Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

Because of the high out-of-pocket costs of new-to-market neurologic drugs that are of similar benefit as older agents, only a small percentage of patients with neurologic disorders have access to these cutting-edge medications, new research shows.

“Our study of people with neurologic conditions found that fewer than 20% were being treated with new medications,” study author Brian C. Callaghan, MD, with University of Michigan Health in Ann Arbor, said in a statement.

“For new, high-cost medications that have similar effectiveness to older drugs, limited use is likely appropriate. However, future studies are needed to look into whether the high costs are barriers to those new medications that can really make a difference for people living with neurologic disease,” Dr. Callaghan said.

The study was published online in Neurology.
 

Most expensive drugs

Using insurance claims data, the investigators compared the utilization and costs of new-to-market drugs from 2014 to 2018 with those for existing guideline-supported medications for treating 11 neurologic conditions.

The new drugs included:

• erenumab, fremanezumab, and galcanezumab for migraine.
• ocrelizumab and peginterferon beta-1a for multiple sclerosis (MS).
• pimavanserin and safinamide for Parkinson’s disease.
• droxidopa for orthostatic hypertension.
• eculizumab for myasthenia gravis (MG).
• edaravone for amyotrophic lateral sclerosis (ALS).
• deutetrabenazine and valbenazine for Huntington’s disease and tardive dyskinesia.
• patisiran and inotersen for transthyretin amyloidosis (ATTR).
• eteplirsen and deflazacort for Duchenne disease.
• nusinersen for spinal muscular atrophy (SMA).

Utilization of new drugs was modest – they accounted for one in five prescriptions for every condition except tardive dyskinesia (32% for valbenazine), the researchers noted.

Mean out-of-pocket costs were significantly higher for the new medications, although there was large variability among individual drugs.

The two most expensive drugs were edaravone, for ALS, with a mean out-of-pocket cost of $713 for a 30-day supply, and eculizumab, for MG, which costs $91 per month.

“For new-to-market medications, the distribution of out-of-pocket costs were highly variable and the trends over time were unpredictable compared with existing guideline-supported medications,” the authors reported.

They noted that potential reasons for low utilization of newer agents include delay in provider uptake and prescriber and/or patient avoidance because of high cost.

Given that most of the new neurologic agents offer little advantage compared with existing treatments – exceptions being new drugs for SMA and ATTR – drug costs should be a key consideration in prescribing decisions, Dr. Callaghan and colleagues concluded.

One limitation of the study is that follow-up time was short for some of the recently approved medications. Another limitation is that the number of people in the study who had rare diseases was small.
 

Revolution in neurotherapeutics

“We are living in a time when new treatments bring hope to people with neurologic diseases and disorders,” Orly Avitzur, MD, president of the American Academy of Neurology, said in a statement.

“However, even existing prescription medication can be expensive and drug prices continue to rise. In order for neurologists to provide people with the highest quality care, it is imperative that new drugs are accessible and affordable to the people who need them,” Dr. Avitzur added.

Writing in a linked editorial, A. Gordon Smith, MD, professor and chair, department of neurology, Virginia Commonwealth University, Richmond, said there is a revolution in neurotherapeutics, with particularly robust growth in new drug approvals for orphan diseases (those affecting < 200,000 Americans).

“This study adds to a growing literature indicating rising drug prices are a threat to the health care system. No matter how effective a disease-modifying therapy may be, if a patient cannot afford the cost, it doesn’t work,” Dr. Smith wrote.

He added that neurologists must be “diligent in assessing for financial toxicity and appropriately tailor individual treatment recommendations. We must insist on development of point-of-care tools to accurately estimate each patient’s potential financial toxicity including RTBT [real-time benefit tools].

“Neurologists’ primary obligation is to the individual patient, but we are also compelled to support access to high-quality care for all people, which requires advocacy for appropriate policy reforms to ensure value based and fair drug pricing and treatment success,” Dr. Smith added.

The study was funded by the American Academy of Neurology Health Services Research Subcommittee. Dr. Callaghan consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology, and performs medical/legal consultations, including consultations for the Vaccine Injury Compensation Program. Dr. Smith has disclosed no relevant financial relationships.

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

As a severe shortage drags on and prices soar, transplant centers have been struggling to cope with the paucity and price of fludarabine, a chemotherapy drug that has become an essential component of stem-cell transplants for some blood cancers.

At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.

Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.

“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”

In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
 

In new treatment era, fludarabine remains crucial

In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.

Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.

But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.

Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
 

As shortage continues, price hike brings yet another hit

The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.

Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.

In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”

“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.

In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.

Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”

The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
 

Alternatives abound, but do they suffice?

There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.

Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.

The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”

In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”

If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”

Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”

Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.

As a severe shortage drags on and prices soar, transplant centers have been struggling to cope with the paucity and price of fludarabine, a chemotherapy drug that has become an essential component of stem-cell transplants for some blood cancers.

At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.

Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.

“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”

In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
 

In new treatment era, fludarabine remains crucial

In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.

Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.

But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.

Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
 

As shortage continues, price hike brings yet another hit

The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.

Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.

In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”

“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.

In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.

Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”

The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
 

Alternatives abound, but do they suffice?

There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.

Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.

The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”

In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”

If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”

Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”

Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.

As a severe shortage drags on and prices soar, transplant centers have been struggling to cope with the paucity and price of fludarabine, a chemotherapy drug that has become an essential component of stem-cell transplants for some blood cancers.

At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.

Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.

“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”

In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
 

In new treatment era, fludarabine remains crucial

In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.

Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.

But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.

Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
 

As shortage continues, price hike brings yet another hit

The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.

Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.

In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”

“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.

In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.

Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”

The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
 

Alternatives abound, but do they suffice?

There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.

Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.

The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”

In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”

If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”

Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”

Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.

Visceral adipose tissue is significantly reduced with the green Mediterranean diet (MED), which consists of polyphenols and reduced red meat intake, according to a new analysis of the 18-month Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed (DIRECT-PLUS) trial.

The new results indicate that the green Mediterranean diet lowered visceral fat by twice as much as the standard Mediterranean diet (14% vs. 7%), reported Iris Shai, PhD, of Ben-Gurion University of the Negev in Be’er Sheva, Israel, and colleagues.

“This study may suggest an improved dietary protocol for treating visceral adiposity,” the authors wrote in their article, published recently in BMC Medicine.

“A healthy lifestyle is a strong basis for any weight-loss program. We learned from the results of our experiment that the quality of food is no less important than the number of calories consumed and the goal today is to understand the mechanisms of various nutrients, for example, positive ones such as the polyphenols, and negative ones such as empty carbohydrates and processed red meat, on the pace of fat cell differentiation and their aggregation in the viscera,” Dr. Shai said in a press release from Ben‐Gurion University.

“A 14% reduction in visceral fat is a dramatic achievement for making simple changes to your diet and lifestyle. Weight loss is an important goal only if it is accompanied by impressive results in reducing adipose tissue,” added coauthor Hila Zelicha, RD, PhD, also of Ben‐Gurion University of the Negev.

Previous randomized controlled trials have shown that dietary changes with a higher polyphenol content tend to produce better cardiometabolic outcomes and appear to mobilize particular ectopic fat depots, the researchers noted.

The main results of the DIRECT-PLUS trial were published in 2020 in Heart. Almost 300 participants with abdominal obesity/dyslipidemia were randomized to one of three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean diet, and the so-called green Mediterranean diet. The mean age of participants was 51 years, and men comprised 88% of the study cohort.

Participants in both Mediterranean diet groups ate 28 grams/day of walnuts, which accounted for about 440 mg/day of polyphenols. Participants in the green Mediterranean group also ate 100 grams/day of frozen cubes of a Wolffia globosa (duckweed strain) plant green shake, and three to four cups/day of green tea, which contributed to consumption of 800 mg/day of polyphenols, and decreased red meat consumption.

Both the green and standard Mediterranean diet groups achieved similar weight loss (–6.2 kg and –5.4 kg) compared with the HDG group (–1.5 kg; P < .001). However, the green Mediterranean diet group had a greater reduction in waist circumference (–8.6 cm) than the standard Mediterranean diet group (–6.8 cm; P = .033) and HDG group (–4.3 cm; P < .001). Stratification by gender showed these differences were significant only among men.

Explaining the rationale for the study, the researchers noted that visceral adipose tissue accumulation is a key factor that differentiates metabolic healthy and unhealthy obese individuals, is closely related to the development of multiple cardiovascular risk factors, including hypertension, dyslipidemia, and type 2 diabetes, and is an independent marker of mortality.

Now, their latest data show the green Mediterranean diet group lost approximately twice as much visceral adipose tissue compared with the standard Mediterranean diet and HDG groups (−14.1%, −6.0%, and − 4.2%; P < .05 independent of weight loss, sex, waist circumference, or age).

Lower red meat consumption, greater dietary consumption of walnuts, Wolffia globosa, and green tea, increased urine urolithin A polyphenol, and elevated total plasma polyphenols were significantly associated with greater visceral adipose tissue loss (P < .05, multivariate models).

“A green Mediterranean diet enriched with polyphenols and decreased red meat consumption might serve as an improved version of the Mediterranean diet for targeted VAT reduction. Future studies are needed to explore the exact mechanisms of specific polyphenol-rich foods on visceral adiposity,” the study authors concluded.

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

Visceral adipose tissue is significantly reduced with the green Mediterranean diet (MED), which consists of polyphenols and reduced red meat intake, according to a new analysis of the 18-month Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed (DIRECT-PLUS) trial.

The new results indicate that the green Mediterranean diet lowered visceral fat by twice as much as the standard Mediterranean diet (14% vs. 7%), reported Iris Shai, PhD, of Ben-Gurion University of the Negev in Be’er Sheva, Israel, and colleagues.

“This study may suggest an improved dietary protocol for treating visceral adiposity,” the authors wrote in their article, published recently in BMC Medicine.

“A healthy lifestyle is a strong basis for any weight-loss program. We learned from the results of our experiment that the quality of food is no less important than the number of calories consumed and the goal today is to understand the mechanisms of various nutrients, for example, positive ones such as the polyphenols, and negative ones such as empty carbohydrates and processed red meat, on the pace of fat cell differentiation and their aggregation in the viscera,” Dr. Shai said in a press release from Ben‐Gurion University.

