The U.S. Food and Drug Administration approved finerenone (Kerendia), the first agent from a new class of nonsteroidal mineralocorticoid receptor antagonists (MRAs), on July 9 for treating patients with chronic kidney disease (CKD) associated with type 2 diabetes.

Janani Rangaswami, MD, a nephrologist not involved with finerenone’s development, hailed the action as a “welcome addition to therapies in the cardiorenal space.”

She also highlighted that until more evidence accumulates, finerenone will take a back seat to two more established renal-protective drug classes for patients with type 2 diabetes, the renin-angiotensin system inhibitors (RASIs), and the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

RASIs, which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, remain first-line treatments for slowing the progression of CKD in patients with type 2 diabetes. The efficacy and safety of these agents are well-established. The trial that led to the FDA’s decision to approve finerenone, FIDELIO-DKD, compared it against placebo in more than 5,700 patients with type 2 diabetes who were all already taking a maximum-tolerated dose of an RASI.
 

Scant data on combining finerenone with an SGLT2 inhibitor

Two agents in the SGLT2 inhibitor class, approved initially for type 2 diabetes, received additional FDA approvals for slowing kidney disease: Canagliflozin (Invokana), which was approved in September 2019 on the basis of the CREDENCE trial, and dapagliflozin (Forxiga/Farxiga), which was approved in April 2021 on the basis of DAPA-CKD. Nephrologists now speak of this drug class as “practice changing.”

When FIDELIO-DKD enrolled patients from September 2015 to June 2018, it was still early days for use of SGLT2 inhibitors for patients with type 2 diabetes; hence, fewer than 5% of enrolled patients received an SGLT2 inhibitor, making it impossible to say how well finerenone works when taken along with one of these drugs.

“The big question that persists is the incremental benefit [from finerenone] on top of an SGLT2 inhibitor,” commented Dr. Rangaswami, director of the cardiorenal program at George Washington University, Washington, and chair-elect of the Council on the Kidney in Cardiovascular Disease of the American Heart Association.

“It is hard to extrapolate incremental benefit from existing finerenone trial data given the low background use of SGLT2 inhibitors [in FIDELIO-DKD],” she said in an interview.

George Bakris, MD, lead investigator for FIDELIO-DKD, agrees.
 

SGLT2 inhibitors are a ‘must’ for CKD

An SGLT2 inhibitor “must be used, period,” for patients with type 2 diabetes and CKD. “The evidence is very strong,” said Dr. Bakris, speaking in June 2021 during a session of the virtual annual Congress of the European Renal Association and European Dialysis and Transplant Association.

Because of inadequate evidence on how finerenone works when administered in addition to an SGLT2 inhibitor, for the time being, the combination must be considered investigational, he added.

Study results “need to show that combination therapy [with an SGLT2 inhibitor and finerenone] is better” than an SGLT2 inhibitor alone, said Dr. Bakris, professor of medicine and director of the Comprehensive Hypertension Center of the University of Chicago.

During his June talk, Dr. Bakris predicted that by 2023, enough data will exist from patients treated with both an SGLT2 inhibitor and finerenone to allow an evidence-based approach to combination treatment.

Finerenone’s approval makes it an immediate choice for patients with type 2 diabetes and CKD secondary to polycystic kidney disease, a group who are not candidates for an SGLT2 inhibitor, said Dr. Rangaswami.

But “if a patient is eligible for an SGLT2 inhibitor, I would not stop that in favor of starting finerenone” on the basis of current knowledge, she noted.
 

‘Not your mother’s spironolactone’

Although finerenone is classified an MRA, the class that also includes the steroidal agents spironolactone and eplerenone, the nonsteroidal structure of finerenone means “it has nothing to do with spironolactone. It’s a different molecule with different chemistry,” Dr. Bakris said in his June talk.

Although the risk for hyperkalemia has been a limiting factor and a deterrent to routine use of steroidal MRAs for preventing progression of CKD, hyperkalemia is much less of a problem with finerenone.

Main results from FIDELIO-DKD, published in late 2020, showed that the percentage of patients receiving finerenone who permanently stopped taking the drug because of hyperkalemia was 2.3%, higher than the 0.9% rate among patients in the trial who received placebo but about a third of the rate of patients treated with spironolactone in a historical cohort.

“You need to pay attention” to the potential development of hyperkalemia in patients taking finerenone, “but it is not a major issue,” Dr. Bakris said. “Finerenone is not your mother’s spironolactone,” he declared.

FIDELIO-DKD’s primary outcome, a combination of several adverse renal events, showed that treatment with finerenone cut this endpoint by a significant 18% compared with placebo. The study’s main secondary endpoint showed that finerenone cut the incidence of combined cardiovascular disease events by a significant 14% compared with placebo. Adverse events were similar in the finerenone and placebo arms.
 

Finerenone also shows promise for reducing CVD events

Bayer, the company that developed and will market finerenone, announced in May 2021 topline results from a companion trial, FIGARO-DKD. That trial also enrolled patients with type 2 diabetes and CKD, but a primary endpoint of that trial combined the rates of cardiovascular death and nonfatal cardiovascular disease events. The results from this trial showed a significant difference in favor of finerenone compared with placebo.

“Given the common pathways that progression of CKD and cardiovascular disease share with respect to [moderating] inflammation and [slowing development of] fibrosis, it is not surprising that a signal for benefit was seen at the different ends of the cardiorenal spectrum,” Dr. Rangaswami said.

FIDELIO-DKD and FIGARO-DKD were sponsored by Bayer, the company that markets finerenone (Kerendia). Dr. Bakris has been a consultant to and has received research funding from Bayer and from numerous other companies. Dr. Rangaswami has disclosed no relevant financial relationships.

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

The U.S. Food and Drug Administration approved finerenone (Kerendia), the first agent from a new class of nonsteroidal mineralocorticoid receptor antagonists (MRAs), on July 9 for treating patients with chronic kidney disease (CKD) associated with type 2 diabetes.

Janani Rangaswami, MD, a nephrologist not involved with finerenone’s development, hailed the action as a “welcome addition to therapies in the cardiorenal space.”

She also highlighted that until more evidence accumulates, finerenone will take a back seat to two more established renal-protective drug classes for patients with type 2 diabetes, the renin-angiotensin system inhibitors (RASIs), and the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

RASIs, which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, remain first-line treatments for slowing the progression of CKD in patients with type 2 diabetes. The efficacy and safety of these agents are well-established. The trial that led to the FDA’s decision to approve finerenone, FIDELIO-DKD, compared it against placebo in more than 5,700 patients with type 2 diabetes who were all already taking a maximum-tolerated dose of an RASI.
 

Scant data on combining finerenone with an SGLT2 inhibitor

Two agents in the SGLT2 inhibitor class, approved initially for type 2 diabetes, received additional FDA approvals for slowing kidney disease: Canagliflozin (Invokana), which was approved in September 2019 on the basis of the CREDENCE trial, and dapagliflozin (Forxiga/Farxiga), which was approved in April 2021 on the basis of DAPA-CKD. Nephrologists now speak of this drug class as “practice changing.”

When FIDELIO-DKD enrolled patients from September 2015 to June 2018, it was still early days for use of SGLT2 inhibitors for patients with type 2 diabetes; hence, fewer than 5% of enrolled patients received an SGLT2 inhibitor, making it impossible to say how well finerenone works when taken along with one of these drugs.

“The big question that persists is the incremental benefit [from finerenone] on top of an SGLT2 inhibitor,” commented Dr. Rangaswami, director of the cardiorenal program at George Washington University, Washington, and chair-elect of the Council on the Kidney in Cardiovascular Disease of the American Heart Association.

“It is hard to extrapolate incremental benefit from existing finerenone trial data given the low background use of SGLT2 inhibitors [in FIDELIO-DKD],” she said in an interview.

George Bakris, MD, lead investigator for FIDELIO-DKD, agrees.
 

SGLT2 inhibitors are a ‘must’ for CKD

An SGLT2 inhibitor “must be used, period,” for patients with type 2 diabetes and CKD. “The evidence is very strong,” said Dr. Bakris, speaking in June 2021 during a session of the virtual annual Congress of the European Renal Association and European Dialysis and Transplant Association.

Because of inadequate evidence on how finerenone works when administered in addition to an SGLT2 inhibitor, for the time being, the combination must be considered investigational, he added.

Study results “need to show that combination therapy [with an SGLT2 inhibitor and finerenone] is better” than an SGLT2 inhibitor alone, said Dr. Bakris, professor of medicine and director of the Comprehensive Hypertension Center of the University of Chicago.

During his June talk, Dr. Bakris predicted that by 2023, enough data will exist from patients treated with both an SGLT2 inhibitor and finerenone to allow an evidence-based approach to combination treatment.

Finerenone’s approval makes it an immediate choice for patients with type 2 diabetes and CKD secondary to polycystic kidney disease, a group who are not candidates for an SGLT2 inhibitor, said Dr. Rangaswami.

But “if a patient is eligible for an SGLT2 inhibitor, I would not stop that in favor of starting finerenone” on the basis of current knowledge, she noted.
 

‘Not your mother’s spironolactone’

Although finerenone is classified an MRA, the class that also includes the steroidal agents spironolactone and eplerenone, the nonsteroidal structure of finerenone means “it has nothing to do with spironolactone. It’s a different molecule with different chemistry,” Dr. Bakris said in his June talk.

Although the risk for hyperkalemia has been a limiting factor and a deterrent to routine use of steroidal MRAs for preventing progression of CKD, hyperkalemia is much less of a problem with finerenone.

Main results from FIDELIO-DKD, published in late 2020, showed that the percentage of patients receiving finerenone who permanently stopped taking the drug because of hyperkalemia was 2.3%, higher than the 0.9% rate among patients in the trial who received placebo but about a third of the rate of patients treated with spironolactone in a historical cohort.

“You need to pay attention” to the potential development of hyperkalemia in patients taking finerenone, “but it is not a major issue,” Dr. Bakris said. “Finerenone is not your mother’s spironolactone,” he declared.

FIDELIO-DKD’s primary outcome, a combination of several adverse renal events, showed that treatment with finerenone cut this endpoint by a significant 18% compared with placebo. The study’s main secondary endpoint showed that finerenone cut the incidence of combined cardiovascular disease events by a significant 14% compared with placebo. Adverse events were similar in the finerenone and placebo arms.
 

Finerenone also shows promise for reducing CVD events

Bayer, the company that developed and will market finerenone, announced in May 2021 topline results from a companion trial, FIGARO-DKD. That trial also enrolled patients with type 2 diabetes and CKD, but a primary endpoint of that trial combined the rates of cardiovascular death and nonfatal cardiovascular disease events. The results from this trial showed a significant difference in favor of finerenone compared with placebo.

“Given the common pathways that progression of CKD and cardiovascular disease share with respect to [moderating] inflammation and [slowing development of] fibrosis, it is not surprising that a signal for benefit was seen at the different ends of the cardiorenal spectrum,” Dr. Rangaswami said.

FIDELIO-DKD and FIGARO-DKD were sponsored by Bayer, the company that markets finerenone (Kerendia). Dr. Bakris has been a consultant to and has received research funding from Bayer and from numerous other companies. Dr. Rangaswami has disclosed no relevant financial relationships.

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

The U.S. Food and Drug Administration approved finerenone (Kerendia), the first agent from a new class of nonsteroidal mineralocorticoid receptor antagonists (MRAs), on July 9 for treating patients with chronic kidney disease (CKD) associated with type 2 diabetes.

Janani Rangaswami, MD, a nephrologist not involved with finerenone’s development, hailed the action as a “welcome addition to therapies in the cardiorenal space.”

She also highlighted that until more evidence accumulates, finerenone will take a back seat to two more established renal-protective drug classes for patients with type 2 diabetes, the renin-angiotensin system inhibitors (RASIs), and the sodium-glucose cotransporter 2 (SGLT2) inhibitors.

RASIs, which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, remain first-line treatments for slowing the progression of CKD in patients with type 2 diabetes. The efficacy and safety of these agents are well-established. The trial that led to the FDA’s decision to approve finerenone, FIDELIO-DKD, compared it against placebo in more than 5,700 patients with type 2 diabetes who were all already taking a maximum-tolerated dose of an RASI.
 

Scant data on combining finerenone with an SGLT2 inhibitor

Two agents in the SGLT2 inhibitor class, approved initially for type 2 diabetes, received additional FDA approvals for slowing kidney disease: Canagliflozin (Invokana), which was approved in September 2019 on the basis of the CREDENCE trial, and dapagliflozin (Forxiga/Farxiga), which was approved in April 2021 on the basis of DAPA-CKD. Nephrologists now speak of this drug class as “practice changing.”

When FIDELIO-DKD enrolled patients from September 2015 to June 2018, it was still early days for use of SGLT2 inhibitors for patients with type 2 diabetes; hence, fewer than 5% of enrolled patients received an SGLT2 inhibitor, making it impossible to say how well finerenone works when taken along with one of these drugs.

“The big question that persists is the incremental benefit [from finerenone] on top of an SGLT2 inhibitor,” commented Dr. Rangaswami, director of the cardiorenal program at George Washington University, Washington, and chair-elect of the Council on the Kidney in Cardiovascular Disease of the American Heart Association.

“It is hard to extrapolate incremental benefit from existing finerenone trial data given the low background use of SGLT2 inhibitors [in FIDELIO-DKD],” she said in an interview.

George Bakris, MD, lead investigator for FIDELIO-DKD, agrees.
 

SGLT2 inhibitors are a ‘must’ for CKD

An SGLT2 inhibitor “must be used, period,” for patients with type 2 diabetes and CKD. “The evidence is very strong,” said Dr. Bakris, speaking in June 2021 during a session of the virtual annual Congress of the European Renal Association and European Dialysis and Transplant Association.

Because of inadequate evidence on how finerenone works when administered in addition to an SGLT2 inhibitor, for the time being, the combination must be considered investigational, he added.

Study results “need to show that combination therapy [with an SGLT2 inhibitor and finerenone] is better” than an SGLT2 inhibitor alone, said Dr. Bakris, professor of medicine and director of the Comprehensive Hypertension Center of the University of Chicago.

During his June talk, Dr. Bakris predicted that by 2023, enough data will exist from patients treated with both an SGLT2 inhibitor and finerenone to allow an evidence-based approach to combination treatment.

Finerenone’s approval makes it an immediate choice for patients with type 2 diabetes and CKD secondary to polycystic kidney disease, a group who are not candidates for an SGLT2 inhibitor, said Dr. Rangaswami.

But “if a patient is eligible for an SGLT2 inhibitor, I would not stop that in favor of starting finerenone” on the basis of current knowledge, she noted.
 

‘Not your mother’s spironolactone’

Although finerenone is classified an MRA, the class that also includes the steroidal agents spironolactone and eplerenone, the nonsteroidal structure of finerenone means “it has nothing to do with spironolactone. It’s a different molecule with different chemistry,” Dr. Bakris said in his June talk.

Although the risk for hyperkalemia has been a limiting factor and a deterrent to routine use of steroidal MRAs for preventing progression of CKD, hyperkalemia is much less of a problem with finerenone.

Main results from FIDELIO-DKD, published in late 2020, showed that the percentage of patients receiving finerenone who permanently stopped taking the drug because of hyperkalemia was 2.3%, higher than the 0.9% rate among patients in the trial who received placebo but about a third of the rate of patients treated with spironolactone in a historical cohort.

“You need to pay attention” to the potential development of hyperkalemia in patients taking finerenone, “but it is not a major issue,” Dr. Bakris said. “Finerenone is not your mother’s spironolactone,” he declared.

FIDELIO-DKD’s primary outcome, a combination of several adverse renal events, showed that treatment with finerenone cut this endpoint by a significant 18% compared with placebo. The study’s main secondary endpoint showed that finerenone cut the incidence of combined cardiovascular disease events by a significant 14% compared with placebo. Adverse events were similar in the finerenone and placebo arms.
 

