35 mg in 5-mg increments to determine a tolerable dose leading to a full “on” period within 45 minutes. Patients self-administered this achieved dose of SL-apo for up to five “off” episodes per day with a minimum of 2 hours between doses for the full 48-week study period.

The study protocol prohibited antiemetic use except when clinically warranted at the investigator’s discretion. Of the 176 patients, 31 (18%) received the antiemetic trimethobenzamide and 145 (82%) did not.

Of the 176 patients, 76% received their effective and tolerated dose within the first three doses. Just over half (55%) received 10 mg or 15 mg. Only 24% received the highest doses of 25 mg or 30 mg.

About 52%of patients who received trimethobenzamide experienced treatment-related nausea and 13% experienced vomiting; in comparison, 13% not receiving trimethobenzamide had nausea and 1% had vomiting. About 10%of patients in the former group and none in the latter discontinued the study because of nausea and/or vomiting.

Good news

Commenting on the study, Ludy Shih, MD, MMSc, from Boston University, noted that the drug label reports that “13%-15% had oropharyngeal soft tissue swelling or pain ... and 7% had oral ulcers and stomatitis.”

In addition, oral trimethobenzamide has been discontinued, although an injectable form is still available. This situation may present a problem, she said. “Most antinausea drugs block dopamine, so ... I would say they’re contraindicated for treating people with Parkinson’s disease. But trimethobenzamide in particular is one that we often reach for. ... But that appears to be constrained and may, in fact, be expensive for patients.”

Turning to the study findings, she said they suggest that “not everyone needs prophylactic use of trimethobenzamide before they take the apomorphine sublingual film, which is good news that helps doctors try to decide whether or not it’s reasonable to recommend people trying it without the trimethobenzamide.”

Although some patients did experience mild nausea, she said the fact that no needle is involved may attract some patients. Moreover, taking this medication may be easier than administering an injection during an “off” episode.

Dr. Ondo is a consultant for Sunovion Pharmaceuticals, which sponsored the study. Dr. Shih had no relevant disclosures.

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

Omaveloxolone, an activator of the protein Nrf2 that protects against inflammation, has shown a potentially beneficial effect in slowing the progression of Friedreich’s ataxia out to more than 2 years, according to results of a clinical trial presented as a late-breaking abstract at the International Congress of Parkinson’s Disease and Movement Disorders.

The study, labeled the Delayed-Start Study, is an extension study of the two-part MOXIE phase 2 trial of omaveloxolone.

“This study shows two things,” said David Lynch, MD, PhD, of Children’s Hospital of Philadelphia. “It doesn’t matter when you started omaveloxolone for you to see a benefit; and that the benefit that the active group saw in the first part of the study was maintained as they went into the delayed-start part. So in fact omaveloxolone does modify the long-term behavior of the disease.”

Friedreich’s ataxia only affects about 22,000 people worldwide, and children typically present between the ages of 5 and 15, Dr. Lynch said.

The extension study included 73 patients who completed either of the first two parts of the MOXIe trial. The MOXIe trial randomized patients on a 3:1 basis to either omaveloxolone 2.5-300 mg or placebo for 12 weeks in the first part. The second part was a double-blind trial of 103 patients randomized on a 1:1 basis to 150 mg omaveloxolone or placebo for 48 weeks. Participants had a baseline modified Friedreich’s ataxia scale (mFARS) of 20-80 and were aged 16-40 years.

Patients in the extension study did not have severe pes cavus. The extension study was a 72-week evaluation of patients who were in either the treatment or placebo groups in the first two parts. There was a 4-week off-treatment period between the end of MOXIe part 2 and the beginning of the extension study, in which all patients received omaveloxolone.

At the end of the placebo-controlled study, patients taking omaveloxolone showed a –2.18-point (±0.96) difference in improvement in mFARS score (P = .027), compared with the placebo group, which was preserved at the end of the delayed-start period, with a –2.92-point (±2.13) improvement (P = .179), Dr. Lynch said.

In the extension study, former placebo patients who went on omaveloxolone had annualized mFARS slopes similar to the previously treated patients – 0.29 (±0.68) and 0.17 (±0.61), respectively (P = .85) – from weeks 48 to 144, Dr. Lynch said.

“This study showed that, when analyzed in a delayed-start fashion, it does not matter when you start omaveloxolone to see a benefit: Each cohort benefited almost equally once they started the drug,” Dr. Lynch said in an interview. “Also, in both groups, once they started omaveloxolone, they changed slower than people in natural history studies.”
 

A clinically meaningful difference?

Reached for comment, Massimo Pandolfo, MD, a neurologist at McGill University, Montreal, noted that the Delayed-Start Study included only patients without pes cavus, an indication that the patients had less severe disease. “It would be important to see how overall patients with Friedreich’s ataxia would have responded to the medication without this kind of selection,” Dr. Pandolfo said in an interview.

He also noted that the seemingly modest improvement in mFARS score could be an issue. “It’s a very difficult question: What is a clinically meaningful difference in this kind of rating scale? I would argue that probably 2 points is not a huge difference by itself, but it may be meaningful and one indicator of that is that if it was accompanied by also a significant difference in activities of daily living scale.”

In any event, Dr. Pandolfo said this is the first medication for Friedreich’s ataxia that has “survived” a randomized clinical trial.

Dr. Lynch said the study sponsor, Reata, may prepare a new drug application for omaveloxolone in patients ages 16 and older. “That would leave a need for investigation in younger FA patients.”

Dr. Lynch disclosed that his institution receives a grant from trial sponsor Reata to conduct the MOXIe trial. Dr. Pandolfo reports financial relationships with Design Therapeutics, Exicure and Voyager Therapeutics.
 

Omaveloxolone, an activator of the protein Nrf2 that protects against inflammation, has shown a potentially beneficial effect in slowing the progression of Friedreich’s ataxia out to more than 2 years, according to results of a clinical trial presented as a late-breaking abstract at the International Congress of Parkinson’s Disease and Movement Disorders.

The study, labeled the Delayed-Start Study, is an extension study of the two-part MOXIE phase 2 trial of omaveloxolone.

“This study shows two things,” said David Lynch, MD, PhD, of Children’s Hospital of Philadelphia. “It doesn’t matter when you started omaveloxolone for you to see a benefit; and that the benefit that the active group saw in the first part of the study was maintained as they went into the delayed-start part. So in fact omaveloxolone does modify the long-term behavior of the disease.”

Friedreich’s ataxia only affects about 22,000 people worldwide, and children typically present between the ages of 5 and 15, Dr. Lynch said.

The extension study included 73 patients who completed either of the first two parts of the MOXIe trial. The MOXIe trial randomized patients on a 3:1 basis to either omaveloxolone 2.5-300 mg or placebo for 12 weeks in the first part. The second part was a double-blind trial of 103 patients randomized on a 1:1 basis to 150 mg omaveloxolone or placebo for 48 weeks. Participants had a baseline modified Friedreich’s ataxia scale (mFARS) of 20-80 and were aged 16-40 years.

Patients in the extension study did not have severe pes cavus. The extension study was a 72-week evaluation of patients who were in either the treatment or placebo groups in the first two parts. There was a 4-week off-treatment period between the end of MOXIe part 2 and the beginning of the extension study, in which all patients received omaveloxolone.

At the end of the placebo-controlled study, patients taking omaveloxolone showed a –2.18-point (±0.96) difference in improvement in mFARS score (P = .027), compared with the placebo group, which was preserved at the end of the delayed-start period, with a –2.92-point (±2.13) improvement (P = .179), Dr. Lynch said.

In the extension study, former placebo patients who went on omaveloxolone had annualized mFARS slopes similar to the previously treated patients – 0.29 (±0.68) and 0.17 (±0.61), respectively (P = .85) – from weeks 48 to 144, Dr. Lynch said.

“This study showed that, when analyzed in a delayed-start fashion, it does not matter when you start omaveloxolone to see a benefit: Each cohort benefited almost equally once they started the drug,” Dr. Lynch said in an interview. “Also, in both groups, once they started omaveloxolone, they changed slower than people in natural history studies.”
 

A clinically meaningful difference?

Reached for comment, Massimo Pandolfo, MD, a neurologist at McGill University, Montreal, noted that the Delayed-Start Study included only patients without pes cavus, an indication that the patients had less severe disease. “It would be important to see how overall patients with Friedreich’s ataxia would have responded to the medication without this kind of selection,” Dr. Pandolfo said in an interview.

He also noted that the seemingly modest improvement in mFARS score could be an issue. “It’s a very difficult question: What is a clinically meaningful difference in this kind of rating scale? I would argue that probably 2 points is not a huge difference by itself, but it may be meaningful and one indicator of that is that if it was accompanied by also a significant difference in activities of daily living scale.”

In any event, Dr. Pandolfo said this is the first medication for Friedreich’s ataxia that has “survived” a randomized clinical trial.

Dr. Lynch said the study sponsor, Reata, may prepare a new drug application for omaveloxolone in patients ages 16 and older. “That would leave a need for investigation in younger FA patients.”

Dr. Lynch disclosed that his institution receives a grant from trial sponsor Reata to conduct the MOXIe trial. Dr. Pandolfo reports financial relationships with Design Therapeutics, Exicure and Voyager Therapeutics.
 

Omaveloxolone, an activator of the protein Nrf2 that protects against inflammation, has shown a potentially beneficial effect in slowing the progression of Friedreich’s ataxia out to more than 2 years, according to results of a clinical trial presented as a late-breaking abstract at the International Congress of Parkinson’s Disease and Movement Disorders.

The study, labeled the Delayed-Start Study, is an extension study of the two-part MOXIE phase 2 trial of omaveloxolone.

“This study shows two things,” said David Lynch, MD, PhD, of Children’s Hospital of Philadelphia. “It doesn’t matter when you started omaveloxolone for you to see a benefit; and that the benefit that the active group saw in the first part of the study was maintained as they went into the delayed-start part. So in fact omaveloxolone does modify the long-term behavior of the disease.”

Friedreich’s ataxia only affects about 22,000 people worldwide, and children typically present between the ages of 5 and 15, Dr. Lynch said.

The extension study included 73 patients who completed either of the first two parts of the MOXIe trial. The MOXIe trial randomized patients on a 3:1 basis to either omaveloxolone 2.5-300 mg or placebo for 12 weeks in the first part. The second part was a double-blind trial of 103 patients randomized on a 1:1 basis to 150 mg omaveloxolone or placebo for 48 weeks. Participants had a baseline modified Friedreich’s ataxia scale (mFARS) of 20-80 and were aged 16-40 years.

Patients in the extension study did not have severe pes cavus. The extension study was a 72-week evaluation of patients who were in either the treatment or placebo groups in the first two parts. There was a 4-week off-treatment period between the end of MOXIe part 2 and the beginning of the extension study, in which all patients received omaveloxolone.

At the end of the placebo-controlled study, patients taking omaveloxolone showed a –2.18-point (±0.96) difference in improvement in mFARS score (P = .027), compared with the placebo group, which was preserved at the end of the delayed-start period, with a –2.92-point (±2.13) improvement (P = .179), Dr. Lynch said.

In the extension study, former placebo patients who went on omaveloxolone had annualized mFARS slopes similar to the previously treated patients – 0.29 (±0.68) and 0.17 (±0.61), respectively (P = .85) – from weeks 48 to 144, Dr. Lynch said.

“This study showed that, when analyzed in a delayed-start fashion, it does not matter when you start omaveloxolone to see a benefit: Each cohort benefited almost equally once they started the drug,” Dr. Lynch said in an interview. “Also, in both groups, once they started omaveloxolone, they changed slower than people in natural history studies.”
 

A clinically meaningful difference?

Reached for comment, Massimo Pandolfo, MD, a neurologist at McGill University, Montreal, noted that the Delayed-Start Study included only patients without pes cavus, an indication that the patients had less severe disease. “It would be important to see how overall patients with Friedreich’s ataxia would have responded to the medication without this kind of selection,” Dr. Pandolfo said in an interview.

He also noted that the seemingly modest improvement in mFARS score could be an issue. “It’s a very difficult question: What is a clinically meaningful difference in this kind of rating scale? I would argue that probably 2 points is not a huge difference by itself, but it may be meaningful and one indicator of that is that if it was accompanied by also a significant difference in activities of daily living scale.”

In any event, Dr. Pandolfo said this is the first medication for Friedreich’s ataxia that has “survived” a randomized clinical trial.

Dr. Lynch said the study sponsor, Reata, may prepare a new drug application for omaveloxolone in patients ages 16 and older. “That would leave a need for investigation in younger FA patients.”

Dr. Lynch disclosed that his institution receives a grant from trial sponsor Reata to conduct the MOXIe trial. Dr. Pandolfo reports financial relationships with Design Therapeutics, Exicure and Voyager Therapeutics.
 

Before getting to work on developing guidelines for genetic testing in Parkinson’s disease, a task force of the Movement Disorders Society surveyed members worldwide to identify concerns they have about using genetic testing in practice. In results presented as a late-breaking abstract at the International Congress of Parkinson’s Disease and Movement Disorders, the survey found that clinicians have concerns about test costs, availability of genetic counseling and finding the time for both testing and genetic counseling, among a host of others.

“Some of the major outstanding issues are the clinical actionability of genetic testing – and this was highlighted by some survey participants,” senior study author Rachel Saunders-Pullman, MD, MPH, professor of neurology at the Icahn School of Medicine at Mount Sinai, New York, said in an interview. The issue is “dynamic,” and will change even more radically when genetic therapies for Parkinson’s disease become available. “It is planned that, in the development of the MDS Task Force guidelines, scenarios which outline the changes in consideration of testing will depend on the availability of clinically actionable data,” she said.
 

Barriers to genetic testing

The MDS Task Force for Genetic Testing in Parkinson Disease conducted the survey, completed online by 568 MDS members. Respondents were from the four regions from which the MDS draws members: Africa, Europe, Asia/Oceania, and Pan-America. Half of the respondents considered themselves movement disorder specialists and 31% as general neurologists, said Maggie Markgraf, research coordinator at Mount Sinai Beth Israel in New York, who presented the survey findings.

Barriers to genetic testing that the clinicians cited included cost (57%), lack of availability of genetic counseling (37%), time for testing (20%) or time for counseling (17%). About 14%also cited a lack of knowledge, and only 8.5 % said they saw no barriers for genetic testing. Other concerns included a lack of therapeutic options if tests are positive and low overall positivity rates.

