User login
Inebilizumab beneficial across genotypes in NMOSD
NATIONAL HARBOR, MD. – – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.
The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.
A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.
Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.
“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.
“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.
The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
B-cell depletion
Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.
The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.
Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.
Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.
This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.
With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.
Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.
To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.
The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.
Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
No significant differences
Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.
During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.
The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.
However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.
“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.
“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.
Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.
Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
A new era?
Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.
“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.
He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.
The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.
“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”
The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NATIONAL HARBOR, MD. – – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.
The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.
A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.
Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.
“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.
“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.
The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
B-cell depletion
Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.
The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.
Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.
Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.
This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.
With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.
Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.
To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.
The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.
Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
No significant differences
Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.
During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.
The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.
However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.
“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.
“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.
Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.
Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
A new era?
Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.
“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.
He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.
The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.
“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”
The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NATIONAL HARBOR, MD. – – including a common genetic variation linked to reduced response to anti-CD20 therapies, new research shows.
The phase 3 N-MOmentum Study previously showed safety and efficacy for inebilizumab over placebo in more than 200 adults with NMOSD.
A new analysis focused on participants who were carriers of either the F/F allele, which is known to reduce the effectiveness of certain monoclonal antibodies, or the rs396991 V-allele, which has not been associated with a reduced response.
Results showed no significant differences between the two carrier groups in NMOSD activity, including annual rates of new/enlarging T2 lesions, during the trial and up to 6 months after treatment with inebilizumab.
“These data illustrate how mechanistic precision in treatment design can help patients gain benefit from their regimen regardless of the genetic make-up of their immune systems,” coinvestigator Bruce Cree, MD, PhD, professor of clinical neurology at the University of California, San Francisco, Weill Institute for Neurosciences, said in a press release.
“The combination of efficacy, safety, and ease of administration with twice-yearly infusions make this product an excellent choice for first-line therapy in NMOSD,” Dr. Cree said.
The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
B-cell depletion
Inebilizumab has also been approved in China, Japan, and South Korea for the treatment of NMOSD, a rare and severe autoantibody-mediated disease of the central nervous system that includes NMO and related syndromes.
The drug’s B-cell depletion capability is credited with reducing inflammation, lesion formation, and astrocyte damage. The latter can cause severe effects in an NMOSD attack, affecting the optic nerve, spinal cord, and brain.
Manifestations can range from loss of vision to paralysis, loss of sensation, bladder and bowel dysfunction, nerve pain or respiratory failure. Attacks can also result in cumulative damage and disability, the researchers noted.
Results from the original double-blind trial of 230 adults with NMOSD showed that treatment with inebilizumab demonstrated efficacy and safety over placebo. However, questions have remained regarding the treatment’s effectiveness, specifically among patients with the FCGR3A (F/F) allele, a genetic variant that encodes the low-affinity Fc gamma receptor IIIa.
This genotype is known to reduce the effectiveness of certain monoclonal antibodies and anti-CD20 therapies, notably rituximab, in disorders such as NMOSD.
With up to 40% of White and Black individuals known to carry the F/F allele, inebilizumab was designed specifically with that risk in mind, with strong binding to the allele.
Although inebilizumab joins two other Food and Drug Administration–approved treatments for NMOSD – eculizumab and satralizumab – neither of those have a mechanism involving the FCGRA3 receptor. Therefore, those drugs are not a concern for individuals with those genotypes.
To evaluate inebilizumab’s effects among patients with the F/F allele, Dr. Cree and colleagues assessed data on a subset of 142 patients from the N-MOmentum trial.
The study included a 28-week randomized controlled period in which adults with NMOSD received either 300 mg of intravenous inebilizumab or placebo on days 1 and 15, followed by an optional open-label period of at least 2 years. During the open-label phase, all patients received 300 mg of IV inebilizumab every 26 weeks.
Of the 142 patients in the genetic analysis, 104 received inebilizumab and 38 received placebo. In addition, 68 group participants were carriers of the F/F allele, while 74 carried the rs396991 V-allele.
No significant differences
Prior to the trial, annualized attack rates (AARs) and disability, as assessed by change in the Expanded Disability Status Scale (EDSS) scores, were nominally higher in the V allele group from disease onset to trial enrollment.
During the trial’s first 6 months, AARs and annual rates of new/enlarging T2 lesions were nominally lower in inebilizumab-treated V allele participants compared with the F/F allele participants, although the differences were not statistically significant.
The AAR was 0.1 for the V allele group vs. 0.3 for the F/F allele group (hazard ratio, 0.40; P = .17). The annual rate of new/enlarging T2 lesions was 1.4 vs. 1.7 (risk ratio, 0.91; P = .88), respectively.
However, at the end of the randomized controlled period, there were no significant differences between the two genotype groups. There was also little difference in clinical metrics of NMOSD activity or B-cell depletion between the two genotype groups during the open-label period involving the long-term repeated inebilizumab dosing.
“Though greater B-cell depletion was observed in inebilizumab-treated V allele participants, compared with F/F participants during the first 6 months, no significant difference in NMOSD activity was observed during this time period,” the investigators reported.
“No differences in B-cell depletion or NMOSD disease activity were observed after 6 months of inebilizumab treatment,” they added.
Dr. Cree noted the study showed that, overall, inebiluzumab’s efficacy was not adversely affected by a polymorphism in the Fc gamma receptor. “These types of genetic analyses may help inform future screening mechanisms to tailor treatment strategies that can optimize the response rate for each patient,” he said.
Dr. Cree added the higher degree of disease activity among those carrying the alleles at baseline is notable and deserves further investigation. That finding “suggests that the presence of the F/F allele is to some extent protective of the detrimental effects the auto-antibody directed against aquaporin-4 that underlies NMOSD pathogenesis,” he said.
A new era?
Commenting on the study, Marcelo Matiello, MD, assistant professor of neurology at Harvard Medical School and associate director of the Neuromyelitis Optica clinic at Massachusetts General Hospital, both in Boston, said the findings provide valuable insights into risks for key patient subgroups.
“The data is quite important because we know that with other conditions, such as rheumatoid arthritis, people with this particular genotype do have lower response and are more likely to be refractory,” said Dr. Matiello, who was not involved with the research.
He noted that rituximab is the most commonly used medication in the United States for NMOSD. “It’s not FDA approved, but because of extensive experience, and many case series and small prospective studies, most NMO patients are using rituximab,” Dr. Matiello said. However, the drug’s mechanism “can be compromised” by the F/F allele, he added.
The new findings “provide a good understanding that this medication would likely be superior to patients with this genotype,” he said.
“I think it’s a new era,” Dr. Matiello added. “Not only do we have approved medication for this very severe disease, but we can find out who can benefit most. So, I think this is exciting and is a major step in more individualized appropriate use.”
The study was funded by Horizon Therapeutics. Dr. Cree has consulted for Horizon Therapeutics. Dr. Matiello reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT CMSC 2022
FDA expands indication for spinal muscular atrophy drug
As previously reported, the FDA first approved oral risdiplam for SMA in children older than age 2 years in 2020.
The FDA expanded the indication for risdiplam to include babies younger than 2 months old because of interim safety and efficacy data from the ongoing RAINBOWFISH study. It includes 25 babies from birth to 6 weeks of age at first dose, all of whom have genetically diagnosed SMA but are not yet presenting with symptoms.
After 12 months of risdiplam treatment, the majority of presymptomatic infants with SMA reached key motor milestones, Genentech said in a news release.
Of the six babies with two or three copies of the SMN2 gene, all were able to sit after 1 year of active treatment, roughly two-thirds could stand, and half could walk independently.
All babies were alive at 12 months without permanent ventilation.
“The approval of Evrysdi for presymptomatic babies is particularly important, as early treatment of SMA, before symptoms start to arise, can help babies to achieve motor milestones,” Richard Finkel, MD, principal investigator of the trial, said in the release.
“With the inclusion of SMA in newborn screening programs, this approval provides the opportunity to start treating at home with Evrysdi soon after the diagnosis is confirmed,” added Dr. Finkel, who is director of the experimental neuroscience program, St. Jude Children’s Research Hospital, Memphis.
From newborns to older adults?
SMA is a rare and often fatal genetic disease that causes muscle weakness and progressive loss of movement.
SMA, which affects about 1 in 10,000 babies, is caused by a mutation in the survival motor neuron 1 (SMN1) gene. The gene encodes the SMN protein, which is critical for the maintenance and function of motor neurons.
Risdiplam is an orally administered, centrally and peripherally distributed small molecule that modulates survival motor neuron 2 (SMN2) premessenger RNA splicing to increase SMN protein levels.
As part of the label extension, the prescribing information for risdiplam has also been updated to include 2-year pooled data from parts 1 and 2 of the FIREFISH study, which demonstrated long-term efficacy and safety in symptomatic infants with Type 1 SMA, the company noted.
“Because of its efficacy in multiple settings, Evrysdi is now available for people with SMA, from presymptomatic newborns to older adults,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Genentech, said in the release.
“We are proud of this achievement, which has the potential to make a real difference to those living with SMA and their caregivers,” Dr. Garraway added.
A version of this article first appeared on Medscape.com.
As previously reported, the FDA first approved oral risdiplam for SMA in children older than age 2 years in 2020.
The FDA expanded the indication for risdiplam to include babies younger than 2 months old because of interim safety and efficacy data from the ongoing RAINBOWFISH study. It includes 25 babies from birth to 6 weeks of age at first dose, all of whom have genetically diagnosed SMA but are not yet presenting with symptoms.
After 12 months of risdiplam treatment, the majority of presymptomatic infants with SMA reached key motor milestones, Genentech said in a news release.
Of the six babies with two or three copies of the SMN2 gene, all were able to sit after 1 year of active treatment, roughly two-thirds could stand, and half could walk independently.
All babies were alive at 12 months without permanent ventilation.
“The approval of Evrysdi for presymptomatic babies is particularly important, as early treatment of SMA, before symptoms start to arise, can help babies to achieve motor milestones,” Richard Finkel, MD, principal investigator of the trial, said in the release.
“With the inclusion of SMA in newborn screening programs, this approval provides the opportunity to start treating at home with Evrysdi soon after the diagnosis is confirmed,” added Dr. Finkel, who is director of the experimental neuroscience program, St. Jude Children’s Research Hospital, Memphis.
From newborns to older adults?
SMA is a rare and often fatal genetic disease that causes muscle weakness and progressive loss of movement.