Finerenone also shows promise for reducing CVD events

Bayer, the company that developed and will market finerenone, announced in May 2021 topline results from a companion trial, FIGARO-DKD. That trial also enrolled patients with type 2 diabetes and CKD, but a primary endpoint of that trial combined the rates of cardiovascular death and nonfatal cardiovascular disease events. The results from this trial showed a significant difference in favor of finerenone compared with placebo.

“Given the common pathways that progression of CKD and cardiovascular disease share with respect to [moderating] inflammation and [slowing development of] fibrosis, it is not surprising that a signal for benefit was seen at the different ends of the cardiorenal spectrum,” Dr. Rangaswami said.

FIDELIO-DKD and FIGARO-DKD were sponsored by Bayer, the company that markets finerenone (Kerendia). Dr. Bakris has been a consultant to and has received research funding from Bayer and from numerous other companies. Dr. Rangaswami has disclosed no relevant financial relationships.

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

Compared with oral propranolol for the treatment of infantile hemangiomas, oral nadolol resulted in faster and greater size involution and color resolution with a similar safety profile out to 52 weeks, results from a prospective analysis of 71 patients showed.

“In clinical practice, we notice that nadolol works very well in terms of controlling the size and the appearance of the hemangioma,” lead study author Elena Pope, MD, MSc, said during the annual meeting of the Society for Pediatric Dermatology. Hence, she and her colleagues were interested in comparing their clinical experience with the standard treatment with propranolol, and designed a prospective, randomized, controlled, double-blinded study, with the aim of proving that “nadolol is noninferior to propranolol, with a margin of noninferiority of 10%.”

Between 2016 and 2020, Dr. Pope and colleagues at two academic Canadian pediatric dermatology centers enrolled 71 infants aged 1-6 months with significant hemangioma that had either the potential for functional impairment or cosmetic deformity, defined as a lesion greater than 1.5 cm on the face or greater than 3 cm on another body part. Treatment consisted of oral propranolol or nadolol in escalating doses up to 2 mg/kg per day. “The blinding portion of the study was for 24 weeks with a follow-up up to 52 weeks,” said Dr. Pope, professor of pediatrics at the University of Toronto and section head of pediatric dermatology at The Hospital for Sick Children, also in Toronto. “After the unblinding at 24 weeks, patients were allowed to switch their intervention if they were not happy with the results.”

Of the 71 patients, 35 received nadolol and 36 received propranolol. The two groups were similar in terms of clinical and demographic characteristics. Their mean age at enrollment was 3.15 months, 80% were female, 61% were White, 20% were Asian, and the rest were from other ethnic backgrounds.

At 24 weeks, the researchers found that the mean size involution was 97.94% in the nadolol group and 89.14% in the propranolol group (P = .005), while the mean color fading on the visual analogue scale (VAS) was 94.47% in the nadolol group and 80.54% in the propranolol group (P < .001). At 52 weeks, the mean size involution was 99.63% in the nadolol group and 93.63% in the propranolol group (P = .001), while the mean VAS color fading was 97.34% in the nadolol group and 87.23% in the propranolol group (P = .001).

According to Dr. Pope, Kaplan-Meir analysis showed that patients in the propranolol group responded slower to treatment (P = .019), while safety data was similar between the two groups. For example, between weeks 25 and 52, 84.2% of patients in the nadolol group experienced an adverse event, compared with 74.2% of patients in the propranolol group (P = .466). The most common respiratory adverse event was upper respiratory tract infection, which affected 87.5% of patients in the nadolol group, compared with 100% of patients in the propranolol group (P = 0.341).

The most common gastrointestinal adverse event was diarrhea, which affected 66.7% of patients in both groups. One patient in the propranolol group was admitted to the hospital with pneumonia and fully recovered. The incident was not suspected to be related to the medication.

“We believe that this data backs up our clinical experience and it may offer an alternative treatment in other centers where patients experience propranolol unresponsiveness, side effects, or intolerance, or where a fast response is needed,” Dr. Pope said. As for the potential cost implications, “nadolol is cheaper than the Hemangiol but comparable with the compounded formulation of propranolol.”

Concern over the safety of nadolol was raised in a case report published in Pediatrics in 2020. Authors from Alberta reported the case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity,” the authors wrote.

In a reply to the authors in the same issue of Pediatrics, Dr. Pope, Cathryn Sibbald, MD, and Erin Chung, PhD, pointed out that postmortem redistribution of medications “is complex and measured postmortem cardiac blood concentrations may be significantly higher than the true blood nadolol concentration at the time of death due to significant diffusion from the peripheral tissues.”

They added that the report did not address “other potential errors such as in compounding, dispensing, and administration of the solution,” they wrote, adding: “Finally, we are aware of a Canadian case of death in an infant receiving propranolol, although the cause of death in that case was unable to be determined (ISMP Canada 2016 Safety Bulletin).We agree with the authors that careful consideration of the risks and benefits of beta-blocker therapy should be employed, parents need to be informed when to discontinue therapy and that further research into the pharmacokinetics and pharmacogenetics of beta-blockers are warranted.”

Following publication of the case report in Pediatrics, Dr. Pope said that the only change she made in her practice was to ask families to temporarily discontinue nadolol if their child had constipation for more than 5 days.

The study was supported by a grant from Physician Services, Inc. Dr. Pope reported having no financial disclosures.

[email protected]

Compared with oral propranolol for the treatment of infantile hemangiomas, oral nadolol resulted in faster and greater size involution and color resolution with a similar safety profile out to 52 weeks, results from a prospective analysis of 71 patients showed.

“In clinical practice, we notice that nadolol works very well in terms of controlling the size and the appearance of the hemangioma,” lead study author Elena Pope, MD, MSc, said during the annual meeting of the Society for Pediatric Dermatology. Hence, she and her colleagues were interested in comparing their clinical experience with the standard treatment with propranolol, and designed a prospective, randomized, controlled, double-blinded study, with the aim of proving that “nadolol is noninferior to propranolol, with a margin of noninferiority of 10%.”

Between 2016 and 2020, Dr. Pope and colleagues at two academic Canadian pediatric dermatology centers enrolled 71 infants aged 1-6 months with significant hemangioma that had either the potential for functional impairment or cosmetic deformity, defined as a lesion greater than 1.5 cm on the face or greater than 3 cm on another body part. Treatment consisted of oral propranolol or nadolol in escalating doses up to 2 mg/kg per day. “The blinding portion of the study was for 24 weeks with a follow-up up to 52 weeks,” said Dr. Pope, professor of pediatrics at the University of Toronto and section head of pediatric dermatology at The Hospital for Sick Children, also in Toronto. “After the unblinding at 24 weeks, patients were allowed to switch their intervention if they were not happy with the results.”

Of the 71 patients, 35 received nadolol and 36 received propranolol. The two groups were similar in terms of clinical and demographic characteristics. Their mean age at enrollment was 3.15 months, 80% were female, 61% were White, 20% were Asian, and the rest were from other ethnic backgrounds.

At 24 weeks, the researchers found that the mean size involution was 97.94% in the nadolol group and 89.14% in the propranolol group (P = .005), while the mean color fading on the visual analogue scale (VAS) was 94.47% in the nadolol group and 80.54% in the propranolol group (P < .001). At 52 weeks, the mean size involution was 99.63% in the nadolol group and 93.63% in the propranolol group (P = .001), while the mean VAS color fading was 97.34% in the nadolol group and 87.23% in the propranolol group (P = .001).

According to Dr. Pope, Kaplan-Meir analysis showed that patients in the propranolol group responded slower to treatment (P = .019), while safety data was similar between the two groups. For example, between weeks 25 and 52, 84.2% of patients in the nadolol group experienced an adverse event, compared with 74.2% of patients in the propranolol group (P = .466). The most common respiratory adverse event was upper respiratory tract infection, which affected 87.5% of patients in the nadolol group, compared with 100% of patients in the propranolol group (P = 0.341).

The most common gastrointestinal adverse event was diarrhea, which affected 66.7% of patients in both groups. One patient in the propranolol group was admitted to the hospital with pneumonia and fully recovered. The incident was not suspected to be related to the medication.

“We believe that this data backs up our clinical experience and it may offer an alternative treatment in other centers where patients experience propranolol unresponsiveness, side effects, or intolerance, or where a fast response is needed,” Dr. Pope said. As for the potential cost implications, “nadolol is cheaper than the Hemangiol but comparable with the compounded formulation of propranolol.”

Concern over the safety of nadolol was raised in a case report published in Pediatrics in 2020. Authors from Alberta reported the case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity,” the authors wrote.

In a reply to the authors in the same issue of Pediatrics, Dr. Pope, Cathryn Sibbald, MD, and Erin Chung, PhD, pointed out that postmortem redistribution of medications “is complex and measured postmortem cardiac blood concentrations may be significantly higher than the true blood nadolol concentration at the time of death due to significant diffusion from the peripheral tissues.”

They added that the report did not address “other potential errors such as in compounding, dispensing, and administration of the solution,” they wrote, adding: “Finally, we are aware of a Canadian case of death in an infant receiving propranolol, although the cause of death in that case was unable to be determined (ISMP Canada 2016 Safety Bulletin).We agree with the authors that careful consideration of the risks and benefits of beta-blocker therapy should be employed, parents need to be informed when to discontinue therapy and that further research into the pharmacokinetics and pharmacogenetics of beta-blockers are warranted.”

Following publication of the case report in Pediatrics, Dr. Pope said that the only change she made in her practice was to ask families to temporarily discontinue nadolol if their child had constipation for more than 5 days.

The study was supported by a grant from Physician Services, Inc. Dr. Pope reported having no financial disclosures.

[email protected]

Compared with oral propranolol for the treatment of infantile hemangiomas, oral nadolol resulted in faster and greater size involution and color resolution with a similar safety profile out to 52 weeks, results from a prospective analysis of 71 patients showed.

“In clinical practice, we notice that nadolol works very well in terms of controlling the size and the appearance of the hemangioma,” lead study author Elena Pope, MD, MSc, said during the annual meeting of the Society for Pediatric Dermatology. Hence, she and her colleagues were interested in comparing their clinical experience with the standard treatment with propranolol, and designed a prospective, randomized, controlled, double-blinded study, with the aim of proving that “nadolol is noninferior to propranolol, with a margin of noninferiority of 10%.”

Between 2016 and 2020, Dr. Pope and colleagues at two academic Canadian pediatric dermatology centers enrolled 71 infants aged 1-6 months with significant hemangioma that had either the potential for functional impairment or cosmetic deformity, defined as a lesion greater than 1.5 cm on the face or greater than 3 cm on another body part. Treatment consisted of oral propranolol or nadolol in escalating doses up to 2 mg/kg per day. “The blinding portion of the study was for 24 weeks with a follow-up up to 52 weeks,” said Dr. Pope, professor of pediatrics at the University of Toronto and section head of pediatric dermatology at The Hospital for Sick Children, also in Toronto. “After the unblinding at 24 weeks, patients were allowed to switch their intervention if they were not happy with the results.”

Of the 71 patients, 35 received nadolol and 36 received propranolol. The two groups were similar in terms of clinical and demographic characteristics. Their mean age at enrollment was 3.15 months, 80% were female, 61% were White, 20% were Asian, and the rest were from other ethnic backgrounds.

At 24 weeks, the researchers found that the mean size involution was 97.94% in the nadolol group and 89.14% in the propranolol group (P = .005), while the mean color fading on the visual analogue scale (VAS) was 94.47% in the nadolol group and 80.54% in the propranolol group (P < .001). At 52 weeks, the mean size involution was 99.63% in the nadolol group and 93.63% in the propranolol group (P = .001), while the mean VAS color fading was 97.34% in the nadolol group and 87.23% in the propranolol group (P = .001).

According to Dr. Pope, Kaplan-Meir analysis showed that patients in the propranolol group responded slower to treatment (P = .019), while safety data was similar between the two groups. For example, between weeks 25 and 52, 84.2% of patients in the nadolol group experienced an adverse event, compared with 74.2% of patients in the propranolol group (P = .466). The most common respiratory adverse event was upper respiratory tract infection, which affected 87.5% of patients in the nadolol group, compared with 100% of patients in the propranolol group (P = 0.341).

The most common gastrointestinal adverse event was diarrhea, which affected 66.7% of patients in both groups. One patient in the propranolol group was admitted to the hospital with pneumonia and fully recovered. The incident was not suspected to be related to the medication.

“We believe that this data backs up our clinical experience and it may offer an alternative treatment in other centers where patients experience propranolol unresponsiveness, side effects, or intolerance, or where a fast response is needed,” Dr. Pope said. As for the potential cost implications, “nadolol is cheaper than the Hemangiol but comparable with the compounded formulation of propranolol.”

Concern over the safety of nadolol was raised in a case report published in Pediatrics in 2020. Authors from Alberta reported the case of a 10-week-old girl who was started on nadolol for infantile hemangioma, died 7 weeks later, and was found to have an elevated postmortem cardiac blood nadolol level of 0.94 mg/L. “The infant had no bowel movements for 10 days before her death, which we hypothesize contributed to nadolol toxicity,” the authors wrote.

In a reply to the authors in the same issue of Pediatrics, Dr. Pope, Cathryn Sibbald, MD, and Erin Chung, PhD, pointed out that postmortem redistribution of medications “is complex and measured postmortem cardiac blood concentrations may be significantly higher than the true blood nadolol concentration at the time of death due to significant diffusion from the peripheral tissues.”

They added that the report did not address “other potential errors such as in compounding, dispensing, and administration of the solution,” they wrote, adding: “Finally, we are aware of a Canadian case of death in an infant receiving propranolol, although the cause of death in that case was unable to be determined (ISMP Canada 2016 Safety Bulletin).We agree with the authors that careful consideration of the risks and benefits of beta-blocker therapy should be employed, parents need to be informed when to discontinue therapy and that further research into the pharmacokinetics and pharmacogenetics of beta-blockers are warranted.”

Following publication of the case report in Pediatrics, Dr. Pope said that the only change she made in her practice was to ask families to temporarily discontinue nadolol if their child had constipation for more than 5 days.

The study was supported by a grant from Physician Services, Inc. Dr. Pope reported having no financial disclosures.

[email protected]

The reported prevalence and severity of obstructive sleep apnea in women is lower, compared with men, but the consequences of the disease are “at least the same, if not worse,” with women appearing to have greater susceptibility to adverse OSA-related cardiovascular consequences – particularly as it pertains to endothelial dysfunction, Reena Mehra, MD, MS, said at the virtual annual meeting of the Associated Professional Sleep Societies.

Women more so than men have endothelial dysfunction associated with OSA, “suggesting there is an enhanced sensitivity of the female vascular endothelium to intermittent hypoxia,” said Dr. Mehra, director of sleep disorders research at the Cleveland Clinic and professor of medicine at Case Western Reserve University, also in Cleveland.

Sex-specific differences in the anatomic and physiological characteristics of the upper airway, in fat distribution and in respiratory stability as they relate to OSA have been documented for some time – and today, these and other differences relating to the diagnosis, treatment, and consequences of sleep apnea continue to be studied and elucidated, said Dr. Mehra, Anita Rajagopal, MD, and Chitra Lal, MD, in a session on OSA in women. Each spoke about the breath and implications of these differences, and of increasing recognition of the significance of OSA in women.
 

Likely underdiagnosis

Epidemiologic studies have suggested a three- to fivefold higher prevalence of OSA in men than in women in the general population. But it has also been estimated that 17%-25% of women have sleep apnea, and the prevalence reported in various studies has generally increased with time, said Dr. Rajagopal, department medical director for sleep medicine at Community Physician Network in Indianapolis, and medical director of the Community Health Network Sleep/Wake Disorders Center, also in Indianapolis.