“Perceived barriers for general neurologists differed slightly, with limited knowledge being the most widely reported barrier, followed closely by cost and access to testing and genetic counseling,” Ms. Markgraf said.

Respondents were also asked to identify what they thought their patients perceived as barriers to genetic testing. The major one was cost (65%), followed by limited knowledge about genetics (43%), lack of access to genetic counseling (34%), and lack of access to testing separate from cost (30%). “Across all MDS regions, the perceived level of a patient’s knowledge about genetic testing is considered to be exceedingly low,” Ms. Markgraf said.

Europe had the highest availability to genetic tests, with 41.8% saying they’re accessible to general neurologists, followed by Asia/Oceania (31%) and Pan-America (30%).

“The area of most unmet need when it comes to PD genetic testing was cost for each MDS region, although the intertwined issue of access was also high, and over 50% reported that knowledge was an unmet need in their region,” Dr. Saunders-Pullman said.

Insurance coverage was another issue the survey respondents identified. In Europe, 53.6% said insurance or government programs cover genetic testing for PD, while only 14% in Pan-America and 10.3% in Asia/Oceania (and 0% in Africa) said such coverage was available.

“While there are limitations to this study, greater awareness of availability and barriers to genetic testing and counseling across different regions, as well as disparities among regions, will help inform development of the MDS Task Force guidelines,” Dr. Saunders-Pullman said.
 

Unmet needs

Connie Marras, MD, PhD, a professor of neurology at the University of Toronto, noted the survey suggested neurologists exhibit a “lack of comfort or lack of time” with genetic testing and counseling for Parkinson’s disease. “Even if we make genetic testing more widely available, we need health care providers that are comfortable and available to counsel patients before and after the testing, and clearly these are unmet needs,” Dr. Marras said in an interview.

“To date, pharmacologic treatment of Parkinson’s disease did not depend on genetics,” Dr. Marras said. “This may well change in the near future with treatments specifically targeting mechanisms related to two of the most common genetic risk factors for PD: LRRK2 and GBA gene variants being in clinical trials.” These developments may soon raise the urgency to reduce barriers to genetic testing.

Dr. Saunders-Pullman and Dr. Marras have no relevant relationships to disclose.

Before getting to work on developing guidelines for genetic testing in Parkinson’s disease, a task force of the Movement Disorders Society surveyed members worldwide to identify concerns they have about using genetic testing in practice. In results presented as a late-breaking abstract at the International Congress of Parkinson’s Disease and Movement Disorders, the survey found that clinicians have concerns about test costs, availability of genetic counseling and finding the time for both testing and genetic counseling, among a host of others.

“Some of the major outstanding issues are the clinical actionability of genetic testing – and this was highlighted by some survey participants,” senior study author Rachel Saunders-Pullman, MD, MPH, professor of neurology at the Icahn School of Medicine at Mount Sinai, New York, said in an interview. The issue is “dynamic,” and will change even more radically when genetic therapies for Parkinson’s disease become available. “It is planned that, in the development of the MDS Task Force guidelines, scenarios which outline the changes in consideration of testing will depend on the availability of clinically actionable data,” she said.
 

Barriers to genetic testing

The MDS Task Force for Genetic Testing in Parkinson Disease conducted the survey, completed online by 568 MDS members. Respondents were from the four regions from which the MDS draws members: Africa, Europe, Asia/Oceania, and Pan-America. Half of the respondents considered themselves movement disorder specialists and 31% as general neurologists, said Maggie Markgraf, research coordinator at Mount Sinai Beth Israel in New York, who presented the survey findings.

Barriers to genetic testing that the clinicians cited included cost (57%), lack of availability of genetic counseling (37%), time for testing (20%) or time for counseling (17%). About 14%also cited a lack of knowledge, and only 8.5 % said they saw no barriers for genetic testing. Other concerns included a lack of therapeutic options if tests are positive and low overall positivity rates.

“Perceived barriers for general neurologists differed slightly, with limited knowledge being the most widely reported barrier, followed closely by cost and access to testing and genetic counseling,” Ms. Markgraf said.

Respondents were also asked to identify what they thought their patients perceived as barriers to genetic testing. The major one was cost (65%), followed by limited knowledge about genetics (43%), lack of access to genetic counseling (34%), and lack of access to testing separate from cost (30%). “Across all MDS regions, the perceived level of a patient’s knowledge about genetic testing is considered to be exceedingly low,” Ms. Markgraf said.

Europe had the highest availability to genetic tests, with 41.8% saying they’re accessible to general neurologists, followed by Asia/Oceania (31%) and Pan-America (30%).

“The area of most unmet need when it comes to PD genetic testing was cost for each MDS region, although the intertwined issue of access was also high, and over 50% reported that knowledge was an unmet need in their region,” Dr. Saunders-Pullman said.

Insurance coverage was another issue the survey respondents identified. In Europe, 53.6% said insurance or government programs cover genetic testing for PD, while only 14% in Pan-America and 10.3% in Asia/Oceania (and 0% in Africa) said such coverage was available.

“While there are limitations to this study, greater awareness of availability and barriers to genetic testing and counseling across different regions, as well as disparities among regions, will help inform development of the MDS Task Force guidelines,” Dr. Saunders-Pullman said.
 

Unmet needs

Connie Marras, MD, PhD, a professor of neurology at the University of Toronto, noted the survey suggested neurologists exhibit a “lack of comfort or lack of time” with genetic testing and counseling for Parkinson’s disease. “Even if we make genetic testing more widely available, we need health care providers that are comfortable and available to counsel patients before and after the testing, and clearly these are unmet needs,” Dr. Marras said in an interview.

“To date, pharmacologic treatment of Parkinson’s disease did not depend on genetics,” Dr. Marras said. “This may well change in the near future with treatments specifically targeting mechanisms related to two of the most common genetic risk factors for PD: LRRK2 and GBA gene variants being in clinical trials.” These developments may soon raise the urgency to reduce barriers to genetic testing.

Dr. Saunders-Pullman and Dr. Marras have no relevant relationships to disclose.

Before getting to work on developing guidelines for genetic testing in Parkinson’s disease, a task force of the Movement Disorders Society surveyed members worldwide to identify concerns they have about using genetic testing in practice. In results presented as a late-breaking abstract at the International Congress of Parkinson’s Disease and Movement Disorders, the survey found that clinicians have concerns about test costs, availability of genetic counseling and finding the time for both testing and genetic counseling, among a host of others.

“Some of the major outstanding issues are the clinical actionability of genetic testing – and this was highlighted by some survey participants,” senior study author Rachel Saunders-Pullman, MD, MPH, professor of neurology at the Icahn School of Medicine at Mount Sinai, New York, said in an interview. The issue is “dynamic,” and will change even more radically when genetic therapies for Parkinson’s disease become available. “It is planned that, in the development of the MDS Task Force guidelines, scenarios which outline the changes in consideration of testing will depend on the availability of clinically actionable data,” she said.
 

Barriers to genetic testing

The MDS Task Force for Genetic Testing in Parkinson Disease conducted the survey, completed online by 568 MDS members. Respondents were from the four regions from which the MDS draws members: Africa, Europe, Asia/Oceania, and Pan-America. Half of the respondents considered themselves movement disorder specialists and 31% as general neurologists, said Maggie Markgraf, research coordinator at Mount Sinai Beth Israel in New York, who presented the survey findings.

Barriers to genetic testing that the clinicians cited included cost (57%), lack of availability of genetic counseling (37%), time for testing (20%) or time for counseling (17%). About 14%also cited a lack of knowledge, and only 8.5 % said they saw no barriers for genetic testing. Other concerns included a lack of therapeutic options if tests are positive and low overall positivity rates.

“Perceived barriers for general neurologists differed slightly, with limited knowledge being the most widely reported barrier, followed closely by cost and access to testing and genetic counseling,” Ms. Markgraf said.

Respondents were also asked to identify what they thought their patients perceived as barriers to genetic testing. The major one was cost (65%), followed by limited knowledge about genetics (43%), lack of access to genetic counseling (34%), and lack of access to testing separate from cost (30%). “Across all MDS regions, the perceived level of a patient’s knowledge about genetic testing is considered to be exceedingly low,” Ms. Markgraf said.

Europe had the highest availability to genetic tests, with 41.8% saying they’re accessible to general neurologists, followed by Asia/Oceania (31%) and Pan-America (30%).

“The area of most unmet need when it comes to PD genetic testing was cost for each MDS region, although the intertwined issue of access was also high, and over 50% reported that knowledge was an unmet need in their region,” Dr. Saunders-Pullman said.

Insurance coverage was another issue the survey respondents identified. In Europe, 53.6% said insurance or government programs cover genetic testing for PD, while only 14% in Pan-America and 10.3% in Asia/Oceania (and 0% in Africa) said such coverage was available.

“While there are limitations to this study, greater awareness of availability and barriers to genetic testing and counseling across different regions, as well as disparities among regions, will help inform development of the MDS Task Force guidelines,” Dr. Saunders-Pullman said.
 

Unmet needs

Connie Marras, MD, PhD, a professor of neurology at the University of Toronto, noted the survey suggested neurologists exhibit a “lack of comfort or lack of time” with genetic testing and counseling for Parkinson’s disease. “Even if we make genetic testing more widely available, we need health care providers that are comfortable and available to counsel patients before and after the testing, and clearly these are unmet needs,” Dr. Marras said in an interview.

“To date, pharmacologic treatment of Parkinson’s disease did not depend on genetics,” Dr. Marras said. “This may well change in the near future with treatments specifically targeting mechanisms related to two of the most common genetic risk factors for PD: LRRK2 and GBA gene variants being in clinical trials.” These developments may soon raise the urgency to reduce barriers to genetic testing.

Dr. Saunders-Pullman and Dr. Marras have no relevant relationships to disclose.

Medicare reimbursement for a group of 46 common dermatologic procedures dropped by a mean of 4.8% from 2007 to 2021, after adjusting for inflation, according to a new analysis.

Large increases in mean reimbursement for skin biopsies (+30.3%) and shave removal (+24.6%) were not enough to offset lower rates for procedures such as simple repair (–38.7%), premalignant destruction (–19.6%), Mohs micrographic surgery (–14.4%), and flap repair (–14.1%), Rishabh S. Mazmudar, BS, of Case Western Reserve University, Cleveland, and associates said.

“Given Medicare’s contribution to a large proportion of health care expenditures, changes in Medicare reimbursement rates may result in parallel changes in private insurance reimbursement,” they wrote in JAMA Dermatology.

A recently published study showed that Medicare reimbursement for 20 dermatologic service codes had fallen by 10% between the two comparison years, 2000 and 2020. The current study expanded the number of procedures to 46 (divided into nine categories) and used historical Medicare fee schedules to examine annual trends over a 15-year period, Mr. Mazmudar and associates explained.

Other specialties have seen reimbursement fall by more than 4.8%, including emergency medicine (–21.2% from 2000 to 2020) and general surgery (–24.4% from 2000 to 2018), but “these comparisons are likely skewed by the disproportionate increase in reimbursement rates for biopsies and shave removals during this time period,” the investigators said.

If those two procedure categories were excluded from the analysis, the mean change in overall reimbursement for the remaining dermatologic procedures would be −9.6%, they noted.

Detailed payment information provided for 15 of the 46 procedures shows that only intermediate repair (+4.5%) and benign destruction (+2.3%) joined biopsies and shave excisions with increased reimbursement from 2007 to 2021. The smallest drop among the other procedures was –1.9% for malignant destruction, the research team reported.

The inflation-adjusted, year-by-year analysis showed that reimbursement for the nine procedure categories has gradually declined since peaking in 2011, with the most notable exceptions being biopsies and shave excisions. Both had been following the trend until 2013, when reimbursement for shave removals jumped by almost 30 percentage points, and 2019, when rates for biopsies soared by more than 30 percentage points, according to the investigators.

The increase for skin biopsies followed the split of the original CPT code into three categories, but “the jump in reimbursement for shave removals in 2013 requires further investigation,” Mr. Mazmudar and associates wrote.

The investigators did not disclose any conflicts of interest.

rfranki@mdedge.com

Medicare reimbursement for a group of 46 common dermatologic procedures dropped by a mean of 4.8% from 2007 to 2021, after adjusting for inflation, according to a new analysis.

Large increases in mean reimbursement for skin biopsies (+30.3%) and shave removal (+24.6%) were not enough to offset lower rates for procedures such as simple repair (–38.7%), premalignant destruction (–19.6%), Mohs micrographic surgery (–14.4%), and flap repair (–14.1%), Rishabh S. Mazmudar, BS, of Case Western Reserve University, Cleveland, and associates said.

“Given Medicare’s contribution to a large proportion of health care expenditures, changes in Medicare reimbursement rates may result in parallel changes in private insurance reimbursement,” they wrote in JAMA Dermatology.

A recently published study showed that Medicare reimbursement for 20 dermatologic service codes had fallen by 10% between the two comparison years, 2000 and 2020. The current study expanded the number of procedures to 46 (divided into nine categories) and used historical Medicare fee schedules to examine annual trends over a 15-year period, Mr. Mazmudar and associates explained.

Other specialties have seen reimbursement fall by more than 4.8%, including emergency medicine (–21.2% from 2000 to 2020) and general surgery (–24.4% from 2000 to 2018), but “these comparisons are likely skewed by the disproportionate increase in reimbursement rates for biopsies and shave removals during this time period,” the investigators said.

If those two procedure categories were excluded from the analysis, the mean change in overall reimbursement for the remaining dermatologic procedures would be −9.6%, they noted.

Detailed payment information provided for 15 of the 46 procedures shows that only intermediate repair (+4.5%) and benign destruction (+2.3%) joined biopsies and shave excisions with increased reimbursement from 2007 to 2021. The smallest drop among the other procedures was –1.9% for malignant destruction, the research team reported.

The inflation-adjusted, year-by-year analysis showed that reimbursement for the nine procedure categories has gradually declined since peaking in 2011, with the most notable exceptions being biopsies and shave excisions. Both had been following the trend until 2013, when reimbursement for shave removals jumped by almost 30 percentage points, and 2019, when rates for biopsies soared by more than 30 percentage points, according to the investigators.

The increase for skin biopsies followed the split of the original CPT code into three categories, but “the jump in reimbursement for shave removals in 2013 requires further investigation,” Mr. Mazmudar and associates wrote.