SMA, which affects about 1 in 10,000 babies, is caused by a mutation in the survival motor neuron 1 (SMN1) gene. The gene encodes the SMN protein, which is critical for the maintenance and function of motor neurons.
Risdiplam is an orally administered, centrally and peripherally distributed small molecule that modulates survival motor neuron 2 (SMN2) premessenger RNA splicing to increase SMN protein levels.
As part of the label extension, the prescribing information for risdiplam has also been updated to include 2-year pooled data from parts 1 and 2 of the FIREFISH study, which demonstrated long-term efficacy and safety in symptomatic infants with Type 1 SMA, the company noted.
“Because of its efficacy in multiple settings, Evrysdi is now available for people with SMA, from presymptomatic newborns to older adults,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Genentech, said in the release.
“We are proud of this achievement, which has the potential to make a real difference to those living with SMA and their caregivers,” Dr. Garraway added.
A version of this article first appeared on Medscape.com.
As previously reported, the FDA first approved oral risdiplam for SMA in children older than age 2 years in 2020.
The FDA expanded the indication for risdiplam to include babies younger than 2 months old because of interim safety and efficacy data from the ongoing RAINBOWFISH study. It includes 25 babies from birth to 6 weeks of age at first dose, all of whom have genetically diagnosed SMA but are not yet presenting with symptoms.
After 12 months of risdiplam treatment, the majority of presymptomatic infants with SMA reached key motor milestones, Genentech said in a news release.
Of the six babies with two or three copies of the SMN2 gene, all were able to sit after 1 year of active treatment, roughly two-thirds could stand, and half could walk independently.
All babies were alive at 12 months without permanent ventilation.
“The approval of Evrysdi for presymptomatic babies is particularly important, as early treatment of SMA, before symptoms start to arise, can help babies to achieve motor milestones,” Richard Finkel, MD, principal investigator of the trial, said in the release.
“With the inclusion of SMA in newborn screening programs, this approval provides the opportunity to start treating at home with Evrysdi soon after the diagnosis is confirmed,” added Dr. Finkel, who is director of the experimental neuroscience program, St. Jude Children’s Research Hospital, Memphis.
From newborns to older adults?
SMA is a rare and often fatal genetic disease that causes muscle weakness and progressive loss of movement.
SMA, which affects about 1 in 10,000 babies, is caused by a mutation in the survival motor neuron 1 (SMN1) gene. The gene encodes the SMN protein, which is critical for the maintenance and function of motor neurons.
Risdiplam is an orally administered, centrally and peripherally distributed small molecule that modulates survival motor neuron 2 (SMN2) premessenger RNA splicing to increase SMN protein levels.
As part of the label extension, the prescribing information for risdiplam has also been updated to include 2-year pooled data from parts 1 and 2 of the FIREFISH study, which demonstrated long-term efficacy and safety in symptomatic infants with Type 1 SMA, the company noted.
“Because of its efficacy in multiple settings, Evrysdi is now available for people with SMA, from presymptomatic newborns to older adults,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Genentech, said in the release.
“We are proud of this achievement, which has the potential to make a real difference to those living with SMA and their caregivers,” Dr. Garraway added.
A version of this article first appeared on Medscape.com.
Meet a miracle: Man with trisomy 13 to celebrate 20th birthday
Lloyd Tyler Rochez, born in 2002 with trisomy 13, a genetic disorder that can involve severe learning problems and health woes that affect nearly every organ.
Lloyd’s diagnosis was confirmed shortly after he was born, when his doctors noticed that his facial features weren’t measuring right for a baby of his size, he had an extra finger on his left hand, and his fingers were joined on the right. His heart was also on the right side of his chest instead of the left. When he had breathing issues, he was quickly rushed to the neonatal ICU (NICU) in the New York City hospital where he was born.
Ms. Nunez wasn’t sure exactly what was wrong with her newborn, but the next morning, a genetics expert came to her room to discuss her medical history and whether anyone in the family had Down syndrome. That same health care provider told her that the next step was to run some tests and do more bloodwork.
Four days later, when Ms. Nunez was told that Lloyd had trisomy 13 and was likely to live for only 2 weeks, she was unable to come to terms with the news.
“There was so much information being told to me at once,” recalls Ms. Nunez, now 42, who is also the mom of two daughters, ages 8 and 10. “I had just turned 22, and this was my first experience giving birth. I can’t even remember everything the doctors told me.”
But she does remember her doctor telling her something about faith.
“After he tried to explain trisomy 13 to me, the downside and the prognosis, at the end he said, ‘I don’t know if you believe in some supernatural being, but if you want to ask that someone for a miracle, I would advise you to do that. Pray for your miracle, and you may get it.’”
Prepared for the worst, Ms. Nunez, who now works from her Martinsburg, WV, home as a case manager for unaccompanied minors coming to the U.S., decided that she would commit to providing the best possible care for her new baby no matter how long he lived.
Thus began an incredible story of Lloyd defying all the odds. While he stayed in the hospital for 2 weeks, his breathing soon began to stabilize, and he could eat by mouth. With that, he was discharged and allowed to go home.
“I was this inexperienced first-time mom who had been told to watch for all sorts of things, like making sure he didn’t turn blue at night,” she says. “I spent so many sleepless nights, but I was dedicated to Lloyd.”
Then, when Lloyd was 6 months old, Ms. Nunez made another important choice.
“I decided that I wasn’t going to live each day as if he was going to die,” she says. “I decided, instead, to enjoy him every day.”
But many health complications still came about, including a serious intestine issue at 8 months, at which point Lloyd’s doctors suggested waiting until he was a year old to have surgery.
Lloyd was able to get through the procedure, but while he was in the recovery room, he stopped breathing.
“I started screaming ‘my son is dying,’” Ms. Nunez recalls. “The nurses put me in a room, and I think I was in there for 10 minutes, but it felt like an eternity of me screaming.”She soon learned that Lloyd had had a seizure. He spent the next 3 weeks in the hospital.
“That was our life,” she says. “He would have respiratory pneumonia, for example, and we would go back to the hospital. We were in and out and in and out.”
But she kept the faith, and since then, Lloyd’s health has mostly stabilized. Ms. Nunez can care for him at home on her own and with family members who help out from time to time.
And, while Lloyd is unable to speak, he smiles and laughs when he’s happy, he’s quiet when he feels ill, and, when he wants to be alone, he groans, Ms. Nunez says. He can stand up, and he crawls from place to place. He also can’t go to the bathroom on his own and is fed by a gastrostomy tube, or G-tube.
In December, when Lloyd was diagnosed with COVID-19, Ms. Nunez started worrying all over again.
“Seeing him in the ICU, all I could think of was ‘please don’t make my son suffer,’” she says. “If he goes, I want him to go in peace, and I don’t want to see him in a machine and suffering.”
But Lloyd once again defied the odds against him and came home again. He has since faced yet another health challenge: He recently had a pelvic fracture.
“When I saw the orthopedist, he told me that Lloyd has a bone deficiency and that his bones don’t have enough room to grow,” she says. “I’m afraid this will be the beginning of a new journey.”
How this mom finds strength
While Ms. Nunez doesn’t go to a support group or speak with a mental health professional about all that she’s juggling, she says she draws strength from Lloyd himself.
“I’m very private, and I come from a culture where you don’t want people feeling sorry for you,” she says. “But I want to give Lloyd everything – he goes to school, we go to church, he had a quinceañera when he was 15, we’ve been to Disney, and we’ve both gotten on a roller coaster. I haven’t limited his life.”
She also draws comfort from her daughters.
“Everyone calls him ‘Baby Lloyd,’” she says. “My girls come right home from school, wash their hands, and throw themselves on his bed and watch TV with him. They also worry about him a lot. When he goes to the hospital, they suffer more than I do.”
In the end, Ms. Nunez hopes her story inspires others to think beyond a prognosis.
“Don’t lose hope,” she says. “I want people to feel hopeful when they read about Lloyd. He’s going to be 20 years old, and no one ever believed he would be here today ... I feel blessed.”
A version of this article first appeared on WebMD.com.
Lloyd Tyler Rochez, born in 2002 with trisomy 13, a genetic disorder that can involve severe learning problems and health woes that affect nearly every organ.
Lloyd’s diagnosis was confirmed shortly after he was born, when his doctors noticed that his facial features weren’t measuring right for a baby of his size, he had an extra finger on his left hand, and his fingers were joined on the right. His heart was also on the right side of his chest instead of the left. When he had breathing issues, he was quickly rushed to the neonatal ICU (NICU) in the New York City hospital where he was born.
Ms. Nunez wasn’t sure exactly what was wrong with her newborn, but the next morning, a genetics expert came to her room to discuss her medical history and whether anyone in the family had Down syndrome. That same health care provider told her that the next step was to run some tests and do more bloodwork.
Four days later, when Ms. Nunez was told that Lloyd had trisomy 13 and was likely to live for only 2 weeks, she was unable to come to terms with the news.
“There was so much information being told to me at once,” recalls Ms. Nunez, now 42, who is also the mom of two daughters, ages 8 and 10. “I had just turned 22, and this was my first experience giving birth. I can’t even remember everything the doctors told me.”
But she does remember her doctor telling her something about faith.
“After he tried to explain trisomy 13 to me, the downside and the prognosis, at the end he said, ‘I don’t know if you believe in some supernatural being, but if you want to ask that someone for a miracle, I would advise you to do that. Pray for your miracle, and you may get it.’”
Prepared for the worst, Ms. Nunez, who now works from her Martinsburg, WV, home as a case manager for unaccompanied minors coming to the U.S., decided that she would commit to providing the best possible care for her new baby no matter how long he lived.
Thus began an incredible story of Lloyd defying all the odds. While he stayed in the hospital for 2 weeks, his breathing soon began to stabilize, and he could eat by mouth. With that, he was discharged and allowed to go home.
“I was this inexperienced first-time mom who had been told to watch for all sorts of things, like making sure he didn’t turn blue at night,” she says. “I spent so many sleepless nights, but I was dedicated to Lloyd.”
Then, when Lloyd was 6 months old, Ms. Nunez made another important choice.
“I decided that I wasn’t going to live each day as if he was going to die,” she says. “I decided, instead, to enjoy him every day.”
But many health complications still came about, including a serious intestine issue at 8 months, at which point Lloyd’s doctors suggested waiting until he was a year old to have surgery.
Lloyd was able to get through the procedure, but while he was in the recovery room, he stopped breathing.