One population-based study in Sweden, reported in 2013, found OSA (defined as an apnea-hypopnea index [AHI] ≥5) in 50% of women aged 20-70, she noted.

It’s quite possible women are being misdiagnosed or underdiagnosed because of their reporting of different symptoms, Dr. Rajagopal said. The Epworth Sleepiness Scale, commonly used to screen for OSA, has not been validated for use in women and has not been strongly associated with daytime sleepiness in women in population-based studies, she said, noting that women who report similar levels of daytime sleepiness to men are less likely to have an ESS score greater than 10.

“We shouldn’t rule out obstructive sleep apnea in women with a low ESS,” Dr. Rajagopal said in an interview after the meeting. Attentiveness to the symptoms more often reported by women – generalized daytime fatigue/lack of energy, insomnia, morning headaches, mood disturbances, and nightmares – is important, as is performance of overnight polysomnography when a home sleep study is negative and there is clinical suspicion of OSA.Respiratory disturbances in women are frequently associated with arousals – which induce less ventilatory instability in women than in men – rather than oxygen desaturations, leading to underestimation of OSA on home sleep testing. Insomnia associated with OSA in women may also increase the likelihood of a false negative result, Dr. Rajagopal said at the meeting.

“It’s really important [in sleep testing] to consider your AHI values in women,” she said. “The AHI value may not provide a true indication of the degree of sleep fragmentation being experienced by patients.” That OSA symptoms manifest in women with lower AHIs has been elucidated in research showing, for instance, that those with an AHI of 2-5 per hour have a similar level of symptoms to men with an AHI of at least 15 per hour, she said.

Women tend to have a clustering of apnea during REM sleep, and it’s possible that “the long-term effects of REM disruption contribute to greater symptomatology at lower AHI values in women compared to men,” Dr. Rajagopal said.

Also at play are when it comes to testing and diagnosis are several other key sex differences, she said. For one, the upper airways in women are less collapsible and more stable during sleep (most evident during non-REM sleep), and respiratory events during sleep are less frequently associated with complete upper airway collapse.

Women also have shorter apneic episodes, but “the longest apneas are associated with a more severe oxygen desaturation,” she said. Moreover, they have more episodes of upper airway resistance during sleep, which in and of itself “has been shown to produce clinical symptoms such as daytime fatigue and clinical depression.”

In her presentation, Dr. Mehra similarly commented on a likely underdiagnosis of OSA in women. In addition to differing symptoms, including palpitations, “women are less likely to have arousals, and have a lesser degree of nocturnal hypoxia compared to men ... perhaps leading to even more of an underdiagnosis.”
 

Unique consequences

Differences in upper airway physiology and other sex-specific differences impacting OSA susceptibility are at least partly attributable to sex hormones, said Dr. Mehra and Dr. Lal, associate professor of medicine at the Medical University of South Carolina, Charleston.

A significant increase in prevalence is seen after menopause, and research has shown that each additional year in menopause is associated with a greater AHI – a “dose-response effect,” Dr. Lal said. An inverse association between hormone replacement therapy and OSA severity has been seen in epidemiological studies including the Sleep Heart Health Study, Dr. Mehra said. But in prospective studies, Dr. Lal noted, hormone replacement therapy has not been shown to decrease AHI.

Experimental and clinical studies suggest that the vascular endothelium is influenced by sex hormones, Dr. Mehra said. Estrogen is known to improve endothelial function by inducing increased nitric oxide bioavailability – important in the setting of hypoxemia, which leads to reduced bioavailability of nitric oxide. “Alterations of sex-specific hormones in OSA may represent a key factor in increasing vulnerability to vascular dysfunction,” Dr. Mehra added.

The Sleep Heart Health Study also documented sex-specific differences, showing a graded increase of troponin with increasing OSA severity category as well as an increase in left ventricular mass thickness, and a 30% increased risk of heart failure or death in women with moderate/severe OSA, compared with women without OSA or with mild OSA, Dr. Mehra said. These findings were not observed in men.

The dominance of REM-related OSA in women raises risk because sleep disturbances during REM sleep are associated with adverse cardiometabolic outcomes including prevalent and incident hypertension, Dr. Mehra noted. “REM-related OSA may also adversely impact glucose metabolism,” she said, “even in the absence of non-REM obstructive sleep apnea.”

Regarding OSA treatment and responsivity, Dr. Mehra said that preliminary, post hoc data from a randomized, controlled trial of the impact of continuous positive airway pressure (CPAP) therapy on cardiovascular biomarkers showed a sex-specific effect. “There were differences in men versus women in terms of responsiveness with regards to biomarkers of inflammation and oxidative stress ... with reductions from CPAP observed in women but not in men,” said Dr. Mehra, a co-investigator of the study.

The data suggests, she said that “these biomarkers may be more responsive to treatment and a reversal of sleep apnea pathophysiology in women.”

Women also appear to respond better than men to upper airway nerve stimulation (UAS), she said, referring to an international registry study showing a 3.6-fold higher odds of responsiveness to the therapy relative to men. Women in the study were 60% less likely to be approved by insurance for UAS, however, making it “a public policy issue, said Dr. Mehra, a coinvestigator.

Dr. Rajagopal, Dr. Mehra, and Dr. Lal all reported that they had no potential conflicts of interest.

The reported prevalence and severity of obstructive sleep apnea in women is lower, compared with men, but the consequences of the disease are “at least the same, if not worse,” with women appearing to have greater susceptibility to adverse OSA-related cardiovascular consequences – particularly as it pertains to endothelial dysfunction, Reena Mehra, MD, MS, said at the virtual annual meeting of the Associated Professional Sleep Societies.

Women more so than men have endothelial dysfunction associated with OSA, “suggesting there is an enhanced sensitivity of the female vascular endothelium to intermittent hypoxia,” said Dr. Mehra, director of sleep disorders research at the Cleveland Clinic and professor of medicine at Case Western Reserve University, also in Cleveland.

Sex-specific differences in the anatomic and physiological characteristics of the upper airway, in fat distribution and in respiratory stability as they relate to OSA have been documented for some time – and today, these and other differences relating to the diagnosis, treatment, and consequences of sleep apnea continue to be studied and elucidated, said Dr. Mehra, Anita Rajagopal, MD, and Chitra Lal, MD, in a session on OSA in women. Each spoke about the breath and implications of these differences, and of increasing recognition of the significance of OSA in women.
 

Likely underdiagnosis

Epidemiologic studies have suggested a three- to fivefold higher prevalence of OSA in men than in women in the general population. But it has also been estimated that 17%-25% of women have sleep apnea, and the prevalence reported in various studies has generally increased with time, said Dr. Rajagopal, department medical director for sleep medicine at Community Physician Network in Indianapolis, and medical director of the Community Health Network Sleep/Wake Disorders Center, also in Indianapolis.

One population-based study in Sweden, reported in 2013, found OSA (defined as an apnea-hypopnea index [AHI] ≥5) in 50% of women aged 20-70, she noted.

It’s quite possible women are being misdiagnosed or underdiagnosed because of their reporting of different symptoms, Dr. Rajagopal said. The Epworth Sleepiness Scale, commonly used to screen for OSA, has not been validated for use in women and has not been strongly associated with daytime sleepiness in women in population-based studies, she said, noting that women who report similar levels of daytime sleepiness to men are less likely to have an ESS score greater than 10.

“We shouldn’t rule out obstructive sleep apnea in women with a low ESS,” Dr. Rajagopal said in an interview after the meeting. Attentiveness to the symptoms more often reported by women – generalized daytime fatigue/lack of energy, insomnia, morning headaches, mood disturbances, and nightmares – is important, as is performance of overnight polysomnography when a home sleep study is negative and there is clinical suspicion of OSA.Respiratory disturbances in women are frequently associated with arousals – which induce less ventilatory instability in women than in men – rather than oxygen desaturations, leading to underestimation of OSA on home sleep testing. Insomnia associated with OSA in women may also increase the likelihood of a false negative result, Dr. Rajagopal said at the meeting.

“It’s really important [in sleep testing] to consider your AHI values in women,” she said. “The AHI value may not provide a true indication of the degree of sleep fragmentation being experienced by patients.” That OSA symptoms manifest in women with lower AHIs has been elucidated in research showing, for instance, that those with an AHI of 2-5 per hour have a similar level of symptoms to men with an AHI of at least 15 per hour, she said.

Women tend to have a clustering of apnea during REM sleep, and it’s possible that “the long-term effects of REM disruption contribute to greater symptomatology at lower AHI values in women compared to men,” Dr. Rajagopal said.

Also at play are when it comes to testing and diagnosis are several other key sex differences, she said. For one, the upper airways in women are less collapsible and more stable during sleep (most evident during non-REM sleep), and respiratory events during sleep are less frequently associated with complete upper airway collapse.

Women also have shorter apneic episodes, but “the longest apneas are associated with a more severe oxygen desaturation,” she said. Moreover, they have more episodes of upper airway resistance during sleep, which in and of itself “has been shown to produce clinical symptoms such as daytime fatigue and clinical depression.”

In her presentation, Dr. Mehra similarly commented on a likely underdiagnosis of OSA in women. In addition to differing symptoms, including palpitations, “women are less likely to have arousals, and have a lesser degree of nocturnal hypoxia compared to men ... perhaps leading to even more of an underdiagnosis.”
 

Unique consequences

Differences in upper airway physiology and other sex-specific differences impacting OSA susceptibility are at least partly attributable to sex hormones, said Dr. Mehra and Dr. Lal, associate professor of medicine at the Medical University of South Carolina, Charleston.

A significant increase in prevalence is seen after menopause, and research has shown that each additional year in menopause is associated with a greater AHI – a “dose-response effect,” Dr. Lal said. An inverse association between hormone replacement therapy and OSA severity has been seen in epidemiological studies including the Sleep Heart Health Study, Dr. Mehra said. But in prospective studies, Dr. Lal noted, hormone replacement therapy has not been shown to decrease AHI.

Experimental and clinical studies suggest that the vascular endothelium is influenced by sex hormones, Dr. Mehra said. Estrogen is known to improve endothelial function by inducing increased nitric oxide bioavailability – important in the setting of hypoxemia, which leads to reduced bioavailability of nitric oxide. “Alterations of sex-specific hormones in OSA may represent a key factor in increasing vulnerability to vascular dysfunction,” Dr. Mehra added.

The Sleep Heart Health Study also documented sex-specific differences, showing a graded increase of troponin with increasing OSA severity category as well as an increase in left ventricular mass thickness, and a 30% increased risk of heart failure or death in women with moderate/severe OSA, compared with women without OSA or with mild OSA, Dr. Mehra said. These findings were not observed in men.

The dominance of REM-related OSA in women raises risk because sleep disturbances during REM sleep are associated with adverse cardiometabolic outcomes including prevalent and incident hypertension, Dr. Mehra noted. “REM-related OSA may also adversely impact glucose metabolism,” she said, “even in the absence of non-REM obstructive sleep apnea.”

Regarding OSA treatment and responsivity, Dr. Mehra said that preliminary, post hoc data from a randomized, controlled trial of the impact of continuous positive airway pressure (CPAP) therapy on cardiovascular biomarkers showed a sex-specific effect. “There were differences in men versus women in terms of responsiveness with regards to biomarkers of inflammation and oxidative stress ... with reductions from CPAP observed in women but not in men,” said Dr. Mehra, a co-investigator of the study.

The data suggests, she said that “these biomarkers may be more responsive to treatment and a reversal of sleep apnea pathophysiology in women.”

Women also appear to respond better than men to upper airway nerve stimulation (UAS), she said, referring to an international registry study showing a 3.6-fold higher odds of responsiveness to the therapy relative to men. Women in the study were 60% less likely to be approved by insurance for UAS, however, making it “a public policy issue, said Dr. Mehra, a coinvestigator.

Dr. Rajagopal, Dr. Mehra, and Dr. Lal all reported that they had no potential conflicts of interest.

The reported prevalence and severity of obstructive sleep apnea in women is lower, compared with men, but the consequences of the disease are “at least the same, if not worse,” with women appearing to have greater susceptibility to adverse OSA-related cardiovascular consequences – particularly as it pertains to endothelial dysfunction, Reena Mehra, MD, MS, said at the virtual annual meeting of the Associated Professional Sleep Societies.

Women more so than men have endothelial dysfunction associated with OSA, “suggesting there is an enhanced sensitivity of the female vascular endothelium to intermittent hypoxia,” said Dr. Mehra, director of sleep disorders research at the Cleveland Clinic and professor of medicine at Case Western Reserve University, also in Cleveland.

Sex-specific differences in the anatomic and physiological characteristics of the upper airway, in fat distribution and in respiratory stability as they relate to OSA have been documented for some time – and today, these and other differences relating to the diagnosis, treatment, and consequences of sleep apnea continue to be studied and elucidated, said Dr. Mehra, Anita Rajagopal, MD, and Chitra Lal, MD, in a session on OSA in women. Each spoke about the breath and implications of these differences, and of increasing recognition of the significance of OSA in women.
 

Likely underdiagnosis

Epidemiologic studies have suggested a three- to fivefold higher prevalence of OSA in men than in women in the general population. But it has also been estimated that 17%-25% of women have sleep apnea, and the prevalence reported in various studies has generally increased with time, said Dr. Rajagopal, department medical director for sleep medicine at Community Physician Network in Indianapolis, and medical director of the Community Health Network Sleep/Wake Disorders Center, also in Indianapolis.

One population-based study in Sweden, reported in 2013, found OSA (defined as an apnea-hypopnea index [AHI] ≥5) in 50% of women aged 20-70, she noted.

It’s quite possible women are being misdiagnosed or underdiagnosed because of their reporting of different symptoms, Dr. Rajagopal said. The Epworth Sleepiness Scale, commonly used to screen for OSA, has not been validated for use in women and has not been strongly associated with daytime sleepiness in women in population-based studies, she said, noting that women who report similar levels of daytime sleepiness to men are less likely to have an ESS score greater than 10.

“We shouldn’t rule out obstructive sleep apnea in women with a low ESS,” Dr. Rajagopal said in an interview after the meeting. Attentiveness to the symptoms more often reported by women – generalized daytime fatigue/lack of energy, insomnia, morning headaches, mood disturbances, and nightmares – is important, as is performance of overnight polysomnography when a home sleep study is negative and there is clinical suspicion of OSA.Respiratory disturbances in women are frequently associated with arousals – which induce less ventilatory instability in women than in men – rather than oxygen desaturations, leading to underestimation of OSA on home sleep testing. Insomnia associated with OSA in women may also increase the likelihood of a false negative result, Dr. Rajagopal said at the meeting.

“It’s really important [in sleep testing] to consider your AHI values in women,” she said. “The AHI value may not provide a true indication of the degree of sleep fragmentation being experienced by patients.” That OSA symptoms manifest in women with lower AHIs has been elucidated in research showing, for instance, that those with an AHI of 2-5 per hour have a similar level of symptoms to men with an AHI of at least 15 per hour, she said.

Women tend to have a clustering of apnea during REM sleep, and it’s possible that “the long-term effects of REM disruption contribute to greater symptomatology at lower AHI values in women compared to men,” Dr. Rajagopal said.

Also at play are when it comes to testing and diagnosis are several other key sex differences, she said. For one, the upper airways in women are less collapsible and more stable during sleep (most evident during non-REM sleep), and respiratory events during sleep are less frequently associated with complete upper airway collapse.

Women also have shorter apneic episodes, but “the longest apneas are associated with a more severe oxygen desaturation,” she said. Moreover, they have more episodes of upper airway resistance during sleep, which in and of itself “has been shown to produce clinical symptoms such as daytime fatigue and clinical depression.”

In her presentation, Dr. Mehra similarly commented on a likely underdiagnosis of OSA in women. In addition to differing symptoms, including palpitations, “women are less likely to have arousals, and have a lesser degree of nocturnal hypoxia compared to men ... perhaps leading to even more of an underdiagnosis.”
 