The investigators did not disclose any conflicts of interest.

rfranki@mdedge.com

Medicare reimbursement for a group of 46 common dermatologic procedures dropped by a mean of 4.8% from 2007 to 2021, after adjusting for inflation, according to a new analysis.

Large increases in mean reimbursement for skin biopsies (+30.3%) and shave removal (+24.6%) were not enough to offset lower rates for procedures such as simple repair (–38.7%), premalignant destruction (–19.6%), Mohs micrographic surgery (–14.4%), and flap repair (–14.1%), Rishabh S. Mazmudar, BS, of Case Western Reserve University, Cleveland, and associates said.

“Given Medicare’s contribution to a large proportion of health care expenditures, changes in Medicare reimbursement rates may result in parallel changes in private insurance reimbursement,” they wrote in JAMA Dermatology.

A recently published study showed that Medicare reimbursement for 20 dermatologic service codes had fallen by 10% between the two comparison years, 2000 and 2020. The current study expanded the number of procedures to 46 (divided into nine categories) and used historical Medicare fee schedules to examine annual trends over a 15-year period, Mr. Mazmudar and associates explained.

Other specialties have seen reimbursement fall by more than 4.8%, including emergency medicine (–21.2% from 2000 to 2020) and general surgery (–24.4% from 2000 to 2018), but “these comparisons are likely skewed by the disproportionate increase in reimbursement rates for biopsies and shave removals during this time period,” the investigators said.

If those two procedure categories were excluded from the analysis, the mean change in overall reimbursement for the remaining dermatologic procedures would be −9.6%, they noted.

Detailed payment information provided for 15 of the 46 procedures shows that only intermediate repair (+4.5%) and benign destruction (+2.3%) joined biopsies and shave excisions with increased reimbursement from 2007 to 2021. The smallest drop among the other procedures was –1.9% for malignant destruction, the research team reported.

The inflation-adjusted, year-by-year analysis showed that reimbursement for the nine procedure categories has gradually declined since peaking in 2011, with the most notable exceptions being biopsies and shave excisions. Both had been following the trend until 2013, when reimbursement for shave removals jumped by almost 30 percentage points, and 2019, when rates for biopsies soared by more than 30 percentage points, according to the investigators.

The increase for skin biopsies followed the split of the original CPT code into three categories, but “the jump in reimbursement for shave removals in 2013 requires further investigation,” Mr. Mazmudar and associates wrote.

The investigators did not disclose any conflicts of interest.

rfranki@mdedge.com

“Evidence alone is not sufficient for clinical decision-making, particularly in chronic pain,” said Jason Busse, DC, PhD, director of Michael G. DeGroote Centre for Medicinal Cannabis Research at McMaster University, Hamilton, Ont., and lead author of a newly released rapid guideline on medical cannabis or cannabinoids for chronic pain.

McMaster University

The recommendations, published online Sept. 9, 2021 in the British Medical Journal, suggest that providers offer patients with chronic pain a trial of noninhaled medical cannabis or cannabinoids if standard care or management is ineffective. However, the “weak” rating attached to the recommendation may compel some clinicians to automatically write off the panel’s recommendations.

“Because of the close balance between benefits and harms and wide variability in patient attitudes, the panel came to the conclusion that [some] patients presented with the current best evidence would likely choose to engage in a trial of medicinal cannabis, if their current care was felt to be suboptimal,” Dr. Busse explained in an interview.

But more importantly, “the recommendation allows for shared decision making to occur, and for different patients to make different decisions based on individual preferences and circumstances,” he said.
 

Evidence supports improved pain and sleep quality, physical functioning

Evidence supporting the use of medical cannabis in chronic pain is derived from a rigorous systematic review and meta-analysis of 32 studies enrolling 5,174 patients randomized to oral (capsule, spray, sublingual drops) or topical (transdermal cream) medical cannabis or placebo. Of note, three types of cannabinoids were represented: phytocannabinoids, synthetic, and endocannabinoids.

The studies included both patients with chronic noncancer pain (28 studies, n = 3,812) and chronic cancer pain not receiving palliative care (4 studies, n = 1,362). On average, baseline pain scores were a median 6.28 cm on a 10-cm visual analog scale (VAS), and median participant age was 53 years. 60% of trials reporting sex differences enrolled female participants. Overall, patients were followed for roughly 2 months (median, 50 days).

Findings (27 studies, n = 3,939) showed that, compared with placebo, medical cannabis resulted in a small, albeit important, improvement in the proportion of patients experiencing pain relief at or above the minimally important difference (MID) (moderate-certainty evidence, 10% modeled risk difference [RD; 95% confidence interval, 5%-15%] for achieving at least the MID of 1 cm).

Medical cannabis (15 studies, n = 2,425) also provided a small increase in the proportion of patients experiencing improvements in physical functioning at or above the MID (high certainty evidence, 4% modeled RD [95% CI, 0.1%-8%] for achieving at least a MID of 10 points).

Additionally, participants experienced significant improvements in sleep quality, compared with placebo (16 studies, 3,124 participants, high-quality evidence), demonstrating a weighted mean difference of –0.53 cm on a 10-cm VAS (95% CI, –0.75 to –0.30 cm). A total of nine larger trials (n = 2,652, high-certainty evidence) saw a small increase in the proportion of patients experiencing improved sleep quality at or above the MID: 6% modeled RD (95% CI, 2%-9%).

On the other hand, benefits did not extend to emotional, role, or social functioning (high-certainty evidence).

First do no harm: Start low, go slow

While these findings provide a rationale for medical cannabis in chronic pain, exploring options with patients can be challenging. Studies on medical cannabis consistently note that patients want information, but data also show that many providers express a lack of knowledge to provide adequate counseling.

There are also legal hurdles. Despite the authorization of medicinal cannabis across a majority of states and territories, cannabis is still a schedule I substance under the Federal Controlled Substances Act. In addition, the absence of standards around formulations, potency, and dosing has also been cited as a major barrier to recommending medical cannabis, as have concerns about adverse events (AEs), especially with inhaled and tetrahydrocannabinol (THC)-predominant formulations.

Like most medications, medical cannabis dosing should be individualized depending on product, patient, and ability to titrate the dose, but the guidelines provide a general rule of thumb. Providers considering therapeutic noninhaled medical cannabis trials are encouraged to start with a low-dose cannabidiol (CBD) oral tablet, spray, or sublingual oil drops 5 mg twice daily, increasing it by 10 mg every 2-3 days depending on the clinical response (to a maximum daily dose of 40 mg/day). If patient response is unsatisfactory, they should consider adding 1-2.5 mg THC/daily, titrated every 2-7 days to a maximum of 40 mg/day.

Still, an important caveat is whether or not adjunctive CBD alone is effective for chronic pain.

Dr. Ziva Cooper

“While we know that one out of seven U.S. adults are using cannabidiol, we know very little about its therapeutic effects when given by itself for pain,” Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, and an associate professor at-large of psychology and behavioral science, said in an interview. (Dr. Cooper was not involved in the guideline development.)

“But patients tend to self-report that CBD is helpful, and at low doses, we know that it is unlikely to have adverse effects of any significant concern,” Dr. Cooper noted.

Depending on its components, medical cannabis is associated with a wide range of AEs. Studies comprising the evidence base for the guideline reported transient cognitive impairment (relative risk, 2.39; 95% CI, 1.06-5.38), vomiting (RR, 1.46; 95% CI, 1.07-1.99), and drowsiness (RR, 2.14; 95% CI, 1.55-2.95), attention impairment (RR, 4.04; 95% CI, 1.67-9.74), and nausea (RR, 1.59; 95% CI, 1.28-1.99). Of note, findings of a subgroup analysis showed that the risk of dizziness increased with treatment duration, starting at 3 months (test of interaction P = .002).

However, Dr. Cooper explained that, because the included studies were inconsistent in terms of cannabis type (e.g., some looked at synthetic THC or THC-like substances where others looked at a THC/CBD combination) and formulation (capsules, oral mucosal sprays), it’s difficult to tease out component-specific AEs.

“These are really important things to note, especially when you think about different populations that might be using these types of medicines moving forward,” she said.

Toward that end, the guideline specifically states that there is “no reason why the expected benefits would be systematically different among adolescents and emerging adults.”

Among children with cancer, prior study findings reinforce the conclusion that benefits are similar to adults, but studies in this area are limited to end-of-life treatment, childhood cancer with primarily palliative intent, or progressive or relapsed cancer. Because THC’s safety profile is less certain in children, it’s also important to consider adverse neurocognitive effects before initiating a medical cannabis trial in this population.
 

Navigating the landscape

Although promising, the medical cannabis landscape is undoubtedly difficult to navigate, with land mines ranging from a limited inability to simply pick up a prescribing pad to quality control.

With the exception of three Food and Drug Administration–approved products – dronabinol, cannabidiol Rx, and nabilone – U.S. providers are only able to ‘certify,’ not prescribe, medical cannabis for chronic pain, and only if it is included within the state cannabis board’s list of eligible conditions. (A state-by-state guide is available.)

Dr. Jenny Wilkerson

Quality control also varies by product but is critical. “You want to look for certificates of quality assurance,” Jenny Wilkerson, PhD, a research assistant professor of pharmacodynamics at the University of Florida, Gainesville, said in an interview. (Dr. Wilkerson was not involved in the guideline development.)

“A good dispensary should have that information or at least be willing to get that information, but generally speaking, that is something that patients need to ask for,” she emphasized, noting that “most available mass readouts are not divided by lots.”

Initial counseling and AE monitoring and regular follow-up is important, especially among patients who’ve never tried medical cannabis (or older patients whose prior experience may be limited to weaker recreational marijuana).

Notably, the reliance on medical dispensaries to deliver the right information at the right time may prove to be faulty. While recent data show that frontline dispensary workers regularly provide information to customers on their medical conditions and available products, they rarely, if ever, base recommendations on provider input, and never or rarely discuss potential AEs and other risks.

Per the new guideline, inexperienced patients should be seen monthly until a stable dose is achieved; longer times between visits can be considered in those who are more experienced. Still, patients should be advised to contact their provider when pain relief or other goals are insufficient, or when response or problematic AEs occur. This facilitates down-titration to a previously tolerated dose, up-titration in CBD and/or THC, or a different route of administration/formulation altogether.

Dr. Wilkerson pointed out that follow-up visits also provide an opportunity to do a blood draw and ask the lab to conduct pharmacokinetic analysis.

If possible, “ask patients to [ensure that they] take a standard dose before the visit so that the lab can assess the blood percentage of primary compounds and metabolites in the product that they are using,” she explained, noting that the information is helping to determine how “the different ratios may be affecting therapeutic response in individual patients.”

Granted, the guideline is only a start. But it is a good one.

“A lot of physicians want to be able to hang their hat on evidence of the safety and efficacy of these products, and the analysis that was leveraged for this guideline was very rigorous,” Dr. Cooper said.

Not only do they reinforce that “oral cannabinoids can produce small improvements in pain and provide a dosing structure that minimizes risk to the patient, [but they] should be able to help educate physicians who [are looking] for a sense of what the literature tells us at this time,” she added.

“With chronic pain, we often find that different treatments will show small potential benefits and they have a certain risk profile,” Dr. Busse said.

“It’s almost impossible to know what patients think about this option unless you present them with the evidence and ask them to make a decision based on their values and preferences,” he said.

The Michael G. DeGroote Centre for Medicinal Cannabis Research funded the MAGIC Evidence Ecosystem Foundation to support the creation of the guideline. The center receives no funding from industry Dr. Busse, Dr. Cooper, and Dr. Wilkerson reported having no relevant financial relationships.

“Evidence alone is not sufficient for clinical decision-making, particularly in chronic pain,” said Jason Busse, DC, PhD, director of Michael G. DeGroote Centre for Medicinal Cannabis Research at McMaster University, Hamilton, Ont., and lead author of a newly released rapid guideline on medical cannabis or cannabinoids for chronic pain.

McMaster University

The recommendations, published online Sept. 9, 2021 in the British Medical Journal, suggest that providers offer patients with chronic pain a trial of noninhaled medical cannabis or cannabinoids if standard care or management is ineffective. However, the “weak” rating attached to the recommendation may compel some clinicians to automatically write off the panel’s recommendations.

“Because of the close balance between benefits and harms and wide variability in patient attitudes, the panel came to the conclusion that [some] patients presented with the current best evidence would likely choose to engage in a trial of medicinal cannabis, if their current care was felt to be suboptimal,” Dr. Busse explained in an interview.

But more importantly, “the recommendation allows for shared decision making to occur, and for different patients to make different decisions based on individual preferences and circumstances,” he said.
 

Evidence supports improved pain and sleep quality, physical functioning

Evidence supporting the use of medical cannabis in chronic pain is derived from a rigorous systematic review and meta-analysis of 32 studies enrolling 5,174 patients randomized to oral (capsule, spray, sublingual drops) or topical (transdermal cream) medical cannabis or placebo. Of note, three types of cannabinoids were represented: phytocannabinoids, synthetic, and endocannabinoids.

The studies included both patients with chronic noncancer pain (28 studies, n = 3,812) and chronic cancer pain not receiving palliative care (4 studies, n = 1,362). On average, baseline pain scores were a median 6.28 cm on a 10-cm visual analog scale (VAS), and median participant age was 53 years. 60% of trials reporting sex differences enrolled female participants. Overall, patients were followed for roughly 2 months (median, 50 days).

Findings (27 studies, n = 3,939) showed that, compared with placebo, medical cannabis resulted in a small, albeit important, improvement in the proportion of patients experiencing pain relief at or above the minimally important difference (MID) (moderate-certainty evidence, 10% modeled risk difference [RD; 95% confidence interval, 5%-15%] for achieving at least the MID of 1 cm).

Medical cannabis (15 studies, n = 2,425) also provided a small increase in the proportion of patients experiencing improvements in physical functioning at or above the MID (high certainty evidence, 4% modeled RD [95% CI, 0.1%-8%] for achieving at least a MID of 10 points).

Additionally, participants experienced significant improvements in sleep quality, compared with placebo (16 studies, 3,124 participants, high-quality evidence), demonstrating a weighted mean difference of –0.53 cm on a 10-cm VAS (95% CI, –0.75 to –0.30 cm). A total of nine larger trials (n = 2,652, high-certainty evidence) saw a small increase in the proportion of patients experiencing improved sleep quality at or above the MID: 6% modeled RD (95% CI, 2%-9%).