“A 14% reduction in visceral fat is a dramatic achievement for making simple changes to your diet and lifestyle. Weight loss is an important goal only if it is accompanied by impressive results in reducing adipose tissue,” added coauthor Hila Zelicha, RD, PhD, also of Ben‐Gurion University of the Negev.

Previous randomized controlled trials have shown that dietary changes with a higher polyphenol content tend to produce better cardiometabolic outcomes and appear to mobilize particular ectopic fat depots, the researchers noted.

The main results of the DIRECT-PLUS trial were published in 2020 in Heart. Almost 300 participants with abdominal obesity/dyslipidemia were randomized to one of three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean diet, and the so-called green Mediterranean diet. The mean age of participants was 51 years, and men comprised 88% of the study cohort.

Participants in both Mediterranean diet groups ate 28 grams/day of walnuts, which accounted for about 440 mg/day of polyphenols. Participants in the green Mediterranean group also ate 100 grams/day of frozen cubes of a Wolffia globosa (duckweed strain) plant green shake, and three to four cups/day of green tea, which contributed to consumption of 800 mg/day of polyphenols, and decreased red meat consumption.

Both the green and standard Mediterranean diet groups achieved similar weight loss (–6.2 kg and –5.4 kg) compared with the HDG group (–1.5 kg; P < .001). However, the green Mediterranean diet group had a greater reduction in waist circumference (–8.6 cm) than the standard Mediterranean diet group (–6.8 cm; P = .033) and HDG group (–4.3 cm; P < .001). Stratification by gender showed these differences were significant only among men.

Explaining the rationale for the study, the researchers noted that visceral adipose tissue accumulation is a key factor that differentiates metabolic healthy and unhealthy obese individuals, is closely related to the development of multiple cardiovascular risk factors, including hypertension, dyslipidemia, and type 2 diabetes, and is an independent marker of mortality.

Now, their latest data show the green Mediterranean diet group lost approximately twice as much visceral adipose tissue compared with the standard Mediterranean diet and HDG groups (−14.1%, −6.0%, and − 4.2%; P < .05 independent of weight loss, sex, waist circumference, or age).

Lower red meat consumption, greater dietary consumption of walnuts, Wolffia globosa, and green tea, increased urine urolithin A polyphenol, and elevated total plasma polyphenols were significantly associated with greater visceral adipose tissue loss (P < .05, multivariate models).

“A green Mediterranean diet enriched with polyphenols and decreased red meat consumption might serve as an improved version of the Mediterranean diet for targeted VAT reduction. Future studies are needed to explore the exact mechanisms of specific polyphenol-rich foods on visceral adiposity,” the study authors concluded.

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

Visceral adipose tissue is significantly reduced with the green Mediterranean diet (MED), which consists of polyphenols and reduced red meat intake, according to a new analysis of the 18-month Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed (DIRECT-PLUS) trial.

The new results indicate that the green Mediterranean diet lowered visceral fat by twice as much as the standard Mediterranean diet (14% vs. 7%), reported Iris Shai, PhD, of Ben-Gurion University of the Negev in Be’er Sheva, Israel, and colleagues.

“This study may suggest an improved dietary protocol for treating visceral adiposity,” the authors wrote in their article, published recently in BMC Medicine.

“A healthy lifestyle is a strong basis for any weight-loss program. We learned from the results of our experiment that the quality of food is no less important than the number of calories consumed and the goal today is to understand the mechanisms of various nutrients, for example, positive ones such as the polyphenols, and negative ones such as empty carbohydrates and processed red meat, on the pace of fat cell differentiation and their aggregation in the viscera,” Dr. Shai said in a press release from Ben‐Gurion University.

“A 14% reduction in visceral fat is a dramatic achievement for making simple changes to your diet and lifestyle. Weight loss is an important goal only if it is accompanied by impressive results in reducing adipose tissue,” added coauthor Hila Zelicha, RD, PhD, also of Ben‐Gurion University of the Negev.

Previous randomized controlled trials have shown that dietary changes with a higher polyphenol content tend to produce better cardiometabolic outcomes and appear to mobilize particular ectopic fat depots, the researchers noted.

The main results of the DIRECT-PLUS trial were published in 2020 in Heart. Almost 300 participants with abdominal obesity/dyslipidemia were randomized to one of three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean diet, and the so-called green Mediterranean diet. The mean age of participants was 51 years, and men comprised 88% of the study cohort.

Participants in both Mediterranean diet groups ate 28 grams/day of walnuts, which accounted for about 440 mg/day of polyphenols. Participants in the green Mediterranean group also ate 100 grams/day of frozen cubes of a Wolffia globosa (duckweed strain) plant green shake, and three to four cups/day of green tea, which contributed to consumption of 800 mg/day of polyphenols, and decreased red meat consumption.

Both the green and standard Mediterranean diet groups achieved similar weight loss (–6.2 kg and –5.4 kg) compared with the HDG group (–1.5 kg; P < .001). However, the green Mediterranean diet group had a greater reduction in waist circumference (–8.6 cm) than the standard Mediterranean diet group (–6.8 cm; P = .033) and HDG group (–4.3 cm; P < .001). Stratification by gender showed these differences were significant only among men.

Explaining the rationale for the study, the researchers noted that visceral adipose tissue accumulation is a key factor that differentiates metabolic healthy and unhealthy obese individuals, is closely related to the development of multiple cardiovascular risk factors, including hypertension, dyslipidemia, and type 2 diabetes, and is an independent marker of mortality.

Now, their latest data show the green Mediterranean diet group lost approximately twice as much visceral adipose tissue compared with the standard Mediterranean diet and HDG groups (−14.1%, −6.0%, and − 4.2%; P < .05 independent of weight loss, sex, waist circumference, or age).

Lower red meat consumption, greater dietary consumption of walnuts, Wolffia globosa, and green tea, increased urine urolithin A polyphenol, and elevated total plasma polyphenols were significantly associated with greater visceral adipose tissue loss (P < .05, multivariate models).

“A green Mediterranean diet enriched with polyphenols and decreased red meat consumption might serve as an improved version of the Mediterranean diet for targeted VAT reduction. Future studies are needed to explore the exact mechanisms of specific polyphenol-rich foods on visceral adiposity,” the study authors concluded.

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

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

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

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

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

The American Academy of Pediatrics is cautioning physicians and parents to be on the lookout for unnecessary diagnostic testing associated with several common pediatric conditions.

Children seen for these conditions in emergency settings and even in primary care offices could experience avoidable pain, exposure to harmful radiation, and other harms, according to the group.

“The emergency department has the ability to rapidly perform myriad diagnostic tests and receive results quickly,” said Paul Mullan, MD, MPH, chair of the AAP’s Section of Emergency Medicine’s Choosing Wisely task force. “However, this comes with the danger of diagnostic overtesting.”

The five recommendations are as follows:

• Radiographs should not be obtained for children with bronchiolitis, croup, asthma, or first-time wheezing.
• Laboratory tests for screening should not be undertaken in the medical clearance process of children who require inpatient psychiatric admission unless clinically indicated.
• Laboratory testing or a CT scan of the head should not be ordered for a child with an unprovoked, generalized seizure or a simple febrile seizure whose mental status has returned to baseline.
• Abdominal radiographs should not be obtained for suspected constipation.
• Comprehensive viral panel testing should not be undertaken for children who are suspected of having respiratory viral illnesses.

The AAP task force partnered with Choosing Wisely Canada to create the recommendations. The list is the first of its kind to be published jointly by two countries, according to the release.

“We hope this Choosing Wisely list will encourage clinicians to rely on their clinical skills and avoid unnecessary tests,” said Dr. Mullan, who is also a physician at Children’s Hospital of the King’s Daughters and professor of pediatrics at Eastern Virginia Medical School, Norfolk.

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

The offspring of mothers who sustain unintentional injuries during pregnancy appear to have a modest 33% increased risk of developing cerebral palsy (CP) – higher when injuries are more severe, multiple, or lead to delivery soon afterward, a Canadian birth cohort study found.

Such children may benefit from long-term monitoring for neurodevelpmental issues, wrote a group led by Asma Ahmed, MD, PhD, MPH, a pediatric epidemiologist at the Hospital for Sick Children Research Institute in Toronto in JAMA Pediatrics.

“We need to provide better support for babies whose mothers have been injured in pregnancy, especially after severe injuries,” Dr. Ahmed said in a press release. “As well, these findings suggest the need for early monitoring of babies’ development, regular check-ups, and longer-term neurodevelopmental assessments.” Future studies should directly measure injury severity and its possible link to CP.

Current guidelines, however, focus on monitoring fetal condition immediately after injury with little attention to its long-term effects.

In their findings from the population-based linkage study of 2,110,177 children born in Ontario’s public health system during 2002-2017 and followed to 2018 with a median follow-up of 8 years:

• A total of 81,281 fetuses were exposed in utero to unintentional maternal injury.
• Overall, 0.3% children were diagnosed with CP, and the mean CP incidence rates were 4.36 per 10,000 child-years for the exposed versus 2.93 for the unexposed.
• In those exposed, the hazard ratio was 1.33 (95% confidence interval, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics.
• Injuries resulting in hospitalization or delivery within 1 week were linked to higher adjusted hazard ratios of 2.18 (95% CI, 1.29-3.68) and 3.40 (95% CI, 1.93-6.00), respectively.
• Injuries most frequently resulted from transportation mishaps, falls, and being struck by a person or object. They were most commonly associated with age younger than 20 years, substance use disorder, residence in rural and under-resourced areas, and lower socioeconomic status.

The authors noted that complications after maternal injuries – which affect 6%-8% of pregnant women – include uterine rupture, preterm delivery, and placental abruption and are linked to fetal complications such as asphyxia. The association with an offspring’s neurodevelopment has been rarely investigated. One U.K. population study, however, suggested a link between vehicular crashes and higher CP risk in preterm infants.

A related editorial on the study noted that while CP affects about two to four children per 1,000 live births each year in high-income countries, the etiological causes of most cases remain unknown. “This large population-based cohort study ... should inspire more research into preventing and mitigating factors for maternal injuries and offspring CP development,” wrote Zeyan Liew, PhD, MPH, and Haoran Zhuo, MPH, of Yale University School of Public Health in New Haven, Conn.