“I started screaming ‘my son is dying,’” Ms. Nunez recalls. “The nurses put me in a room, and I think I was in there for 10 minutes, but it felt like an eternity of me screaming.”She soon learned that Lloyd had had a seizure. He spent the next 3 weeks in the hospital.
“That was our life,” she says. “He would have respiratory pneumonia, for example, and we would go back to the hospital. We were in and out and in and out.”
But she kept the faith, and since then, Lloyd’s health has mostly stabilized. Ms. Nunez can care for him at home on her own and with family members who help out from time to time.
And, while Lloyd is unable to speak, he smiles and laughs when he’s happy, he’s quiet when he feels ill, and, when he wants to be alone, he groans, Ms. Nunez says. He can stand up, and he crawls from place to place. He also can’t go to the bathroom on his own and is fed by a gastrostomy tube, or G-tube.
In December, when Lloyd was diagnosed with COVID-19, Ms. Nunez started worrying all over again.
“Seeing him in the ICU, all I could think of was ‘please don’t make my son suffer,’” she says. “If he goes, I want him to go in peace, and I don’t want to see him in a machine and suffering.”
But Lloyd once again defied the odds against him and came home again. He has since faced yet another health challenge: He recently had a pelvic fracture.
“When I saw the orthopedist, he told me that Lloyd has a bone deficiency and that his bones don’t have enough room to grow,” she says. “I’m afraid this will be the beginning of a new journey.”
How this mom finds strength
While Ms. Nunez doesn’t go to a support group or speak with a mental health professional about all that she’s juggling, she says she draws strength from Lloyd himself.
“I’m very private, and I come from a culture where you don’t want people feeling sorry for you,” she says. “But I want to give Lloyd everything – he goes to school, we go to church, he had a quinceañera when he was 15, we’ve been to Disney, and we’ve both gotten on a roller coaster. I haven’t limited his life.”
She also draws comfort from her daughters.
“Everyone calls him ‘Baby Lloyd,’” she says. “My girls come right home from school, wash their hands, and throw themselves on his bed and watch TV with him. They also worry about him a lot. When he goes to the hospital, they suffer more than I do.”
In the end, Ms. Nunez hopes her story inspires others to think beyond a prognosis.
“Don’t lose hope,” she says. “I want people to feel hopeful when they read about Lloyd. He’s going to be 20 years old, and no one ever believed he would be here today ... I feel blessed.”
A version of this article first appeared on WebMD.com.
Lloyd Tyler Rochez, born in 2002 with trisomy 13, a genetic disorder that can involve severe learning problems and health woes that affect nearly every organ.
Lloyd’s diagnosis was confirmed shortly after he was born, when his doctors noticed that his facial features weren’t measuring right for a baby of his size, he had an extra finger on his left hand, and his fingers were joined on the right. His heart was also on the right side of his chest instead of the left. When he had breathing issues, he was quickly rushed to the neonatal ICU (NICU) in the New York City hospital where he was born.
Ms. Nunez wasn’t sure exactly what was wrong with her newborn, but the next morning, a genetics expert came to her room to discuss her medical history and whether anyone in the family had Down syndrome. That same health care provider told her that the next step was to run some tests and do more bloodwork.
Four days later, when Ms. Nunez was told that Lloyd had trisomy 13 and was likely to live for only 2 weeks, she was unable to come to terms with the news.
“There was so much information being told to me at once,” recalls Ms. Nunez, now 42, who is also the mom of two daughters, ages 8 and 10. “I had just turned 22, and this was my first experience giving birth. I can’t even remember everything the doctors told me.”
But she does remember her doctor telling her something about faith.
“After he tried to explain trisomy 13 to me, the downside and the prognosis, at the end he said, ‘I don’t know if you believe in some supernatural being, but if you want to ask that someone for a miracle, I would advise you to do that. Pray for your miracle, and you may get it.’”
Prepared for the worst, Ms. Nunez, who now works from her Martinsburg, WV, home as a case manager for unaccompanied minors coming to the U.S., decided that she would commit to providing the best possible care for her new baby no matter how long he lived.
Thus began an incredible story of Lloyd defying all the odds. While he stayed in the hospital for 2 weeks, his breathing soon began to stabilize, and he could eat by mouth. With that, he was discharged and allowed to go home.
“I was this inexperienced first-time mom who had been told to watch for all sorts of things, like making sure he didn’t turn blue at night,” she says. “I spent so many sleepless nights, but I was dedicated to Lloyd.”
Then, when Lloyd was 6 months old, Ms. Nunez made another important choice.
“I decided that I wasn’t going to live each day as if he was going to die,” she says. “I decided, instead, to enjoy him every day.”
But many health complications still came about, including a serious intestine issue at 8 months, at which point Lloyd’s doctors suggested waiting until he was a year old to have surgery.
Lloyd was able to get through the procedure, but while he was in the recovery room, he stopped breathing.
“I started screaming ‘my son is dying,’” Ms. Nunez recalls. “The nurses put me in a room, and I think I was in there for 10 minutes, but it felt like an eternity of me screaming.”She soon learned that Lloyd had had a seizure. He spent the next 3 weeks in the hospital.
“That was our life,” she says. “He would have respiratory pneumonia, for example, and we would go back to the hospital. We were in and out and in and out.”
But she kept the faith, and since then, Lloyd’s health has mostly stabilized. Ms. Nunez can care for him at home on her own and with family members who help out from time to time.
And, while Lloyd is unable to speak, he smiles and laughs when he’s happy, he’s quiet when he feels ill, and, when he wants to be alone, he groans, Ms. Nunez says. He can stand up, and he crawls from place to place. He also can’t go to the bathroom on his own and is fed by a gastrostomy tube, or G-tube.
In December, when Lloyd was diagnosed with COVID-19, Ms. Nunez started worrying all over again.
“Seeing him in the ICU, all I could think of was ‘please don’t make my son suffer,’” she says. “If he goes, I want him to go in peace, and I don’t want to see him in a machine and suffering.”
But Lloyd once again defied the odds against him and came home again. He has since faced yet another health challenge: He recently had a pelvic fracture.
“When I saw the orthopedist, he told me that Lloyd has a bone deficiency and that his bones don’t have enough room to grow,” she says. “I’m afraid this will be the beginning of a new journey.”
How this mom finds strength
While Ms. Nunez doesn’t go to a support group or speak with a mental health professional about all that she’s juggling, she says she draws strength from Lloyd himself.
“I’m very private, and I come from a culture where you don’t want people feeling sorry for you,” she says. “But I want to give Lloyd everything – he goes to school, we go to church, he had a quinceañera when he was 15, we’ve been to Disney, and we’ve both gotten on a roller coaster. I haven’t limited his life.”
She also draws comfort from her daughters.
“Everyone calls him ‘Baby Lloyd,’” she says. “My girls come right home from school, wash their hands, and throw themselves on his bed and watch TV with him. They also worry about him a lot. When he goes to the hospital, they suffer more than I do.”
In the end, Ms. Nunez hopes her story inspires others to think beyond a prognosis.
“Don’t lose hope,” she says. “I want people to feel hopeful when they read about Lloyd. He’s going to be 20 years old, and no one ever believed he would be here today ... I feel blessed.”
A version of this article first appeared on WebMD.com.
CDC updates guidelines for hepatitis outbreak among children
The Centers for Disease Control and Prevention updated its recommendations for doctors and public health officials regarding the unusual outbreak of acute hepatitis among children.
As of May 5, the CDC and state health departments are investigating 109 children with hepatitis of unknown origin across 25 states and territories.
More than half have tested positive for adenovirus, the CDC said. More than 90% have been hospitalized, and 14% have had liver transplants. Five deaths are under investigation.
This week’s CDC alert provides updated recommendations for testing, given the potential association between adenovirus infection and pediatric hepatitis, or liver inflammation.
“Clinicians are recommended to consider adenovirus testing for patients with hepatitis of unknown etiology and to report such cases to their state or jurisdictional public health authorities,” the CDC said.
Doctors should also consider collecting a blood sample, respiratory sample, and stool sample. They may also collect liver tissue if a biopsy occurred or an autopsy is available.
In November 2021, clinicians at a large children’s hospital in Alabama notified the CDC about five pediatric patients with significant liver injury, including three with acute liver failure, who also tested positive for adenovirus. All children were previously healthy, and none had COVID-19, according to a CDC alert in April.
Four additional pediatric patients with hepatitis and adenovirus infection were identified. After lab testing found adenovirus infection in all nine patients in the initial cluster, public health officials began investigating a possible association between pediatric hepatitis and adenovirus. Among the five specimens that could be sequenced, they were all adenovirus type 41.
Unexplained hepatitis cases have been reported in children worldwide, reaching 450 cases and 11 deaths, according to the latest update from the European Centre for Disease Prevention and Control.
The cases have been reported in more than two dozen countries around the world, with 14 countries reporting more than five cases. The United Kingdom and the United States have reported the largest case counts so far.
In the United Kingdom, officials have identified 163 cases in children under age 16 years, including 11 that required liver transplants.
In the European Union, 14 countries have reported 106 cases collectively, with Italy reporting 35 cases and Spain reporting 22 cases. Outside of the European Union, Brazil has reported 16, Indonesia has reported 15, and Israel has reported 12.
Among the 11 deaths reported globally, the Uniyed States has reported five, Indonesia has reported five, and Palestine has reported one.
The cause of severe hepatitis remains a mystery, according to Ars Technica. Some cases have been identified retrospectively, dating back to the beginning of October 2021.
About 70% of the cases that have been tested for an adenovirus have tested positive, and subtype testing continues to show adenovirus type 41. The cases don’t appear to be linked to common causes, such as hepatitis viruses A, B, C, D, or E, which can cause liver inflammation and injury.
Adenoviruses aren’t known to cause hepatitis in healthy children, though the viruses have been linked to liver damage in children with compromised immune systems, according to Ars Technica. Adenoviruses typically cause respiratory infections in children, although type 41 tends to cause gastrointestinal illness.
“At present, the leading hypotheses remain those which involve adenovirus,” Philippa Easterbrook, a senior scientist at the WHO, said May 10 during a press briefing.
“I think [there’s] also still an important consideration about the role of COVID as well, either as a co-infection or as a past infection,” she said.
WHO officials expect data within a week from U.K. cases, Ms. Easterbrook said, which may indicate whether the adenovirus is an incidental infection or a more direct cause.
A version of this article first appeared on Medscape.com.