On the other hand, benefits did not extend to emotional, role, or social functioning (high-certainty evidence).

First do no harm: Start low, go slow

While these findings provide a rationale for medical cannabis in chronic pain, exploring options with patients can be challenging. Studies on medical cannabis consistently note that patients want information, but data also show that many providers express a lack of knowledge to provide adequate counseling.

There are also legal hurdles. Despite the authorization of medicinal cannabis across a majority of states and territories, cannabis is still a schedule I substance under the Federal Controlled Substances Act. In addition, the absence of standards around formulations, potency, and dosing has also been cited as a major barrier to recommending medical cannabis, as have concerns about adverse events (AEs), especially with inhaled and tetrahydrocannabinol (THC)-predominant formulations.

Like most medications, medical cannabis dosing should be individualized depending on product, patient, and ability to titrate the dose, but the guidelines provide a general rule of thumb. Providers considering therapeutic noninhaled medical cannabis trials are encouraged to start with a low-dose cannabidiol (CBD) oral tablet, spray, or sublingual oil drops 5 mg twice daily, increasing it by 10 mg every 2-3 days depending on the clinical response (to a maximum daily dose of 40 mg/day). If patient response is unsatisfactory, they should consider adding 1-2.5 mg THC/daily, titrated every 2-7 days to a maximum of 40 mg/day.

Still, an important caveat is whether or not adjunctive CBD alone is effective for chronic pain.

Dr. Ziva Cooper

“While we know that one out of seven U.S. adults are using cannabidiol, we know very little about its therapeutic effects when given by itself for pain,” Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, and an associate professor at-large of psychology and behavioral science, said in an interview. (Dr. Cooper was not involved in the guideline development.)

“But patients tend to self-report that CBD is helpful, and at low doses, we know that it is unlikely to have adverse effects of any significant concern,” Dr. Cooper noted.

Depending on its components, medical cannabis is associated with a wide range of AEs. Studies comprising the evidence base for the guideline reported transient cognitive impairment (relative risk, 2.39; 95% CI, 1.06-5.38), vomiting (RR, 1.46; 95% CI, 1.07-1.99), and drowsiness (RR, 2.14; 95% CI, 1.55-2.95), attention impairment (RR, 4.04; 95% CI, 1.67-9.74), and nausea (RR, 1.59; 95% CI, 1.28-1.99). Of note, findings of a subgroup analysis showed that the risk of dizziness increased with treatment duration, starting at 3 months (test of interaction P = .002).

However, Dr. Cooper explained that, because the included studies were inconsistent in terms of cannabis type (e.g., some looked at synthetic THC or THC-like substances where others looked at a THC/CBD combination) and formulation (capsules, oral mucosal sprays), it’s difficult to tease out component-specific AEs.

“These are really important things to note, especially when you think about different populations that might be using these types of medicines moving forward,” she said.

Toward that end, the guideline specifically states that there is “no reason why the expected benefits would be systematically different among adolescents and emerging adults.”

Among children with cancer, prior study findings reinforce the conclusion that benefits are similar to adults, but studies in this area are limited to end-of-life treatment, childhood cancer with primarily palliative intent, or progressive or relapsed cancer. Because THC’s safety profile is less certain in children, it’s also important to consider adverse neurocognitive effects before initiating a medical cannabis trial in this population.
 

Navigating the landscape

Although promising, the medical cannabis landscape is undoubtedly difficult to navigate, with land mines ranging from a limited inability to simply pick up a prescribing pad to quality control.

With the exception of three Food and Drug Administration–approved products – dronabinol, cannabidiol Rx, and nabilone – U.S. providers are only able to ‘certify,’ not prescribe, medical cannabis for chronic pain, and only if it is included within the state cannabis board’s list of eligible conditions. (A state-by-state guide is available.)

Dr. Jenny Wilkerson

Quality control also varies by product but is critical. “You want to look for certificates of quality assurance,” Jenny Wilkerson, PhD, a research assistant professor of pharmacodynamics at the University of Florida, Gainesville, said in an interview. (Dr. Wilkerson was not involved in the guideline development.)

“A good dispensary should have that information or at least be willing to get that information, but generally speaking, that is something that patients need to ask for,” she emphasized, noting that “most available mass readouts are not divided by lots.”

Initial counseling and AE monitoring and regular follow-up is important, especially among patients who’ve never tried medical cannabis (or older patients whose prior experience may be limited to weaker recreational marijuana).

Notably, the reliance on medical dispensaries to deliver the right information at the right time may prove to be faulty. While recent data show that frontline dispensary workers regularly provide information to customers on their medical conditions and available products, they rarely, if ever, base recommendations on provider input, and never or rarely discuss potential AEs and other risks.

Per the new guideline, inexperienced patients should be seen monthly until a stable dose is achieved; longer times between visits can be considered in those who are more experienced. Still, patients should be advised to contact their provider when pain relief or other goals are insufficient, or when response or problematic AEs occur. This facilitates down-titration to a previously tolerated dose, up-titration in CBD and/or THC, or a different route of administration/formulation altogether.

Dr. Wilkerson pointed out that follow-up visits also provide an opportunity to do a blood draw and ask the lab to conduct pharmacokinetic analysis.

If possible, “ask patients to [ensure that they] take a standard dose before the visit so that the lab can assess the blood percentage of primary compounds and metabolites in the product that they are using,” she explained, noting that the information is helping to determine how “the different ratios may be affecting therapeutic response in individual patients.”

Granted, the guideline is only a start. But it is a good one.

“A lot of physicians want to be able to hang their hat on evidence of the safety and efficacy of these products, and the analysis that was leveraged for this guideline was very rigorous,” Dr. Cooper said.

Not only do they reinforce that “oral cannabinoids can produce small improvements in pain and provide a dosing structure that minimizes risk to the patient, [but they] should be able to help educate physicians who [are looking] for a sense of what the literature tells us at this time,” she added.

“With chronic pain, we often find that different treatments will show small potential benefits and they have a certain risk profile,” Dr. Busse said.

“It’s almost impossible to know what patients think about this option unless you present them with the evidence and ask them to make a decision based on their values and preferences,” he said.

The Michael G. DeGroote Centre for Medicinal Cannabis Research funded the MAGIC Evidence Ecosystem Foundation to support the creation of the guideline. The center receives no funding from industry Dr. Busse, Dr. Cooper, and Dr. Wilkerson reported having no relevant financial relationships.

“Evidence alone is not sufficient for clinical decision-making, particularly in chronic pain,” said Jason Busse, DC, PhD, director of Michael G. DeGroote Centre for Medicinal Cannabis Research at McMaster University, Hamilton, Ont., and lead author of a newly released rapid guideline on medical cannabis or cannabinoids for chronic pain.

McMaster University

The recommendations, published online Sept. 9, 2021 in the British Medical Journal, suggest that providers offer patients with chronic pain a trial of noninhaled medical cannabis or cannabinoids if standard care or management is ineffective. However, the “weak” rating attached to the recommendation may compel some clinicians to automatically write off the panel’s recommendations.

“Because of the close balance between benefits and harms and wide variability in patient attitudes, the panel came to the conclusion that [some] patients presented with the current best evidence would likely choose to engage in a trial of medicinal cannabis, if their current care was felt to be suboptimal,” Dr. Busse explained in an interview.

But more importantly, “the recommendation allows for shared decision making to occur, and for different patients to make different decisions based on individual preferences and circumstances,” he said.
 

Evidence supports improved pain and sleep quality, physical functioning

Evidence supporting the use of medical cannabis in chronic pain is derived from a rigorous systematic review and meta-analysis of 32 studies enrolling 5,174 patients randomized to oral (capsule, spray, sublingual drops) or topical (transdermal cream) medical cannabis or placebo. Of note, three types of cannabinoids were represented: phytocannabinoids, synthetic, and endocannabinoids.

The studies included both patients with chronic noncancer pain (28 studies, n = 3,812) and chronic cancer pain not receiving palliative care (4 studies, n = 1,362). On average, baseline pain scores were a median 6.28 cm on a 10-cm visual analog scale (VAS), and median participant age was 53 years. 60% of trials reporting sex differences enrolled female participants. Overall, patients were followed for roughly 2 months (median, 50 days).

Findings (27 studies, n = 3,939) showed that, compared with placebo, medical cannabis resulted in a small, albeit important, improvement in the proportion of patients experiencing pain relief at or above the minimally important difference (MID) (moderate-certainty evidence, 10% modeled risk difference [RD; 95% confidence interval, 5%-15%] for achieving at least the MID of 1 cm).

Medical cannabis (15 studies, n = 2,425) also provided a small increase in the proportion of patients experiencing improvements in physical functioning at or above the MID (high certainty evidence, 4% modeled RD [95% CI, 0.1%-8%] for achieving at least a MID of 10 points).

Additionally, participants experienced significant improvements in sleep quality, compared with placebo (16 studies, 3,124 participants, high-quality evidence), demonstrating a weighted mean difference of –0.53 cm on a 10-cm VAS (95% CI, –0.75 to –0.30 cm). A total of nine larger trials (n = 2,652, high-certainty evidence) saw a small increase in the proportion of patients experiencing improved sleep quality at or above the MID: 6% modeled RD (95% CI, 2%-9%).

On the other hand, benefits did not extend to emotional, role, or social functioning (high-certainty evidence).

First do no harm: Start low, go slow

While these findings provide a rationale for medical cannabis in chronic pain, exploring options with patients can be challenging. Studies on medical cannabis consistently note that patients want information, but data also show that many providers express a lack of knowledge to provide adequate counseling.

There are also legal hurdles. Despite the authorization of medicinal cannabis across a majority of states and territories, cannabis is still a schedule I substance under the Federal Controlled Substances Act. In addition, the absence of standards around formulations, potency, and dosing has also been cited as a major barrier to recommending medical cannabis, as have concerns about adverse events (AEs), especially with inhaled and tetrahydrocannabinol (THC)-predominant formulations.

Like most medications, medical cannabis dosing should be individualized depending on product, patient, and ability to titrate the dose, but the guidelines provide a general rule of thumb. Providers considering therapeutic noninhaled medical cannabis trials are encouraged to start with a low-dose cannabidiol (CBD) oral tablet, spray, or sublingual oil drops 5 mg twice daily, increasing it by 10 mg every 2-3 days depending on the clinical response (to a maximum daily dose of 40 mg/day). If patient response is unsatisfactory, they should consider adding 1-2.5 mg THC/daily, titrated every 2-7 days to a maximum of 40 mg/day.

Still, an important caveat is whether or not adjunctive CBD alone is effective for chronic pain.

Dr. Ziva Cooper

“While we know that one out of seven U.S. adults are using cannabidiol, we know very little about its therapeutic effects when given by itself for pain,” Ziva Cooper, PhD, director of the Cannabis Research Initiative at the University of California, Los Angeles, and an associate professor at-large of psychology and behavioral science, said in an interview. (Dr. Cooper was not involved in the guideline development.)

“But patients tend to self-report that CBD is helpful, and at low doses, we know that it is unlikely to have adverse effects of any significant concern,” Dr. Cooper noted.

Depending on its components, medical cannabis is associated with a wide range of AEs. Studies comprising the evidence base for the guideline reported transient cognitive impairment (relative risk, 2.39; 95% CI, 1.06-5.38), vomiting (RR, 1.46; 95% CI, 1.07-1.99), and drowsiness (RR, 2.14; 95% CI, 1.55-2.95), attention impairment (RR, 4.04; 95% CI, 1.67-9.74), and nausea (RR, 1.59; 95% CI, 1.28-1.99). Of note, findings of a subgroup analysis showed that the risk of dizziness increased with treatment duration, starting at 3 months (test of interaction P = .002).

However, Dr. Cooper explained that, because the included studies were inconsistent in terms of cannabis type (e.g., some looked at synthetic THC or THC-like substances where others looked at a THC/CBD combination) and formulation (capsules, oral mucosal sprays), it’s difficult to tease out component-specific AEs.

“These are really important things to note, especially when you think about different populations that might be using these types of medicines moving forward,” she said.

Toward that end, the guideline specifically states that there is “no reason why the expected benefits would be systematically different among adolescents and emerging adults.”

Among children with cancer, prior study findings reinforce the conclusion that benefits are similar to adults, but studies in this area are limited to end-of-life treatment, childhood cancer with primarily palliative intent, or progressive or relapsed cancer. Because THC’s safety profile is less certain in children, it’s also important to consider adverse neurocognitive effects before initiating a medical cannabis trial in this population.
 

Navigating the landscape

Although promising, the medical cannabis landscape is undoubtedly difficult to navigate, with land mines ranging from a limited inability to simply pick up a prescribing pad to quality control.

With the exception of three Food and Drug Administration–approved products – dronabinol, cannabidiol Rx, and nabilone – U.S. providers are only able to ‘certify,’ not prescribe, medical cannabis for chronic pain, and only if it is included within the state cannabis board’s list of eligible conditions. (A state-by-state guide is available.)

Dr. Jenny Wilkerson

Quality control also varies by product but is critical. “You want to look for certificates of quality assurance,” Jenny Wilkerson, PhD, a research assistant professor of pharmacodynamics at the University of Florida, Gainesville, said in an interview. (Dr. Wilkerson was not involved in the guideline development.)

“A good dispensary should have that information or at least be willing to get that information, but generally speaking, that is something that patients need to ask for,” she emphasized, noting that “most available mass readouts are not divided by lots.”

Initial counseling and AE monitoring and regular follow-up is important, especially among patients who’ve never tried medical cannabis (or older patients whose prior experience may be limited to weaker recreational marijuana).

Notably, the reliance on medical dispensaries to deliver the right information at the right time may prove to be faulty. While recent data show that frontline dispensary workers regularly provide information to customers on their medical conditions and available products, they rarely, if ever, base recommendations on provider input, and never or rarely discuss potential AEs and other risks.

Per the new guideline, inexperienced patients should be seen monthly until a stable dose is achieved; longer times between visits can be considered in those who are more experienced. Still, patients should be advised to contact their provider when pain relief or other goals are insufficient, or when response or problematic AEs occur. This facilitates down-titration to a previously tolerated dose, up-titration in CBD and/or THC, or a different route of administration/formulation altogether.