This study was supported by Santé-Québec and ICES, a research institute funded by the Ontario Ministry of Health and the Ministry of Long-Term Care.

Dr. Ahmed and coauthor Seungmi Yang, PhD, reported research funding from Santé-Québec during the conduct of the study.

The offspring of mothers who sustain unintentional injuries during pregnancy appear to have a modest 33% increased risk of developing cerebral palsy (CP) – higher when injuries are more severe, multiple, or lead to delivery soon afterward, a Canadian birth cohort study found.

Such children may benefit from long-term monitoring for neurodevelpmental issues, wrote a group led by Asma Ahmed, MD, PhD, MPH, a pediatric epidemiologist at the Hospital for Sick Children Research Institute in Toronto in JAMA Pediatrics.

“We need to provide better support for babies whose mothers have been injured in pregnancy, especially after severe injuries,” Dr. Ahmed said in a press release. “As well, these findings suggest the need for early monitoring of babies’ development, regular check-ups, and longer-term neurodevelopmental assessments.” Future studies should directly measure injury severity and its possible link to CP.

Current guidelines, however, focus on monitoring fetal condition immediately after injury with little attention to its long-term effects.

In their findings from the population-based linkage study of 2,110,177 children born in Ontario’s public health system during 2002-2017 and followed to 2018 with a median follow-up of 8 years:

• A total of 81,281 fetuses were exposed in utero to unintentional maternal injury.
• Overall, 0.3% children were diagnosed with CP, and the mean CP incidence rates were 4.36 per 10,000 child-years for the exposed versus 2.93 for the unexposed.
• In those exposed, the hazard ratio was 1.33 (95% confidence interval, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics.
• Injuries resulting in hospitalization or delivery within 1 week were linked to higher adjusted hazard ratios of 2.18 (95% CI, 1.29-3.68) and 3.40 (95% CI, 1.93-6.00), respectively.
• Injuries most frequently resulted from transportation mishaps, falls, and being struck by a person or object. They were most commonly associated with age younger than 20 years, substance use disorder, residence in rural and under-resourced areas, and lower socioeconomic status.

The authors noted that complications after maternal injuries – which affect 6%-8% of pregnant women – include uterine rupture, preterm delivery, and placental abruption and are linked to fetal complications such as asphyxia. The association with an offspring’s neurodevelopment has been rarely investigated. One U.K. population study, however, suggested a link between vehicular crashes and higher CP risk in preterm infants.

A related editorial on the study noted that while CP affects about two to four children per 1,000 live births each year in high-income countries, the etiological causes of most cases remain unknown. “This large population-based cohort study ... should inspire more research into preventing and mitigating factors for maternal injuries and offspring CP development,” wrote Zeyan Liew, PhD, MPH, and Haoran Zhuo, MPH, of Yale University School of Public Health in New Haven, Conn.

This study was supported by Santé-Québec and ICES, a research institute funded by the Ontario Ministry of Health and the Ministry of Long-Term Care.

Dr. Ahmed and coauthor Seungmi Yang, PhD, reported research funding from Santé-Québec during the conduct of the study.

The offspring of mothers who sustain unintentional injuries during pregnancy appear to have a modest 33% increased risk of developing cerebral palsy (CP) – higher when injuries are more severe, multiple, or lead to delivery soon afterward, a Canadian birth cohort study found.

Such children may benefit from long-term monitoring for neurodevelpmental issues, wrote a group led by Asma Ahmed, MD, PhD, MPH, a pediatric epidemiologist at the Hospital for Sick Children Research Institute in Toronto in JAMA Pediatrics.

“We need to provide better support for babies whose mothers have been injured in pregnancy, especially after severe injuries,” Dr. Ahmed said in a press release. “As well, these findings suggest the need for early monitoring of babies’ development, regular check-ups, and longer-term neurodevelopmental assessments.” Future studies should directly measure injury severity and its possible link to CP.

Current guidelines, however, focus on monitoring fetal condition immediately after injury with little attention to its long-term effects.

In their findings from the population-based linkage study of 2,110,177 children born in Ontario’s public health system during 2002-2017 and followed to 2018 with a median follow-up of 8 years:

• A total of 81,281 fetuses were exposed in utero to unintentional maternal injury.
• Overall, 0.3% children were diagnosed with CP, and the mean CP incidence rates were 4.36 per 10,000 child-years for the exposed versus 2.93 for the unexposed.
• In those exposed, the hazard ratio was 1.33 (95% confidence interval, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics.
• Injuries resulting in hospitalization or delivery within 1 week were linked to higher adjusted hazard ratios of 2.18 (95% CI, 1.29-3.68) and 3.40 (95% CI, 1.93-6.00), respectively.
• Injuries most frequently resulted from transportation mishaps, falls, and being struck by a person or object. They were most commonly associated with age younger than 20 years, substance use disorder, residence in rural and under-resourced areas, and lower socioeconomic status.

The authors noted that complications after maternal injuries – which affect 6%-8% of pregnant women – include uterine rupture, preterm delivery, and placental abruption and are linked to fetal complications such as asphyxia. The association with an offspring’s neurodevelopment has been rarely investigated. One U.K. population study, however, suggested a link between vehicular crashes and higher CP risk in preterm infants.

A related editorial on the study noted that while CP affects about two to four children per 1,000 live births each year in high-income countries, the etiological causes of most cases remain unknown. “This large population-based cohort study ... should inspire more research into preventing and mitigating factors for maternal injuries and offspring CP development,” wrote Zeyan Liew, PhD, MPH, and Haoran Zhuo, MPH, of Yale University School of Public Health in New Haven, Conn.

This study was supported by Santé-Québec and ICES, a research institute funded by the Ontario Ministry of Health and the Ministry of Long-Term Care.

Dr. Ahmed and coauthor Seungmi Yang, PhD, reported research funding from Santé-Québec during the conduct of the study.

(Reuters) – Eli Lilly’s COVID-19 drug bebtelovimab is not currently authorized for emergency use in the United States, the Food and Drug Administration said, citing it is not expected to neutralize the dominant BQ.1 and BQ.1.1 subvariants of Omicron.

The announcement on Nov. 30 takes away authorization from the last COVID-19 monoclonal antibody treatment, leaving Pfizer’s antiviral drug Paxlovid, Merck’s Lagevrio, and Gilead Sciences’ Veklury as treatments for the disease, besides convalescent plasma for some patients.

AstraZeneca’s monoclonal antibody Evusheld is also authorized for protection against COVID-19 infection in some people.

Eli Lilly and its authorized distributors have paused commercial distribution of the monoclonal antibody until further notice from the agency, while the U.S. government has also paused fulfillment of any pending requests under its scheme to help uninsured and underinsured Americans access the drug.

The drug, which was discovered by Abcellera and commercialized by Eli Lilly, received an authorization from the FDA in February.

BQ.1 and BQ.1.1 have become the dominant strains in the United States after a steady increase in prevalence over the last 2 months, surpassing Omicron’s BA.5 subvariant, which had driven cases earlier in the year.

The subvariants accounted for around 57% of the cases nationally, as per government data last week.

Reuters Health Information © 2022 

(Reuters) – Eli Lilly’s COVID-19 drug bebtelovimab is not currently authorized for emergency use in the United States, the Food and Drug Administration said, citing it is not expected to neutralize the dominant BQ.1 and BQ.1.1 subvariants of Omicron.

The announcement on Nov. 30 takes away authorization from the last COVID-19 monoclonal antibody treatment, leaving Pfizer’s antiviral drug Paxlovid, Merck’s Lagevrio, and Gilead Sciences’ Veklury as treatments for the disease, besides convalescent plasma for some patients.

AstraZeneca’s monoclonal antibody Evusheld is also authorized for protection against COVID-19 infection in some people.

Eli Lilly and its authorized distributors have paused commercial distribution of the monoclonal antibody until further notice from the agency, while the U.S. government has also paused fulfillment of any pending requests under its scheme to help uninsured and underinsured Americans access the drug.

The drug, which was discovered by Abcellera and commercialized by Eli Lilly, received an authorization from the FDA in February.

BQ.1 and BQ.1.1 have become the dominant strains in the United States after a steady increase in prevalence over the last 2 months, surpassing Omicron’s BA.5 subvariant, which had driven cases earlier in the year.

The subvariants accounted for around 57% of the cases nationally, as per government data last week.

Reuters Health Information © 2022 

(Reuters) – Eli Lilly’s COVID-19 drug bebtelovimab is not currently authorized for emergency use in the United States, the Food and Drug Administration said, citing it is not expected to neutralize the dominant BQ.1 and BQ.1.1 subvariants of Omicron.

The announcement on Nov. 30 takes away authorization from the last COVID-19 monoclonal antibody treatment, leaving Pfizer’s antiviral drug Paxlovid, Merck’s Lagevrio, and Gilead Sciences’ Veklury as treatments for the disease, besides convalescent plasma for some patients.

AstraZeneca’s monoclonal antibody Evusheld is also authorized for protection against COVID-19 infection in some people.

Eli Lilly and its authorized distributors have paused commercial distribution of the monoclonal antibody until further notice from the agency, while the U.S. government has also paused fulfillment of any pending requests under its scheme to help uninsured and underinsured Americans access the drug.

The drug, which was discovered by Abcellera and commercialized by Eli Lilly, received an authorization from the FDA in February.

BQ.1 and BQ.1.1 have become the dominant strains in the United States after a steady increase in prevalence over the last 2 months, surpassing Omicron’s BA.5 subvariant, which had driven cases earlier in the year.

The subvariants accounted for around 57% of the cases nationally, as per government data last week.

Reuters Health Information © 2022 

A new study supports the hypothesis that changes in levels of amyloid and tau occur many years before the emergence of clinical symptoms of Alzheimer’s disease (AD).

“Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations,” the investigators note.

“These data may suggest that there is a short therapeutic window for slowing AD pathogenesis prior to the emergence of clinical symptoms – and that this window may occur after amyloid accumulation begins but before amyloid has substantial impacts on tau accumulation,” study investigator Corinne Pettigrew, PhD, department of neurology, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

The study was published online in Alzheimer’s and Dementia.
 

Novel long-term CSF data

The study builds on previous research by examining changes in cerebrospinal fluid (CSF) biomarkers over longer periods than had been done previously, particularly among largely middle-aged and cognitively normal at baseline individuals.