Unique consequences

Differences in upper airway physiology and other sex-specific differences impacting OSA susceptibility are at least partly attributable to sex hormones, said Dr. Mehra and Dr. Lal, associate professor of medicine at the Medical University of South Carolina, Charleston.

A significant increase in prevalence is seen after menopause, and research has shown that each additional year in menopause is associated with a greater AHI – a “dose-response effect,” Dr. Lal said. An inverse association between hormone replacement therapy and OSA severity has been seen in epidemiological studies including the Sleep Heart Health Study, Dr. Mehra said. But in prospective studies, Dr. Lal noted, hormone replacement therapy has not been shown to decrease AHI.

Experimental and clinical studies suggest that the vascular endothelium is influenced by sex hormones, Dr. Mehra said. Estrogen is known to improve endothelial function by inducing increased nitric oxide bioavailability – important in the setting of hypoxemia, which leads to reduced bioavailability of nitric oxide. “Alterations of sex-specific hormones in OSA may represent a key factor in increasing vulnerability to vascular dysfunction,” Dr. Mehra added.

The Sleep Heart Health Study also documented sex-specific differences, showing a graded increase of troponin with increasing OSA severity category as well as an increase in left ventricular mass thickness, and a 30% increased risk of heart failure or death in women with moderate/severe OSA, compared with women without OSA or with mild OSA, Dr. Mehra said. These findings were not observed in men.

The dominance of REM-related OSA in women raises risk because sleep disturbances during REM sleep are associated with adverse cardiometabolic outcomes including prevalent and incident hypertension, Dr. Mehra noted. “REM-related OSA may also adversely impact glucose metabolism,” she said, “even in the absence of non-REM obstructive sleep apnea.”

Regarding OSA treatment and responsivity, Dr. Mehra said that preliminary, post hoc data from a randomized, controlled trial of the impact of continuous positive airway pressure (CPAP) therapy on cardiovascular biomarkers showed a sex-specific effect. “There were differences in men versus women in terms of responsiveness with regards to biomarkers of inflammation and oxidative stress ... with reductions from CPAP observed in women but not in men,” said Dr. Mehra, a co-investigator of the study.

The data suggests, she said that “these biomarkers may be more responsive to treatment and a reversal of sleep apnea pathophysiology in women.”

Women also appear to respond better than men to upper airway nerve stimulation (UAS), she said, referring to an international registry study showing a 3.6-fold higher odds of responsiveness to the therapy relative to men. Women in the study were 60% less likely to be approved by insurance for UAS, however, making it “a public policy issue, said Dr. Mehra, a coinvestigator.

Dr. Rajagopal, Dr. Mehra, and Dr. Lal all reported that they had no potential conflicts of interest.

Immigration and Customs Enforcement will no longer detain most migrant women who are pregnant, postpartum, or nursing for deportation. This reverses the policy previously put in place by the Trump administration.

Under the new directive, ICE officials generally will not detain or arrest women who are pregnant or nursing, or who have given birth within the previous year. In a July 1 memo signed by ICE Acting Director Tae Johnson, ICE officers are directed to house women in “an appropriate facility to manage their care.”

The memo goes on to state that “generally ICE should not detain, arrest, or take into custody for an administrative violation of the immigration laws individuals known to be pregnant, post partum, or nursing unless release is prohibited by law or exceptional circumstances exist.”

In addition, ICE is also required to evaluate those individuals who are already in custody “to determine if continued detention is appropriate.”

During the Obama administration, pregnant women were generally not detained except under extraordinary circumstances. However, these policies were reversed after Donald Trump took office, and there was an 80% increase in the number of times ICE detained pregnant women in the year that followed implementation of the new directive – from 1,160 in 2017 to 2,097 in 2018.

The new guidance now goes even further than the directive issued under President Obama as it also includes women who are nursing and the 1-year postpartum period.

This policy stems from the Biden-Harris administration’s plan to reform the immigration system, part of which was to create a more humane asylum system. In a statement released early in February 2021, the White House stated that the “Trump administration’s policies at the border have caused chaos, cruelty, and confusion,” and that they will now “begin to roll back the most damaging policies adopted by the prior administration, while taking effective action to manage migration across the region.” After migrant women are taken into custody, pregnancy tests are administered as part of regular health screenings. If women are found to be pregnant, the new ICE policy states that they “generally” should be released from detention.

However, there will still be circumstances when pregnant and postpartum women may be detained, such as when there is a high risk that the individual is violent or a national security concern. In these cases, a field office director must approve the arrest and detention as well as making sure that the women receive appropriate medical care.

“The harmful consequences of immigration detention have been documented for years,” said Rebekah Wolf, JD, staff attorney with the American Immigration Council. “Our 2017 joint complaint urging a thorough investigation into the increasing numbers of pregnant women facing harm in detention, illustrated the disturbing practice of detaining pregnant women and the lack of quality medical care provided to these women.”

She added that the “federal government should not be in the business of detaining pregnant or nursing individuals, and it’s good to see the Biden administration directing ICE to finally take meaningful steps to limit enforcement activities in this manner. We are hopeful that this announcement is an indication of a broader shift on detention policy.”

There are currently 13 pregnant women in ICE custody, and they are being considered for release under the new policy.

Immigration and Customs Enforcement will no longer detain most migrant women who are pregnant, postpartum, or nursing for deportation. This reverses the policy previously put in place by the Trump administration.

Under the new directive, ICE officials generally will not detain or arrest women who are pregnant or nursing, or who have given birth within the previous year. In a July 1 memo signed by ICE Acting Director Tae Johnson, ICE officers are directed to house women in “an appropriate facility to manage their care.”

The memo goes on to state that “generally ICE should not detain, arrest, or take into custody for an administrative violation of the immigration laws individuals known to be pregnant, post partum, or nursing unless release is prohibited by law or exceptional circumstances exist.”

In addition, ICE is also required to evaluate those individuals who are already in custody “to determine if continued detention is appropriate.”

During the Obama administration, pregnant women were generally not detained except under extraordinary circumstances. However, these policies were reversed after Donald Trump took office, and there was an 80% increase in the number of times ICE detained pregnant women in the year that followed implementation of the new directive – from 1,160 in 2017 to 2,097 in 2018.

The new guidance now goes even further than the directive issued under President Obama as it also includes women who are nursing and the 1-year postpartum period.

This policy stems from the Biden-Harris administration’s plan to reform the immigration system, part of which was to create a more humane asylum system. In a statement released early in February 2021, the White House stated that the “Trump administration’s policies at the border have caused chaos, cruelty, and confusion,” and that they will now “begin to roll back the most damaging policies adopted by the prior administration, while taking effective action to manage migration across the region.” After migrant women are taken into custody, pregnancy tests are administered as part of regular health screenings. If women are found to be pregnant, the new ICE policy states that they “generally” should be released from detention.

However, there will still be circumstances when pregnant and postpartum women may be detained, such as when there is a high risk that the individual is violent or a national security concern. In these cases, a field office director must approve the arrest and detention as well as making sure that the women receive appropriate medical care.

“The harmful consequences of immigration detention have been documented for years,” said Rebekah Wolf, JD, staff attorney with the American Immigration Council. “Our 2017 joint complaint urging a thorough investigation into the increasing numbers of pregnant women facing harm in detention, illustrated the disturbing practice of detaining pregnant women and the lack of quality medical care provided to these women.”

She added that the “federal government should not be in the business of detaining pregnant or nursing individuals, and it’s good to see the Biden administration directing ICE to finally take meaningful steps to limit enforcement activities in this manner. We are hopeful that this announcement is an indication of a broader shift on detention policy.”

There are currently 13 pregnant women in ICE custody, and they are being considered for release under the new policy.

Immigration and Customs Enforcement will no longer detain most migrant women who are pregnant, postpartum, or nursing for deportation. This reverses the policy previously put in place by the Trump administration.

Under the new directive, ICE officials generally will not detain or arrest women who are pregnant or nursing, or who have given birth within the previous year. In a July 1 memo signed by ICE Acting Director Tae Johnson, ICE officers are directed to house women in “an appropriate facility to manage their care.”

The memo goes on to state that “generally ICE should not detain, arrest, or take into custody for an administrative violation of the immigration laws individuals known to be pregnant, post partum, or nursing unless release is prohibited by law or exceptional circumstances exist.”

In addition, ICE is also required to evaluate those individuals who are already in custody “to determine if continued detention is appropriate.”

During the Obama administration, pregnant women were generally not detained except under extraordinary circumstances. However, these policies were reversed after Donald Trump took office, and there was an 80% increase in the number of times ICE detained pregnant women in the year that followed implementation of the new directive – from 1,160 in 2017 to 2,097 in 2018.

The new guidance now goes even further than the directive issued under President Obama as it also includes women who are nursing and the 1-year postpartum period.

This policy stems from the Biden-Harris administration’s plan to reform the immigration system, part of which was to create a more humane asylum system. In a statement released early in February 2021, the White House stated that the “Trump administration’s policies at the border have caused chaos, cruelty, and confusion,” and that they will now “begin to roll back the most damaging policies adopted by the prior administration, while taking effective action to manage migration across the region.” After migrant women are taken into custody, pregnancy tests are administered as part of regular health screenings. If women are found to be pregnant, the new ICE policy states that they “generally” should be released from detention.

However, there will still be circumstances when pregnant and postpartum women may be detained, such as when there is a high risk that the individual is violent or a national security concern. In these cases, a field office director must approve the arrest and detention as well as making sure that the women receive appropriate medical care.

“The harmful consequences of immigration detention have been documented for years,” said Rebekah Wolf, JD, staff attorney with the American Immigration Council. “Our 2017 joint complaint urging a thorough investigation into the increasing numbers of pregnant women facing harm in detention, illustrated the disturbing practice of detaining pregnant women and the lack of quality medical care provided to these women.”

She added that the “federal government should not be in the business of detaining pregnant or nursing individuals, and it’s good to see the Biden administration directing ICE to finally take meaningful steps to limit enforcement activities in this manner. We are hopeful that this announcement is an indication of a broader shift on detention policy.”

There are currently 13 pregnant women in ICE custody, and they are being considered for release under the new policy.

Editor’s note: This article has been provided by The Doctors Company, the exclusively endorsed medical malpractice carrier for the Society of Hospital Medicine.

The pandemic has raised pressing questions around preventive measures, vaccines, and safe treatment, but it has also obscured one key lingering uncertainty for medical professionals: Where are all the medical malpractice claims?

A variety of factors create a cloud of uncertainty around when, if ever, we will see the claims we expected from care provided just before the pandemic, much less claims deriving from care during the pandemic of both COVID-19 and non–COVID-19 patients.
 

Malpractice claims take time to surface

We won’t know until 2022 or later whether there will be an increase in claims related to the pandemic. When a medical error occurs, it’s not like an automobile accident. Everybody nearby knows when there’s been an automobile accident because they hear screeching tires, a loud crash, and then sirens. But when a medical error occurs, generally speaking, neither the doctor nor the patient immediately knows that something is amiss. It can take months or years for people to realize that something untoward has occurred.

Claims from medical errors that occurred before the pandemic bring additional uncertainties. In 2020, we saw fewer than expected overall claims filed from events occurring 18-24 months before the pandemic. In total, 20% fewer claims were filed than in 2019. This may have had to do with courts shutting down, people being reluctant to meet with attorneys to discuss a claim, and/or lawyers working from home. We may see these claims filed later than expected, or maybe we won’t see them at all.

But without a doubt, pandemic-related claims will be filed. The pandemic’s impact on physicians increases the risk of claims. Burnout is a major cause of medical errors, and a recent study found that out of 60 countries, U.S. health care providers showed the highest rates of burnout. We’re concerned about the stress affecting physicians’ performance – not just the physical stress of the demands put on them while treating COVID-19 patients, but all of the worry. For instance, a lot of doctors at the start of this pandemic stayed at hotels because they didn’t want to bring the virus home to their families – if they got exposed. Those sorts of stressors from life disruptions, on top of the stress of treating COVID-19 patients and the stress of treating non–COVID-19 patients within overtaxed health care systems, contribute to the possibilities for error.
 

Immunity protections are not fail-safe

And while health care providers have medical liability protections during the pandemic, these protections may not prevent claims. Health care provider pandemic-related liability laws vary from state to state, and they will be tested in the courts as to whether they’re constitutional. For example, there is pending legislation in New York state that would repeal the provider protections created there at the start of the pandemic. Further, some expert witnesses will couch their statements in terms of what it takes to get around one of these statutes. Therefore, physicians do have reason for concern, even in states with strong liability protections.

The following case example, which is one of about 40 COVID-19–related claims made against our members so far, is a poster child for why these protections are necessary: A quadriplegic patient with COVID-19 had reached the point of organ failure before he reached the ED. There was really nothing medical science could do for him at that point, in terms of a chance at recovery. Therefore, the patient’s physician and conservator placed him in assisted living for palliative care. This was a sad but reasonable decision during a pandemic, with hospital beds needed for patients with a shot at surviving. Following that patient’s death, the physician is being sued.
 

Defending claims regarding treatment vs. regarding infection control

We are very confident in our ability to protect our members against claims where they are being sued over the treatment of the disease. Claims arising out of treatment are not concerning to us because there is no cure for COVID-19 – one can only treat the symptoms as the virus runs its course.

On the other hand, suits harder to defend would be those that revolve around transmitting the disease because providers didn’t follow guidelines from the Centers for Disease Control and Prevention or there wasn’t enough personal protective equipment. That’s why we stress the importance of following CDC guidelines, and why we’ve taken proactive steps to communicate with the entire medical community throughout the pandemic as part of our commitment to serve those who provide care.

Mr. White is chief operating officer at The Doctors Company. The guidelines suggested here are not rules, do not constitute legal advice, and do not ensure a successful outcome. The ultimate decision regarding the appropriateness of any treatment must be made by each health care provider considering the circumstances of the individual situation and in accordance with the laws of the jurisdiction in which the care is rendered.

Editor’s note: This article has been provided by The Doctors Company, the exclusively endorsed medical malpractice carrier for the Society of Hospital Medicine.

The pandemic has raised pressing questions around preventive measures, vaccines, and safe treatment, but it has also obscured one key lingering uncertainty for medical professionals: Where are all the medical malpractice claims?

A variety of factors create a cloud of uncertainty around when, if ever, we will see the claims we expected from care provided just before the pandemic, much less claims deriving from care during the pandemic of both COVID-19 and non–COVID-19 patients.
 

Malpractice claims take time to surface

We won’t know until 2022 or later whether there will be an increase in claims related to the pandemic. When a medical error occurs, it’s not like an automobile accident. Everybody nearby knows when there’s been an automobile accident because they hear screeching tires, a loud crash, and then sirens. But when a medical error occurs, generally speaking, neither the doctor nor the patient immediately knows that something is amiss. It can take months or years for people to realize that something untoward has occurred.

Claims from medical errors that occurred before the pandemic bring additional uncertainties. In 2020, we saw fewer than expected overall claims filed from events occurring 18-24 months before the pandemic. In total, 20% fewer claims were filed than in 2019. This may have had to do with courts shutting down, people being reluctant to meet with attorneys to discuss a claim, and/or lawyers working from home. We may see these claims filed later than expected, or maybe we won’t see them at all.

But without a doubt, pandemic-related claims will be filed. The pandemic’s impact on physicians increases the risk of claims. Burnout is a major cause of medical errors, and a recent study found that out of 60 countries, U.S. health care providers showed the highest rates of burnout. We’re concerned about the stress affecting physicians’ performance – not just the physical stress of the demands put on them while treating COVID-19 patients, but all of the worry. For instance, a lot of doctors at the start of this pandemic stayed at hotels because they didn’t want to bring the virus home to their families – if they got exposed. Those sorts of stressors from life disruptions, on top of the stress of treating COVID-19 patients and the stress of treating non–COVID-19 patients within overtaxed health care systems, contribute to the possibilities for error.
 