The Centers for Disease Control and Prevention updated its recommendations for doctors and public health officials regarding the unusual outbreak of acute hepatitis among children.
As of May 5, the CDC and state health departments are investigating 109 children with hepatitis of unknown origin across 25 states and territories.
More than half have tested positive for adenovirus, the CDC said. More than 90% have been hospitalized, and 14% have had liver transplants. Five deaths are under investigation.
This week’s CDC alert provides updated recommendations for testing, given the potential association between adenovirus infection and pediatric hepatitis, or liver inflammation.
“Clinicians are recommended to consider adenovirus testing for patients with hepatitis of unknown etiology and to report such cases to their state or jurisdictional public health authorities,” the CDC said.
Doctors should also consider collecting a blood sample, respiratory sample, and stool sample. They may also collect liver tissue if a biopsy occurred or an autopsy is available.
In November 2021, clinicians at a large children’s hospital in Alabama notified the CDC about five pediatric patients with significant liver injury, including three with acute liver failure, who also tested positive for adenovirus. All children were previously healthy, and none had COVID-19, according to a CDC alert in April.
Four additional pediatric patients with hepatitis and adenovirus infection were identified. After lab testing found adenovirus infection in all nine patients in the initial cluster, public health officials began investigating a possible association between pediatric hepatitis and adenovirus. Among the five specimens that could be sequenced, they were all adenovirus type 41.
Unexplained hepatitis cases have been reported in children worldwide, reaching 450 cases and 11 deaths, according to the latest update from the European Centre for Disease Prevention and Control.
The cases have been reported in more than two dozen countries around the world, with 14 countries reporting more than five cases. The United Kingdom and the United States have reported the largest case counts so far.
In the United Kingdom, officials have identified 163 cases in children under age 16 years, including 11 that required liver transplants.
In the European Union, 14 countries have reported 106 cases collectively, with Italy reporting 35 cases and Spain reporting 22 cases. Outside of the European Union, Brazil has reported 16, Indonesia has reported 15, and Israel has reported 12.
Among the 11 deaths reported globally, the Uniyed States has reported five, Indonesia has reported five, and Palestine has reported one.
The cause of severe hepatitis remains a mystery, according to Ars Technica. Some cases have been identified retrospectively, dating back to the beginning of October 2021.
About 70% of the cases that have been tested for an adenovirus have tested positive, and subtype testing continues to show adenovirus type 41. The cases don’t appear to be linked to common causes, such as hepatitis viruses A, B, C, D, or E, which can cause liver inflammation and injury.
Adenoviruses aren’t known to cause hepatitis in healthy children, though the viruses have been linked to liver damage in children with compromised immune systems, according to Ars Technica. Adenoviruses typically cause respiratory infections in children, although type 41 tends to cause gastrointestinal illness.
“At present, the leading hypotheses remain those which involve adenovirus,” Philippa Easterbrook, a senior scientist at the WHO, said May 10 during a press briefing.
“I think [there’s] also still an important consideration about the role of COVID as well, either as a co-infection or as a past infection,” she said.
WHO officials expect data within a week from U.K. cases, Ms. Easterbrook said, which may indicate whether the adenovirus is an incidental infection or a more direct cause.
A version of this article first appeared on Medscape.com.
The Centers for Disease Control and Prevention updated its recommendations for doctors and public health officials regarding the unusual outbreak of acute hepatitis among children.
As of May 5, the CDC and state health departments are investigating 109 children with hepatitis of unknown origin across 25 states and territories.
More than half have tested positive for adenovirus, the CDC said. More than 90% have been hospitalized, and 14% have had liver transplants. Five deaths are under investigation.
This week’s CDC alert provides updated recommendations for testing, given the potential association between adenovirus infection and pediatric hepatitis, or liver inflammation.
“Clinicians are recommended to consider adenovirus testing for patients with hepatitis of unknown etiology and to report such cases to their state or jurisdictional public health authorities,” the CDC said.
Doctors should also consider collecting a blood sample, respiratory sample, and stool sample. They may also collect liver tissue if a biopsy occurred or an autopsy is available.
In November 2021, clinicians at a large children’s hospital in Alabama notified the CDC about five pediatric patients with significant liver injury, including three with acute liver failure, who also tested positive for adenovirus. All children were previously healthy, and none had COVID-19, according to a CDC alert in April.
Four additional pediatric patients with hepatitis and adenovirus infection were identified. After lab testing found adenovirus infection in all nine patients in the initial cluster, public health officials began investigating a possible association between pediatric hepatitis and adenovirus. Among the five specimens that could be sequenced, they were all adenovirus type 41.
Unexplained hepatitis cases have been reported in children worldwide, reaching 450 cases and 11 deaths, according to the latest update from the European Centre for Disease Prevention and Control.
The cases have been reported in more than two dozen countries around the world, with 14 countries reporting more than five cases. The United Kingdom and the United States have reported the largest case counts so far.
In the United Kingdom, officials have identified 163 cases in children under age 16 years, including 11 that required liver transplants.
In the European Union, 14 countries have reported 106 cases collectively, with Italy reporting 35 cases and Spain reporting 22 cases. Outside of the European Union, Brazil has reported 16, Indonesia has reported 15, and Israel has reported 12.
Among the 11 deaths reported globally, the Uniyed States has reported five, Indonesia has reported five, and Palestine has reported one.
The cause of severe hepatitis remains a mystery, according to Ars Technica. Some cases have been identified retrospectively, dating back to the beginning of October 2021.
About 70% of the cases that have been tested for an adenovirus have tested positive, and subtype testing continues to show adenovirus type 41. The cases don’t appear to be linked to common causes, such as hepatitis viruses A, B, C, D, or E, which can cause liver inflammation and injury.
Adenoviruses aren’t known to cause hepatitis in healthy children, though the viruses have been linked to liver damage in children with compromised immune systems, according to Ars Technica. Adenoviruses typically cause respiratory infections in children, although type 41 tends to cause gastrointestinal illness.
“At present, the leading hypotheses remain those which involve adenovirus,” Philippa Easterbrook, a senior scientist at the WHO, said May 10 during a press briefing.
“I think [there’s] also still an important consideration about the role of COVID as well, either as a co-infection or as a past infection,” she said.
WHO officials expect data within a week from U.K. cases, Ms. Easterbrook said, which may indicate whether the adenovirus is an incidental infection or a more direct cause.
A version of this article first appeared on Medscape.com.
Low butyrylcholinesterase: A possible biomarker of SIDS risk?
Reduced levels of the cholinergic-system enzyme butyrylcholinesterase (BChE) may provide another piece of the puzzle for sudden infant death syndrome (SIDS), preliminary data from Australian researchers suggested.
A small case-control study led by Carmel T. Harrington, PhD,* a sleep medicine expert and honorary research fellow at the Children’s Hospital at Westmead (Australia), found that measurements in 722 dried blood spots taken during neonatal screening 2 or 3 days after birth were lower in babies who subsequently died of SIDS, compared with those of matched surviving controls and other babies who died of non-SIDS causes.
In groups in which cases were reported as SIDS death (n = 26) there was strong evidence that lower BChE-specific activity was associated with death (odds ratio, 0.73 per U/mg; 95% confidence interval, 0.60-0.89, P = .0014). In groups with a non-SIDS death (n = 41), there was no evidence of a linear association between BChE activity and death (OR, 1.001 per U/mg; 95% CI, 0.89-1.13, P = .99). A cohort of 655 age- and sex-matched controls served as a reference group.
Writing online in eBioMedicine, the researchers concluded that a previously unidentified cholinergic deficit, identifiable by abnormal BChE-specific activity, is present at birth in SIDS babies and represents a measurable, specific vulnerability prior to their death. “The finding presents the possibility of identifying infants at future risk for SIDS and it provides a specific avenue for future research into interventions prior to death.”
They hypothesized that the association is evidence of an altered cholinergic homeostasis and claim theirs is the first study to identify a measurable biochemical marker in babies who succumbed to SIDS. The marker “could plausibly produce functional alterations to an infant’s autonomic and arousal responses to an exogenous stressor leaving them vulnerable to sudden death.”
Commenting in a press release, Dr. Harrington said that “babies have a very powerful mechanism to let us know when they are not happy. Usually, if a baby is confronted with a life-threatening situation, such as difficulty breathing during sleep because they are on their tummies, they will arouse and cry out. What this research shows is that some babies don’t have this same robust arousal response.” Despite the sparse data, she believes that BChE is likely involved.
Providing a U.S. perspective on the study but not involved in it, Fern R. Hauck, MD, MS, a professor of family medicine and public health at the University of Virginia, Charlottesville, said that “the media coverage presenting this as the ‘cause of SIDS,’ for which we may find a cure within 5 years, is very disturbing and very misleading. The data are very preliminary and results are based on only 26 SIDS cases.” In addition, the blood samples were more than 2 years old.
This research needs to be repeated in other labs in larger and diverse SIDS populations, she added. “Furthermore, we are not provided any racial-ethnic information about the SIDS cases in this study. In the U.S., the infants who are at greatest risk of dying from SIDS are most commonly African American and Native American/Alaska Native, and thus, these studies would need to be repeated in U.S. populations.”
Dr. Hauck added that, while the differences in blood levels of this enzyme were statistically different, even if this is confirmed by larger studies, there was enough overlap in the blood levels between cases and controls that it could not be used as a blood test at this point with any reasonable predictive value.
As the authors pointed out, she said, the leading theory of SIDS causation is that multiple factors interact. “While everyone would be happy to find one single explanation, it is not so simple. This research does, however, bring into focus the issues of arousal in SIDS and work on biomarkers. The arousal issue is one researchers have been working on for a long time.”
The SIDS research community has long been interested in biomarkers, Dr. Hauck continued. “Dr. Hannah Kinney’s first autoradiography study reported decreased muscarinic cholinergic receptor binding in the arcuate nucleus in SIDS, which the butyrylcholinesterase work further elaborates. More recently, Dr. Kinney reported abnormal cholinergic binding in the mesopontine reticular formation that is related to arousal and REM.”
Moreover, Robin Haynes and colleagues reported in 2017 that differences in serotonin can similarly be found in newborns on a newborn blood test, she said. “Like the butyrylcholinesterase research, there is a lot of work to do before understanding how specifically it can identify risk. The problem with using it prematurely is that it will unnecessarily alarm parents that their baby will die, and, to make it worse, be inaccurate in our warning.”