The researchers examined changes in amyloid beta (Aβ) 42/Aβ40, phosphorylated tau181 (p-tau181), and total tau (t-tau) in CSF over an average of 10.7 years (and up to 23 years) among 278 individuals who were largely middle-aged persons who were cognitively normal at baseline.

“To our knowledge, no prior study among initially cognitively normal, primarily middle-aged individuals has described CSF AD biomarker changes over this duration of follow-up,” the researchers write.

During follow-up, 94 individuals who initially had normal cognition developed mild cognitive impairment (MCI).

Lower baseline levels of amyloid were associated with greater increases in tau (more strongly in men than women), while accelerations in tau were more closely linked to onset of MCI, the researchers report.

Among individuals who developed MCI, biomarker levels were more abnormal and tau increased to a greater extent prior to the onset of MCI symptoms, they found.
 

Clear impact of APOE4

The findings also suggest that among APOE4 carriers, amyloid onset occurs at an earlier age and rates of amyloid positivity are higher, but there are no differences in rates of change in amyloid over time.

“APOE4 genetic status was not related to changes in CSF beta-amyloid after accounting for the fact that APOE4 carriers have higher rates of amyloid positivity,” said Dr. Pettigrew.

“These findings suggest that APOE4 genetic status shifts the age of onset of amyloid accumulation (with APOE4 carriers having an earlier age of onset compared to non-carriers), but that APOE4 is not related to rates of change in CSF beta-amyloid over time,” she added.

“Thus, cognitively normal APOE4 carriers may be in more advanced preclinical AD stages at younger ages than individuals who are not APOE4 carriers, which is likely relevant for optimizing clinical trial recruitment strategies,” she said.

Funding for the study was provided by the National Institutes of Health. Dr. Pettigrew has disclosed no relevant financial relationships. The original article contains a complete list of author disclosures.

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

A new study supports the hypothesis that changes in levels of amyloid and tau occur many years before the emergence of clinical symptoms of Alzheimer’s disease (AD).

“Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations,” the investigators note.

“These data may suggest that there is a short therapeutic window for slowing AD pathogenesis prior to the emergence of clinical symptoms – and that this window may occur after amyloid accumulation begins but before amyloid has substantial impacts on tau accumulation,” study investigator Corinne Pettigrew, PhD, department of neurology, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

The study was published online in Alzheimer’s and Dementia.
 

Novel long-term CSF data

The study builds on previous research by examining changes in cerebrospinal fluid (CSF) biomarkers over longer periods than had been done previously, particularly among largely middle-aged and cognitively normal at baseline individuals.

The researchers examined changes in amyloid beta (Aβ) 42/Aβ40, phosphorylated tau181 (p-tau181), and total tau (t-tau) in CSF over an average of 10.7 years (and up to 23 years) among 278 individuals who were largely middle-aged persons who were cognitively normal at baseline.

“To our knowledge, no prior study among initially cognitively normal, primarily middle-aged individuals has described CSF AD biomarker changes over this duration of follow-up,” the researchers write.

During follow-up, 94 individuals who initially had normal cognition developed mild cognitive impairment (MCI).

Lower baseline levels of amyloid were associated with greater increases in tau (more strongly in men than women), while accelerations in tau were more closely linked to onset of MCI, the researchers report.

Among individuals who developed MCI, biomarker levels were more abnormal and tau increased to a greater extent prior to the onset of MCI symptoms, they found.
 

Clear impact of APOE4

The findings also suggest that among APOE4 carriers, amyloid onset occurs at an earlier age and rates of amyloid positivity are higher, but there are no differences in rates of change in amyloid over time.

“APOE4 genetic status was not related to changes in CSF beta-amyloid after accounting for the fact that APOE4 carriers have higher rates of amyloid positivity,” said Dr. Pettigrew.

“These findings suggest that APOE4 genetic status shifts the age of onset of amyloid accumulation (with APOE4 carriers having an earlier age of onset compared to non-carriers), but that APOE4 is not related to rates of change in CSF beta-amyloid over time,” she added.

“Thus, cognitively normal APOE4 carriers may be in more advanced preclinical AD stages at younger ages than individuals who are not APOE4 carriers, which is likely relevant for optimizing clinical trial recruitment strategies,” she said.

Funding for the study was provided by the National Institutes of Health. Dr. Pettigrew has disclosed no relevant financial relationships. The original article contains a complete list of author disclosures.

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

A new study supports the hypothesis that changes in levels of amyloid and tau occur many years before the emergence of clinical symptoms of Alzheimer’s disease (AD).

“Our results confirm accelerated biomarker changes during preclinical AD and highlight the important role of amyloid levels in tau accelerations,” the investigators note.

“These data may suggest that there is a short therapeutic window for slowing AD pathogenesis prior to the emergence of clinical symptoms – and that this window may occur after amyloid accumulation begins but before amyloid has substantial impacts on tau accumulation,” study investigator Corinne Pettigrew, PhD, department of neurology, Johns Hopkins University School of Medicine, Baltimore, told this news organization.

The study was published online in Alzheimer’s and Dementia.
 

Novel long-term CSF data

The study builds on previous research by examining changes in cerebrospinal fluid (CSF) biomarkers over longer periods than had been done previously, particularly among largely middle-aged and cognitively normal at baseline individuals.

The researchers examined changes in amyloid beta (Aβ) 42/Aβ40, phosphorylated tau181 (p-tau181), and total tau (t-tau) in CSF over an average of 10.7 years (and up to 23 years) among 278 individuals who were largely middle-aged persons who were cognitively normal at baseline.

“To our knowledge, no prior study among initially cognitively normal, primarily middle-aged individuals has described CSF AD biomarker changes over this duration of follow-up,” the researchers write.

During follow-up, 94 individuals who initially had normal cognition developed mild cognitive impairment (MCI).

Lower baseline levels of amyloid were associated with greater increases in tau (more strongly in men than women), while accelerations in tau were more closely linked to onset of MCI, the researchers report.

Among individuals who developed MCI, biomarker levels were more abnormal and tau increased to a greater extent prior to the onset of MCI symptoms, they found.
 

Clear impact of APOE4

The findings also suggest that among APOE4 carriers, amyloid onset occurs at an earlier age and rates of amyloid positivity are higher, but there are no differences in rates of change in amyloid over time.

“APOE4 genetic status was not related to changes in CSF beta-amyloid after accounting for the fact that APOE4 carriers have higher rates of amyloid positivity,” said Dr. Pettigrew.

“These findings suggest that APOE4 genetic status shifts the age of onset of amyloid accumulation (with APOE4 carriers having an earlier age of onset compared to non-carriers), but that APOE4 is not related to rates of change in CSF beta-amyloid over time,” she added.

“Thus, cognitively normal APOE4 carriers may be in more advanced preclinical AD stages at younger ages than individuals who are not APOE4 carriers, which is likely relevant for optimizing clinical trial recruitment strategies,” she said.

Funding for the study was provided by the National Institutes of Health. Dr. Pettigrew has disclosed no relevant financial relationships. The original article contains a complete list of author disclosures.

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

The Diagnosis: Mid-Borderline Multibacillary Leprosy

The biopsies showed a granulomatous dermatitis involving the dermis and subcutaneous adipose tissue (Figure, A). Fite staining also revealed numerous acid-fast bacilli (AFB) throughout the dermis (Figure, B); however, polymerase chain reaction (PCR) for Mycobacterium tuberculosis was negative, and concomitant AFB tissue culture showed no growth after 8 weeks of incubation from the left wrist biopsy (Table). Interestingly, a left inguinal lymph node biopsy performed 6 months prior to presentation that helped to establish the diagnosis of follicular lymphoma also revealed nonnecrotizing granulomas and the presence of rare AFB; this formalin-fixed specimen subsequently tested negative for M tuberculosis and nontuberculous mycobacteria (NTM) by broad-range PCR. Due to a high index of suspicion, another unpreserved skin biopsy of the right knee was sent for NTM testing with PCR. Primers to 16S ribosomal RNA and the beta subunit of RNA polymerase, rpoB, gene detected Mycobacterium leprae DNA, leading to the diagnosis of mid-borderline (or borderline-borderline) multibacillary leprosy. Our patient subsequently reported subtle hypoesthesia of the plaques on the knees. He recalled eating undercooked armadillo meat in the southern United States more than 30 years prior to admission. In addition, he had a history of being incarcerated in the northeastern United States. This case was reported to the National Hansen’s Disease Program, and our patient was started on a 2-year course of daily clarithromycin, daily minocycline, and once-monthly moxifloxacin. His family also was evaluated and did not have any skin lesions concerning for leprosy.

Leprosy is a major global health concern, transmitted via breaks in the skin, respiratory secretions, and contact with armadillos. It continues to be endemic in India, Brazil, and Indonesia.¹ In the United States where leprosy is nonendemic, 159 new cases were detected in 2020; the most notable risk factors in the United States are armadillo exposure and travel history.^2,3Mycobacterium leprae are intracellular bacilli that preferentially infect macrophages and Schwann cells, resulting in erythematous or hypopigmented skin lesions that often are anesthetic. Mycobacterium leprae has the longest doubling time of all bacteria with unknown in vitro growth requirements and a typical in vivo incubation period of 2 to 10 years.⁴ Therefore, in vitro cultures will yield no growth, as seen in our case. In our patient, Fite stain showed acid-fast organisms in multiple tissue specimens, but AFB cultures demonstrated no growth after 8 weeks of incubation. Although clinicopathologic correlation is most important, PCR analysis can help to assist in the diagnosis of leprosy. Unpreserved tissue should be used when possible, as the fixation process may adversely affect the analytic sensitivity of subsequent PCR-based assays.⁵ In our case, NTM were not detected by PCR in the inguinal lymph node specimen despite demonstrating rare AFB staining. This result likely was multifactorial, including the effect of formalin fixation and paraffin embedding as well as concomitant low biomass.