Immunity protections are not fail-safe

And while health care providers have medical liability protections during the pandemic, these protections may not prevent claims. Health care provider pandemic-related liability laws vary from state to state, and they will be tested in the courts as to whether they’re constitutional. For example, there is pending legislation in New York state that would repeal the provider protections created there at the start of the pandemic. Further, some expert witnesses will couch their statements in terms of what it takes to get around one of these statutes. Therefore, physicians do have reason for concern, even in states with strong liability protections.

The following case example, which is one of about 40 COVID-19–related claims made against our members so far, is a poster child for why these protections are necessary: A quadriplegic patient with COVID-19 had reached the point of organ failure before he reached the ED. There was really nothing medical science could do for him at that point, in terms of a chance at recovery. Therefore, the patient’s physician and conservator placed him in assisted living for palliative care. This was a sad but reasonable decision during a pandemic, with hospital beds needed for patients with a shot at surviving. Following that patient’s death, the physician is being sued.
 

Defending claims regarding treatment vs. regarding infection control

We are very confident in our ability to protect our members against claims where they are being sued over the treatment of the disease. Claims arising out of treatment are not concerning to us because there is no cure for COVID-19 – one can only treat the symptoms as the virus runs its course.

On the other hand, suits harder to defend would be those that revolve around transmitting the disease because providers didn’t follow guidelines from the Centers for Disease Control and Prevention or there wasn’t enough personal protective equipment. That’s why we stress the importance of following CDC guidelines, and why we’ve taken proactive steps to communicate with the entire medical community throughout the pandemic as part of our commitment to serve those who provide care.

Mr. White is chief operating officer at The Doctors Company. The guidelines suggested here are not rules, do not constitute legal advice, and do not ensure a successful outcome. The ultimate decision regarding the appropriateness of any treatment must be made by each health care provider considering the circumstances of the individual situation and in accordance with the laws of the jurisdiction in which the care is rendered.

Editor’s note: This article has been provided by The Doctors Company, the exclusively endorsed medical malpractice carrier for the Society of Hospital Medicine.

The pandemic has raised pressing questions around preventive measures, vaccines, and safe treatment, but it has also obscured one key lingering uncertainty for medical professionals: Where are all the medical malpractice claims?

A variety of factors create a cloud of uncertainty around when, if ever, we will see the claims we expected from care provided just before the pandemic, much less claims deriving from care during the pandemic of both COVID-19 and non–COVID-19 patients.
 

Malpractice claims take time to surface

We won’t know until 2022 or later whether there will be an increase in claims related to the pandemic. When a medical error occurs, it’s not like an automobile accident. Everybody nearby knows when there’s been an automobile accident because they hear screeching tires, a loud crash, and then sirens. But when a medical error occurs, generally speaking, neither the doctor nor the patient immediately knows that something is amiss. It can take months or years for people to realize that something untoward has occurred.

Claims from medical errors that occurred before the pandemic bring additional uncertainties. In 2020, we saw fewer than expected overall claims filed from events occurring 18-24 months before the pandemic. In total, 20% fewer claims were filed than in 2019. This may have had to do with courts shutting down, people being reluctant to meet with attorneys to discuss a claim, and/or lawyers working from home. We may see these claims filed later than expected, or maybe we won’t see them at all.

But without a doubt, pandemic-related claims will be filed. The pandemic’s impact on physicians increases the risk of claims. Burnout is a major cause of medical errors, and a recent study found that out of 60 countries, U.S. health care providers showed the highest rates of burnout. We’re concerned about the stress affecting physicians’ performance – not just the physical stress of the demands put on them while treating COVID-19 patients, but all of the worry. For instance, a lot of doctors at the start of this pandemic stayed at hotels because they didn’t want to bring the virus home to their families – if they got exposed. Those sorts of stressors from life disruptions, on top of the stress of treating COVID-19 patients and the stress of treating non–COVID-19 patients within overtaxed health care systems, contribute to the possibilities for error.
 

Immunity protections are not fail-safe

And while health care providers have medical liability protections during the pandemic, these protections may not prevent claims. Health care provider pandemic-related liability laws vary from state to state, and they will be tested in the courts as to whether they’re constitutional. For example, there is pending legislation in New York state that would repeal the provider protections created there at the start of the pandemic. Further, some expert witnesses will couch their statements in terms of what it takes to get around one of these statutes. Therefore, physicians do have reason for concern, even in states with strong liability protections.

The following case example, which is one of about 40 COVID-19–related claims made against our members so far, is a poster child for why these protections are necessary: A quadriplegic patient with COVID-19 had reached the point of organ failure before he reached the ED. There was really nothing medical science could do for him at that point, in terms of a chance at recovery. Therefore, the patient’s physician and conservator placed him in assisted living for palliative care. This was a sad but reasonable decision during a pandemic, with hospital beds needed for patients with a shot at surviving. Following that patient’s death, the physician is being sued.
 

Defending claims regarding treatment vs. regarding infection control

We are very confident in our ability to protect our members against claims where they are being sued over the treatment of the disease. Claims arising out of treatment are not concerning to us because there is no cure for COVID-19 – one can only treat the symptoms as the virus runs its course.

On the other hand, suits harder to defend would be those that revolve around transmitting the disease because providers didn’t follow guidelines from the Centers for Disease Control and Prevention or there wasn’t enough personal protective equipment. That’s why we stress the importance of following CDC guidelines, and why we’ve taken proactive steps to communicate with the entire medical community throughout the pandemic as part of our commitment to serve those who provide care.

Mr. White is chief operating officer at The Doctors Company. The guidelines suggested here are not rules, do not constitute legal advice, and do not ensure a successful outcome. The ultimate decision regarding the appropriateness of any treatment must be made by each health care provider considering the circumstances of the individual situation and in accordance with the laws of the jurisdiction in which the care is rendered.

Acne & Rosacea

• Rosacea phenotypes
• Erythema and flushing
• Aggressive treatment of acne
• Energy-based rosacea therapy
• Diet and acne

Acne & Rosacea

• Rosacea phenotypes
• Erythema and flushing
• Aggressive treatment of acne
• Energy-based rosacea therapy
• Diet and acne

Acne & Rosacea

• Rosacea phenotypes
• Erythema and flushing
• Aggressive treatment of acne
• Energy-based rosacea therapy
• Diet and acne

In a real-world test, tofacitinib had a similar safety profile to what was seen in clinical trials. The majority of adverse events seen were infections, and few were serious; however, the study did find evidence of rare venous thromboembolism (VTE) in patients with preexisting risk factors, which suggests that precaution is warranted in this group.

Tofacitinib, a Janus kinase inhibitor, was approved by the Food and Drug Administration in 2018 for adults with moderate to severe ulcerative colitis (UC). Three phase 3 clinical trials and an open-label, long-term extension trial found that the drug was associated with increased infection rates and higher lipid levels.

In rheumatoid arthritis patients, an interim analysis of a safety clinical trial of twice-daily doses of 10 mg tofacitinib showed increased rates of pulmonary embolism and all-cause mortality, compared to treatment with a dose of 5 mg or a tumor necrosis factor antagonist. That finding led to a black box label warning against thrombosis.

The current study, published in Clinical Gastroenterology and Hepatology, included patients from six centers in the United States.

The findings suggest that patients should be counseled about the potential risk for herpes zoster (HZ) reactivation, especially older patients taking corticosteroids. The authors also recommended vaccination with an inactivated HZ vaccine. “Our data suggest a careful risk-benefit discussion before starting tofacitinib, especially in patients with preexisting risk factors for VTE, dose deescalation to the lowest clinically feasible dose, and monitoring for clinical signs of VTE, especially among those who continue on a dose of 10 mg twice a day,” the authors wrote.

The researchers followed 260 patients over a median of 6 months (median age, 38 years; 58.1% male; 71.9% non-Hispanic). Overall, 88.5% had previously received treatment with a biologic, most often an anti–TNF-alpha agent (76.5%). During follow-up, 15.7% experienced adverse events, most commonly infections (5.0%) and rash (3.5%). Joint pain (1.5%) and anemia (1.5%) also occurred. The incidence rate for any adverse event was 27.2 per 100 person-years. Adverse events occurred more often in older patients (mean age, 42 vs. 37 years; P = .02) and those who had not undergone previous anti-TNF therapy (63.4% vs 79.8%; P = .03). There was no association between concomitant steroid use and adverse events on univariate analysis. Of the overall cohort, 5.8% experienced a severe adverse event, with the most common being herpes zoster rash (26.7% of severe adverse events). Therapy was discontinued by 4.6%.

Five patients developed herpes zoster (3.29 per 100 person-years; 95% CI, 1.37-7.90). Risk factors for VTE were seen in 31.2% of the cohort, and two cases of VTE occurred during follow-up (1.32 per 100 person-years; 95% CI, 0.33-5.28), both in patients with extensive UC. There was no increased risk of complications following abdominal surgery.

At baseline, 38.4% had an abnormal lipid profile, and this increased to 48.3% following 8 weeks of treatment.

Overall, 45% of patients were anemic at baseline. Females experienced a significant improvement by week 26 (median hemoglobin level, 13.0 g/dL; interquartile range, 12.5-13.8), while a similar improvement occurred by week 52 in males (median hemoglobin level, 13.6 g/dL; IQR, 12.57-14.0). At 52 weeks, the mean increase in hemoglobin was 5% (IQR, 0%-11.1%). The increase was greater in females (7.7%; IQR, 4.2%-11.7%) than in males (2.1%; IQR, –0.5% to 11.3%).

Limitations of the study include its retrospective nature and that the tools by which data were collected could have missed some adverse events because they were not adequately captured in the treating clinician’s notes. However, the data trend similarly to a prospective study.

“In summary, we report safety signals on a real-world cohort of patients with UC initiated on tofacitinib in whom increasing age is a risk factor for AEs and consistent with recent reports of a dose-dependent risk of HZ reactivation and VTE events in patients with a risk factor for VTE on the 10-mg twice-daily dosing,” the authors concluded.

The study was funded by the American College of Gastroenterology, the Crohn’s and Colitis Foundation, the Givin’ it all for Guts Foundation, and the Lawrence C. Pakula, MD, Inflammatory Bowel Disease Research Innovation and Education Fund. The authors have financial ties with various pharmaceutical companies.

This article was updated July 19, 2021.

In a real-world test, tofacitinib had a similar safety profile to what was seen in clinical trials. The majority of adverse events seen were infections, and few were serious; however, the study did find evidence of rare venous thromboembolism (VTE) in patients with preexisting risk factors, which suggests that precaution is warranted in this group.

Tofacitinib, a Janus kinase inhibitor, was approved by the Food and Drug Administration in 2018 for adults with moderate to severe ulcerative colitis (UC). Three phase 3 clinical trials and an open-label, long-term extension trial found that the drug was associated with increased infection rates and higher lipid levels.

In rheumatoid arthritis patients, an interim analysis of a safety clinical trial of twice-daily doses of 10 mg tofacitinib showed increased rates of pulmonary embolism and all-cause mortality, compared to treatment with a dose of 5 mg or a tumor necrosis factor antagonist. That finding led to a black box label warning against thrombosis.

The current study, published in Clinical Gastroenterology and Hepatology, included patients from six centers in the United States.

The findings suggest that patients should be counseled about the potential risk for herpes zoster (HZ) reactivation, especially older patients taking corticosteroids. The authors also recommended vaccination with an inactivated HZ vaccine. “Our data suggest a careful risk-benefit discussion before starting tofacitinib, especially in patients with preexisting risk factors for VTE, dose deescalation to the lowest clinically feasible dose, and monitoring for clinical signs of VTE, especially among those who continue on a dose of 10 mg twice a day,” the authors wrote.

The researchers followed 260 patients over a median of 6 months (median age, 38 years; 58.1% male; 71.9% non-Hispanic). Overall, 88.5% had previously received treatment with a biologic, most often an anti–TNF-alpha agent (76.5%). During follow-up, 15.7% experienced adverse events, most commonly infections (5.0%) and rash (3.5%). Joint pain (1.5%) and anemia (1.5%) also occurred. The incidence rate for any adverse event was 27.2 per 100 person-years. Adverse events occurred more often in older patients (mean age, 42 vs. 37 years; P = .02) and those who had not undergone previous anti-TNF therapy (63.4% vs 79.8%; P = .03). There was no association between concomitant steroid use and adverse events on univariate analysis. Of the overall cohort, 5.8% experienced a severe adverse event, with the most common being herpes zoster rash (26.7% of severe adverse events). Therapy was discontinued by 4.6%.

Five patients developed herpes zoster (3.29 per 100 person-years; 95% CI, 1.37-7.90). Risk factors for VTE were seen in 31.2% of the cohort, and two cases of VTE occurred during follow-up (1.32 per 100 person-years; 95% CI, 0.33-5.28), both in patients with extensive UC. There was no increased risk of complications following abdominal surgery.

At baseline, 38.4% had an abnormal lipid profile, and this increased to 48.3% following 8 weeks of treatment.

Overall, 45% of patients were anemic at baseline. Females experienced a significant improvement by week 26 (median hemoglobin level, 13.0 g/dL; interquartile range, 12.5-13.8), while a similar improvement occurred by week 52 in males (median hemoglobin level, 13.6 g/dL; IQR, 12.57-14.0). At 52 weeks, the mean increase in hemoglobin was 5% (IQR, 0%-11.1%). The increase was greater in females (7.7%; IQR, 4.2%-11.7%) than in males (2.1%; IQR, –0.5% to 11.3%).

Limitations of the study include its retrospective nature and that the tools by which data were collected could have missed some adverse events because they were not adequately captured in the treating clinician’s notes. However, the data trend similarly to a prospective study.

“In summary, we report safety signals on a real-world cohort of patients with UC initiated on tofacitinib in whom increasing age is a risk factor for AEs and consistent with recent reports of a dose-dependent risk of HZ reactivation and VTE events in patients with a risk factor for VTE on the 10-mg twice-daily dosing,” the authors concluded.

The study was funded by the American College of Gastroenterology, the Crohn’s and Colitis Foundation, the Givin’ it all for Guts Foundation, and the Lawrence C. Pakula, MD, Inflammatory Bowel Disease Research Innovation and Education Fund. The authors have financial ties with various pharmaceutical companies.

This article was updated July 19, 2021.

In a real-world test, tofacitinib had a similar safety profile to what was seen in clinical trials. The majority of adverse events seen were infections, and few were serious; however, the study did find evidence of rare venous thromboembolism (VTE) in patients with preexisting risk factors, which suggests that precaution is warranted in this group.

Tofacitinib, a Janus kinase inhibitor, was approved by the Food and Drug Administration in 2018 for adults with moderate to severe ulcerative colitis (UC). Three phase 3 clinical trials and an open-label, long-term extension trial found that the drug was associated with increased infection rates and higher lipid levels.

In rheumatoid arthritis patients, an interim analysis of a safety clinical trial of twice-daily doses of 10 mg tofacitinib showed increased rates of pulmonary embolism and all-cause mortality, compared to treatment with a dose of 5 mg or a tumor necrosis factor antagonist. That finding led to a black box label warning against thrombosis.

The current study, published in Clinical Gastroenterology and Hepatology, included patients from six centers in the United States.

The findings suggest that patients should be counseled about the potential risk for herpes zoster (HZ) reactivation, especially older patients taking corticosteroids. The authors also recommended vaccination with an inactivated HZ vaccine. “Our data suggest a careful risk-benefit discussion before starting tofacitinib, especially in patients with preexisting risk factors for VTE, dose deescalation to the lowest clinically feasible dose, and monitoring for clinical signs of VTE, especially among those who continue on a dose of 10 mg twice a day,” the authors wrote.