Dr. Wilkerson pointed out that follow-up visits also provide an opportunity to do a blood draw and ask the lab to conduct pharmacokinetic analysis.

If possible, “ask patients to [ensure that they] take a standard dose before the visit so that the lab can assess the blood percentage of primary compounds and metabolites in the product that they are using,” she explained, noting that the information is helping to determine how “the different ratios may be affecting therapeutic response in individual patients.”

Granted, the guideline is only a start. But it is a good one.

“A lot of physicians want to be able to hang their hat on evidence of the safety and efficacy of these products, and the analysis that was leveraged for this guideline was very rigorous,” Dr. Cooper said.

Not only do they reinforce that “oral cannabinoids can produce small improvements in pain and provide a dosing structure that minimizes risk to the patient, [but they] should be able to help educate physicians who [are looking] for a sense of what the literature tells us at this time,” she added.

“With chronic pain, we often find that different treatments will show small potential benefits and they have a certain risk profile,” Dr. Busse said.

“It’s almost impossible to know what patients think about this option unless you present them with the evidence and ask them to make a decision based on their values and preferences,” he said.

The Michael G. DeGroote Centre for Medicinal Cannabis Research funded the MAGIC Evidence Ecosystem Foundation to support the creation of the guideline. The center receives no funding from industry Dr. Busse, Dr. Cooper, and Dr. Wilkerson reported having no relevant financial relationships.

The Diagnosis: Dermatitis Neglecta

A punch biopsy of the abdomen revealed hyperkeratosis and mild papillomatosis (Figure), which can be seen in dermatitis neglecta (DN) and acanthosis nigricans (AN) as well as confluent and reticulated papillomatosis (CARP). Due to the patient’s history of mood and psychotic disorders, collateral information was obtained from the patient’s family, who reported that the patient had a depressed mood in the last few months and was not showering or caring for herself during this period. There was no additional personal or family history of skin disease. Clinical and histopathologic findings led to a diagnosis of DN. Following recommendations for daily cleansing with soap and water along with topical ammonium lactate, near-complete resolution of the rash was achieved in 3 weeks.

Dermatitis neglecta, or unwashed dermatosis, is a skin condition that occurs secondary to poor hygiene, which was first reported in 1995 by Poskitt et al.¹ Avoidance of washing in affected areas can be due to physical disability, pain after injury, neurological deficit, or psychologically induced fear or neglect. Sebum, sweat, corneocytes, and bacteria combine into compact adherent crusts of dirt, which appear as hyperkeratotic plaques with cornflakelike scale.^2,3 Despite its innate simplicity, DN is a diagnostic challenge, as it clinically and histologically mimics other dermatoses including AN, terra firmaforme dermatosis, and CARP.^2,4 Ultimately, the diagnosis of DN can be made when a history of poor hygiene is probable or elicited, and lesions can be removed with soap and water. Treatment of DN includes daily cleansing with soap and water; however, resistant lesions or extensive disease may require keratolytic agents, as in our patient.^2-4 In contrast, terra firma-forme dermatosis, which may look similar, is not due to poor hygiene, and the lesions typically are resistant to soap and water, classically requiring isopropyl alcohol for removal. Overall, maintained awareness of DN is imperative, as early diagnosis can avoid unnecessary biopsies and more complex treatment measures as well as facilitate coordination of care when additional medical or psychiatric concerns are present.

Although the diagnoses of DN and terra firma-forme dermatosis can be distinguished based on the patient’s clinical history and response to simple cleansing measures alone, the alternate diagnoses can be excluded based on different clinical distributions and response to other treatment modalities but sometimes may require clinicopathologic correlation for definitive diagnosis. Our patient had a biopsy diagnosis of psoriasiform dermatitis from an outside provider, but neither her clinical disease nor repeated histopathologic findings supported a diagnosis of psoriasis or other classic psoriasiform dermatoses such as contact dermatitis, dermatophyte/ candidal infection, seborrheic dermatitis, pityriasis rubra pilaris, pityriasis rosea, scabies, or syphilis.

It is imperative to exclude alternative diagnoses because they can have systemic implications and can misguide treatment, as was done initially with our patient. Psoriasis vulgaris in its classic form is a chronic inflammatory skin disease that manifests as sharply demarcated, erythematous plaques with overlying thick silvery scale; it has the additional histologic findings of neutrophilic spongiform pustules in the epidermis, tortuous blood vessels in the papillary dermis, and neutrophils and parakeratosis in the stratum corneum. In its benign form, AN is associated with endocrinopathies, most commonly obesity and insulin-resistant diabetes mellitus, and presents as hyperkeratotic, velvety, hyperpigmented plaques typically limited to the neck and axillae. Malignant AN spontaneously arises in association with systemic malignancy and can be extensive and generalized.⁵ Treatment of AN primarily focuses on resolution of the underlying systemic disease; however, cosmetic treatment with topical or oral retinoids may hasten resolution of cutaneous disease.⁶ Confluent and reticulated papillomatosis is characterized by reticulated hyperkeratotic plaques with a common distribution over the central and upper trunk. Unlike DN and AN, which may occur at any age, CARP typically is seen in adolescents and young adults.⁷ There is no evidence-based gold standard for the management of CARP; however, the successful use of various antibiotics, antifungals, and retinoids—alone or in combination—has been reported.⁸ Overall, compared to the other entities in the differential diagnosis, DN easily can be prevented with consistent use of soap and water and may be underreported given the asymptomatic nature of the disease and the typical patient population.

The Diagnosis: Dermatitis Neglecta

A punch biopsy of the abdomen revealed hyperkeratosis and mild papillomatosis (Figure), which can be seen in dermatitis neglecta (DN) and acanthosis nigricans (AN) as well as confluent and reticulated papillomatosis (CARP). Due to the patient’s history of mood and psychotic disorders, collateral information was obtained from the patient’s family, who reported that the patient had a depressed mood in the last few months and was not showering or caring for herself during this period. There was no additional personal or family history of skin disease. Clinical and histopathologic findings led to a diagnosis of DN. Following recommendations for daily cleansing with soap and water along with topical ammonium lactate, near-complete resolution of the rash was achieved in 3 weeks.

Dermatitis neglecta, or unwashed dermatosis, is a skin condition that occurs secondary to poor hygiene, which was first reported in 1995 by Poskitt et al.¹ Avoidance of washing in affected areas can be due to physical disability, pain after injury, neurological deficit, or psychologically induced fear or neglect. Sebum, sweat, corneocytes, and bacteria combine into compact adherent crusts of dirt, which appear as hyperkeratotic plaques with cornflakelike scale.^2,3 Despite its innate simplicity, DN is a diagnostic challenge, as it clinically and histologically mimics other dermatoses including AN, terra firmaforme dermatosis, and CARP.^2,4 Ultimately, the diagnosis of DN can be made when a history of poor hygiene is probable or elicited, and lesions can be removed with soap and water. Treatment of DN includes daily cleansing with soap and water; however, resistant lesions or extensive disease may require keratolytic agents, as in our patient.^2-4 In contrast, terra firma-forme dermatosis, which may look similar, is not due to poor hygiene, and the lesions typically are resistant to soap and water, classically requiring isopropyl alcohol for removal. Overall, maintained awareness of DN is imperative, as early diagnosis can avoid unnecessary biopsies and more complex treatment measures as well as facilitate coordination of care when additional medical or psychiatric concerns are present.

Although the diagnoses of DN and terra firma-forme dermatosis can be distinguished based on the patient’s clinical history and response to simple cleansing measures alone, the alternate diagnoses can be excluded based on different clinical distributions and response to other treatment modalities but sometimes may require clinicopathologic correlation for definitive diagnosis. Our patient had a biopsy diagnosis of psoriasiform dermatitis from an outside provider, but neither her clinical disease nor repeated histopathologic findings supported a diagnosis of psoriasis or other classic psoriasiform dermatoses such as contact dermatitis, dermatophyte/ candidal infection, seborrheic dermatitis, pityriasis rubra pilaris, pityriasis rosea, scabies, or syphilis.

It is imperative to exclude alternative diagnoses because they can have systemic implications and can misguide treatment, as was done initially with our patient. Psoriasis vulgaris in its classic form is a chronic inflammatory skin disease that manifests as sharply demarcated, erythematous plaques with overlying thick silvery scale; it has the additional histologic findings of neutrophilic spongiform pustules in the epidermis, tortuous blood vessels in the papillary dermis, and neutrophils and parakeratosis in the stratum corneum. In its benign form, AN is associated with endocrinopathies, most commonly obesity and insulin-resistant diabetes mellitus, and presents as hyperkeratotic, velvety, hyperpigmented plaques typically limited to the neck and axillae. Malignant AN spontaneously arises in association with systemic malignancy and can be extensive and generalized.⁵ Treatment of AN primarily focuses on resolution of the underlying systemic disease; however, cosmetic treatment with topical or oral retinoids may hasten resolution of cutaneous disease.⁶ Confluent and reticulated papillomatosis is characterized by reticulated hyperkeratotic plaques with a common distribution over the central and upper trunk. Unlike DN and AN, which may occur at any age, CARP typically is seen in adolescents and young adults.⁷ There is no evidence-based gold standard for the management of CARP; however, the successful use of various antibiotics, antifungals, and retinoids—alone or in combination—has been reported.⁸ Overall, compared to the other entities in the differential diagnosis, DN easily can be prevented with consistent use of soap and water and may be underreported given the asymptomatic nature of the disease and the typical patient population.

The Diagnosis: Dermatitis Neglecta

A punch biopsy of the abdomen revealed hyperkeratosis and mild papillomatosis (Figure), which can be seen in dermatitis neglecta (DN) and acanthosis nigricans (AN) as well as confluent and reticulated papillomatosis (CARP). Due to the patient’s history of mood and psychotic disorders, collateral information was obtained from the patient’s family, who reported that the patient had a depressed mood in the last few months and was not showering or caring for herself during this period. There was no additional personal or family history of skin disease. Clinical and histopathologic findings led to a diagnosis of DN. Following recommendations for daily cleansing with soap and water along with topical ammonium lactate, near-complete resolution of the rash was achieved in 3 weeks.

Dermatitis neglecta, or unwashed dermatosis, is a skin condition that occurs secondary to poor hygiene, which was first reported in 1995 by Poskitt et al.¹ Avoidance of washing in affected areas can be due to physical disability, pain after injury, neurological deficit, or psychologically induced fear or neglect. Sebum, sweat, corneocytes, and bacteria combine into compact adherent crusts of dirt, which appear as hyperkeratotic plaques with cornflakelike scale.^2,3 Despite its innate simplicity, DN is a diagnostic challenge, as it clinically and histologically mimics other dermatoses including AN, terra firmaforme dermatosis, and CARP.^2,4 Ultimately, the diagnosis of DN can be made when a history of poor hygiene is probable or elicited, and lesions can be removed with soap and water. Treatment of DN includes daily cleansing with soap and water; however, resistant lesions or extensive disease may require keratolytic agents, as in our patient.^2-4 In contrast, terra firma-forme dermatosis, which may look similar, is not due to poor hygiene, and the lesions typically are resistant to soap and water, classically requiring isopropyl alcohol for removal. Overall, maintained awareness of DN is imperative, as early diagnosis can avoid unnecessary biopsies and more complex treatment measures as well as facilitate coordination of care when additional medical or psychiatric concerns are present.

Although the diagnoses of DN and terra firma-forme dermatosis can be distinguished based on the patient’s clinical history and response to simple cleansing measures alone, the alternate diagnoses can be excluded based on different clinical distributions and response to other treatment modalities but sometimes may require clinicopathologic correlation for definitive diagnosis. Our patient had a biopsy diagnosis of psoriasiform dermatitis from an outside provider, but neither her clinical disease nor repeated histopathologic findings supported a diagnosis of psoriasis or other classic psoriasiform dermatoses such as contact dermatitis, dermatophyte/ candidal infection, seborrheic dermatitis, pityriasis rubra pilaris, pityriasis rosea, scabies, or syphilis.

It is imperative to exclude alternative diagnoses because they can have systemic implications and can misguide treatment, as was done initially with our patient. Psoriasis vulgaris in its classic form is a chronic inflammatory skin disease that manifests as sharply demarcated, erythematous plaques with overlying thick silvery scale; it has the additional histologic findings of neutrophilic spongiform pustules in the epidermis, tortuous blood vessels in the papillary dermis, and neutrophils and parakeratosis in the stratum corneum. In its benign form, AN is associated with endocrinopathies, most commonly obesity and insulin-resistant diabetes mellitus, and presents as hyperkeratotic, velvety, hyperpigmented plaques typically limited to the neck and axillae. Malignant AN spontaneously arises in association with systemic malignancy and can be extensive and generalized.⁵ Treatment of AN primarily focuses on resolution of the underlying systemic disease; however, cosmetic treatment with topical or oral retinoids may hasten resolution of cutaneous disease.⁶ Confluent and reticulated papillomatosis is characterized by reticulated hyperkeratotic plaques with a common distribution over the central and upper trunk. Unlike DN and AN, which may occur at any age, CARP typically is seen in adolescents and young adults.⁷ There is no evidence-based gold standard for the management of CARP; however, the successful use of various antibiotics, antifungals, and retinoids—alone or in combination—has been reported.⁸ Overall, compared to the other entities in the differential diagnosis, DN easily can be prevented with consistent use of soap and water and may be underreported given the asymptomatic nature of the disease and the typical patient population.

I began thinking of a topic for this column weeks ago determined to discuss anything except COVID-19. Yet, news reports from all sources blasted daily reminders of rising COVID-19 cases overall and specifically in children.

In August, school resumed for many of our patients and the battle over mandating masks for school attendance was in full swing. The fact that it is a Centers for Disease Control and Prevention recommendation supported by both the American Academy of Pediatrics and the Pediatric Infectious Disease Society fell on deaf ears. One day, I heard a report that over 25,000 students attending Texas public schools were diagnosed with COVID-19 between Aug. 23 and Aug. 29. This peak in activity occurred just 2 weeks after the start of school and led to the closure of 45 school districts. Texas does not have a monopoly on these rising cases. Delta, a more contagious variant, began circulating in June 2021 and by July it was the most predominant. Emergency department visits and hospitalizations have increased nationwide. During the latter 2 weeks of August 2021, COVID-19–related ED visits and hospitalizations for persons aged 0-17 years were 3.4 and 3.7 times higher in states with the lowest vaccination coverage, compared with states with high vaccination coverage (MMWR Morb Mortal Wkly Rep. 2021;70:1249-54). Specifically, the rates of hospitalization the week ending Aug. 14, 2021, were nearly 5 times the rates for the week ending June 26, 2021, for 0- to 17-year-olds and nearly 10 times the rates for children 0-4 years of age. Hospitalization rates were 10.1 times higher for unimmunized adolescents than for fully vaccinated ones (MMWR Morb Mortal Wkly Rep. 2021;70:1255-60).