Leprosy is known as a great imitator, and clinical manifestations (both neurologic and cutaneous) depend on host immune response to the mycobacteria. Although tuberculoid leprosy (associated with T helper type 1 immune response) is distinguished by few asymmetric, well-demarcated, and often hypopigmented plaques, lepromatous leprosy (associated with T helper type 2 response) is characterized by numerous symmetric and poorly defined lesions. Borderline leprosy, as seen in our patient, is the most common type of leprosy and shows features of both tuberculoid and lepromatous leprosy.⁴ It also may be particularly difficult to diagnose.^6,7 Borderline-borderline leprosy involves lesions that mostly are of the lepromatous type and symmetric but also may include raised plaques, as in tuberculoid leprosy.⁴ Plaques in an annular configuration with central clearing, as seen in our patient, are considered suggestive.⁸ Histopathology of borderline-borderline leprosy lesions shows subepidermal clear zones, and granulomas are more diffuse than in tuberculoid leprosy.⁴

Given the noncaseating granulomatous dermatitis seen on histopathology and the relatively higher incidence of sarcoidosis in our region of practice, our initial differential included sarcoidosis and other granulomatous disorders such as granuloma annulare. Interestingly, sarcoidosis has been misdiagnosed as leprosy on multiple occasions in countries where leprosy is endemic.^9,10 Localized cutaneous leishmaniasis typically presents with infiltrated plaques and nodules that may ulcerate; diffuse and disseminated as well as mucocutaneous presentations may occur depending on the species and severity of infection. Parasitized macrophages containing amastigotes may be seen in the dermis highlighted by CD1a immunostaining. Mycosis fungoides presents as papulosquamous patches or plaques, often favoring sunprotected sites; the hypopigmented variant may mimic the central clearing seen in leprosy.

The diagnosis of leprosy can be challenging due to varying clinical presentation; indolent growth of the causative organism; and indeterminate nature of stains, including the Fite stain. Although leprosy is an uncommon diagnosis, this case underscores the need to keep it in the differential of granulomatous dermatoses in the appropriate clinical setting, particularly in patients with risk factors for exposure.⁸

The Diagnosis: Mid-Borderline Multibacillary Leprosy

The biopsies showed a granulomatous dermatitis involving the dermis and subcutaneous adipose tissue (Figure, A). Fite staining also revealed numerous acid-fast bacilli (AFB) throughout the dermis (Figure, B); however, polymerase chain reaction (PCR) for Mycobacterium tuberculosis was negative, and concomitant AFB tissue culture showed no growth after 8 weeks of incubation from the left wrist biopsy (Table). Interestingly, a left inguinal lymph node biopsy performed 6 months prior to presentation that helped to establish the diagnosis of follicular lymphoma also revealed nonnecrotizing granulomas and the presence of rare AFB; this formalin-fixed specimen subsequently tested negative for M tuberculosis and nontuberculous mycobacteria (NTM) by broad-range PCR. Due to a high index of suspicion, another unpreserved skin biopsy of the right knee was sent for NTM testing with PCR. Primers to 16S ribosomal RNA and the beta subunit of RNA polymerase, rpoB, gene detected Mycobacterium leprae DNA, leading to the diagnosis of mid-borderline (or borderline-borderline) multibacillary leprosy. Our patient subsequently reported subtle hypoesthesia of the plaques on the knees. He recalled eating undercooked armadillo meat in the southern United States more than 30 years prior to admission. In addition, he had a history of being incarcerated in the northeastern United States. This case was reported to the National Hansen’s Disease Program, and our patient was started on a 2-year course of daily clarithromycin, daily minocycline, and once-monthly moxifloxacin. His family also was evaluated and did not have any skin lesions concerning for leprosy.

Leprosy is a major global health concern, transmitted via breaks in the skin, respiratory secretions, and contact with armadillos. It continues to be endemic in India, Brazil, and Indonesia.¹ In the United States where leprosy is nonendemic, 159 new cases were detected in 2020; the most notable risk factors in the United States are armadillo exposure and travel history.^2,3Mycobacterium leprae are intracellular bacilli that preferentially infect macrophages and Schwann cells, resulting in erythematous or hypopigmented skin lesions that often are anesthetic. Mycobacterium leprae has the longest doubling time of all bacteria with unknown in vitro growth requirements and a typical in vivo incubation period of 2 to 10 years.⁴ Therefore, in vitro cultures will yield no growth, as seen in our case. In our patient, Fite stain showed acid-fast organisms in multiple tissue specimens, but AFB cultures demonstrated no growth after 8 weeks of incubation. Although clinicopathologic correlation is most important, PCR analysis can help to assist in the diagnosis of leprosy. Unpreserved tissue should be used when possible, as the fixation process may adversely affect the analytic sensitivity of subsequent PCR-based assays.⁵ In our case, NTM were not detected by PCR in the inguinal lymph node specimen despite demonstrating rare AFB staining. This result likely was multifactorial, including the effect of formalin fixation and paraffin embedding as well as concomitant low biomass.

Leprosy is known as a great imitator, and clinical manifestations (both neurologic and cutaneous) depend on host immune response to the mycobacteria. Although tuberculoid leprosy (associated with T helper type 1 immune response) is distinguished by few asymmetric, well-demarcated, and often hypopigmented plaques, lepromatous leprosy (associated with T helper type 2 response) is characterized by numerous symmetric and poorly defined lesions. Borderline leprosy, as seen in our patient, is the most common type of leprosy and shows features of both tuberculoid and lepromatous leprosy.⁴ It also may be particularly difficult to diagnose.^6,7 Borderline-borderline leprosy involves lesions that mostly are of the lepromatous type and symmetric but also may include raised plaques, as in tuberculoid leprosy.⁴ Plaques in an annular configuration with central clearing, as seen in our patient, are considered suggestive.⁸ Histopathology of borderline-borderline leprosy lesions shows subepidermal clear zones, and granulomas are more diffuse than in tuberculoid leprosy.⁴

Given the noncaseating granulomatous dermatitis seen on histopathology and the relatively higher incidence of sarcoidosis in our region of practice, our initial differential included sarcoidosis and other granulomatous disorders such as granuloma annulare. Interestingly, sarcoidosis has been misdiagnosed as leprosy on multiple occasions in countries where leprosy is endemic.^9,10 Localized cutaneous leishmaniasis typically presents with infiltrated plaques and nodules that may ulcerate; diffuse and disseminated as well as mucocutaneous presentations may occur depending on the species and severity of infection. Parasitized macrophages containing amastigotes may be seen in the dermis highlighted by CD1a immunostaining. Mycosis fungoides presents as papulosquamous patches or plaques, often favoring sunprotected sites; the hypopigmented variant may mimic the central clearing seen in leprosy.

The diagnosis of leprosy can be challenging due to varying clinical presentation; indolent growth of the causative organism; and indeterminate nature of stains, including the Fite stain. Although leprosy is an uncommon diagnosis, this case underscores the need to keep it in the differential of granulomatous dermatoses in the appropriate clinical setting, particularly in patients with risk factors for exposure.⁸

The Diagnosis: Mid-Borderline Multibacillary Leprosy

The biopsies showed a granulomatous dermatitis involving the dermis and subcutaneous adipose tissue (Figure, A). Fite staining also revealed numerous acid-fast bacilli (AFB) throughout the dermis (Figure, B); however, polymerase chain reaction (PCR) for Mycobacterium tuberculosis was negative, and concomitant AFB tissue culture showed no growth after 8 weeks of incubation from the left wrist biopsy (Table). Interestingly, a left inguinal lymph node biopsy performed 6 months prior to presentation that helped to establish the diagnosis of follicular lymphoma also revealed nonnecrotizing granulomas and the presence of rare AFB; this formalin-fixed specimen subsequently tested negative for M tuberculosis and nontuberculous mycobacteria (NTM) by broad-range PCR. Due to a high index of suspicion, another unpreserved skin biopsy of the right knee was sent for NTM testing with PCR. Primers to 16S ribosomal RNA and the beta subunit of RNA polymerase, rpoB, gene detected Mycobacterium leprae DNA, leading to the diagnosis of mid-borderline (or borderline-borderline) multibacillary leprosy. Our patient subsequently reported subtle hypoesthesia of the plaques on the knees. He recalled eating undercooked armadillo meat in the southern United States more than 30 years prior to admission. In addition, he had a history of being incarcerated in the northeastern United States. This case was reported to the National Hansen’s Disease Program, and our patient was started on a 2-year course of daily clarithromycin, daily minocycline, and once-monthly moxifloxacin. His family also was evaluated and did not have any skin lesions concerning for leprosy.

Leprosy is a major global health concern, transmitted via breaks in the skin, respiratory secretions, and contact with armadillos. It continues to be endemic in India, Brazil, and Indonesia.¹ In the United States where leprosy is nonendemic, 159 new cases were detected in 2020; the most notable risk factors in the United States are armadillo exposure and travel history.^2,3Mycobacterium leprae are intracellular bacilli that preferentially infect macrophages and Schwann cells, resulting in erythematous or hypopigmented skin lesions that often are anesthetic. Mycobacterium leprae has the longest doubling time of all bacteria with unknown in vitro growth requirements and a typical in vivo incubation period of 2 to 10 years.⁴ Therefore, in vitro cultures will yield no growth, as seen in our case. In our patient, Fite stain showed acid-fast organisms in multiple tissue specimens, but AFB cultures demonstrated no growth after 8 weeks of incubation. Although clinicopathologic correlation is most important, PCR analysis can help to assist in the diagnosis of leprosy. Unpreserved tissue should be used when possible, as the fixation process may adversely affect the analytic sensitivity of subsequent PCR-based assays.⁵ In our case, NTM were not detected by PCR in the inguinal lymph node specimen despite demonstrating rare AFB staining. This result likely was multifactorial, including the effect of formalin fixation and paraffin embedding as well as concomitant low biomass.