She also expressed concern that with the focus on a biomarker, parents will forget that SIDS and other sleep-related infant deaths have come down considerably in the United States thanks to greater emphasis on promoting safe infant sleep behaviors.
The research was supported by a crowdfunding campaign and by NSW Health Pathology. The authors disclosed no conflicts of interest. Dr. Hauck disclosed no conflicts of interest.
* This story was corrected on 5/20/2022.
Reduced levels of the cholinergic-system enzyme butyrylcholinesterase (BChE) may provide another piece of the puzzle for sudden infant death syndrome (SIDS), preliminary data from Australian researchers suggested.
A small case-control study led by Carmel T. Harrington, PhD,* a sleep medicine expert and honorary research fellow at the Children’s Hospital at Westmead (Australia), found that measurements in 722 dried blood spots taken during neonatal screening 2 or 3 days after birth were lower in babies who subsequently died of SIDS, compared with those of matched surviving controls and other babies who died of non-SIDS causes.
In groups in which cases were reported as SIDS death (n = 26) there was strong evidence that lower BChE-specific activity was associated with death (odds ratio, 0.73 per U/mg; 95% confidence interval, 0.60-0.89, P = .0014). In groups with a non-SIDS death (n = 41), there was no evidence of a linear association between BChE activity and death (OR, 1.001 per U/mg; 95% CI, 0.89-1.13, P = .99). A cohort of 655 age- and sex-matched controls served as a reference group.
Writing online in eBioMedicine, the researchers concluded that a previously unidentified cholinergic deficit, identifiable by abnormal BChE-specific activity, is present at birth in SIDS babies and represents a measurable, specific vulnerability prior to their death. “The finding presents the possibility of identifying infants at future risk for SIDS and it provides a specific avenue for future research into interventions prior to death.”
They hypothesized that the association is evidence of an altered cholinergic homeostasis and claim theirs is the first study to identify a measurable biochemical marker in babies who succumbed to SIDS. The marker “could plausibly produce functional alterations to an infant’s autonomic and arousal responses to an exogenous stressor leaving them vulnerable to sudden death.”
Commenting in a press release, Dr. Harrington said that “babies have a very powerful mechanism to let us know when they are not happy. Usually, if a baby is confronted with a life-threatening situation, such as difficulty breathing during sleep because they are on their tummies, they will arouse and cry out. What this research shows is that some babies don’t have this same robust arousal response.” Despite the sparse data, she believes that BChE is likely involved.
Providing a U.S. perspective on the study but not involved in it, Fern R. Hauck, MD, MS, a professor of family medicine and public health at the University of Virginia, Charlottesville, said that “the media coverage presenting this as the ‘cause of SIDS,’ for which we may find a cure within 5 years, is very disturbing and very misleading. The data are very preliminary and results are based on only 26 SIDS cases.” In addition, the blood samples were more than 2 years old.
This research needs to be repeated in other labs in larger and diverse SIDS populations, she added. “Furthermore, we are not provided any racial-ethnic information about the SIDS cases in this study. In the U.S., the infants who are at greatest risk of dying from SIDS are most commonly African American and Native American/Alaska Native, and thus, these studies would need to be repeated in U.S. populations.”
Dr. Hauck added that, while the differences in blood levels of this enzyme were statistically different, even if this is confirmed by larger studies, there was enough overlap in the blood levels between cases and controls that it could not be used as a blood test at this point with any reasonable predictive value.
As the authors pointed out, she said, the leading theory of SIDS causation is that multiple factors interact. “While everyone would be happy to find one single explanation, it is not so simple. This research does, however, bring into focus the issues of arousal in SIDS and work on biomarkers. The arousal issue is one researchers have been working on for a long time.”
The SIDS research community has long been interested in biomarkers, Dr. Hauck continued. “Dr. Hannah Kinney’s first autoradiography study reported decreased muscarinic cholinergic receptor binding in the arcuate nucleus in SIDS, which the butyrylcholinesterase work further elaborates. More recently, Dr. Kinney reported abnormal cholinergic binding in the mesopontine reticular formation that is related to arousal and REM.”
Moreover, Robin Haynes and colleagues reported in 2017 that differences in serotonin can similarly be found in newborns on a newborn blood test, she said. “Like the butyrylcholinesterase research, there is a lot of work to do before understanding how specifically it can identify risk. The problem with using it prematurely is that it will unnecessarily alarm parents that their baby will die, and, to make it worse, be inaccurate in our warning.”
She also expressed concern that with the focus on a biomarker, parents will forget that SIDS and other sleep-related infant deaths have come down considerably in the United States thanks to greater emphasis on promoting safe infant sleep behaviors.
The research was supported by a crowdfunding campaign and by NSW Health Pathology. The authors disclosed no conflicts of interest. Dr. Hauck disclosed no conflicts of interest.
* This story was corrected on 5/20/2022.
Reduced levels of the cholinergic-system enzyme butyrylcholinesterase (BChE) may provide another piece of the puzzle for sudden infant death syndrome (SIDS), preliminary data from Australian researchers suggested.
A small case-control study led by Carmel T. Harrington, PhD,* a sleep medicine expert and honorary research fellow at the Children’s Hospital at Westmead (Australia), found that measurements in 722 dried blood spots taken during neonatal screening 2 or 3 days after birth were lower in babies who subsequently died of SIDS, compared with those of matched surviving controls and other babies who died of non-SIDS causes.
In groups in which cases were reported as SIDS death (n = 26) there was strong evidence that lower BChE-specific activity was associated with death (odds ratio, 0.73 per U/mg; 95% confidence interval, 0.60-0.89, P = .0014). In groups with a non-SIDS death (n = 41), there was no evidence of a linear association between BChE activity and death (OR, 1.001 per U/mg; 95% CI, 0.89-1.13, P = .99). A cohort of 655 age- and sex-matched controls served as a reference group.
Writing online in eBioMedicine, the researchers concluded that a previously unidentified cholinergic deficit, identifiable by abnormal BChE-specific activity, is present at birth in SIDS babies and represents a measurable, specific vulnerability prior to their death. “The finding presents the possibility of identifying infants at future risk for SIDS and it provides a specific avenue for future research into interventions prior to death.”
They hypothesized that the association is evidence of an altered cholinergic homeostasis and claim theirs is the first study to identify a measurable biochemical marker in babies who succumbed to SIDS. The marker “could plausibly produce functional alterations to an infant’s autonomic and arousal responses to an exogenous stressor leaving them vulnerable to sudden death.”
Commenting in a press release, Dr. Harrington said that “babies have a very powerful mechanism to let us know when they are not happy. Usually, if a baby is confronted with a life-threatening situation, such as difficulty breathing during sleep because they are on their tummies, they will arouse and cry out. What this research shows is that some babies don’t have this same robust arousal response.” Despite the sparse data, she believes that BChE is likely involved.
Providing a U.S. perspective on the study but not involved in it, Fern R. Hauck, MD, MS, a professor of family medicine and public health at the University of Virginia, Charlottesville, said that “the media coverage presenting this as the ‘cause of SIDS,’ for which we may find a cure within 5 years, is very disturbing and very misleading. The data are very preliminary and results are based on only 26 SIDS cases.” In addition, the blood samples were more than 2 years old.
This research needs to be repeated in other labs in larger and diverse SIDS populations, she added. “Furthermore, we are not provided any racial-ethnic information about the SIDS cases in this study. In the U.S., the infants who are at greatest risk of dying from SIDS are most commonly African American and Native American/Alaska Native, and thus, these studies would need to be repeated in U.S. populations.”
Dr. Hauck added that, while the differences in blood levels of this enzyme were statistically different, even if this is confirmed by larger studies, there was enough overlap in the blood levels between cases and controls that it could not be used as a blood test at this point with any reasonable predictive value.
As the authors pointed out, she said, the leading theory of SIDS causation is that multiple factors interact. “While everyone would be happy to find one single explanation, it is not so simple. This research does, however, bring into focus the issues of arousal in SIDS and work on biomarkers. The arousal issue is one researchers have been working on for a long time.”
The SIDS research community has long been interested in biomarkers, Dr. Hauck continued. “Dr. Hannah Kinney’s first autoradiography study reported decreased muscarinic cholinergic receptor binding in the arcuate nucleus in SIDS, which the butyrylcholinesterase work further elaborates. More recently, Dr. Kinney reported abnormal cholinergic binding in the mesopontine reticular formation that is related to arousal and REM.”
Moreover, Robin Haynes and colleagues reported in 2017 that differences in serotonin can similarly be found in newborns on a newborn blood test, she said. “Like the butyrylcholinesterase research, there is a lot of work to do before understanding how specifically it can identify risk. The problem with using it prematurely is that it will unnecessarily alarm parents that their baby will die, and, to make it worse, be inaccurate in our warning.”
She also expressed concern that with the focus on a biomarker, parents will forget that SIDS and other sleep-related infant deaths have come down considerably in the United States thanks to greater emphasis on promoting safe infant sleep behaviors.
The research was supported by a crowdfunding campaign and by NSW Health Pathology. The authors disclosed no conflicts of interest. Dr. Hauck disclosed no conflicts of interest.
* This story was corrected on 5/20/2022.
FROM EBIOMEDICINE
FDA approves oral form of ALS drug edaravone
Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.
Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.
Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.
The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.
The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.
Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.
The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.
A version of this article first appeared on Medscape.com.
Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.
Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.
Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.
The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.
The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.
Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.
The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.
A version of this article first appeared on Medscape.com.
Edaravone is a pyrazolone free-radical scavenger thought to lessen the effects of oxidative stress, which is a probable factor in ALS onset and progression. The drug was first approved in 2017 as an intravenous (IV) infusion to treat ALS.
Radicava ORS is self-administered and can be taken at home. After fasting overnight, Radicava ORS should be taken in the morning orally or through a feeding tube. The oral version has the same dosing regimen as the original IV version, with an initial treatment cycle of daily dosing for 14 days, followed by a 14-day drug-free period and subsequent treatment cycles consisting of daily dosing for 10 out of 14-day periods, followed by 14-day drug-free periods.
Compared with the IV formation of Radicava, Radicava ORS has been shown to generate comparable levels of active drug in the bloodstream, the FDA said.
The FDA determined that IV Radicava was effective based on a 6-month clinical trial in Japan involving 137 individuals who were randomly chosen to receive either the drug or a placebo. At 24 weeks, individuals receiving Radicava showed less decline on a clinical assessment of daily functioning, compared with those receiving placebo.