Multiple elected state leaders have opposed interventions such as mandating masks in school, and our children are paying for it. These leaders have relinquished their responsibility to local school boards. Several have reinforced the no-mask mandate while others have had the courage and insight to ignore state government leaders and have established mask mandates.

How is this lack of enforcement of national recommendations affecting our patients? Let’s look at two neighboring school districts in Texas. School districts have COVID-19 dashboards that are updated daily and accessible to the general public. School District A requires masks for school entry. It serves 196,171 students and has 27,195 teachers and staff. Since school opened in August, 1,606 cumulative cases of COVID-19 in students (0.8%) and 282 in staff (1%) have been reported. Fifty-five percent of the student cases occurred in elementary schools. In contrast, School District B located in the adjacent county serves 64,517 students and has 3,906 teachers and staff with no mask mandate. Since August, there have been 4,506 cumulative COVID-19 cases in students (6.9%) and 578 (14.7%) in staff. Information regarding the specific school type was not provided; however, the dashboard indicates that 2,924 cases (64.8%) occurred in children younger than 11 years of age. County data indicate 62% of those older than 12 years of age were fully vaccinated in District A, compared with 54% of persons older than 12 years in District B. The county COVID-19 positivity rate in District A is 17.6% and in District B it is 20%. Both counties are experiencing increased COVID-19 activity yet have had strikingly different outcomes in the student/staff population. While supporting the case for wearing masks to prevent disease transmission, one can’t ignore the adolescents who were infected and vaccine eligible (District A: 706; District B: 1,582). Their vaccination status could not be determined.

As pediatricians we have played an integral part in the elimination of diseases through educating and administering vaccinations. Adolescents are relatively healthy, thus limiting the number of encounters with them. The majority complete the 11-year visit; however, many fail to return for the 16- to 18-year visit.

So how are we doing? CDC data from 10 U.S. jurisdictions demonstrated a substantial decrease in vaccine administration between March and May of 2020, compared with the same period in 2018 and 2019. A decline was anticipated because of the nationwide lockdown. Doses of HPV administered declined almost 64% and 71% for 9- to 12-year-olds and 13- to 17-year-olds, respectively. Tdap administration declined 66% and 61% for the same respective age groups. Although administered doses increased between June and September of 2020, it was not sufficient to achieve catch-up coverage. Compared to the same period in 2018-2019, administration of the HPV vaccine declined 12.8% and 28% (ages 9-12 and ages 13-17) and for Tdap it was 21% and 30% lower (ages 9-12 and ages 13-17) (MMWR Morb Mortal Wkly Rep. 2021;70:840-5).

Now, we have another adolescent vaccine to discuss and encourage our patients to receive. We also need to address their concerns and/or to at least direct them to a reliable source to obtain accurate information. For the first time, a recommended vaccine may not be available at their medical home. Many don’t know where to go to receive it (http://www.vaccines.gov). Results of a Kaiser Family Foundation COVID-19 survey (August 2021) indicated that parents trusted their pediatricians most often (78%) for vaccine advice. The respondents voiced concern about trusting the location where the child would be immunized and long-term effects especially related to fertility. Parents who received communications regarding the benefits of vaccination were twice as likely to have their adolescents immunized. Finally, remember: Like parent, like child. An immunized parent is more likely to immunize the adolescent. (See Fig. 1.)

Dr. Word is a pediatric infectious disease specialist and director of the Houston Travel Medicine Clinic. She said she had no relevant financial disclosures.

I began thinking of a topic for this column weeks ago determined to discuss anything except COVID-19. Yet, news reports from all sources blasted daily reminders of rising COVID-19 cases overall and specifically in children.

In August, school resumed for many of our patients and the battle over mandating masks for school attendance was in full swing. The fact that it is a Centers for Disease Control and Prevention recommendation supported by both the American Academy of Pediatrics and the Pediatric Infectious Disease Society fell on deaf ears. One day, I heard a report that over 25,000 students attending Texas public schools were diagnosed with COVID-19 between Aug. 23 and Aug. 29. This peak in activity occurred just 2 weeks after the start of school and led to the closure of 45 school districts. Texas does not have a monopoly on these rising cases. Delta, a more contagious variant, began circulating in June 2021 and by July it was the most predominant. Emergency department visits and hospitalizations have increased nationwide. During the latter 2 weeks of August 2021, COVID-19–related ED visits and hospitalizations for persons aged 0-17 years were 3.4 and 3.7 times higher in states with the lowest vaccination coverage, compared with states with high vaccination coverage (MMWR Morb Mortal Wkly Rep. 2021;70:1249-54). Specifically, the rates of hospitalization the week ending Aug. 14, 2021, were nearly 5 times the rates for the week ending June 26, 2021, for 0- to 17-year-olds and nearly 10 times the rates for children 0-4 years of age. Hospitalization rates were 10.1 times higher for unimmunized adolescents than for fully vaccinated ones (MMWR Morb Mortal Wkly Rep. 2021;70:1255-60).

Multiple elected state leaders have opposed interventions such as mandating masks in school, and our children are paying for it. These leaders have relinquished their responsibility to local school boards. Several have reinforced the no-mask mandate while others have had the courage and insight to ignore state government leaders and have established mask mandates.

How is this lack of enforcement of national recommendations affecting our patients? Let’s look at two neighboring school districts in Texas. School districts have COVID-19 dashboards that are updated daily and accessible to the general public. School District A requires masks for school entry. It serves 196,171 students and has 27,195 teachers and staff. Since school opened in August, 1,606 cumulative cases of COVID-19 in students (0.8%) and 282 in staff (1%) have been reported. Fifty-five percent of the student cases occurred in elementary schools. In contrast, School District B located in the adjacent county serves 64,517 students and has 3,906 teachers and staff with no mask mandate. Since August, there have been 4,506 cumulative COVID-19 cases in students (6.9%) and 578 (14.7%) in staff. Information regarding the specific school type was not provided; however, the dashboard indicates that 2,924 cases (64.8%) occurred in children younger than 11 years of age. County data indicate 62% of those older than 12 years of age were fully vaccinated in District A, compared with 54% of persons older than 12 years in District B. The county COVID-19 positivity rate in District A is 17.6% and in District B it is 20%. Both counties are experiencing increased COVID-19 activity yet have had strikingly different outcomes in the student/staff population. While supporting the case for wearing masks to prevent disease transmission, one can’t ignore the adolescents who were infected and vaccine eligible (District A: 706; District B: 1,582). Their vaccination status could not be determined.

As pediatricians we have played an integral part in the elimination of diseases through educating and administering vaccinations. Adolescents are relatively healthy, thus limiting the number of encounters with them. The majority complete the 11-year visit; however, many fail to return for the 16- to 18-year visit.

So how are we doing? CDC data from 10 U.S. jurisdictions demonstrated a substantial decrease in vaccine administration between March and May of 2020, compared with the same period in 2018 and 2019. A decline was anticipated because of the nationwide lockdown. Doses of HPV administered declined almost 64% and 71% for 9- to 12-year-olds and 13- to 17-year-olds, respectively. Tdap administration declined 66% and 61% for the same respective age groups. Although administered doses increased between June and September of 2020, it was not sufficient to achieve catch-up coverage. Compared to the same period in 2018-2019, administration of the HPV vaccine declined 12.8% and 28% (ages 9-12 and ages 13-17) and for Tdap it was 21% and 30% lower (ages 9-12 and ages 13-17) (MMWR Morb Mortal Wkly Rep. 2021;70:840-5).

Now, we have another adolescent vaccine to discuss and encourage our patients to receive. We also need to address their concerns and/or to at least direct them to a reliable source to obtain accurate information. For the first time, a recommended vaccine may not be available at their medical home. Many don’t know where to go to receive it (http://www.vaccines.gov). Results of a Kaiser Family Foundation COVID-19 survey (August 2021) indicated that parents trusted their pediatricians most often (78%) for vaccine advice. The respondents voiced concern about trusting the location where the child would be immunized and long-term effects especially related to fertility. Parents who received communications regarding the benefits of vaccination were twice as likely to have their adolescents immunized. Finally, remember: Like parent, like child. An immunized parent is more likely to immunize the adolescent. (See Fig. 1.)

Dr. Word is a pediatric infectious disease specialist and director of the Houston Travel Medicine Clinic. She said she had no relevant financial disclosures.

I began thinking of a topic for this column weeks ago determined to discuss anything except COVID-19. Yet, news reports from all sources blasted daily reminders of rising COVID-19 cases overall and specifically in children.

In August, school resumed for many of our patients and the battle over mandating masks for school attendance was in full swing. The fact that it is a Centers for Disease Control and Prevention recommendation supported by both the American Academy of Pediatrics and the Pediatric Infectious Disease Society fell on deaf ears. One day, I heard a report that over 25,000 students attending Texas public schools were diagnosed with COVID-19 between Aug. 23 and Aug. 29. This peak in activity occurred just 2 weeks after the start of school and led to the closure of 45 school districts. Texas does not have a monopoly on these rising cases. Delta, a more contagious variant, began circulating in June 2021 and by July it was the most predominant. Emergency department visits and hospitalizations have increased nationwide. During the latter 2 weeks of August 2021, COVID-19–related ED visits and hospitalizations for persons aged 0-17 years were 3.4 and 3.7 times higher in states with the lowest vaccination coverage, compared with states with high vaccination coverage (MMWR Morb Mortal Wkly Rep. 2021;70:1249-54). Specifically, the rates of hospitalization the week ending Aug. 14, 2021, were nearly 5 times the rates for the week ending June 26, 2021, for 0- to 17-year-olds and nearly 10 times the rates for children 0-4 years of age. Hospitalization rates were 10.1 times higher for unimmunized adolescents than for fully vaccinated ones (MMWR Morb Mortal Wkly Rep. 2021;70:1255-60).

Multiple elected state leaders have opposed interventions such as mandating masks in school, and our children are paying for it. These leaders have relinquished their responsibility to local school boards. Several have reinforced the no-mask mandate while others have had the courage and insight to ignore state government leaders and have established mask mandates.

How is this lack of enforcement of national recommendations affecting our patients? Let’s look at two neighboring school districts in Texas. School districts have COVID-19 dashboards that are updated daily and accessible to the general public. School District A requires masks for school entry. It serves 196,171 students and has 27,195 teachers and staff. Since school opened in August, 1,606 cumulative cases of COVID-19 in students (0.8%) and 282 in staff (1%) have been reported. Fifty-five percent of the student cases occurred in elementary schools. In contrast, School District B located in the adjacent county serves 64,517 students and has 3,906 teachers and staff with no mask mandate. Since August, there have been 4,506 cumulative COVID-19 cases in students (6.9%) and 578 (14.7%) in staff. Information regarding the specific school type was not provided; however, the dashboard indicates that 2,924 cases (64.8%) occurred in children younger than 11 years of age. County data indicate 62% of those older than 12 years of age were fully vaccinated in District A, compared with 54% of persons older than 12 years in District B. The county COVID-19 positivity rate in District A is 17.6% and in District B it is 20%. Both counties are experiencing increased COVID-19 activity yet have had strikingly different outcomes in the student/staff population. While supporting the case for wearing masks to prevent disease transmission, one can’t ignore the adolescents who were infected and vaccine eligible (District A: 706; District B: 1,582). Their vaccination status could not be determined.

As pediatricians we have played an integral part in the elimination of diseases through educating and administering vaccinations. Adolescents are relatively healthy, thus limiting the number of encounters with them. The majority complete the 11-year visit; however, many fail to return for the 16- to 18-year visit.

So how are we doing? CDC data from 10 U.S. jurisdictions demonstrated a substantial decrease in vaccine administration between March and May of 2020, compared with the same period in 2018 and 2019. A decline was anticipated because of the nationwide lockdown. Doses of HPV administered declined almost 64% and 71% for 9- to 12-year-olds and 13- to 17-year-olds, respectively. Tdap administration declined 66% and 61% for the same respective age groups. Although administered doses increased between June and September of 2020, it was not sufficient to achieve catch-up coverage. Compared to the same period in 2018-2019, administration of the HPV vaccine declined 12.8% and 28% (ages 9-12 and ages 13-17) and for Tdap it was 21% and 30% lower (ages 9-12 and ages 13-17) (MMWR Morb Mortal Wkly Rep. 2021;70:840-5).

Now, we have another adolescent vaccine to discuss and encourage our patients to receive. We also need to address their concerns and/or to at least direct them to a reliable source to obtain accurate information. For the first time, a recommended vaccine may not be available at their medical home. Many don’t know where to go to receive it (http://www.vaccines.gov). Results of a Kaiser Family Foundation COVID-19 survey (August 2021) indicated that parents trusted their pediatricians most often (78%) for vaccine advice. The respondents voiced concern about trusting the location where the child would be immunized and long-term effects especially related to fertility. Parents who received communications regarding the benefits of vaccination were twice as likely to have their adolescents immunized. Finally, remember: Like parent, like child. An immunized parent is more likely to immunize the adolescent. (See Fig. 1.)

Dr. Word is a pediatric infectious disease specialist and director of the Houston Travel Medicine Clinic. She said she had no relevant financial disclosures.

In December 2019, cases of pulmonary infection secondary to a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2, were first identified in the city of Wuhan, China.

The clinical disease caused by the virus, COVID-19, has resulted in a worldwide pandemic that has portended significant morbidity and mortality throughout the United States. Three highly efficacious COVID-19 vaccines have received emergency use authorization (EUA) by the Food and Drug Administration to help prevent COVID-19, all of which are effective at preventing severe COVID-19.^1-3 The Pfizer vaccine was given full FDA approval on Aug. 23, 2021.⁴

Patients with inflammatory bowel disease (IBD) are commonly treated with immune-modifying therapies that may increase their risk for serious and opportunistic infections. As such, there was concern at the beginning of the pandemic that patients with IBD may be at increased risk of contracting COVID-19 and/or developing severe disease (that is, ICU-level care, mechanical ventilation, and/or death). There is evidence that the incidence of COVID-19 in the IBD population is similar to that of the general population.^5-7 Furthermore, most patients with IBD are not at increased risk of severe disease, including those on biologic therapies. Several studies demonstrated that those on corticosteroids are at increased risk of severe COVID-19, while those on other immune-modifying therapies such as tumor necrosis factor inhibitors (anti-TNFs) are not at increased risk.^5,7-10 Patients with IBD with other well-known risk factors for severe disease include comorbidities such as diabetes and obesity.