Leprosy is known as a great imitator, and clinical manifestations (both neurologic and cutaneous) depend on host immune response to the mycobacteria. Although tuberculoid leprosy (associated with T helper type 1 immune response) is distinguished by few asymmetric, well-demarcated, and often hypopigmented plaques, lepromatous leprosy (associated with T helper type 2 response) is characterized by numerous symmetric and poorly defined lesions. Borderline leprosy, as seen in our patient, is the most common type of leprosy and shows features of both tuberculoid and lepromatous leprosy.⁴ It also may be particularly difficult to diagnose.^6,7 Borderline-borderline leprosy involves lesions that mostly are of the lepromatous type and symmetric but also may include raised plaques, as in tuberculoid leprosy.⁴ Plaques in an annular configuration with central clearing, as seen in our patient, are considered suggestive.⁸ Histopathology of borderline-borderline leprosy lesions shows subepidermal clear zones, and granulomas are more diffuse than in tuberculoid leprosy.⁴

Given the noncaseating granulomatous dermatitis seen on histopathology and the relatively higher incidence of sarcoidosis in our region of practice, our initial differential included sarcoidosis and other granulomatous disorders such as granuloma annulare. Interestingly, sarcoidosis has been misdiagnosed as leprosy on multiple occasions in countries where leprosy is endemic.^9,10 Localized cutaneous leishmaniasis typically presents with infiltrated plaques and nodules that may ulcerate; diffuse and disseminated as well as mucocutaneous presentations may occur depending on the species and severity of infection. Parasitized macrophages containing amastigotes may be seen in the dermis highlighted by CD1a immunostaining. Mycosis fungoides presents as papulosquamous patches or plaques, often favoring sunprotected sites; the hypopigmented variant may mimic the central clearing seen in leprosy.

The diagnosis of leprosy can be challenging due to varying clinical presentation; indolent growth of the causative organism; and indeterminate nature of stains, including the Fite stain. Although leprosy is an uncommon diagnosis, this case underscores the need to keep it in the differential of granulomatous dermatoses in the appropriate clinical setting, particularly in patients with risk factors for exposure.⁸

I don’t do email. Or texting. You want to talk to me and my staff? Pick up a phone.

Some people say I’m old fashioned, or not patient-friendly, or whatever.

I don’t care.

To me there are too many issues with things that can get missed in emails, too many security concerns, too many ways to alter them so it looks like something different was said.

Now, a recent study of an EHR system found that 3% of emails from patients had negative, if not downright nasty, sentiments expressed to their physicians.

Here’s some examples:

“I hope and expect that you will spend eternity in hell. You are an abusive, nasty, cheap person.”

“Your office is full of liars, hypocrites and I will do everything in my power to prevent anyone from going to your bullsh** office again.”

The study also noted that the most common expletive used by patients is the F-bomb, and that words with violent connotations, such as “shoot,” “fight,” and “kill” were often used in such emails. The last are definitely concerning in an era of increased violence directed at doctors and other health care workers who are just trying to do their jobs.

Now, I know doctors are a microcosm of society. Like patients, most are decent people trying their best, but a few are ... not particularly nice.

But still, I don’t think we, or anyone for that matter, need to be getting emails of this nature. It certainly doesn’t put anyone in a good position, or allow for objective, unbiased, care. Even if they’re only 3% of emails, that can still be quite a few.

Who needs that?

One of the issues with email is that it’s easy to type something nasty and hit “send,” then later have it occur to you that maybe you should have calmed down first. Granted, that sort of thing can (and does) happen when talking to another person (by phone or in person), but it’s harder.

Direct personal contact, especially face-to-face, appears to lessen impulsive reactions for most. The other person isn’t an invisible email address, they’re someone you’re talking to. You can read tone-of-voice and facial expressions. Again, I’m aware people still can lose their cool in person, but it’s harder.

In-person communication, or on the phone, adds a greater chance to reason through things, explain misunderstandings, and clarify statements rather than just hitting send and running into the next exam room. Plus, it ensures that all noncritical patient interactions occur during business hours, when we’re in doctor mode, rather than at 2:45 a.m. when we look at the iPhone while waiting for the dog to come back in. That’s a terrible time to receive and send medical (or any) emails for both doctor and patient.

A lot rides on every one of my patient interactions, and that’s why I still want them done directly. If that makes me old-fashioned, so be it.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I don’t do email. Or texting. You want to talk to me and my staff? Pick up a phone.

Some people say I’m old fashioned, or not patient-friendly, or whatever.

I don’t care.

To me there are too many issues with things that can get missed in emails, too many security concerns, too many ways to alter them so it looks like something different was said.

Now, a recent study of an EHR system found that 3% of emails from patients had negative, if not downright nasty, sentiments expressed to their physicians.

Here’s some examples:

“I hope and expect that you will spend eternity in hell. You are an abusive, nasty, cheap person.”

“Your office is full of liars, hypocrites and I will do everything in my power to prevent anyone from going to your bullsh** office again.”

The study also noted that the most common expletive used by patients is the F-bomb, and that words with violent connotations, such as “shoot,” “fight,” and “kill” were often used in such emails. The last are definitely concerning in an era of increased violence directed at doctors and other health care workers who are just trying to do their jobs.

Now, I know doctors are a microcosm of society. Like patients, most are decent people trying their best, but a few are ... not particularly nice.

But still, I don’t think we, or anyone for that matter, need to be getting emails of this nature. It certainly doesn’t put anyone in a good position, or allow for objective, unbiased, care. Even if they’re only 3% of emails, that can still be quite a few.

Who needs that?

One of the issues with email is that it’s easy to type something nasty and hit “send,” then later have it occur to you that maybe you should have calmed down first. Granted, that sort of thing can (and does) happen when talking to another person (by phone or in person), but it’s harder.

Direct personal contact, especially face-to-face, appears to lessen impulsive reactions for most. The other person isn’t an invisible email address, they’re someone you’re talking to. You can read tone-of-voice and facial expressions. Again, I’m aware people still can lose their cool in person, but it’s harder.

In-person communication, or on the phone, adds a greater chance to reason through things, explain misunderstandings, and clarify statements rather than just hitting send and running into the next exam room. Plus, it ensures that all noncritical patient interactions occur during business hours, when we’re in doctor mode, rather than at 2:45 a.m. when we look at the iPhone while waiting for the dog to come back in. That’s a terrible time to receive and send medical (or any) emails for both doctor and patient.

A lot rides on every one of my patient interactions, and that’s why I still want them done directly. If that makes me old-fashioned, so be it.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I don’t do email. Or texting. You want to talk to me and my staff? Pick up a phone.

Some people say I’m old fashioned, or not patient-friendly, or whatever.

I don’t care.

To me there are too many issues with things that can get missed in emails, too many security concerns, too many ways to alter them so it looks like something different was said.

Now, a recent study of an EHR system found that 3% of emails from patients had negative, if not downright nasty, sentiments expressed to their physicians.

Here’s some examples:

“I hope and expect that you will spend eternity in hell. You are an abusive, nasty, cheap person.”

“Your office is full of liars, hypocrites and I will do everything in my power to prevent anyone from going to your bullsh** office again.”

The study also noted that the most common expletive used by patients is the F-bomb, and that words with violent connotations, such as “shoot,” “fight,” and “kill” were often used in such emails. The last are definitely concerning in an era of increased violence directed at doctors and other health care workers who are just trying to do their jobs.

Now, I know doctors are a microcosm of society. Like patients, most are decent people trying their best, but a few are ... not particularly nice.

But still, I don’t think we, or anyone for that matter, need to be getting emails of this nature. It certainly doesn’t put anyone in a good position, or allow for objective, unbiased, care. Even if they’re only 3% of emails, that can still be quite a few.

Who needs that?

One of the issues with email is that it’s easy to type something nasty and hit “send,” then later have it occur to you that maybe you should have calmed down first. Granted, that sort of thing can (and does) happen when talking to another person (by phone or in person), but it’s harder.

Direct personal contact, especially face-to-face, appears to lessen impulsive reactions for most. The other person isn’t an invisible email address, they’re someone you’re talking to. You can read tone-of-voice and facial expressions. Again, I’m aware people still can lose their cool in person, but it’s harder.

In-person communication, or on the phone, adds a greater chance to reason through things, explain misunderstandings, and clarify statements rather than just hitting send and running into the next exam room. Plus, it ensures that all noncritical patient interactions occur during business hours, when we’re in doctor mode, rather than at 2:45 a.m. when we look at the iPhone while waiting for the dog to come back in. That’s a terrible time to receive and send medical (or any) emails for both doctor and patient.

A lot rides on every one of my patient interactions, and that’s why I still want them done directly. If that makes me old-fashioned, so be it.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Doctors suspect the worst respiratory syncytial virus (RSV) season in years just ended, and the story of a child who had a serious respiratory infection provides a glimpse of what health care providers saw in the fall of 2022.

RSV cases peaked in mid-November, according to the latest Centers for Disease Control and Prevention data, with RSV-associated hospitalizations in the United States among patients 0-4 years having maxed out five times higher than they were at the same time in 2021. These surges strained providers and left parents scrambling for care. Fortunately, pediatric hospitalizations appear to be subsiding.

In interviews, the parents of the child who had a severe case of RSV reflected on their son’s bout with the illness, and doctors described challenges to dealing with the surge in RSV cases this season. The physicians also offered advice on how recognize and respond to future cases of the virus.
 

Sebastian Witt’s story

“I didn’t even know what RSV was,” said Malte Witt, whose son, Sebastian, 2, was recently hospitalized for RSV in Denver.

Mr. Witt and his wife, Emily Witt, both 32, thought they were dealing with a typical cold until Sebastian’s condition dramatically deteriorated about 36 hours after symptom onset.

“He basically just slumped over and collapsed, coughing uncontrollably,” Mr. Witt said in an interview. “He couldn’t catch his breath.”

The Witts rushed Sebastian to the ED at Children’s Hospital Colorado, expecting to see a doctor immediately. Instead, they spent the night in an overcrowded waiting room alongside many other families in the same situation.

“There was no room for anyone to sit anywhere,” Mr. Witt said. “There were people sitting on the floor. I counted maybe six children hooked up to oxygen when we walked in.”

After waiting approximately 45 minutes, a nurse checked Sebastian’s oxygen saturation. The readings were 79%-83%. This range is significantly below thresholds for supplemental oxygen described by most pediatric guidelines, which range from 90 to 94%.

The nurse connected Sebastian to bottled oxygen in the waiting room, and a recheck 4 hours later showed that his oxygen saturation had improved.

But the improvement didn’t last.

“At roughly hour 10 in the waiting room – it was 4 in the morning – you could tell that Seb was exhausted, really not acting like himself,” Mr. Witt said. “We thought maybe it’s just late at night, he hasn’t really slept. But then Emily noticed that his oxygen tank had run out.”

Mr. Witt told a nurse, and after another check revealed low oxygen saturation, Sebastian was finally admitted.
 