The most common side effects of Radicava are bruising, problems walking, and headache. Fatigue is also a possible side effect from Radicava ORS. Both formulations can have serious side effects associated with allergic reactions, including hives, rash, and shortness of breath.
Full prescribing information, including additional information on risks associated with Radicava ORS, is available online.
The FDA granted Radicava ORS orphan drug status, priority review, and Fast Track designations.
A version of this article first appeared on Medscape.com.
Myositis guidelines aim to standardize adult and pediatric care
All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.
The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.
“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.
It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.
“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.
Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.
“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.
With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”
Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”
Recommendation highlights
Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.
“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.
Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.
“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.
There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
Separate cancer screening guidelines on cards
“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.
“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”
Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.
The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.
“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.
Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.
“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.
“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.
“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”
Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.
All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.
The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.
“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.
It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.
“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.
Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.
“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.
With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”
Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”
Recommendation highlights
Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.
“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.
Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.
“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.
There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
Separate cancer screening guidelines on cards
“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.
“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”
Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.
The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.
“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.
Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.
“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.
“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.
“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”
Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.
All patients with idiopathic inflammatory myopathies (IIM) should be screened for swallowing difficulties, according to the first evidence-based guideline to be produced.
The guideline, which has been developed by a working group of the British Society for Rheumatology (BSR), also advises that all diagnosed patients should have their myositis antibody levels checked and have their overall well-being assessed. Other recommendations for all patients include the use of glucocorticoids to reduce muscle inflammation and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for long-term treatment.
“Finally, now, we’re able to standardize the way we treat adults and children with IIM,” senior guideline author Hector Chinoy, PhD, said at the society’s annual meeting.
It has been a long labor of love, however, taking 4 years to get the guideline published, said Dr. Chinoy, professor of rheumatology and neuromuscular disease at the University of Manchester (England), and a consultant at Salford (England) Royal Hospital.
“We’re not covering diagnosis, classification, or the investigation of suspected IIM,” said Dr. Chinoy. Inclusion body myositis also is not included.
Altogether, there are 13 recommendations that have been developed using a PICO (patient or population, intervention, comparison, outcome) format, graded based on the quality of the available evidence, and then voted on by the working group members to give a score of the strength of agreement. Dr. Chinoy noted that there was a checklist included in the Supplementary Data section of the guideline to help follow the recommendations.
“The target audience for the guideline reflects the variety of clinicians caring for patients with IIM,” Dr. Chinoy said. So that is not just pediatric and adult rheumatologists, but also neurologists, dermatologists, respiratory physicians, oncologists, gastroenterologists, cardiologists, and of course other health care professionals. This includes rheumatology and neurology nurses, psychologists, speech and language therapists, and podiatrists, as well as rheumatology specialist pharmacists, physiotherapists, and occupational therapists.
With reference to the latter, Liza McCann, MBBS, who co-led the development of the guideline, said in a statement released by the BSR that the guideline “highlights the importance of exercise, led and monitored by specialist physiotherapists and occupational therapists.”
Dr. McCann, a consultant pediatric rheumatologist at Alder Hey Hospital, Liverpool, England, and Honorary Clinical Lecturer at the University of Liverpool, added that the guidelines also cover “the need to address psychological wellbeing as an integral part of treatment, in parallel with pharmacological therapies.”
Recommendation highlights
Some of the highlights of the recommendations include the use of high-dose glucocorticoids to manage skeletal muscle inflammation at the time of treatment induction, with specific guidance on the different doses to use in adults and in children. There also is guidance on the use of csDMARDs in both populations and what to use if there is refractory disease – with the strongest evidence supporting the use of intravenous immunoglobulin (IVIG) or cyclophosphamide, and possibly rituximab and abatacept.
“There is insufficient evidence to recommend JAK inhibition,” Dr. Chinoy said. The data search used to develop the guideline had a cutoff of October 2020, but even now there is only anecdotal evidence from case studies, he added.
Importantly, the guidelines recognize that childhood IIM differs from adult disease and call for children to be managed by pediatric specialists.
“Routine assessment of dysphagia should be considered in all patients,” Dr. Chinoy said, “so ask the question.” The recommendation is that a swallowing assessment should involve a speech and language therapist or gastroenterologist, and that IVIG be considered for active disease and dysphagia that is resistant to other treatments.
There also are recommendations to screen adult patients for interstitial lung disease, consider fracture risk, and screen adult patients for cancer if they have specific risk factors that include older age at onset, male gender, dysphagia, and rapid disease onset, among others.
Separate cancer screening guidelines on cards
“Around one in four patients with myositis will develop cancer within the 3 years either before or after myositis onset,” Alexander Oldroyd, MBChB, PhD, said in a separate presentation at the BSR annual meeting.
“It’s a hugely increased risk compared to the general population, and a great worry for patients,” he added. Exactly why there is an increased risk is not known, but “there’s a big link between the biological onset of cancer and myositis.”
Dr. Oldroyd, who is an NIHR Academic Clinical Lecturer at the University of Manchester in England and a coauthor of the BSR myositis guideline, is part of a special interest group set up by the International Myositis Assessment and Clinical Studies Group (IMACS) that is in the process of developing separate guidelines for cancer screening in people newly diagnosed with IIM.
The aim was to produce evidence-based recommendations that were both “pragmatic and practical,” that could help clinicians answer patient’s questions on their risk and how best and how often to screen them, Dr. Oldroyd explained. Importantly, IMACS has endeavored to create recommendations that should be applicable across different countries and health care systems.
“We had to acknowledge that there’s not a lot of evidence base there,” Dr. Oldroyd said, noting that he and colleagues conducted a systematic literature review and meta-analysis and used a Delphi process to draft 20 recommendations. These cover identifying risk factors for cancer in people with myositis and categorizing people into low, medium, and high-risk categories. The recommendations also cover what should constitute basic and enhanced screening, and how often someone should be screened.
Moreover, the authors make recommendations on the use of imaging modalities such as PET and CT scans, as well as upper and lower gastrointestinal endoscopy and naso-endoscopy.
“As rheumatologists, we don’t talk about cancer a lot,” Dr. Oldroyd said. “We pick up a lot of incidental cancers, but we don’t usually talk about cancer screening with patients.” That’s something that needs to change, he said.
“It’s important – just get it out in the open, talk to people about it,” Dr. Oldroyd said.
“Tell them what you’re wanting to do, how you’re wanting to investigate for it, clearly communicate their risk,” he said. “But also acknowledge the limited evidence as well, and clearly communicate the results.”
Dr. Chinoy acknowledged he had received fees for presentations (UCB, Biogen), consultancy (Alexion, Novartis, Eli Lilly, Orphazyme, AstraZeneca), or grant support (Eli Lilly, UCB) that had been paid via his institution for the purpose of furthering myositis research. Dr. Oldroyd had no conflicts of interest to disclose.
FROM BSR 2022
Prior authorizations delay TNF inhibitors for children with JIA
Children with juvenile idiopathic arthritis (JIA) who need a tumor necrosis factor (TNF) inhibitor after failing conventional disease-modifying antirheumatic drug (DMARD) treatment often experience insurance delays before beginning the new drug because of prior authorization denials, according to research presented at the 2022 annual meeting of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The findings were also published as a research letter in JAMA Network Open.
“Prompt escalation to TNF inhibitors is recommended for children with JIA refractory to DMARDs,” author Jordan Roberts, MD, a clinical fellow of the Harvard Medical School Rheumatology Program, Boston, told CARRA attendees. TNF inhibitors are increasingly used as first-line treatment in JIA since growing evidence suggests better outcomes from early treatment with biologics. “Prior authorization requirements that delay TNF inhibitor initiation among children with JIA are common in clinical practice,” Dr. Roberts said, but little evidence exists to understand the extent of this problem and its causes.
The researchers therefore conducted a retrospective cohort study using a search of electronic health records from January 2018 to December 2019 to find all children at a single center with a new diagnosis of nonsystemic JIA. Then the authors pulled the timing of prior authorization requests, approvals, denials, and first TNF inhibitor dose from the medical notes. They also sought out any children who had been recommended a TNF inhibitor but never started one.
The total population included 54 children with an average age of 10 years, about two-thirds of whom had private insurance (63%). The group was predominantly White (63%), although 13% declined to provide race, and 7% were Hispanic. Most subtypes of disease were represented: oligoarticular persistent (28%), oligoarticular extended (2%), polyarticular rheumatoid factor-negative (15%), polyarticular rheumatoid factor-positive (15%), psoriatic arthritis (26%), enthesitis-related arthritis (12%), and undifferentiated arthritis (2%).
The 44 participants with private insurance had an average of two joints with active disease, while the 10 patients with public insurance had an average of four involved joints. Nearly all the patients (91%) had previously taken or were currently taking DMARDs when the prior authorization was submitted, and 61% had received NSAIDs.
All but one of the patients’ insurance plans required a prior authorization. The first prior authorization was denied for about one-third of the public insurance patients (30%) and a quarter of the private insurance patients. About 1 in 5 patients overall (22%) required a written appeal to override the denial, and 4% required peer-to-peer review. Meanwhile, 7% of patients began another medication because of the denial.
It took a median of 3 days for prior authorizations to be approved and a median of 24 days from the time the TNF inhibitor was recommended to the patient receiving the first dose. However, 22% of patients waited at least 2 weeks before the prior authorization was approved, and more than a quarter of the requests took over 30 days before the patient could begin the medication. In the public insurance group in particular, a quarter of children waited at least 19 days for approval and at least 44 days before starting the medication.
In fact, when the researchers looked at the difference in approval time between those who did and did not receive an initial denial, the difference was stark. Median approval time was 16 days when the prior authorization was denied, compared with a median of 5 days when the first prior authorization was approved. Similarly, time to initiation of the drug after recommendation was a median of 35 days for those whose prior authorization was first denied and 17 days for those with an initial approval.
The most common reason for an initial denial was the insurance company requiring a different TNF inhibitor than the one the rheumatologist wanted to prescribe. “These were all children whose rheumatologist has recommended either infliximab or etanercept that were required to use adalimumab instead,” Dr. Roberts said.
The other reasons for initial denial were similarly familiar ones:
- Required submission to another insurer
- Additional documentation required
- Lack of medical necessity
- Prescription was for an indication not approved by the Food and Drug Administration
- Age of patient
- Nonbiologic DMARD required
- NSAID required for step therapy
Only three children who were advised to begin a TNF inhibitor did not do so, including one who was lost to follow-up, one who had injection-related anxiety, and one who had safety concerns about the medication.