The researchers followed 260 patients over a median of 6 months (median age, 38 years; 58.1% male; 71.9% non-Hispanic). Overall, 88.5% had previously received treatment with a biologic, most often an anti–TNF-alpha agent (76.5%). During follow-up, 15.7% experienced adverse events, most commonly infections (5.0%) and rash (3.5%). Joint pain (1.5%) and anemia (1.5%) also occurred. The incidence rate for any adverse event was 27.2 per 100 person-years. Adverse events occurred more often in older patients (mean age, 42 vs. 37 years; P = .02) and those who had not undergone previous anti-TNF therapy (63.4% vs 79.8%; P = .03). There was no association between concomitant steroid use and adverse events on univariate analysis. Of the overall cohort, 5.8% experienced a severe adverse event, with the most common being herpes zoster rash (26.7% of severe adverse events). Therapy was discontinued by 4.6%.

Five patients developed herpes zoster (3.29 per 100 person-years; 95% CI, 1.37-7.90). Risk factors for VTE were seen in 31.2% of the cohort, and two cases of VTE occurred during follow-up (1.32 per 100 person-years; 95% CI, 0.33-5.28), both in patients with extensive UC. There was no increased risk of complications following abdominal surgery.

At baseline, 38.4% had an abnormal lipid profile, and this increased to 48.3% following 8 weeks of treatment.

Overall, 45% of patients were anemic at baseline. Females experienced a significant improvement by week 26 (median hemoglobin level, 13.0 g/dL; interquartile range, 12.5-13.8), while a similar improvement occurred by week 52 in males (median hemoglobin level, 13.6 g/dL; IQR, 12.57-14.0). At 52 weeks, the mean increase in hemoglobin was 5% (IQR, 0%-11.1%). The increase was greater in females (7.7%; IQR, 4.2%-11.7%) than in males (2.1%; IQR, –0.5% to 11.3%).

Limitations of the study include its retrospective nature and that the tools by which data were collected could have missed some adverse events because they were not adequately captured in the treating clinician’s notes. However, the data trend similarly to a prospective study.

“In summary, we report safety signals on a real-world cohort of patients with UC initiated on tofacitinib in whom increasing age is a risk factor for AEs and consistent with recent reports of a dose-dependent risk of HZ reactivation and VTE events in patients with a risk factor for VTE on the 10-mg twice-daily dosing,” the authors concluded.

The study was funded by the American College of Gastroenterology, the Crohn’s and Colitis Foundation, the Givin’ it all for Guts Foundation, and the Lawrence C. Pakula, MD, Inflammatory Bowel Disease Research Innovation and Education Fund. The authors have financial ties with various pharmaceutical companies.

This article was updated July 19, 2021.

Albuquerque oncologist Barbara McAneny, MD, has a patient in his 30s who experienced rectal bleeding for 6 months in 2020 but didn’t see a physician because he was afraid of catching COVID-19. He hoped it was just hemorrhoids.

When he finally came in to see her recently, Dr. McAneny diagnosed a large colon cancer. She fears the delay could prove fatal. “We’ll do our best to cure him, but I don’t know if he’ll be treatable,” she said. “Six months absolutely can make a difference.”

She and other oncologists around the country are seeing many patients in the past few months with advanced breast, colon, lung, and other cancers who were not diagnosed and treated during the COVID-19 pandemic because the patients didn’t want to come in, or because medical facilities weren’t taking nonemergency or non-COVID patients.

Given that failure to diagnose cancer is among the most common medical malpractice allegations, should oncologists be worried that they are at legal risk?
 

Pandemic provides ‘safe harbor’

In a March survey done by medical malpractice insurer The Doctors Company, one-third of physicians said they were very concerned or somewhat concerned that malpractice claims related to care during the pandemic will rise.

But in most of these cases, physicians and hospitals have little to worry about in terms of medical malpractice liability, according to veteran plaintiff and defense attorneys and the head of a large medical liability insurer.

“You had people with diseases like cancer not getting care because health care systems were overwhelmed,” said Sean Domnick, JD, a malpractice plaintiff attorney in Boca Raton, Fla. “Will those lead to successful malpractice lawsuits? Most likely not.”

“The risks will be low because it’s hard to pin it on the doctor if the patient didn’t want to come in or facilities weren’t scheduling appointments because of the public health emergency,” said Richard Roberts, MD, JD, a professor of family medicine at the University of Wisconsin–Madison who is also a malpractice defense attorney.

In addition, liability protections enacted in more than 30 states because of the COVID-19 pandemic will help shield clinicians from lawsuits. Those laws generally require allegations of gross negligence or reckless conduct far beyond ordinary negligence, which are hard to prove. But the immunity provisions remain largely untested in the courts, and it’s unclear how they will affect cases involving care for conditions other than COVID-19.

Another helpful factor is the widespread public appreciation of the valiant work by health care professionals throughout the pandemic, though that halo effect could fade over the next several years as malpractice claims from the pandemic period are filed and tried.

“In many circumstances, the pandemic will prove to be a safe harbor for providers,” said Steven Wigrizer, JD, a malpractice plaintiff attorney in Philadelphia. “Jurors will be reluctant to impose liability on providers who were doing their best in a global pandemic the world hadn’t seen in 100 years.”
 

Risky situations

These predictions from liability experts should reassure physicians who are anxious over reports that many cancer diagnoses were missed as a result of the COVID-19 pandemic.

Still, there are situations where physicians and hospitals could be vulnerable to malpractice claims despite the pandemic conditions. The highest-risk cases are those where patients recognized a potential cancer symptom like a breast lump or rectal bleeding, and tried to visit a doctor’s office or hospital, but were told they couldn’t be seen.

“Those kinds of cases lend themselves to delayed diagnosis claims,” said Richard Anderson, MD, an oncologist who is chairman and CEO of The Doctors Company. “My guess is we will see claims,” though he expects a reduced number arising from 2020 care scenarios, compared with previous years.

So far, his company has seen 20% fewer claims in 2020, which he said isn’t surprising given that the volume of physician and hospital visits plummeted.

Another risky situation is where physicians – particularly primary care physicians but also specialists like gynecologists and urologists – did not inform patients about concerning test results and order a follow-up test or visit. That is dangerous even if the physician did try to schedule a visit but the patient canceled the appointment.

“The jury will ask, ‘What did you do to get the patient back?’ ” said Sean Byrne, JD, a malpractice defense attorney in Richmond, Va. “The provider will say: ‘I’m sure we called.’ But it’s a difficult defense to say the patient didn’t return the call. I need written proof.”

Mr. Domnick said failures to follow up on suspicious test results could produce viable malpractice claims, pandemic or not. “The question becomes to what extent doctors will try to hide behind COVID to explain otherwise run-of-the-mill negligence,” he said. “We’ll have to see how that plays out.”

There are also worries about missed cancer diagnoses during telemedicine visits. “On telemedicine, I can’t feel a lymph node, I can’t palpate a breast mass, and I can’t see if someone’s liver is enlarged,” Dr. McAneny fretted. “I think you’ll get suits because you’ll miss stuff.”

One other area of exposure cited by the experts: Radiologists and pathologists could be sued for missing tumors in reading imaging tests. “The COVID-19 demand on resources has been immense,” Mr. Byrne said. “If that production pressure resulted in any quality loss in testing services, we could see claims.”
 

Patient protocols provide protection

There’s no question that cancer screenings dropped sharply during the pandemic. In June 2020, the National Cancer Institute estimated there was a 75% decrease in mammograms and colonoscopies during the first few months of the pandemic. It projected that delays in screenings, diagnoses, and treatment likely would result in 10,000 more breast and colorectal cancer deaths than otherwise expected over the next decade.

Delays of even 1 month in treatment for seven common forms of cancer can increase mortality risk by 6%-13%, according to a BMJ study.

While many medical facilities stopped doing preventive screening tests during the height of the pandemic last year, health care professionals still found ways to bring in patients with diagnosed cancers or who were at heightened cancer risk for tests and treatment.

Most facilities convened multidisciplinary tumor boards to decide which patients could wait for treatment, which patients could be maintained on drug therapy, and which ones needed immediate surgery, said Carla Fisher, MD, director of breast surgery at Indiana University, Indianapolis. For breast cancer, they used guidelines from her professional group, the American Society of Breast Surgeons.

Following such protocols for prioritizing patients for treatment during the pandemic should help protect against liability, experts said.

Even if it can be shown that a clinician’s negligence led to delayed diagnosis or treatment of a patient’s cancer, plaintiff attorneys will be wary about filing such claims. That is because it is difficult in most cases to prove that the delay significantly worsened the course of the patient’s disease or the odds of survival. Showing harm may be more possible with certain cancers known to be particularly aggressive.

“The plaintiff attorney will have to get an expert to say that the 3-month delay in getting the patient a mammogram caused her great harm,” said Dr. Roberts. “But it’s hard to calculate that scientifically, and it’s really hard to lay that all on the doctor or health system, because they were supposed to lock down during the pandemic.”
 

Playing catch-up

With patients now feeling more comfortable about coming in for physician visits, Mr. Byrne urges clinicians to make a special effort to mitigate potential liability arising from the past year. Physicians should carefully review patients’ charts and make sure to catch them up on preventive screenings. Some health systems, like Kaiser Permanente, have been doing proactive patient outreach for cancer screening throughout the pandemic.

“Providers may need to be extra diligent, and consider expanding the exam into a wellness visit and remind patients about cancer surveillance,” he said.

Overall, however, the expert consensus is that physicians should focus on providing the best quality care going forward, and not worry excessively about the care they wish they could have delivered over the past year during the extraordinary pandemic conditions.

“Liability risks will be decreased, because state laws have changed and doctors will be cut some slack, not just by judges and juries but by patients themselves,” Dr. Roberts said. “As you are running down the hall to take care of the next person, don’t be looking over your shoulder or you’ll run into the wall.”

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

Albuquerque oncologist Barbara McAneny, MD, has a patient in his 30s who experienced rectal bleeding for 6 months in 2020 but didn’t see a physician because he was afraid of catching COVID-19. He hoped it was just hemorrhoids.

When he finally came in to see her recently, Dr. McAneny diagnosed a large colon cancer. She fears the delay could prove fatal. “We’ll do our best to cure him, but I don’t know if he’ll be treatable,” she said. “Six months absolutely can make a difference.”

She and other oncologists around the country are seeing many patients in the past few months with advanced breast, colon, lung, and other cancers who were not diagnosed and treated during the COVID-19 pandemic because the patients didn’t want to come in, or because medical facilities weren’t taking nonemergency or non-COVID patients.

Given that failure to diagnose cancer is among the most common medical malpractice allegations, should oncologists be worried that they are at legal risk?
 

Pandemic provides ‘safe harbor’

In a March survey done by medical malpractice insurer The Doctors Company, one-third of physicians said they were very concerned or somewhat concerned that malpractice claims related to care during the pandemic will rise.

But in most of these cases, physicians and hospitals have little to worry about in terms of medical malpractice liability, according to veteran plaintiff and defense attorneys and the head of a large medical liability insurer.

“You had people with diseases like cancer not getting care because health care systems were overwhelmed,” said Sean Domnick, JD, a malpractice plaintiff attorney in Boca Raton, Fla. “Will those lead to successful malpractice lawsuits? Most likely not.”

“The risks will be low because it’s hard to pin it on the doctor if the patient didn’t want to come in or facilities weren’t scheduling appointments because of the public health emergency,” said Richard Roberts, MD, JD, a professor of family medicine at the University of Wisconsin–Madison who is also a malpractice defense attorney.

In addition, liability protections enacted in more than 30 states because of the COVID-19 pandemic will help shield clinicians from lawsuits. Those laws generally require allegations of gross negligence or reckless conduct far beyond ordinary negligence, which are hard to prove. But the immunity provisions remain largely untested in the courts, and it’s unclear how they will affect cases involving care for conditions other than COVID-19.

Another helpful factor is the widespread public appreciation of the valiant work by health care professionals throughout the pandemic, though that halo effect could fade over the next several years as malpractice claims from the pandemic period are filed and tried.

“In many circumstances, the pandemic will prove to be a safe harbor for providers,” said Steven Wigrizer, JD, a malpractice plaintiff attorney in Philadelphia. “Jurors will be reluctant to impose liability on providers who were doing their best in a global pandemic the world hadn’t seen in 100 years.”
 

Risky situations

These predictions from liability experts should reassure physicians who are anxious over reports that many cancer diagnoses were missed as a result of the COVID-19 pandemic.

Still, there are situations where physicians and hospitals could be vulnerable to malpractice claims despite the pandemic conditions. The highest-risk cases are those where patients recognized a potential cancer symptom like a breast lump or rectal bleeding, and tried to visit a doctor’s office or hospital, but were told they couldn’t be seen.

“Those kinds of cases lend themselves to delayed diagnosis claims,” said Richard Anderson, MD, an oncologist who is chairman and CEO of The Doctors Company. “My guess is we will see claims,” though he expects a reduced number arising from 2020 care scenarios, compared with previous years.

So far, his company has seen 20% fewer claims in 2020, which he said isn’t surprising given that the volume of physician and hospital visits plummeted.

Another risky situation is where physicians – particularly primary care physicians but also specialists like gynecologists and urologists – did not inform patients about concerning test results and order a follow-up test or visit. That is dangerous even if the physician did try to schedule a visit but the patient canceled the appointment.

“The jury will ask, ‘What did you do to get the patient back?’ ” said Sean Byrne, JD, a malpractice defense attorney in Richmond, Va. “The provider will say: ‘I’m sure we called.’ But it’s a difficult defense to say the patient didn’t return the call. I need written proof.”

Mr. Domnick said failures to follow up on suspicious test results could produce viable malpractice claims, pandemic or not. “The question becomes to what extent doctors will try to hide behind COVID to explain otherwise run-of-the-mill negligence,” he said. “We’ll have to see how that plays out.”

There are also worries about missed cancer diagnoses during telemedicine visits. “On telemedicine, I can’t feel a lymph node, I can’t palpate a breast mass, and I can’t see if someone’s liver is enlarged,” Dr. McAneny fretted. “I think you’ll get suits because you’ll miss stuff.”

One other area of exposure cited by the experts: Radiologists and pathologists could be sued for missing tumors in reading imaging tests. “The COVID-19 demand on resources has been immense,” Mr. Byrne said. “If that production pressure resulted in any quality loss in testing services, we could see claims.”
 

Patient protocols provide protection

There’s no question that cancer screenings dropped sharply during the pandemic. In June 2020, the National Cancer Institute estimated there was a 75% decrease in mammograms and colonoscopies during the first few months of the pandemic. It projected that delays in screenings, diagnoses, and treatment likely would result in 10,000 more breast and colorectal cancer deaths than otherwise expected over the next decade.

Delays of even 1 month in treatment for seven common forms of cancer can increase mortality risk by 6%-13%, according to a BMJ study.

While many medical facilities stopped doing preventive screening tests during the height of the pandemic last year, health care professionals still found ways to bring in patients with diagnosed cancers or who were at heightened cancer risk for tests and treatment.

Most facilities convened multidisciplinary tumor boards to decide which patients could wait for treatment, which patients could be maintained on drug therapy, and which ones needed immediate surgery, said Carla Fisher, MD, director of breast surgery at Indiana University, Indianapolis. For breast cancer, they used guidelines from her professional group, the American Society of Breast Surgeons.

Following such protocols for prioritizing patients for treatment during the pandemic should help protect against liability, experts said.

Even if it can be shown that a clinician’s negligence led to delayed diagnosis or treatment of a patient’s cancer, plaintiff attorneys will be wary about filing such claims. That is because it is difficult in most cases to prove that the delay significantly worsened the course of the patient’s disease or the odds of survival. Showing harm may be more possible with certain cancers known to be particularly aggressive.