It is known that patients with IBD on certain immune-modifying therapies such as anti-TNFs, especially those on combination therapy, may have a blunted immune response to certain vaccines.¹¹ Neither patients with IBD nor patients on immunosuppressive therapy were included in phase 3 clinical trials for COVID-19 vaccine development, contributing to uncertainty regarding the safety and efficacy in our patient population. The risk of adverse events following COVID-19 vaccination in the IBD population has been found to be similar to that of the general population.¹² It has also been reported that those who have had reactions to injectable therapies in the past may safely be vaccinated against COVID-19.^13,14 With regard to vaccine efficacy, initial studies, including ICARUS, PREVENT-COVID, and CORALE-IBD, have demonstrated that patients with IBD do indeed mount a humoral immune response to the vaccine, including those on immune-modifying therapies.^15-17 Nonhumoral aspects of immunity, such as cell-mediated immunity, have not yet been thoroughly evaluated. In addition, the risk of breakthrough COVID-19 infection after vaccination is low in patients with IBD, including those on immune-modifying therapy.^14-18 While initial studies are reassuring that the vast majority of patients with IBD are able to mount a vaccine response, future studies are needed to determine the effects of immune-modifying therapy on sustained antibody concentrations and other correlates of immunity.

For those who received the Pfizer or Moderna vaccines, on Aug. 12, 2021, the FDA amended their EUA to allow for an additional dose in the initial vaccination series for certain immunocompromised individuals, specifically solid organ transplant recipients or those with conditions that make them equally immunocompromised.¹⁹ Based on evidence suggesting that certain solid organ transplant recipients do not mount an immune response after completing a two-dose series, the Advisory Committee on Immunization Practices, which advises the Centers for Disease Control and Prevention on how to use vaccines, recommended that moderate to severely immunocompromised individuals should complete a three-dose series, with the third dose being given at least 28 days after the second dose.²⁰ This recommendation included those on high-dose corticosteroids defined as oral prednisone at least 20 mg/day, anti-TNFs and biosimilars, and antimetabolites such as azathioprine, mercaptopurine, and methotrexate.

It is worth noting that the role of the ACIP here was to consider the available evidence supporting the use of an additional dose and then make recommendations on which conditions may qualify; the ACIP was not able to provide recommendations for every disease state. At the time of writing this article, no recommendations have been made with regards to an additional dose of the Janssen vaccine. Likewise, in response to the ACIP recommendations, the Crohn’s & Colitis Foundation recommended an additional dose for patients with IBD on immune-modifying therapies.^21,22

Less than one week after the EUA amendment for an additional dose, the Department of Health & Human Services announced that booster shots would likely become available to the general population as early as the week of Sept. 20, 2021 and starting 8 months after an individual’s second dose.²³ Here, it is worth noting that an additional dose is distinct from a booster. An additional dose (or third dose here) refers to the initial vaccination series and is given when the standard schedule is thought to be insufficient in a certain patient population. In contrast, a booster dose is administered when the initial and sufficient immunity gained from a primary vaccination series has likely dissipated. The HHS acknowledged that boosters would likely be needed for those who received the Janssen vaccine but noted that further data and recommendations would be forthcoming.

To summarize, COVID-19 vaccines are safe and effective in the IBD population, and patients should be vaccinated at the earliest opportunity regardless of concurrent therapies. For those that received the Pfizer or Moderna vaccine, the ACIP recommended an additional dose in the initial vaccination series to be given at least 28 days after the second dose for those that are immunosuppressed. This recommendation was largely based off of transplant data. Reassuringly, the available data demonstrates a humoral immune response to a two-dose vaccination series in patients with IBD, including those on immune-modifying therapies. The Crohn’s & Colitis Foundation recommends that patients with IBD on immune-modifying therapy receive an additional dose (i.e., a three-dose series), which should be from the same manufacturer as the first two doses. In addition, at press time, HHS indicated that there will be a movement toward a booster dose for the general population in late September, which would also apply to patients with IBD. The ACIP has yet to comment on this change at the time of preparing this article, but the announcement indicated that a booster could be given “8 months after an individual’s second dose.” It is unclear how those who may receive a three-dose vaccination series will factor in, but it is possible that they would be eligible for a booster 8 months after their most recent dose. Gastroenterologists should also be aware that there is no role for serologic testing in the clinical setting because it has not been validated for such purposes and is primarily used in the research setting. Finally, it is paramount to emphasize that patients with IBD have historically had lower vaccination rates than the general population,²⁴ and we must take an active role in ensuring that our patients are immunized by addressing their concerns, communicating the risks of COVID-19 and the benefits of vaccination, providing information on how to get vaccinated, and strongly recommending vaccination.

• Patients with IBD should be vaccinated against COVID-19 regardless of concurrent therapies.
• Patients with IBD are not at increased risk of severe COVID-19.
• Patients with IBD, including those on immune-modifying therapies, mount a humoral immune response to the vaccine.
• Patients with IBD on immune-modifying therapies, who received either the Pfizer or Moderna vaccine, should receive a three-dose vaccination series, with the third dose at least 28 days after the second dose.
• Patients with IBD on biologic therapy can receive the third dose of the vaccine at any time point and should not interrupt biologic therapy.
• Boosters are likely to become available to the general public in September and would be given at least 8 months after an individual’s second dose.
• Recommendations regarding boosters for those who received a three-dose vaccination series are forthcoming.
• Recommendations regarding boosters and additional doses for those that received the Janssen vaccine are forthcoming.
• Gastroenterologists should take an active role in ensuring that their patients are vaccinated.

Dr. Schell is a second-year graduate student in the division of internal medicine at the University of Wisconsin–Madison. Dr. Caldera is an associate professor of medicine in the division of gastroenterology & hepatology at the University of Wisconsin–Madison. Dr. Schell has no conflicts of interest to disclose. Dr. Caldera has received research support from Takeda Pharmaceuticals and Sanofi. He has been a consultant for Takeda, Arena Pharmaceuticals, GSK, and Celgene.

References

1. Sadoff J et al. N Engl J Med. 2021;384(23):2187-201.

2. Baden LR et al. N Engl J Med. 2021;384(5):403-16.

3. Polack FP et al. N Engl J Med. 2020;383:2603-15.

4. Johnson K et al. U.S. FDA aims to give full approval to Pfizer vaccine on Monday – NYT. Reuters. 2021 Aug 20. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-aims-give-full-nod-pfizers-covid-19-vaccine-monday-new-york-times-2021-08-20/.

5. Allocca M et al. J Clin Med. 2020 Oct;9(11):3533.

6. Monteleone G and Ardizzone S. J Crohns Colitis. 2020 Sep;14(9):1334-6.

7. Papa A et al. Am J Gastroenterol. 2020;115(10):1722-4.

8. Derikx LAAP et al. J Crohn’s Colitis. 2021 Apr 6;15(4):529-39.

9. Brenner EJ et al. Gastroenterology. 2020;159(2):481-91.

10. Ungaro RC et al. Gut. 2021;70(4):725-32.

11. Caldera F et al. Inflamm Bowel Dis. 2020;26(4):593-602.

12. Botwin GJ et al. Am J Gastroenterol. 2021. doi: 10.14309/ajg.0000000000001342.

13. Squire JD et al. Inflamm Bowel Dis. 2021 Jul 27;27(8):1358-60.

14. Hadi YB et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.014.

15. Wong S-Y et al. Gastroenterology. 2021;161:715-8.

16. Kappelman MD et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.016.

17. Pozdnyakova V et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.08.014.

18. Ben-Tov A et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.076.

19. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Additional Vaccine Dose for Certain Immunocompromised Individuals. FDA News Release. 2021. Accessed 2021 Aug 18. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-vaccine-dose-certain-immunocompromised.

20. Centers for Disease Control and Prevention. COVID-19 Vaccines for Moderately to Severely Immunocompromised People. 2021. Accessed 2021 Aug 18. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html.

21. Allocca M et al. J Clin Med. 2020 Oct 31;9(11):3533.

22. Crohn’s & Colitis Foundation. COVID-19 Vaccines: Position Statements. IBD & Coronavirus. 2021. Accessed 2021 Aug 20. https://www.crohnscolitisfoundation.org/coronavirus/vaccine-position-statements.

23. Centers for Disease Control and Prevention. Joint Statement from HHS Public Health and Medical Experts on COVID-19 Booster Shots. https://www.cdc.gov/media/releases/2021/s0818-covid-19-booster-shots.html.

24. Caldera F et al. Inflamm Bowel Dis. 2021;27(1):123-133.

In December 2019, cases of pulmonary infection secondary to a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2, were first identified in the city of Wuhan, China.

The clinical disease caused by the virus, COVID-19, has resulted in a worldwide pandemic that has portended significant morbidity and mortality throughout the United States. Three highly efficacious COVID-19 vaccines have received emergency use authorization (EUA) by the Food and Drug Administration to help prevent COVID-19, all of which are effective at preventing severe COVID-19.^1-3 The Pfizer vaccine was given full FDA approval on Aug. 23, 2021.⁴

Patients with inflammatory bowel disease (IBD) are commonly treated with immune-modifying therapies that may increase their risk for serious and opportunistic infections. As such, there was concern at the beginning of the pandemic that patients with IBD may be at increased risk of contracting COVID-19 and/or developing severe disease (that is, ICU-level care, mechanical ventilation, and/or death). There is evidence that the incidence of COVID-19 in the IBD population is similar to that of the general population.^5-7 Furthermore, most patients with IBD are not at increased risk of severe disease, including those on biologic therapies. Several studies demonstrated that those on corticosteroids are at increased risk of severe COVID-19, while those on other immune-modifying therapies such as tumor necrosis factor inhibitors (anti-TNFs) are not at increased risk.^5,7-10 Patients with IBD with other well-known risk factors for severe disease include comorbidities such as diabetes and obesity.

It is known that patients with IBD on certain immune-modifying therapies such as anti-TNFs, especially those on combination therapy, may have a blunted immune response to certain vaccines.¹¹ Neither patients with IBD nor patients on immunosuppressive therapy were included in phase 3 clinical trials for COVID-19 vaccine development, contributing to uncertainty regarding the safety and efficacy in our patient population. The risk of adverse events following COVID-19 vaccination in the IBD population has been found to be similar to that of the general population.¹² It has also been reported that those who have had reactions to injectable therapies in the past may safely be vaccinated against COVID-19.^13,14 With regard to vaccine efficacy, initial studies, including ICARUS, PREVENT-COVID, and CORALE-IBD, have demonstrated that patients with IBD do indeed mount a humoral immune response to the vaccine, including those on immune-modifying therapies.^15-17 Nonhumoral aspects of immunity, such as cell-mediated immunity, have not yet been thoroughly evaluated. In addition, the risk of breakthrough COVID-19 infection after vaccination is low in patients with IBD, including those on immune-modifying therapy.^14-18 While initial studies are reassuring that the vast majority of patients with IBD are able to mount a vaccine response, future studies are needed to determine the effects of immune-modifying therapy on sustained antibody concentrations and other correlates of immunity.

For those who received the Pfizer or Moderna vaccines, on Aug. 12, 2021, the FDA amended their EUA to allow for an additional dose in the initial vaccination series for certain immunocompromised individuals, specifically solid organ transplant recipients or those with conditions that make them equally immunocompromised.¹⁹ Based on evidence suggesting that certain solid organ transplant recipients do not mount an immune response after completing a two-dose series, the Advisory Committee on Immunization Practices, which advises the Centers for Disease Control and Prevention on how to use vaccines, recommended that moderate to severely immunocompromised individuals should complete a three-dose series, with the third dose being given at least 28 days after the second dose.²⁰ This recommendation included those on high-dose corticosteroids defined as oral prednisone at least 20 mg/day, anti-TNFs and biosimilars, and antimetabolites such as azathioprine, mercaptopurine, and methotrexate.

It is worth noting that the role of the ACIP here was to consider the available evidence supporting the use of an additional dose and then make recommendations on which conditions may qualify; the ACIP was not able to provide recommendations for every disease state. At the time of writing this article, no recommendations have been made with regards to an additional dose of the Janssen vaccine. Likewise, in response to the ACIP recommendations, the Crohn’s & Colitis Foundation recommended an additional dose for patients with IBD on immune-modifying therapies.^21,22

Less than one week after the EUA amendment for an additional dose, the Department of Health & Human Services announced that booster shots would likely become available to the general population as early as the week of Sept. 20, 2021 and starting 8 months after an individual’s second dose.²³ Here, it is worth noting that an additional dose is distinct from a booster. An additional dose (or third dose here) refers to the initial vaccination series and is given when the standard schedule is thought to be insufficient in a certain patient population. In contrast, a booster dose is administered when the initial and sufficient immunity gained from a primary vaccination series has likely dissipated. The HHS acknowledged that boosters would likely be needed for those who received the Janssen vaccine but noted that further data and recommendations would be forthcoming.

To summarize, COVID-19 vaccines are safe and effective in the IBD population, and patients should be vaccinated at the earliest opportunity regardless of concurrent therapies. For those that received the Pfizer or Moderna vaccine, the ACIP recommended an additional dose in the initial vaccination series to be given at least 28 days after the second dose for those that are immunosuppressed. This recommendation was largely based off of transplant data. Reassuringly, the available data demonstrates a humoral immune response to a two-dose vaccination series in patients with IBD, including those on immune-modifying therapies. The Crohn’s & Colitis Foundation recommends that patients with IBD on immune-modifying therapy receive an additional dose (i.e., a three-dose series), which should be from the same manufacturer as the first two doses. In addition, at press time, HHS indicated that there will be a movement toward a booster dose for the general population in late September, which would also apply to patients with IBD. The ACIP has yet to comment on this change at the time of preparing this article, but the announcement indicated that a booster could be given “8 months after an individual’s second dose.” It is unclear how those who may receive a three-dose vaccination series will factor in, but it is possible that they would be eligible for a booster 8 months after their most recent dose. Gastroenterologists should also be aware that there is no role for serologic testing in the clinical setting because it has not been validated for such purposes and is primarily used in the research setting. Finally, it is paramount to emphasize that patients with IBD have historically had lower vaccination rates than the general population,²⁴ and we must take an active role in ensuring that our patients are immunized by addressing their concerns, communicating the risks of COVID-19 and the benefits of vaccination, providing information on how to get vaccinated, and strongly recommending vaccination.