“Several children were required to use alternative TNF inhibitors than the one that was recommended due to restricted formularies, which may reduce shared decisionmaking between physicians and families and may not be the optimal clinical choice for an individual child,” Dr. Roberts said in her conclusion. Most children, however, were able to get approval for the TNF inhibitor originally requested, “suggesting that utilization management strategies present barriers to timely care despite appropriate specialty medication requests,” she said. “Therefore, it’s important for us to advocate for access to medications for children with JIA.”
Findings are not surprising
“I have these same experiences at my institution – often insurance will dictate clinical practice, and step therapy is the only option, causing a delay to initiation of TNFi even if we think, as the pediatric rheumatologist, that a child needs this medicine to be initiated on presentation to our clinic,” Nayimisha Balmuri, MD, assistant professor of pediatrics in the division of allergy, immunology, and rheumatology at the Johns Hopkins School of Medicine, Baltimore, told this news organization.
Dr. Balmuri, who was not involved in the study, noted that in her clinic at Johns Hopkins, it is hit or miss if an appeal to insurance companies or to the state (if it is Medicaid coverage) will be successful. “Unfortunately, [we are] mostly unsuccessful, and we have to try another DMARD for 8 to 12 weeks first before trying to get TNFi,” she said.
Dr. Balmuri called for bringing these issues to the attention of state and federal legislators. “It’s so important for us to continue to advocate for our patients at the state and national level! We are the advocates for our patients, and we are uniquely trained to know the best medications to initiate to help patients maximize their chance to reach remission of arthritis. Insurance companies need to hear our voices!”
Dr. Roberts reported grants from CARRA, the Lupus Foundation of America, and the National Institute of Allergy and Infectious Diseases during the conduct of the study.
A version of this article first appeared on Medscape.com.
Children with juvenile idiopathic arthritis (JIA) who need a tumor necrosis factor (TNF) inhibitor after failing conventional disease-modifying antirheumatic drug (DMARD) treatment often experience insurance delays before beginning the new drug because of prior authorization denials, according to research presented at the 2022 annual meeting of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The findings were also published as a research letter in JAMA Network Open.
“Prompt escalation to TNF inhibitors is recommended for children with JIA refractory to DMARDs,” author Jordan Roberts, MD, a clinical fellow of the Harvard Medical School Rheumatology Program, Boston, told CARRA attendees. TNF inhibitors are increasingly used as first-line treatment in JIA since growing evidence suggests better outcomes from early treatment with biologics. “Prior authorization requirements that delay TNF inhibitor initiation among children with JIA are common in clinical practice,” Dr. Roberts said, but little evidence exists to understand the extent of this problem and its causes.
The researchers therefore conducted a retrospective cohort study using a search of electronic health records from January 2018 to December 2019 to find all children at a single center with a new diagnosis of nonsystemic JIA. Then the authors pulled the timing of prior authorization requests, approvals, denials, and first TNF inhibitor dose from the medical notes. They also sought out any children who had been recommended a TNF inhibitor but never started one.
The total population included 54 children with an average age of 10 years, about two-thirds of whom had private insurance (63%). The group was predominantly White (63%), although 13% declined to provide race, and 7% were Hispanic. Most subtypes of disease were represented: oligoarticular persistent (28%), oligoarticular extended (2%), polyarticular rheumatoid factor-negative (15%), polyarticular rheumatoid factor-positive (15%), psoriatic arthritis (26%), enthesitis-related arthritis (12%), and undifferentiated arthritis (2%).
The 44 participants with private insurance had an average of two joints with active disease, while the 10 patients with public insurance had an average of four involved joints. Nearly all the patients (91%) had previously taken or were currently taking DMARDs when the prior authorization was submitted, and 61% had received NSAIDs.
All but one of the patients’ insurance plans required a prior authorization. The first prior authorization was denied for about one-third of the public insurance patients (30%) and a quarter of the private insurance patients. About 1 in 5 patients overall (22%) required a written appeal to override the denial, and 4% required peer-to-peer review. Meanwhile, 7% of patients began another medication because of the denial.
It took a median of 3 days for prior authorizations to be approved and a median of 24 days from the time the TNF inhibitor was recommended to the patient receiving the first dose. However, 22% of patients waited at least 2 weeks before the prior authorization was approved, and more than a quarter of the requests took over 30 days before the patient could begin the medication. In the public insurance group in particular, a quarter of children waited at least 19 days for approval and at least 44 days before starting the medication.
In fact, when the researchers looked at the difference in approval time between those who did and did not receive an initial denial, the difference was stark. Median approval time was 16 days when the prior authorization was denied, compared with a median of 5 days when the first prior authorization was approved. Similarly, time to initiation of the drug after recommendation was a median of 35 days for those whose prior authorization was first denied and 17 days for those with an initial approval.
The most common reason for an initial denial was the insurance company requiring a different TNF inhibitor than the one the rheumatologist wanted to prescribe. “These were all children whose rheumatologist has recommended either infliximab or etanercept that were required to use adalimumab instead,” Dr. Roberts said.
The other reasons for initial denial were similarly familiar ones:
- Required submission to another insurer
- Additional documentation required
- Lack of medical necessity
- Prescription was for an indication not approved by the Food and Drug Administration
- Age of patient
- Nonbiologic DMARD required
- NSAID required for step therapy
Only three children who were advised to begin a TNF inhibitor did not do so, including one who was lost to follow-up, one who had injection-related anxiety, and one who had safety concerns about the medication.
“Several children were required to use alternative TNF inhibitors than the one that was recommended due to restricted formularies, which may reduce shared decisionmaking between physicians and families and may not be the optimal clinical choice for an individual child,” Dr. Roberts said in her conclusion. Most children, however, were able to get approval for the TNF inhibitor originally requested, “suggesting that utilization management strategies present barriers to timely care despite appropriate specialty medication requests,” she said. “Therefore, it’s important for us to advocate for access to medications for children with JIA.”
Findings are not surprising
“I have these same experiences at my institution – often insurance will dictate clinical practice, and step therapy is the only option, causing a delay to initiation of TNFi even if we think, as the pediatric rheumatologist, that a child needs this medicine to be initiated on presentation to our clinic,” Nayimisha Balmuri, MD, assistant professor of pediatrics in the division of allergy, immunology, and rheumatology at the Johns Hopkins School of Medicine, Baltimore, told this news organization.
Dr. Balmuri, who was not involved in the study, noted that in her clinic at Johns Hopkins, it is hit or miss if an appeal to insurance companies or to the state (if it is Medicaid coverage) will be successful. “Unfortunately, [we are] mostly unsuccessful, and we have to try another DMARD for 8 to 12 weeks first before trying to get TNFi,” she said.
Dr. Balmuri called for bringing these issues to the attention of state and federal legislators. “It’s so important for us to continue to advocate for our patients at the state and national level! We are the advocates for our patients, and we are uniquely trained to know the best medications to initiate to help patients maximize their chance to reach remission of arthritis. Insurance companies need to hear our voices!”
Dr. Roberts reported grants from CARRA, the Lupus Foundation of America, and the National Institute of Allergy and Infectious Diseases during the conduct of the study.
A version of this article first appeared on Medscape.com.
Children with juvenile idiopathic arthritis (JIA) who need a tumor necrosis factor (TNF) inhibitor after failing conventional disease-modifying antirheumatic drug (DMARD) treatment often experience insurance delays before beginning the new drug because of prior authorization denials, according to research presented at the 2022 annual meeting of the Childhood Arthritis and Rheumatology Research Alliance (CARRA). The findings were also published as a research letter in JAMA Network Open.
“Prompt escalation to TNF inhibitors is recommended for children with JIA refractory to DMARDs,” author Jordan Roberts, MD, a clinical fellow of the Harvard Medical School Rheumatology Program, Boston, told CARRA attendees. TNF inhibitors are increasingly used as first-line treatment in JIA since growing evidence suggests better outcomes from early treatment with biologics. “Prior authorization requirements that delay TNF inhibitor initiation among children with JIA are common in clinical practice,” Dr. Roberts said, but little evidence exists to understand the extent of this problem and its causes.
The researchers therefore conducted a retrospective cohort study using a search of electronic health records from January 2018 to December 2019 to find all children at a single center with a new diagnosis of nonsystemic JIA. Then the authors pulled the timing of prior authorization requests, approvals, denials, and first TNF inhibitor dose from the medical notes. They also sought out any children who had been recommended a TNF inhibitor but never started one.
The total population included 54 children with an average age of 10 years, about two-thirds of whom had private insurance (63%). The group was predominantly White (63%), although 13% declined to provide race, and 7% were Hispanic. Most subtypes of disease were represented: oligoarticular persistent (28%), oligoarticular extended (2%), polyarticular rheumatoid factor-negative (15%), polyarticular rheumatoid factor-positive (15%), psoriatic arthritis (26%), enthesitis-related arthritis (12%), and undifferentiated arthritis (2%).
The 44 participants with private insurance had an average of two joints with active disease, while the 10 patients with public insurance had an average of four involved joints. Nearly all the patients (91%) had previously taken or were currently taking DMARDs when the prior authorization was submitted, and 61% had received NSAIDs.
All but one of the patients’ insurance plans required a prior authorization. The first prior authorization was denied for about one-third of the public insurance patients (30%) and a quarter of the private insurance patients. About 1 in 5 patients overall (22%) required a written appeal to override the denial, and 4% required peer-to-peer review. Meanwhile, 7% of patients began another medication because of the denial.
It took a median of 3 days for prior authorizations to be approved and a median of 24 days from the time the TNF inhibitor was recommended to the patient receiving the first dose. However, 22% of patients waited at least 2 weeks before the prior authorization was approved, and more than a quarter of the requests took over 30 days before the patient could begin the medication. In the public insurance group in particular, a quarter of children waited at least 19 days for approval and at least 44 days before starting the medication.
In fact, when the researchers looked at the difference in approval time between those who did and did not receive an initial denial, the difference was stark. Median approval time was 16 days when the prior authorization was denied, compared with a median of 5 days when the first prior authorization was approved. Similarly, time to initiation of the drug after recommendation was a median of 35 days for those whose prior authorization was first denied and 17 days for those with an initial approval.
The most common reason for an initial denial was the insurance company requiring a different TNF inhibitor than the one the rheumatologist wanted to prescribe. “These were all children whose rheumatologist has recommended either infliximab or etanercept that were required to use adalimumab instead,” Dr. Roberts said.