“The plaintiff attorney will have to get an expert to say that the 3-month delay in getting the patient a mammogram caused her great harm,” said Dr. Roberts. “But it’s hard to calculate that scientifically, and it’s really hard to lay that all on the doctor or health system, because they were supposed to lock down during the pandemic.”
 

Playing catch-up

With patients now feeling more comfortable about coming in for physician visits, Mr. Byrne urges clinicians to make a special effort to mitigate potential liability arising from the past year. Physicians should carefully review patients’ charts and make sure to catch them up on preventive screenings. Some health systems, like Kaiser Permanente, have been doing proactive patient outreach for cancer screening throughout the pandemic.

“Providers may need to be extra diligent, and consider expanding the exam into a wellness visit and remind patients about cancer surveillance,” he said.

Overall, however, the expert consensus is that physicians should focus on providing the best quality care going forward, and not worry excessively about the care they wish they could have delivered over the past year during the extraordinary pandemic conditions.

“Liability risks will be decreased, because state laws have changed and doctors will be cut some slack, not just by judges and juries but by patients themselves,” Dr. Roberts said. “As you are running down the hall to take care of the next person, don’t be looking over your shoulder or you’ll run into the wall.”

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

Albuquerque oncologist Barbara McAneny, MD, has a patient in his 30s who experienced rectal bleeding for 6 months in 2020 but didn’t see a physician because he was afraid of catching COVID-19. He hoped it was just hemorrhoids.

When he finally came in to see her recently, Dr. McAneny diagnosed a large colon cancer. She fears the delay could prove fatal. “We’ll do our best to cure him, but I don’t know if he’ll be treatable,” she said. “Six months absolutely can make a difference.”

She and other oncologists around the country are seeing many patients in the past few months with advanced breast, colon, lung, and other cancers who were not diagnosed and treated during the COVID-19 pandemic because the patients didn’t want to come in, or because medical facilities weren’t taking nonemergency or non-COVID patients.

Given that failure to diagnose cancer is among the most common medical malpractice allegations, should oncologists be worried that they are at legal risk?
 

Pandemic provides ‘safe harbor’

In a March survey done by medical malpractice insurer The Doctors Company, one-third of physicians said they were very concerned or somewhat concerned that malpractice claims related to care during the pandemic will rise.

But in most of these cases, physicians and hospitals have little to worry about in terms of medical malpractice liability, according to veteran plaintiff and defense attorneys and the head of a large medical liability insurer.

“You had people with diseases like cancer not getting care because health care systems were overwhelmed,” said Sean Domnick, JD, a malpractice plaintiff attorney in Boca Raton, Fla. “Will those lead to successful malpractice lawsuits? Most likely not.”

“The risks will be low because it’s hard to pin it on the doctor if the patient didn’t want to come in or facilities weren’t scheduling appointments because of the public health emergency,” said Richard Roberts, MD, JD, a professor of family medicine at the University of Wisconsin–Madison who is also a malpractice defense attorney.

In addition, liability protections enacted in more than 30 states because of the COVID-19 pandemic will help shield clinicians from lawsuits. Those laws generally require allegations of gross negligence or reckless conduct far beyond ordinary negligence, which are hard to prove. But the immunity provisions remain largely untested in the courts, and it’s unclear how they will affect cases involving care for conditions other than COVID-19.

Another helpful factor is the widespread public appreciation of the valiant work by health care professionals throughout the pandemic, though that halo effect could fade over the next several years as malpractice claims from the pandemic period are filed and tried.

“In many circumstances, the pandemic will prove to be a safe harbor for providers,” said Steven Wigrizer, JD, a malpractice plaintiff attorney in Philadelphia. “Jurors will be reluctant to impose liability on providers who were doing their best in a global pandemic the world hadn’t seen in 100 years.”
 

Risky situations

These predictions from liability experts should reassure physicians who are anxious over reports that many cancer diagnoses were missed as a result of the COVID-19 pandemic.

Still, there are situations where physicians and hospitals could be vulnerable to malpractice claims despite the pandemic conditions. The highest-risk cases are those where patients recognized a potential cancer symptom like a breast lump or rectal bleeding, and tried to visit a doctor’s office or hospital, but were told they couldn’t be seen.

“Those kinds of cases lend themselves to delayed diagnosis claims,” said Richard Anderson, MD, an oncologist who is chairman and CEO of The Doctors Company. “My guess is we will see claims,” though he expects a reduced number arising from 2020 care scenarios, compared with previous years.

So far, his company has seen 20% fewer claims in 2020, which he said isn’t surprising given that the volume of physician and hospital visits plummeted.

Another risky situation is where physicians – particularly primary care physicians but also specialists like gynecologists and urologists – did not inform patients about concerning test results and order a follow-up test or visit. That is dangerous even if the physician did try to schedule a visit but the patient canceled the appointment.

“The jury will ask, ‘What did you do to get the patient back?’ ” said Sean Byrne, JD, a malpractice defense attorney in Richmond, Va. “The provider will say: ‘I’m sure we called.’ But it’s a difficult defense to say the patient didn’t return the call. I need written proof.”

Mr. Domnick said failures to follow up on suspicious test results could produce viable malpractice claims, pandemic or not. “The question becomes to what extent doctors will try to hide behind COVID to explain otherwise run-of-the-mill negligence,” he said. “We’ll have to see how that plays out.”

There are also worries about missed cancer diagnoses during telemedicine visits. “On telemedicine, I can’t feel a lymph node, I can’t palpate a breast mass, and I can’t see if someone’s liver is enlarged,” Dr. McAneny fretted. “I think you’ll get suits because you’ll miss stuff.”

One other area of exposure cited by the experts: Radiologists and pathologists could be sued for missing tumors in reading imaging tests. “The COVID-19 demand on resources has been immense,” Mr. Byrne said. “If that production pressure resulted in any quality loss in testing services, we could see claims.”
 

Patient protocols provide protection

There’s no question that cancer screenings dropped sharply during the pandemic. In June 2020, the National Cancer Institute estimated there was a 75% decrease in mammograms and colonoscopies during the first few months of the pandemic. It projected that delays in screenings, diagnoses, and treatment likely would result in 10,000 more breast and colorectal cancer deaths than otherwise expected over the next decade.

Delays of even 1 month in treatment for seven common forms of cancer can increase mortality risk by 6%-13%, according to a BMJ study.

While many medical facilities stopped doing preventive screening tests during the height of the pandemic last year, health care professionals still found ways to bring in patients with diagnosed cancers or who were at heightened cancer risk for tests and treatment.

Most facilities convened multidisciplinary tumor boards to decide which patients could wait for treatment, which patients could be maintained on drug therapy, and which ones needed immediate surgery, said Carla Fisher, MD, director of breast surgery at Indiana University, Indianapolis. For breast cancer, they used guidelines from her professional group, the American Society of Breast Surgeons.

Following such protocols for prioritizing patients for treatment during the pandemic should help protect against liability, experts said.

Even if it can be shown that a clinician’s negligence led to delayed diagnosis or treatment of a patient’s cancer, plaintiff attorneys will be wary about filing such claims. That is because it is difficult in most cases to prove that the delay significantly worsened the course of the patient’s disease or the odds of survival. Showing harm may be more possible with certain cancers known to be particularly aggressive.

“The plaintiff attorney will have to get an expert to say that the 3-month delay in getting the patient a mammogram caused her great harm,” said Dr. Roberts. “But it’s hard to calculate that scientifically, and it’s really hard to lay that all on the doctor or health system, because they were supposed to lock down during the pandemic.”
 

Playing catch-up

With patients now feeling more comfortable about coming in for physician visits, Mr. Byrne urges clinicians to make a special effort to mitigate potential liability arising from the past year. Physicians should carefully review patients’ charts and make sure to catch them up on preventive screenings. Some health systems, like Kaiser Permanente, have been doing proactive patient outreach for cancer screening throughout the pandemic.

“Providers may need to be extra diligent, and consider expanding the exam into a wellness visit and remind patients about cancer surveillance,” he said.

Overall, however, the expert consensus is that physicians should focus on providing the best quality care going forward, and not worry excessively about the care they wish they could have delivered over the past year during the extraordinary pandemic conditions.

“Liability risks will be decreased, because state laws have changed and doctors will be cut some slack, not just by judges and juries but by patients themselves,” Dr. Roberts said. “As you are running down the hall to take care of the next person, don’t be looking over your shoulder or you’ll run into the wall.”

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

A network meta-analysis of current first-line dual, triple, and quadruple therapies for Helicobacter pylori infection found that vonoprazan triple therapy was most effective, while standard triple therapy of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin was least effective. Levofloxacin-containing triple therapy performed best in Western countries and West Asia, while reverse hybrid therapy was most effective in East Asia.

The results “[suggest that] a new approach concerning H. pylori treatment is now needed and that the time for transitioning from trial and error to antimicrobial stewardship [of H. pylori infection] has arrived,” wrote Theodore Rokkas, PhD, MD, of the European University of Cyprus in Engomi, and colleagues. Their study was published in Gastroenterology.

H. pylori infection is the primary cause of gastritis, peptic ulcer disease, gastric mucosa–associated lymphoid tissue lymphoma, and gastric cancer.

Since H. pylori infection was first recognized, physicians have employed a range of drugs in double, triple, and quadruple combinations to combat it.

Despite those efforts, treatment success is lower than with many other infectious diseases. A newcomer is the potassium-competing acid blocker vonoprazan, which increases efficacy of amoxicillin combination therapies and has, thereby, generated renewed interest in all combination therapies, according to the study authors. Vonoprazan is currently available in some Asian countries, but not the United States or Europe.

Current guidelines for H. pylori treatment relied on randomized controlled trials and relevant pair-wise meta-analyses, but no previous pairwise analysis has included all currently available medications, the authors noted. Network meta-analyses can help fill this evidence gap: They incorporate both direct and indirect evidence from a collection of randomized controlled trials to estimate the comparative effectiveness of three or more regimens.

The researchers conducted a network meta-analysis that included 68 randomized, controlled trials totaling 22,975 patients. The following regimens were included in the analysis: Concomitant quadruple bismuth treatment (bismuth quadruple therapy), concomitant quadruple nonbismuth treatment (nonbismuth quadruple therapy), high-dose amoxicillin double treatment (Amox-dual therapy), levofloxacin-containing treatment (Levo-therapy), reverse hybrid therapy (R-hybrid therapy), sequential quadruple treatment (sequential therapy), standard triple treatment (triple therapy), and vonoprazan-containing therapy (Vono-triple therapy).

Statistically significant results were found with Vono-triple therapy versus triple therapy (odds ratio, 3.80; 95% confidence interval, 1.62-8.94), sequential therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53), nonbismuth quadruple therapy versus triple therapy (OR, 2.08; 95% CI, 1.45-2.98), bismuth quadruple therapy versus triple therapy (OR, 1.47; 95% CI, 1.02-2.11), and Levo-therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53).

In the overall data, mean cure rates greater than 90% were seen only in Vono-triple therapy (91.4%; 95% CI, 88.5-93.5%) and R-hybrid therapy (93.6%; 95% CI, 90.4-96.8%). Cure rates were lower for Nonbismuth quadruple therapy (84.3%; 95% CI, 82.7-85.8%), Levo-therapy (83.8%; 95% CI, 82.1-85.4%), Sequential therapy (83.7%; 95% CI, 82.7-84.7%), bismuth quadruple therapy (81.3%; 95% CI, 79.5-83.1%), Amox-dual therapy (80.2%; 75.3%-84.4%), and triple therapy (75.7%; 95% CI, 74.9-76.4%). Levo-therapy performed best in Western countries (88.5%; 95% CI, 86.5-90.5%) and West Asia (88.4%; 95% CI, 84.6-91.1%). R-hybrid therapy performed best in East Asia (93.6%; 95% CI, 90.4-96.8%).

A surface under the cumulative ranking (SUCRA) value, which represents the efficacy of the intervention compared to an ideal intervention, was 92.4% for Vono-triple therapy. The second highest SUCRA value was for 68.8% for nonbismuth quadruple therapy. The SUCRA value of standard triple therapy was 4.7%.

A key limitation to the study is that Vono-triple therapy was tested only in Japan, and requires additional study in other geographic regions.

The study received support from the Department of Veteran Affairs. The authors have consulted for and received research funding from various pharmaceutical companies.

A network meta-analysis of current first-line dual, triple, and quadruple therapies for Helicobacter pylori infection found that vonoprazan triple therapy was most effective, while standard triple therapy of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin was least effective. Levofloxacin-containing triple therapy performed best in Western countries and West Asia, while reverse hybrid therapy was most effective in East Asia.

The results “[suggest that] a new approach concerning H. pylori treatment is now needed and that the time for transitioning from trial and error to antimicrobial stewardship [of H. pylori infection] has arrived,” wrote Theodore Rokkas, PhD, MD, of the European University of Cyprus in Engomi, and colleagues. Their study was published in Gastroenterology.

H. pylori infection is the primary cause of gastritis, peptic ulcer disease, gastric mucosa–associated lymphoid tissue lymphoma, and gastric cancer.

Since H. pylori infection was first recognized, physicians have employed a range of drugs in double, triple, and quadruple combinations to combat it.

Despite those efforts, treatment success is lower than with many other infectious diseases. A newcomer is the potassium-competing acid blocker vonoprazan, which increases efficacy of amoxicillin combination therapies and has, thereby, generated renewed interest in all combination therapies, according to the study authors. Vonoprazan is currently available in some Asian countries, but not the United States or Europe.

Current guidelines for H. pylori treatment relied on randomized controlled trials and relevant pair-wise meta-analyses, but no previous pairwise analysis has included all currently available medications, the authors noted. Network meta-analyses can help fill this evidence gap: They incorporate both direct and indirect evidence from a collection of randomized controlled trials to estimate the comparative effectiveness of three or more regimens.

The researchers conducted a network meta-analysis that included 68 randomized, controlled trials totaling 22,975 patients. The following regimens were included in the analysis: Concomitant quadruple bismuth treatment (bismuth quadruple therapy), concomitant quadruple nonbismuth treatment (nonbismuth quadruple therapy), high-dose amoxicillin double treatment (Amox-dual therapy), levofloxacin-containing treatment (Levo-therapy), reverse hybrid therapy (R-hybrid therapy), sequential quadruple treatment (sequential therapy), standard triple treatment (triple therapy), and vonoprazan-containing therapy (Vono-triple therapy).

Statistically significant results were found with Vono-triple therapy versus triple therapy (odds ratio, 3.80; 95% confidence interval, 1.62-8.94), sequential therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53), nonbismuth quadruple therapy versus triple therapy (OR, 2.08; 95% CI, 1.45-2.98), bismuth quadruple therapy versus triple therapy (OR, 1.47; 95% CI, 1.02-2.11), and Levo-therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53).

In the overall data, mean cure rates greater than 90% were seen only in Vono-triple therapy (91.4%; 95% CI, 88.5-93.5%) and R-hybrid therapy (93.6%; 95% CI, 90.4-96.8%). Cure rates were lower for Nonbismuth quadruple therapy (84.3%; 95% CI, 82.7-85.8%), Levo-therapy (83.8%; 95% CI, 82.1-85.4%), Sequential therapy (83.7%; 95% CI, 82.7-84.7%), bismuth quadruple therapy (81.3%; 95% CI, 79.5-83.1%), Amox-dual therapy (80.2%; 75.3%-84.4%), and triple therapy (75.7%; 95% CI, 74.9-76.4%). Levo-therapy performed best in Western countries (88.5%; 95% CI, 86.5-90.5%) and West Asia (88.4%; 95% CI, 84.6-91.1%). R-hybrid therapy performed best in East Asia (93.6%; 95% CI, 90.4-96.8%).

A surface under the cumulative ranking (SUCRA) value, which represents the efficacy of the intervention compared to an ideal intervention, was 92.4% for Vono-triple therapy. The second highest SUCRA value was for 68.8% for nonbismuth quadruple therapy. The SUCRA value of standard triple therapy was 4.7%.