Early RSV surge strains pediatric providers

With RSV-associated hospitalizations peaking at 48 per 100,000 children, Colorado has been among the states hardest hit by the virus. New Mexico – where hospitalizations peaked at 56.4 per 100,000 children – comes in second. Even in states like California, where hospitalization rates have been almost 10-fold lower than New Mexico, pediatric providers have been stretched to their limits.

“Many hospitals are really being overwhelmed with admissions for RSV, both routine RSV – relatively mild hospitalizations with bronchiolitis – as well as kids in the ICU with more severe cases,” said Dean Blumberg, MD, chief of the division of pediatric infectious diseases at UC Davis Health, Sacramento, said in an interview.

Dr. Blumberg believes the severity of the 2022-2023 RSV season is likely COVID related.

“All community-associated respiratory viral infections are out of whack because of the pandemic, and all the masking and social distancing that was occurring,” he said.

This may also explain why older kids are coming down with more severe cases of RSV.

“Some children are getting RSV for the first time as older children,” Dr. Blumberg said, noting that, historically, most children were infected in the first 2 years of life. “There are reports of children 3 or 4 years of age being admitted with their first episode of RSV because of the [COVID] pandemic.”

This year’s RSV season is also notable for arriving early, potentially catching the community off guard, according to Jennifer D. Kusma, MD, a primary care pediatrician at Ann & Robert H. Lurie Children’s Hospital of Chicago.

“People who should have been protected often weren’t protected yet,” Dr. Kusma said in an interview.
 

Treatments new, old, and unproven

On Nov. 17, in the midst of the RSV surge, the American Academy of Pediatrics issued updated guidance for palivizumab, an RSV-targeting monoclonal antibody labeled for children at risk of severe RSV, including those with pre-existing lung or heart conditions, and infants with a history of premature birth (less than or equal to 35 weeks’ gestational age).

“If RSV disease activity persists at high levels in a given region through the fall and winter, the AAP supports providing more than five consecutive doses of palivizumab to eligible children,” the update stated.

Insurance companies appear to be responding in kind, covering additional doses for children in need.

“[Payers] have agreed that, if [palivizumab] needs to be given for an additional month or 2 or 3, then they’re making a commitment that they’ll reimburse hospitals for providing that,” Dr. Blumberg said.

For ineligible patients, such as Sebastian, who was born prematurely at 36 weeks – 1 week shy of the label requirement – treatment relies upon supportive care with oxygen and IV fluids.

At home, parents are left with simpler options.

Dr. Blumberg and Dr. Kusma recommended keeping children hydrated, maintaining humidified air, and using saline nose drops with bulb suction to clear mucus.

In the Witts’ experience, that last step may be easier said than done.

“Every time a nurse would walk into the room, Sebastian would yell: ‘Go away, doctor! I don’t want snot sucker!’” Mr. Witt said.

“If you over snot-suck, that’s really uncomfortable for the kid, and really hard for you,” Ms. Witt said. “And it doesn’t make much of a difference. It’s just very hard to find a middle ground, where you’re helping and keeping them comfortable.”

Some parents are turning to novel strategies, such as nebulized hypertonic saline, currently marketed on Amazon for children with RSV.

Although the AAP offers a weak recommendation for nebulized hypertonic saline in children hospitalized more than 72 hours, they advise against it in the emergency setting, citing inconsistent findings in clinical trials.

To any parents tempted by thousands of positive Amazon reviews, Dr. Blumberg said, “I wouldn’t waste my money on that.”

Dr. Kusma agreed.

“[Nebulized hypertonic saline] can be irritating,” she said. “It’s saltwater, essentially. If a parent is in the position where they’re worried about their child’s breathing to the point that they think they need to use it, I would err on the side of calling your pediatrician and being seen.”
 

Going in, coming home

Dr. Kusma said parents should seek medical attention if a child is breathing faster and working harder to get air. Increased work of breathing is characterized by pulling of the skin at the notch where the throat meets the chest bone (tracheal tugging), and flattening of the belly that makes the ribcage more prominent.

Mr. Witt saw these signs in Sebastian. He knew they were significant, because a friend who is a nurse had previously shown him some examples of children who exhibited these symptoms online.

“That’s how I knew that things were actually really dangerous,” Mr. Witt said. “Had she not shown me those videos a month and a half before this happened, I don’t know that we would have hit the alarm bell as quickly as we did.”

After spending their second night and the following day in a cramped preoperative room converted to manage overflow from the emergency department, Sebastian’s condition improved, and he was discharged. The Witts are relieved to be home, but frustrations from their ordeal remain, especially considering the estimated $5,000 in out-of-pocket costs they expect to pay.

“How is this our health care system?” Ms. Witt asked. “This is unbelievable.”
 

An optimistic outlook

RSV seasons typically demonstrate a clear peak, followed by a decline through the rest of the season, suggesting better times lie ahead; however, this season has been anything but typical.

“I’m hopeful that it will just go away and stay away,” Dr. Kusma said, citing this trend. “But I can’t know for sure.”

To anxious parents, Dr. Blumberg offered an optimistic view of RSV seasons to come.

“There’s hope,” he said. “There are vaccines that are being developed that are very close to FDA approval. So, it’s possible that this time next year, we might have widespread RSV vaccination available for children so that we don’t have to go through this nightmare again.”

Dr. Blumberg and Dr. Kusma disclosed no relevant conflicts of interest.

Doctors suspect the worst respiratory syncytial virus (RSV) season in years just ended, and the story of a child who had a serious respiratory infection provides a glimpse of what health care providers saw in the fall of 2022.

RSV cases peaked in mid-November, according to the latest Centers for Disease Control and Prevention data, with RSV-associated hospitalizations in the United States among patients 0-4 years having maxed out five times higher than they were at the same time in 2021. These surges strained providers and left parents scrambling for care. Fortunately, pediatric hospitalizations appear to be subsiding.

In interviews, the parents of the child who had a severe case of RSV reflected on their son’s bout with the illness, and doctors described challenges to dealing with the surge in RSV cases this season. The physicians also offered advice on how recognize and respond to future cases of the virus.
 

Sebastian Witt’s story

“I didn’t even know what RSV was,” said Malte Witt, whose son, Sebastian, 2, was recently hospitalized for RSV in Denver.

Mr. Witt and his wife, Emily Witt, both 32, thought they were dealing with a typical cold until Sebastian’s condition dramatically deteriorated about 36 hours after symptom onset.

“He basically just slumped over and collapsed, coughing uncontrollably,” Mr. Witt said in an interview. “He couldn’t catch his breath.”

The Witts rushed Sebastian to the ED at Children’s Hospital Colorado, expecting to see a doctor immediately. Instead, they spent the night in an overcrowded waiting room alongside many other families in the same situation.

“There was no room for anyone to sit anywhere,” Mr. Witt said. “There were people sitting on the floor. I counted maybe six children hooked up to oxygen when we walked in.”

After waiting approximately 45 minutes, a nurse checked Sebastian’s oxygen saturation. The readings were 79%-83%. This range is significantly below thresholds for supplemental oxygen described by most pediatric guidelines, which range from 90 to 94%.

The nurse connected Sebastian to bottled oxygen in the waiting room, and a recheck 4 hours later showed that his oxygen saturation had improved.

But the improvement didn’t last.

“At roughly hour 10 in the waiting room – it was 4 in the morning – you could tell that Seb was exhausted, really not acting like himself,” Mr. Witt said. “We thought maybe it’s just late at night, he hasn’t really slept. But then Emily noticed that his oxygen tank had run out.”

Mr. Witt told a nurse, and after another check revealed low oxygen saturation, Sebastian was finally admitted.
 

Early RSV surge strains pediatric providers

With RSV-associated hospitalizations peaking at 48 per 100,000 children, Colorado has been among the states hardest hit by the virus. New Mexico – where hospitalizations peaked at 56.4 per 100,000 children – comes in second. Even in states like California, where hospitalization rates have been almost 10-fold lower than New Mexico, pediatric providers have been stretched to their limits.

“Many hospitals are really being overwhelmed with admissions for RSV, both routine RSV – relatively mild hospitalizations with bronchiolitis – as well as kids in the ICU with more severe cases,” said Dean Blumberg, MD, chief of the division of pediatric infectious diseases at UC Davis Health, Sacramento, said in an interview.

Dr. Blumberg believes the severity of the 2022-2023 RSV season is likely COVID related.

“All community-associated respiratory viral infections are out of whack because of the pandemic, and all the masking and social distancing that was occurring,” he said.

This may also explain why older kids are coming down with more severe cases of RSV.

“Some children are getting RSV for the first time as older children,” Dr. Blumberg said, noting that, historically, most children were infected in the first 2 years of life. “There are reports of children 3 or 4 years of age being admitted with their first episode of RSV because of the [COVID] pandemic.”

This year’s RSV season is also notable for arriving early, potentially catching the community off guard, according to Jennifer D. Kusma, MD, a primary care pediatrician at Ann & Robert H. Lurie Children’s Hospital of Chicago.

“People who should have been protected often weren’t protected yet,” Dr. Kusma said in an interview.
 

Treatments new, old, and unproven

On Nov. 17, in the midst of the RSV surge, the American Academy of Pediatrics issued updated guidance for palivizumab, an RSV-targeting monoclonal antibody labeled for children at risk of severe RSV, including those with pre-existing lung or heart conditions, and infants with a history of premature birth (less than or equal to 35 weeks’ gestational age).

“If RSV disease activity persists at high levels in a given region through the fall and winter, the AAP supports providing more than five consecutive doses of palivizumab to eligible children,” the update stated.

Insurance companies appear to be responding in kind, covering additional doses for children in need.

“[Payers] have agreed that, if [palivizumab] needs to be given for an additional month or 2 or 3, then they’re making a commitment that they’ll reimburse hospitals for providing that,” Dr. Blumberg said.

For ineligible patients, such as Sebastian, who was born prematurely at 36 weeks – 1 week shy of the label requirement – treatment relies upon supportive care with oxygen and IV fluids.

At home, parents are left with simpler options.

Dr. Blumberg and Dr. Kusma recommended keeping children hydrated, maintaining humidified air, and using saline nose drops with bulb suction to clear mucus.

In the Witts’ experience, that last step may be easier said than done.