• Patients with IBD should be vaccinated against COVID-19 regardless of concurrent therapies.
• Patients with IBD are not at increased risk of severe COVID-19.
• Patients with IBD, including those on immune-modifying therapies, mount a humoral immune response to the vaccine.
• Patients with IBD on immune-modifying therapies, who received either the Pfizer or Moderna vaccine, should receive a three-dose vaccination series, with the third dose at least 28 days after the second dose.
• Patients with IBD on biologic therapy can receive the third dose of the vaccine at any time point and should not interrupt biologic therapy.
• Boosters are likely to become available to the general public in September and would be given at least 8 months after an individual’s second dose.
• Recommendations regarding boosters for those who received a three-dose vaccination series are forthcoming.
• Recommendations regarding boosters and additional doses for those that received the Janssen vaccine are forthcoming.
• Gastroenterologists should take an active role in ensuring that their patients are vaccinated.

Dr. Schell is a second-year graduate student in the division of internal medicine at the University of Wisconsin–Madison. Dr. Caldera is an associate professor of medicine in the division of gastroenterology & hepatology at the University of Wisconsin–Madison. Dr. Schell has no conflicts of interest to disclose. Dr. Caldera has received research support from Takeda Pharmaceuticals and Sanofi. He has been a consultant for Takeda, Arena Pharmaceuticals, GSK, and Celgene.

References

1. Sadoff J et al. N Engl J Med. 2021;384(23):2187-201.

2. Baden LR et al. N Engl J Med. 2021;384(5):403-16.

3. Polack FP et al. N Engl J Med. 2020;383:2603-15.

4. Johnson K et al. U.S. FDA aims to give full approval to Pfizer vaccine on Monday – NYT. Reuters. 2021 Aug 20. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-aims-give-full-nod-pfizers-covid-19-vaccine-monday-new-york-times-2021-08-20/.

5. Allocca M et al. J Clin Med. 2020 Oct;9(11):3533.

6. Monteleone G and Ardizzone S. J Crohns Colitis. 2020 Sep;14(9):1334-6.

7. Papa A et al. Am J Gastroenterol. 2020;115(10):1722-4.

8. Derikx LAAP et al. J Crohn’s Colitis. 2021 Apr 6;15(4):529-39.

9. Brenner EJ et al. Gastroenterology. 2020;159(2):481-91.

10. Ungaro RC et al. Gut. 2021;70(4):725-32.

11. Caldera F et al. Inflamm Bowel Dis. 2020;26(4):593-602.

12. Botwin GJ et al. Am J Gastroenterol. 2021. doi: 10.14309/ajg.0000000000001342.

13. Squire JD et al. Inflamm Bowel Dis. 2021 Jul 27;27(8):1358-60.

14. Hadi YB et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.014.

15. Wong S-Y et al. Gastroenterology. 2021;161:715-8.

16. Kappelman MD et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.016.

17. Pozdnyakova V et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.08.014.

18. Ben-Tov A et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.076.

19. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Additional Vaccine Dose for Certain Immunocompromised Individuals. FDA News Release. 2021. Accessed 2021 Aug 18. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-vaccine-dose-certain-immunocompromised.

20. Centers for Disease Control and Prevention. COVID-19 Vaccines for Moderately to Severely Immunocompromised People. 2021. Accessed 2021 Aug 18. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html.

21. Allocca M et al. J Clin Med. 2020 Oct 31;9(11):3533.

22. Crohn’s & Colitis Foundation. COVID-19 Vaccines: Position Statements. IBD & Coronavirus. 2021. Accessed 2021 Aug 20. https://www.crohnscolitisfoundation.org/coronavirus/vaccine-position-statements.

23. Centers for Disease Control and Prevention. Joint Statement from HHS Public Health and Medical Experts on COVID-19 Booster Shots. https://www.cdc.gov/media/releases/2021/s0818-covid-19-booster-shots.html.

24. Caldera F et al. Inflamm Bowel Dis. 2021;27(1):123-133.

In December 2019, cases of pulmonary infection secondary to a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2, were first identified in the city of Wuhan, China.

The clinical disease caused by the virus, COVID-19, has resulted in a worldwide pandemic that has portended significant morbidity and mortality throughout the United States. Three highly efficacious COVID-19 vaccines have received emergency use authorization (EUA) by the Food and Drug Administration to help prevent COVID-19, all of which are effective at preventing severe COVID-19.^1-3 The Pfizer vaccine was given full FDA approval on Aug. 23, 2021.⁴

Patients with inflammatory bowel disease (IBD) are commonly treated with immune-modifying therapies that may increase their risk for serious and opportunistic infections. As such, there was concern at the beginning of the pandemic that patients with IBD may be at increased risk of contracting COVID-19 and/or developing severe disease (that is, ICU-level care, mechanical ventilation, and/or death). There is evidence that the incidence of COVID-19 in the IBD population is similar to that of the general population.^5-7 Furthermore, most patients with IBD are not at increased risk of severe disease, including those on biologic therapies. Several studies demonstrated that those on corticosteroids are at increased risk of severe COVID-19, while those on other immune-modifying therapies such as tumor necrosis factor inhibitors (anti-TNFs) are not at increased risk.^5,7-10 Patients with IBD with other well-known risk factors for severe disease include comorbidities such as diabetes and obesity.

It is known that patients with IBD on certain immune-modifying therapies such as anti-TNFs, especially those on combination therapy, may have a blunted immune response to certain vaccines.¹¹ Neither patients with IBD nor patients on immunosuppressive therapy were included in phase 3 clinical trials for COVID-19 vaccine development, contributing to uncertainty regarding the safety and efficacy in our patient population. The risk of adverse events following COVID-19 vaccination in the IBD population has been found to be similar to that of the general population.¹² It has also been reported that those who have had reactions to injectable therapies in the past may safely be vaccinated against COVID-19.^13,14 With regard to vaccine efficacy, initial studies, including ICARUS, PREVENT-COVID, and CORALE-IBD, have demonstrated that patients with IBD do indeed mount a humoral immune response to the vaccine, including those on immune-modifying therapies.^15-17 Nonhumoral aspects of immunity, such as cell-mediated immunity, have not yet been thoroughly evaluated. In addition, the risk of breakthrough COVID-19 infection after vaccination is low in patients with IBD, including those on immune-modifying therapy.^14-18 While initial studies are reassuring that the vast majority of patients with IBD are able to mount a vaccine response, future studies are needed to determine the effects of immune-modifying therapy on sustained antibody concentrations and other correlates of immunity.

For those who received the Pfizer or Moderna vaccines, on Aug. 12, 2021, the FDA amended their EUA to allow for an additional dose in the initial vaccination series for certain immunocompromised individuals, specifically solid organ transplant recipients or those with conditions that make them equally immunocompromised.¹⁹ Based on evidence suggesting that certain solid organ transplant recipients do not mount an immune response after completing a two-dose series, the Advisory Committee on Immunization Practices, which advises the Centers for Disease Control and Prevention on how to use vaccines, recommended that moderate to severely immunocompromised individuals should complete a three-dose series, with the third dose being given at least 28 days after the second dose.²⁰ This recommendation included those on high-dose corticosteroids defined as oral prednisone at least 20 mg/day, anti-TNFs and biosimilars, and antimetabolites such as azathioprine, mercaptopurine, and methotrexate.

It is worth noting that the role of the ACIP here was to consider the available evidence supporting the use of an additional dose and then make recommendations on which conditions may qualify; the ACIP was not able to provide recommendations for every disease state. At the time of writing this article, no recommendations have been made with regards to an additional dose of the Janssen vaccine. Likewise, in response to the ACIP recommendations, the Crohn’s & Colitis Foundation recommended an additional dose for patients with IBD on immune-modifying therapies.^21,22

Less than one week after the EUA amendment for an additional dose, the Department of Health & Human Services announced that booster shots would likely become available to the general population as early as the week of Sept. 20, 2021 and starting 8 months after an individual’s second dose.²³ Here, it is worth noting that an additional dose is distinct from a booster. An additional dose (or third dose here) refers to the initial vaccination series and is given when the standard schedule is thought to be insufficient in a certain patient population. In contrast, a booster dose is administered when the initial and sufficient immunity gained from a primary vaccination series has likely dissipated. The HHS acknowledged that boosters would likely be needed for those who received the Janssen vaccine but noted that further data and recommendations would be forthcoming.

To summarize, COVID-19 vaccines are safe and effective in the IBD population, and patients should be vaccinated at the earliest opportunity regardless of concurrent therapies. For those that received the Pfizer or Moderna vaccine, the ACIP recommended an additional dose in the initial vaccination series to be given at least 28 days after the second dose for those that are immunosuppressed. This recommendation was largely based off of transplant data. Reassuringly, the available data demonstrates a humoral immune response to a two-dose vaccination series in patients with IBD, including those on immune-modifying therapies. The Crohn’s & Colitis Foundation recommends that patients with IBD on immune-modifying therapy receive an additional dose (i.e., a three-dose series), which should be from the same manufacturer as the first two doses. In addition, at press time, HHS indicated that there will be a movement toward a booster dose for the general population in late September, which would also apply to patients with IBD. The ACIP has yet to comment on this change at the time of preparing this article, but the announcement indicated that a booster could be given “8 months after an individual’s second dose.” It is unclear how those who may receive a three-dose vaccination series will factor in, but it is possible that they would be eligible for a booster 8 months after their most recent dose. Gastroenterologists should also be aware that there is no role for serologic testing in the clinical setting because it has not been validated for such purposes and is primarily used in the research setting. Finally, it is paramount to emphasize that patients with IBD have historically had lower vaccination rates than the general population,²⁴ and we must take an active role in ensuring that our patients are immunized by addressing their concerns, communicating the risks of COVID-19 and the benefits of vaccination, providing information on how to get vaccinated, and strongly recommending vaccination.

• Patients with IBD should be vaccinated against COVID-19 regardless of concurrent therapies.
• Patients with IBD are not at increased risk of severe COVID-19.
• Patients with IBD, including those on immune-modifying therapies, mount a humoral immune response to the vaccine.
• Patients with IBD on immune-modifying therapies, who received either the Pfizer or Moderna vaccine, should receive a three-dose vaccination series, with the third dose at least 28 days after the second dose.
• Patients with IBD on biologic therapy can receive the third dose of the vaccine at any time point and should not interrupt biologic therapy.
• Boosters are likely to become available to the general public in September and would be given at least 8 months after an individual’s second dose.
• Recommendations regarding boosters for those who received a three-dose vaccination series are forthcoming.
• Recommendations regarding boosters and additional doses for those that received the Janssen vaccine are forthcoming.
• Gastroenterologists should take an active role in ensuring that their patients are vaccinated.

Dr. Schell is a second-year graduate student in the division of internal medicine at the University of Wisconsin–Madison. Dr. Caldera is an associate professor of medicine in the division of gastroenterology & hepatology at the University of Wisconsin–Madison. Dr. Schell has no conflicts of interest to disclose. Dr. Caldera has received research support from Takeda Pharmaceuticals and Sanofi. He has been a consultant for Takeda, Arena Pharmaceuticals, GSK, and Celgene.

References

1. Sadoff J et al. N Engl J Med. 2021;384(23):2187-201.

2. Baden LR et al. N Engl J Med. 2021;384(5):403-16.

3. Polack FP et al. N Engl J Med. 2020;383:2603-15.

4. Johnson K et al. U.S. FDA aims to give full approval to Pfizer vaccine on Monday – NYT. Reuters. 2021 Aug 20. https://www.reuters.com/business/healthcare-pharmaceuticals/us-fda-aims-give-full-nod-pfizers-covid-19-vaccine-monday-new-york-times-2021-08-20/.

5. Allocca M et al. J Clin Med. 2020 Oct;9(11):3533.

6. Monteleone G and Ardizzone S. J Crohns Colitis. 2020 Sep;14(9):1334-6.

7. Papa A et al. Am J Gastroenterol. 2020;115(10):1722-4.

8. Derikx LAAP et al. J Crohn’s Colitis. 2021 Apr 6;15(4):529-39.

9. Brenner EJ et al. Gastroenterology. 2020;159(2):481-91.

10. Ungaro RC et al. Gut. 2021;70(4):725-32.

11. Caldera F et al. Inflamm Bowel Dis. 2020;26(4):593-602.

12. Botwin GJ et al. Am J Gastroenterol. 2021. doi: 10.14309/ajg.0000000000001342.

13. Squire JD et al. Inflamm Bowel Dis. 2021 Jul 27;27(8):1358-60.

14. Hadi YB et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.014.

15. Wong S-Y et al. Gastroenterology. 2021;161:715-8.

16. Kappelman MD et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.016.

17. Pozdnyakova V et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.08.014.

18. Ben-Tov A et al. Gastroenterology. 2021. doi: 10.1053/j.gastro.2021.06.076.

19. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Additional Vaccine Dose for Certain Immunocompromised Individuals. FDA News Release. 2021. Accessed 2021 Aug 18. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-vaccine-dose-certain-immunocompromised.

20. Centers for Disease Control and Prevention. COVID-19 Vaccines for Moderately to Severely Immunocompromised People. 2021. Accessed 2021 Aug 18. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html.

21. Allocca M et al. J Clin Med. 2020 Oct 31;9(11):3533.

22. Crohn’s & Colitis Foundation. COVID-19 Vaccines: Position Statements. IBD & Coronavirus. 2021. Accessed 2021 Aug 20. https://www.crohnscolitisfoundation.org/coronavirus/vaccine-position-statements.

23. Centers for Disease Control and Prevention. Joint Statement from HHS Public Health and Medical Experts on COVID-19 Booster Shots. https://www.cdc.gov/media/releases/2021/s0818-covid-19-booster-shots.html.

24. Caldera F et al. Inflamm Bowel Dis. 2021;27(1):123-133.