A key limitation to the study is that Vono-triple therapy was tested only in Japan, and requires additional study in other geographic regions.

The study received support from the Department of Veteran Affairs. The authors have consulted for and received research funding from various pharmaceutical companies.

A network meta-analysis of current first-line dual, triple, and quadruple therapies for Helicobacter pylori infection found that vonoprazan triple therapy was most effective, while standard triple therapy of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin was least effective. Levofloxacin-containing triple therapy performed best in Western countries and West Asia, while reverse hybrid therapy was most effective in East Asia.

The results “[suggest that] a new approach concerning H. pylori treatment is now needed and that the time for transitioning from trial and error to antimicrobial stewardship [of H. pylori infection] has arrived,” wrote Theodore Rokkas, PhD, MD, of the European University of Cyprus in Engomi, and colleagues. Their study was published in Gastroenterology.

H. pylori infection is the primary cause of gastritis, peptic ulcer disease, gastric mucosa–associated lymphoid tissue lymphoma, and gastric cancer.

Since H. pylori infection was first recognized, physicians have employed a range of drugs in double, triple, and quadruple combinations to combat it.

Despite those efforts, treatment success is lower than with many other infectious diseases. A newcomer is the potassium-competing acid blocker vonoprazan, which increases efficacy of amoxicillin combination therapies and has, thereby, generated renewed interest in all combination therapies, according to the study authors. Vonoprazan is currently available in some Asian countries, but not the United States or Europe.

Current guidelines for H. pylori treatment relied on randomized controlled trials and relevant pair-wise meta-analyses, but no previous pairwise analysis has included all currently available medications, the authors noted. Network meta-analyses can help fill this evidence gap: They incorporate both direct and indirect evidence from a collection of randomized controlled trials to estimate the comparative effectiveness of three or more regimens.

The researchers conducted a network meta-analysis that included 68 randomized, controlled trials totaling 22,975 patients. The following regimens were included in the analysis: Concomitant quadruple bismuth treatment (bismuth quadruple therapy), concomitant quadruple nonbismuth treatment (nonbismuth quadruple therapy), high-dose amoxicillin double treatment (Amox-dual therapy), levofloxacin-containing treatment (Levo-therapy), reverse hybrid therapy (R-hybrid therapy), sequential quadruple treatment (sequential therapy), standard triple treatment (triple therapy), and vonoprazan-containing therapy (Vono-triple therapy).

Statistically significant results were found with Vono-triple therapy versus triple therapy (odds ratio, 3.80; 95% confidence interval, 1.62-8.94), sequential therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53), nonbismuth quadruple therapy versus triple therapy (OR, 2.08; 95% CI, 1.45-2.98), bismuth quadruple therapy versus triple therapy (OR, 1.47; 95% CI, 1.02-2.11), and Levo-therapy versus triple therapy (OR, 1.79; 95% CI, 1.26-2.53).

In the overall data, mean cure rates greater than 90% were seen only in Vono-triple therapy (91.4%; 95% CI, 88.5-93.5%) and R-hybrid therapy (93.6%; 95% CI, 90.4-96.8%). Cure rates were lower for Nonbismuth quadruple therapy (84.3%; 95% CI, 82.7-85.8%), Levo-therapy (83.8%; 95% CI, 82.1-85.4%), Sequential therapy (83.7%; 95% CI, 82.7-84.7%), bismuth quadruple therapy (81.3%; 95% CI, 79.5-83.1%), Amox-dual therapy (80.2%; 75.3%-84.4%), and triple therapy (75.7%; 95% CI, 74.9-76.4%). Levo-therapy performed best in Western countries (88.5%; 95% CI, 86.5-90.5%) and West Asia (88.4%; 95% CI, 84.6-91.1%). R-hybrid therapy performed best in East Asia (93.6%; 95% CI, 90.4-96.8%).

A surface under the cumulative ranking (SUCRA) value, which represents the efficacy of the intervention compared to an ideal intervention, was 92.4% for Vono-triple therapy. The second highest SUCRA value was for 68.8% for nonbismuth quadruple therapy. The SUCRA value of standard triple therapy was 4.7%.

A key limitation to the study is that Vono-triple therapy was tested only in Japan, and requires additional study in other geographic regions.

The study received support from the Department of Veteran Affairs. The authors have consulted for and received research funding from various pharmaceutical companies.

In a small study of Hirschsprung’s disease (HSCR) patients, those with a low-fiber colonic mucosal acetylcholinesterase-positive (AChE+) innervation phenotype were more likely to suffer from postoperative enterocolitis, which can be life-threatening.

The study lends insight into crosstalk between the human enteric nervous and immune systems. It suggests a role for acetylcholine-secreting (cholinergic) nerve fibers in aganglionic sections of colon in patients with HSCR, which is a congenital disorder marked by the absence of enteric neuronal cells in the distal part of the gut.

There are also potential clinical implications. “These observations suggest that HSCR patients with low-fiber phenotype might have a higher risk of developing postoperative enterocolitis and that the fiber phenotype could serve as a predictive marker for development of prophylactic therapy,” wrote Simone Keck of the University of Basel (Switzerland) and colleagues in a study published in Cellular and Molecular Gastroenterology and Hepatology.

HSCR is a multigenetic congenital condition that includes a lack of enteric ganglia cells (aganglionosis) in the distal part of the colon, leading to intestinal obstruction and prestenotic megacolon. Treatment consists of pull-through surgery to remove the aganglionic portion of the bowel, but 20%-50% of patients develop life-threatening HSCR-associated enterocolitis before or after surgery. Although the mechanism of the complication is uncertain, immune cells, intestinal barrier function, and the microbiome may play a role.

Mouse models have shown connections between the immune and nervous system, but it has been challenging to study the effects of specific neurotransmitters in humans. There are more than 30 separate neurotransmitters in the enteric nervous system, making it difficult to tease apart individual functions. But there are comparatively few enteric nervous system neurotransmitters in patients with HSCR and the aganglionic colon in these patients contains enlarged AChE+ nerve fibers, “neuronal cholinergic function can be examined particularly well” among these patients. .

The researchers of the current study from analyzed tissue from 44 pediatric HSCR patients who underwent pull-through surgery, along with 6 non-HSCR controls who had surgery for various other reasons. Tissue samples were semiquantitatively categorized according to the extent of colonic mucosal AChE+ innervation: Low-fiber rectosigmoid tissue lacked intrinsic nerve cell bodies and mucosal ACHe+ innervation, while high-fiber tissue lacked nerve cell bodies but had mucosal AChE+ innervation. The researchers also determined tissue cytokine profile and immune cell frequencies, and used confocal immunofluorescence microscopy to determine proximity of macrophages to nerve fibers and 16S-rDNA sequencing to determine microbial populations.

They found that aganglionic low-fiber samples had higher levels of inflammatory cytokines such as interleukin-17, IL-1-beta, and IL6. Levels of these cytokines were lower in both ganglionic sections of the colon and in high-fiber samples with mucosal AChE+ nerve fibers. Low-fiber samples also had elevated Th17 T cells, compared with high-fiber, aganglionic, and ganglionic distal colon samples. Regulatory T cells were highest in cholinergic high-fiber segments.

Out of 42 patients, 9 developed enterocolitis within 1 year of surgery; 7 had a low-fiber phenotype, while 2 were high-fiber. This difference was not statistically significant, but the researchers then performed a retrospective analysis of 29 HSCR patients to validate the findings. Of these, 14 developed enterocolitis after surgery, with 12 of the cases occurring among children with the low-fiber phenotype, and 2 cases occurred among those with the high-fiber phenotype.

The findings could help guide postsurgical management of HSCR by allowing clinicians to employ preventive measures against enterocolitis, such as high-volume enemas, antibiotics, prebiotics, probiotics, or dietary changes. Th17 cells are known to migrate to nearby mesenteric lymph nodes, where they may promote enterocolitis, and this site is usually not removed during HSCR surgery. Fiber phenotype could prompt a surgeon to also remove mesenteric lymph nodes to reduce enterocolitis risk. A potential therapeutic strategy is to target IL-17 or IL-23.

The study was funded by the University of Basel. The authors have no relevant financial disclosures.

In a small study of Hirschsprung’s disease (HSCR) patients, those with a low-fiber colonic mucosal acetylcholinesterase-positive (AChE+) innervation phenotype were more likely to suffer from postoperative enterocolitis, which can be life-threatening.

The study lends insight into crosstalk between the human enteric nervous and immune systems. It suggests a role for acetylcholine-secreting (cholinergic) nerve fibers in aganglionic sections of colon in patients with HSCR, which is a congenital disorder marked by the absence of enteric neuronal cells in the distal part of the gut.

There are also potential clinical implications. “These observations suggest that HSCR patients with low-fiber phenotype might have a higher risk of developing postoperative enterocolitis and that the fiber phenotype could serve as a predictive marker for development of prophylactic therapy,” wrote Simone Keck of the University of Basel (Switzerland) and colleagues in a study published in Cellular and Molecular Gastroenterology and Hepatology.

HSCR is a multigenetic congenital condition that includes a lack of enteric ganglia cells (aganglionosis) in the distal part of the colon, leading to intestinal obstruction and prestenotic megacolon. Treatment consists of pull-through surgery to remove the aganglionic portion of the bowel, but 20%-50% of patients develop life-threatening HSCR-associated enterocolitis before or after surgery. Although the mechanism of the complication is uncertain, immune cells, intestinal barrier function, and the microbiome may play a role.

Mouse models have shown connections between the immune and nervous system, but it has been challenging to study the effects of specific neurotransmitters in humans. There are more than 30 separate neurotransmitters in the enteric nervous system, making it difficult to tease apart individual functions. But there are comparatively few enteric nervous system neurotransmitters in patients with HSCR and the aganglionic colon in these patients contains enlarged AChE+ nerve fibers, “neuronal cholinergic function can be examined particularly well” among these patients. .

The researchers of the current study from analyzed tissue from 44 pediatric HSCR patients who underwent pull-through surgery, along with 6 non-HSCR controls who had surgery for various other reasons. Tissue samples were semiquantitatively categorized according to the extent of colonic mucosal AChE+ innervation: Low-fiber rectosigmoid tissue lacked intrinsic nerve cell bodies and mucosal ACHe+ innervation, while high-fiber tissue lacked nerve cell bodies but had mucosal AChE+ innervation. The researchers also determined tissue cytokine profile and immune cell frequencies, and used confocal immunofluorescence microscopy to determine proximity of macrophages to nerve fibers and 16S-rDNA sequencing to determine microbial populations.

They found that aganglionic low-fiber samples had higher levels of inflammatory cytokines such as interleukin-17, IL-1-beta, and IL6. Levels of these cytokines were lower in both ganglionic sections of the colon and in high-fiber samples with mucosal AChE+ nerve fibers. Low-fiber samples also had elevated Th17 T cells, compared with high-fiber, aganglionic, and ganglionic distal colon samples. Regulatory T cells were highest in cholinergic high-fiber segments.

Out of 42 patients, 9 developed enterocolitis within 1 year of surgery; 7 had a low-fiber phenotype, while 2 were high-fiber. This difference was not statistically significant, but the researchers then performed a retrospective analysis of 29 HSCR patients to validate the findings. Of these, 14 developed enterocolitis after surgery, with 12 of the cases occurring among children with the low-fiber phenotype, and 2 cases occurred among those with the high-fiber phenotype.

The findings could help guide postsurgical management of HSCR by allowing clinicians to employ preventive measures against enterocolitis, such as high-volume enemas, antibiotics, prebiotics, probiotics, or dietary changes. Th17 cells are known to migrate to nearby mesenteric lymph nodes, where they may promote enterocolitis, and this site is usually not removed during HSCR surgery. Fiber phenotype could prompt a surgeon to also remove mesenteric lymph nodes to reduce enterocolitis risk. A potential therapeutic strategy is to target IL-17 or IL-23.

The study was funded by the University of Basel. The authors have no relevant financial disclosures.

In a small study of Hirschsprung’s disease (HSCR) patients, those with a low-fiber colonic mucosal acetylcholinesterase-positive (AChE+) innervation phenotype were more likely to suffer from postoperative enterocolitis, which can be life-threatening.

The study lends insight into crosstalk between the human enteric nervous and immune systems. It suggests a role for acetylcholine-secreting (cholinergic) nerve fibers in aganglionic sections of colon in patients with HSCR, which is a congenital disorder marked by the absence of enteric neuronal cells in the distal part of the gut.

There are also potential clinical implications. “These observations suggest that HSCR patients with low-fiber phenotype might have a higher risk of developing postoperative enterocolitis and that the fiber phenotype could serve as a predictive marker for development of prophylactic therapy,” wrote Simone Keck of the University of Basel (Switzerland) and colleagues in a study published in Cellular and Molecular Gastroenterology and Hepatology.

HSCR is a multigenetic congenital condition that includes a lack of enteric ganglia cells (aganglionosis) in the distal part of the colon, leading to intestinal obstruction and prestenotic megacolon. Treatment consists of pull-through surgery to remove the aganglionic portion of the bowel, but 20%-50% of patients develop life-threatening HSCR-associated enterocolitis before or after surgery. Although the mechanism of the complication is uncertain, immune cells, intestinal barrier function, and the microbiome may play a role.

Mouse models have shown connections between the immune and nervous system, but it has been challenging to study the effects of specific neurotransmitters in humans. There are more than 30 separate neurotransmitters in the enteric nervous system, making it difficult to tease apart individual functions. But there are comparatively few enteric nervous system neurotransmitters in patients with HSCR and the aganglionic colon in these patients contains enlarged AChE+ nerve fibers, “neuronal cholinergic function can be examined particularly well” among these patients. .

The researchers of the current study from analyzed tissue from 44 pediatric HSCR patients who underwent pull-through surgery, along with 6 non-HSCR controls who had surgery for various other reasons. Tissue samples were semiquantitatively categorized according to the extent of colonic mucosal AChE+ innervation: Low-fiber rectosigmoid tissue lacked intrinsic nerve cell bodies and mucosal ACHe+ innervation, while high-fiber tissue lacked nerve cell bodies but had mucosal AChE+ innervation. The researchers also determined tissue cytokine profile and immune cell frequencies, and used confocal immunofluorescence microscopy to determine proximity of macrophages to nerve fibers and 16S-rDNA sequencing to determine microbial populations.

They found that aganglionic low-fiber samples had higher levels of inflammatory cytokines such as interleukin-17, IL-1-beta, and IL6. Levels of these cytokines were lower in both ganglionic sections of the colon and in high-fiber samples with mucosal AChE+ nerve fibers. Low-fiber samples also had elevated Th17 T cells, compared with high-fiber, aganglionic, and ganglionic distal colon samples. Regulatory T cells were highest in cholinergic high-fiber segments.

Out of 42 patients, 9 developed enterocolitis within 1 year of surgery; 7 had a low-fiber phenotype, while 2 were high-fiber. This difference was not statistically significant, but the researchers then performed a retrospective analysis of 29 HSCR patients to validate the findings. Of these, 14 developed enterocolitis after surgery, with 12 of the cases occurring among children with the low-fiber phenotype, and 2 cases occurred among those with the high-fiber phenotype.

The findings could help guide postsurgical management of HSCR by allowing clinicians to employ preventive measures against enterocolitis, such as high-volume enemas, antibiotics, prebiotics, probiotics, or dietary changes. Th17 cells are known to migrate to nearby mesenteric lymph nodes, where they may promote enterocolitis, and this site is usually not removed during HSCR surgery. Fiber phenotype could prompt a surgeon to also remove mesenteric lymph nodes to reduce enterocolitis risk. A potential therapeutic strategy is to target IL-17 or IL-23.

The study was funded by the University of Basel. The authors have no relevant financial disclosures.