The other reasons for initial denial were similarly familiar ones:
- Required submission to another insurer
- Additional documentation required
- Lack of medical necessity
- Prescription was for an indication not approved by the Food and Drug Administration
- Age of patient
- Nonbiologic DMARD required
- NSAID required for step therapy
Only three children who were advised to begin a TNF inhibitor did not do so, including one who was lost to follow-up, one who had injection-related anxiety, and one who had safety concerns about the medication.
“Several children were required to use alternative TNF inhibitors than the one that was recommended due to restricted formularies, which may reduce shared decisionmaking between physicians and families and may not be the optimal clinical choice for an individual child,” Dr. Roberts said in her conclusion. Most children, however, were able to get approval for the TNF inhibitor originally requested, “suggesting that utilization management strategies present barriers to timely care despite appropriate specialty medication requests,” she said. “Therefore, it’s important for us to advocate for access to medications for children with JIA.”
Findings are not surprising
“I have these same experiences at my institution – often insurance will dictate clinical practice, and step therapy is the only option, causing a delay to initiation of TNFi even if we think, as the pediatric rheumatologist, that a child needs this medicine to be initiated on presentation to our clinic,” Nayimisha Balmuri, MD, assistant professor of pediatrics in the division of allergy, immunology, and rheumatology at the Johns Hopkins School of Medicine, Baltimore, told this news organization.
Dr. Balmuri, who was not involved in the study, noted that in her clinic at Johns Hopkins, it is hit or miss if an appeal to insurance companies or to the state (if it is Medicaid coverage) will be successful. “Unfortunately, [we are] mostly unsuccessful, and we have to try another DMARD for 8 to 12 weeks first before trying to get TNFi,” she said.
Dr. Balmuri called for bringing these issues to the attention of state and federal legislators. “It’s so important for us to continue to advocate for our patients at the state and national level! We are the advocates for our patients, and we are uniquely trained to know the best medications to initiate to help patients maximize their chance to reach remission of arthritis. Insurance companies need to hear our voices!”
Dr. Roberts reported grants from CARRA, the Lupus Foundation of America, and the National Institute of Allergy and Infectious Diseases during the conduct of the study.
A version of this article first appeared on Medscape.com.
Alarming global rise in pediatric hepatitis: Expert Q&A
This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.
To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
Tracing the outbreak in the United States
How has this outbreak played out thus far in the United States, and what have we learned from that?
Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.
Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).
By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.
Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.
Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.
The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
European and global cases
What has been the experience with this in Europe and elsewhere globally?
In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.
Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.
On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.
What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?
In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.
The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.
The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.
Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?
Not to my knowledge.
What clinicians need to know
What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?
It may be a collective heightened concern following the emergence of COVID.
Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.
Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?
An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.
In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.
Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.
Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?
Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.
In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.
What do hepatologists need to be doing when presented with suspected cases?
The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.
In addition, it is prudent to check for SARS-CoV-2 by PCR.
What are the major questions that remain and that you’d like to see elucidated going forward?
There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?
Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.
A version of this article first appeared on Medscape.com.
This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.
To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
Tracing the outbreak in the United States
How has this outbreak played out thus far in the United States, and what have we learned from that?
Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.
Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).
By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.
Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.
Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.
The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
European and global cases
What has been the experience with this in Europe and elsewhere globally?
In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.
Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.
On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.
What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?
In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.
The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.
The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.
Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?
Not to my knowledge.
What clinicians need to know
What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?
It may be a collective heightened concern following the emergence of COVID.
Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.
Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?
An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.
In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.
Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.
Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?
Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.
In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.
What do hepatologists need to be doing when presented with suspected cases?
The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.
In addition, it is prudent to check for SARS-CoV-2 by PCR.
What are the major questions that remain and that you’d like to see elucidated going forward?
There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?
Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.
A version of this article first appeared on Medscape.com.
This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.
To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
Tracing the outbreak in the United States
How has this outbreak played out thus far in the United States, and what have we learned from that?
Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.
Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).
By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.
Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.
Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.
The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
European and global cases
What has been the experience with this in Europe and elsewhere globally?
In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.
Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.
On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.
What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?
In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.
The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.
The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.
Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?
Not to my knowledge.
What clinicians need to know
What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?
It may be a collective heightened concern following the emergence of COVID.
Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.
Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?
An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.
In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.
Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.
Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?
Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.
In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.
What do hepatologists need to be doing when presented with suspected cases?
The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.
In addition, it is prudent to check for SARS-CoV-2 by PCR.
What are the major questions that remain and that you’d like to see elucidated going forward?
There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?
Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.
A version of this article first appeared on Medscape.com.
Dodging potholes from cancer care to hospice transitions
I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.
Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.
Transitioning from active therapy to symptom management
Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.
The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones.
When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.
In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.
A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
‘Don’t just put in the hospice order and walk away’
Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.
First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.
Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.
If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.
These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.
As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.
Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.
I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.
Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.
Transitioning from active therapy to symptom management
Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.
The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones.
When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.
In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.
A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
‘Don’t just put in the hospice order and walk away’
Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.
First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.
Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.
If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.
These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.
As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.
Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.
I’m often in the position of caring for patients after they’ve stopped active cancer treatments, but before they’ve made the decision to enroll in hospice. They remain under my care until they feel emotionally ready, or until their care needs have escalated to the point in which hospice is unavoidable.
Jenny, a mom in her 50s with metastatic pancreatic cancer, stopped coming to the clinic. She lived about 40 minutes away from the clinic and was no longer receiving treatment. The car rides were painful and difficult for her. I held weekly video visits with her for 2 months before she eventually went to hospice and passed away. Before she died, she shared with me her sadness that her oncologist – who had taken care of her for 3 years – had “washed his hands of [me].” She rarely heard from him after their final conversation in the clinic when he informed her that she was no longer a candidate for further therapy. The sense of abandonment Jenny described was visceral and devastating. With her permission, I let her oncology team know how she felt and they reached out to her just 1 week before her death. After she died, her husband told me how meaningful it had been for the whole family to hear from Jenny’s oncologist who told them that she had done everything possible to fight her cancer and that “no stone was left unturned.” Her husband felt this final conversation provided Jenny with the closure she needed to pass away peacefully.
Transitioning from active therapy to symptom management
Switching gears from an all-out pursuit of active therapy to focusing on cancer symptoms is often a scary transition for patients and their families. The transition is often viewed as a movement away from hope and optimism to “giving up the fight.” Whether you agree with the warrior language or not, many patients still describe their journey in these terms and thus, experience enrollment in hospice as a sense of having failed.
The sense of failure can be compounded by feelings of abandonment by oncology providers when they are referred without much guidance or continuity through the hospice enrollment process. Unfortunately, the consequences of suboptimal hospice transitions can be damaging, especially for the mental health and well-being of the patient and their surviving loved ones.
When managed poorly, hospice transitions can easily lead to patient and family harm, which is a claim supported by research. A qualitative study published in 2019 included 92 caregivers of patients with terminal cancer. The authors found three common pathways for end-of-life transitions – a frictionless transition in which the patient and family are well prepared in advance by their oncologist; a more turbulent transition in which patient and family had direct conversations with their oncologist about the incurability of the disease and the lack of efficacy of further treatments, but were given no guidance on prognosis; and a third type of transition marked by abrupt shifts toward end-of-life care occurring in extremis and typically in the hospital.
In the latter two groups, caregivers felt their loved ones died very quickly after stopping treatment, taking them by surprise and leaving them rushing to put end-of-life care plans in place without much support from their oncologists. In the last group, caregivers shared they received their first prognostic information from the hospital or ICU doctor caring for their actively dying loved one, leaving them with a sense of anger and betrayal toward their oncologist for allowing them to be so ill-prepared.
A Japanese survey published in 2018 in The Oncologist of families of cancer patients who had passed away under hospice care over a 2-year period (2012-2014), found that about one-quarter felt abandoned by oncologists. Several factors that were associated with feeling either more or less abandonment. Spouses of patients, patients aged less than 60 years, and patients whose oncologists informed them that there was “nothing more to do” felt more abandoned by oncologists; whereas families for whom the oncologist provided reassurance about the trajectory of care, recommended hospice, and engaged with a palliative care team felt less abandoned by oncologists. Families who felt more abandoned had higher levels of depression and grief when measured with standardized instruments.
‘Don’t just put in the hospice order and walk away’
Fortunately, there are a few low-resource interventions that can improve the quality of care-to-hospice transitions and prevent the sense of abandonment felt by many patients and families.
First, don’t just put in the hospice order and walk away. Designate a staffer in your office to contact hospice directly, ensure all medical records are faxed and received, and update the patient and family on this progress throughout the transition. Taking care of details like these ensures the patient enrolls in hospice in a timely manner and reduces the chance the patient, who is likely to be quite sick at this point, will end up in the hospital despite your best efforts to get hospice involved.
Make sure the patient and family understand that you are still their oncologist and still available to them. If they want to continue care with you, have them name you as the “non–hospice-attending physician” so that you can continue to bill for telemedicine and office visits using the terminal diagnosis (with a billing modifier). This does not mean that you will be expected to manage the patient’s hospice problem list or respond to hospice nurse calls at 2 a.m. – the hospice doctor will still do this. It just ensures that patients do not receive a bill if you continue to see them.
If ongoing office or video visits are too much for the patient and family, consider assigning a member of your team to call the patient and family on a weekly basis to check in and offer support. A small 2018 pilot study aimed at improving communication found that when caregivers of advanced cancer patients transitioning to hospice received weekly supportive phone calls by a member of their oncology team (typically a nurse or nurse practitioner), they felt emotionally supported, had good continuity of care throughout the hospice enrollment, and appreciated the ability to have closure with their oncology team. In other words, a sense of abandonment was prevented and the patient-provider relationship was actually deepened through the transition.
These suggestions are not rocket science – they are simple, obvious ways to try to restore patient-centeredness to a transition that for providers can seem routine, but for patients and families is often the first time they have confronted the reality that death is approaching. That reality is terrifying and overwhelming. Patients and caregivers need our support more during hospice transitions than at any other point during their cancer journey – except perhaps at diagnosis.
As with Jenny, my patient who felt abandoned, all it took was a single call by her oncology team to restore the trust and heal the sense of feeling forsaken by the people who cared for her for years. Sometimes, even just one more phone call can feel like a lot to a chronically overburdened provider – but what a difference a simple call can make.
Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.