“Every time a nurse would walk into the room, Sebastian would yell: ‘Go away, doctor! I don’t want snot sucker!’” Mr. Witt said.

“If you over snot-suck, that’s really uncomfortable for the kid, and really hard for you,” Ms. Witt said. “And it doesn’t make much of a difference. It’s just very hard to find a middle ground, where you’re helping and keeping them comfortable.”

Some parents are turning to novel strategies, such as nebulized hypertonic saline, currently marketed on Amazon for children with RSV.

Although the AAP offers a weak recommendation for nebulized hypertonic saline in children hospitalized more than 72 hours, they advise against it in the emergency setting, citing inconsistent findings in clinical trials.

To any parents tempted by thousands of positive Amazon reviews, Dr. Blumberg said, “I wouldn’t waste my money on that.”

Dr. Kusma agreed.

“[Nebulized hypertonic saline] can be irritating,” she said. “It’s saltwater, essentially. If a parent is in the position where they’re worried about their child’s breathing to the point that they think they need to use it, I would err on the side of calling your pediatrician and being seen.”
 

Going in, coming home

Dr. Kusma said parents should seek medical attention if a child is breathing faster and working harder to get air. Increased work of breathing is characterized by pulling of the skin at the notch where the throat meets the chest bone (tracheal tugging), and flattening of the belly that makes the ribcage more prominent.

Mr. Witt saw these signs in Sebastian. He knew they were significant, because a friend who is a nurse had previously shown him some examples of children who exhibited these symptoms online.

“That’s how I knew that things were actually really dangerous,” Mr. Witt said. “Had she not shown me those videos a month and a half before this happened, I don’t know that we would have hit the alarm bell as quickly as we did.”

After spending their second night and the following day in a cramped preoperative room converted to manage overflow from the emergency department, Sebastian’s condition improved, and he was discharged. The Witts are relieved to be home, but frustrations from their ordeal remain, especially considering the estimated $5,000 in out-of-pocket costs they expect to pay.

“How is this our health care system?” Ms. Witt asked. “This is unbelievable.”
 

An optimistic outlook

RSV seasons typically demonstrate a clear peak, followed by a decline through the rest of the season, suggesting better times lie ahead; however, this season has been anything but typical.

“I’m hopeful that it will just go away and stay away,” Dr. Kusma said, citing this trend. “But I can’t know for sure.”

To anxious parents, Dr. Blumberg offered an optimistic view of RSV seasons to come.

“There’s hope,” he said. “There are vaccines that are being developed that are very close to FDA approval. So, it’s possible that this time next year, we might have widespread RSV vaccination available for children so that we don’t have to go through this nightmare again.”

Dr. Blumberg and Dr. Kusma disclosed no relevant conflicts of interest.

Doctors suspect the worst respiratory syncytial virus (RSV) season in years just ended, and the story of a child who had a serious respiratory infection provides a glimpse of what health care providers saw in the fall of 2022.

RSV cases peaked in mid-November, according to the latest Centers for Disease Control and Prevention data, with RSV-associated hospitalizations in the United States among patients 0-4 years having maxed out five times higher than they were at the same time in 2021. These surges strained providers and left parents scrambling for care. Fortunately, pediatric hospitalizations appear to be subsiding.

In interviews, the parents of the child who had a severe case of RSV reflected on their son’s bout with the illness, and doctors described challenges to dealing with the surge in RSV cases this season. The physicians also offered advice on how recognize and respond to future cases of the virus.
 

Sebastian Witt’s story

“I didn’t even know what RSV was,” said Malte Witt, whose son, Sebastian, 2, was recently hospitalized for RSV in Denver.

Mr. Witt and his wife, Emily Witt, both 32, thought they were dealing with a typical cold until Sebastian’s condition dramatically deteriorated about 36 hours after symptom onset.

“He basically just slumped over and collapsed, coughing uncontrollably,” Mr. Witt said in an interview. “He couldn’t catch his breath.”

The Witts rushed Sebastian to the ED at Children’s Hospital Colorado, expecting to see a doctor immediately. Instead, they spent the night in an overcrowded waiting room alongside many other families in the same situation.

“There was no room for anyone to sit anywhere,” Mr. Witt said. “There were people sitting on the floor. I counted maybe six children hooked up to oxygen when we walked in.”

After waiting approximately 45 minutes, a nurse checked Sebastian’s oxygen saturation. The readings were 79%-83%. This range is significantly below thresholds for supplemental oxygen described by most pediatric guidelines, which range from 90 to 94%.

The nurse connected Sebastian to bottled oxygen in the waiting room, and a recheck 4 hours later showed that his oxygen saturation had improved.

But the improvement didn’t last.

“At roughly hour 10 in the waiting room – it was 4 in the morning – you could tell that Seb was exhausted, really not acting like himself,” Mr. Witt said. “We thought maybe it’s just late at night, he hasn’t really slept. But then Emily noticed that his oxygen tank had run out.”

Mr. Witt told a nurse, and after another check revealed low oxygen saturation, Sebastian was finally admitted.
 

Early RSV surge strains pediatric providers

With RSV-associated hospitalizations peaking at 48 per 100,000 children, Colorado has been among the states hardest hit by the virus. New Mexico – where hospitalizations peaked at 56.4 per 100,000 children – comes in second. Even in states like California, where hospitalization rates have been almost 10-fold lower than New Mexico, pediatric providers have been stretched to their limits.

“Many hospitals are really being overwhelmed with admissions for RSV, both routine RSV – relatively mild hospitalizations with bronchiolitis – as well as kids in the ICU with more severe cases,” said Dean Blumberg, MD, chief of the division of pediatric infectious diseases at UC Davis Health, Sacramento, said in an interview.

Dr. Blumberg believes the severity of the 2022-2023 RSV season is likely COVID related.

“All community-associated respiratory viral infections are out of whack because of the pandemic, and all the masking and social distancing that was occurring,” he said.

This may also explain why older kids are coming down with more severe cases of RSV.

“Some children are getting RSV for the first time as older children,” Dr. Blumberg said, noting that, historically, most children were infected in the first 2 years of life. “There are reports of children 3 or 4 years of age being admitted with their first episode of RSV because of the [COVID] pandemic.”

This year’s RSV season is also notable for arriving early, potentially catching the community off guard, according to Jennifer D. Kusma, MD, a primary care pediatrician at Ann & Robert H. Lurie Children’s Hospital of Chicago.

“People who should have been protected often weren’t protected yet,” Dr. Kusma said in an interview.
 

Treatments new, old, and unproven

On Nov. 17, in the midst of the RSV surge, the American Academy of Pediatrics issued updated guidance for palivizumab, an RSV-targeting monoclonal antibody labeled for children at risk of severe RSV, including those with pre-existing lung or heart conditions, and infants with a history of premature birth (less than or equal to 35 weeks’ gestational age).

“If RSV disease activity persists at high levels in a given region through the fall and winter, the AAP supports providing more than five consecutive doses of palivizumab to eligible children,” the update stated.

Insurance companies appear to be responding in kind, covering additional doses for children in need.

“[Payers] have agreed that, if [palivizumab] needs to be given for an additional month or 2 or 3, then they’re making a commitment that they’ll reimburse hospitals for providing that,” Dr. Blumberg said.

For ineligible patients, such as Sebastian, who was born prematurely at 36 weeks – 1 week shy of the label requirement – treatment relies upon supportive care with oxygen and IV fluids.

At home, parents are left with simpler options.

Dr. Blumberg and Dr. Kusma recommended keeping children hydrated, maintaining humidified air, and using saline nose drops with bulb suction to clear mucus.

In the Witts’ experience, that last step may be easier said than done.

“Every time a nurse would walk into the room, Sebastian would yell: ‘Go away, doctor! I don’t want snot sucker!’” Mr. Witt said.

“If you over snot-suck, that’s really uncomfortable for the kid, and really hard for you,” Ms. Witt said. “And it doesn’t make much of a difference. It’s just very hard to find a middle ground, where you’re helping and keeping them comfortable.”

Some parents are turning to novel strategies, such as nebulized hypertonic saline, currently marketed on Amazon for children with RSV.

Although the AAP offers a weak recommendation for nebulized hypertonic saline in children hospitalized more than 72 hours, they advise against it in the emergency setting, citing inconsistent findings in clinical trials.

To any parents tempted by thousands of positive Amazon reviews, Dr. Blumberg said, “I wouldn’t waste my money on that.”

Dr. Kusma agreed.

“[Nebulized hypertonic saline] can be irritating,” she said. “It’s saltwater, essentially. If a parent is in the position where they’re worried about their child’s breathing to the point that they think they need to use it, I would err on the side of calling your pediatrician and being seen.”
 

Going in, coming home

Dr. Kusma said parents should seek medical attention if a child is breathing faster and working harder to get air. Increased work of breathing is characterized by pulling of the skin at the notch where the throat meets the chest bone (tracheal tugging), and flattening of the belly that makes the ribcage more prominent.

Mr. Witt saw these signs in Sebastian. He knew they were significant, because a friend who is a nurse had previously shown him some examples of children who exhibited these symptoms online.

“That’s how I knew that things were actually really dangerous,” Mr. Witt said. “Had she not shown me those videos a month and a half before this happened, I don’t know that we would have hit the alarm bell as quickly as we did.”

After spending their second night and the following day in a cramped preoperative room converted to manage overflow from the emergency department, Sebastian’s condition improved, and he was discharged. The Witts are relieved to be home, but frustrations from their ordeal remain, especially considering the estimated $5,000 in out-of-pocket costs they expect to pay.

“How is this our health care system?” Ms. Witt asked. “This is unbelievable.”
 

An optimistic outlook

RSV seasons typically demonstrate a clear peak, followed by a decline through the rest of the season, suggesting better times lie ahead; however, this season has been anything but typical.

“I’m hopeful that it will just go away and stay away,” Dr. Kusma said, citing this trend. “But I can’t know for sure.”

To anxious parents, Dr. Blumberg offered an optimistic view of RSV seasons to come.

“There’s hope,” he said. “There are vaccines that are being developed that are very close to FDA approval. So, it’s possible that this time next year, we might have widespread RSV vaccination available for children so that we don’t have to go through this nightmare again.”

Dr. Blumberg and Dr. Kusma disclosed no relevant conflicts of interest.