Ted Bosworth

NEW YORK – When data were combined from two parallel phase 3 bronchiectasis treatment trials, inhaled colistimethate sodium failed to significantly reduce the rate of exacerbations associated with Pseudomonas aeruginosa infection, but the disparity in the findings from the two trials, presented at the 6th World Bronchiectasis & NTM Conference (WBC) 2023, strongly suggests that this therapy is effective after all.

“The totality of the evidence supports a consistent and clinically meaningful benefit [of this therapy] outside of pandemic conditions,” reported Charles Haworth, MD, director, Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, England.

The key phrase is “outside of pandemic conditions.” PROMIS I, which was fully enrolled before the COVID-19 pandemic descended, associated the inhaled therapy with highly significant benefits. PROMIS II, which was initiated later and enrolled 40% of its participants during the pandemic, did not.

The difference between these two trials, which were essentially identical, was the timing, according to Dr. Haworth. By starting later, PROMIS II caught the onset of the pandemic, which he believes introduced numerous problems that defeated the opportunity to show an advantage for the inhaled antibiotic.

Injectable colistimethate sodium, a decades-old formulation of colistin, is already approved in the United States for gram-negative infections and is considered helpful even in challenging diseases, such as cystic fibrosis. Positive results from a phase 2 trial with inhaled colistimethate sodium in bronchiectasis patients with P. aeruginosa infection provided the rationale for the phase 3 PROMIS program.

The key entry criterion of PROMIS I and PROMIS II, each with nearly 90 participating study sites, was a history of bronchiectasis and ≥ two P. aeruginosa infections requiring oral therapy or ≥ 1 infection requiring intravenous therapy in the prior 12 months. Patients were randomly assigned to receive colistimethate sodium delivered in the proprietary I-neb nebulizer (CMS I-neb) or a matching placebo.

On the primary endpoint of annualized rate of exacerbations, the figures per year were 0.58 for CMS I-neb and 0.95 for placebo in the PROMIS I trial. This produced a rate ratio of 0.65, signaling a significant 35% (P = .00101) reduction in risk. In PROMIS II, the annualized rates of exacerbation were essentially identical in the experimental and control arms (0.089 vs. 0.088; P = .97).

With “no signal of benefit” in the PROMIS II trial, the numerical advantage of CMS I-neb for the combined data did not reach statistical significance, Dr. Haworth reported.

Other endpoints told the same story. For example, the time to first exacerbation was reduced by 41% in PROMIS I (HR, 0.59; P = .0074) but was not reduced significantly (P = .603) in PROMIS II. In PROMIS I, there was a nearly 60% reduction in the risk of severe exacerbations associated with CMS I-neb, but the risk ratio of severe infections was slightly but not significantly higher on CMS I-neb in PROMIS II.

There were signals of benefit in PROMIS II. For example, the reductions in P. aeruginosa density were similar in the two studies (P < .00001 in both), and assessment with the Severe Exacerbations and Quality of Life (SQOL) tool associated CMS I-neb with end-of-study improvement in QOL for the experimental arm in both studies.

While Dr. Haworth acknowledged that he recognizes the “issues of post hoc analysis with any data,” he argued that there is compelling evidence that the pandemic “severely disrupted the conduct of the trial,” obscuring a benefit that would have been otherwise shown.

Besides the dramatic reduction in rates of hospitalization during the pandemic, an obstacle for showing differences in exacerbations, and other COVID-related factors with the potential to skew results, Dr. Haworth also provided several sets of objective data to make his point.

Most importantly, Dr. Haworth and his coinvestigators conducted a meta-analysis that combined data from the phase 2 trial, data from PROMIS I, and data from the patients enrolled in PROMIS II prior to the COVID pandemic. In this analysis the rate ratio for annualized exacerbations was a “pretty impressive” 0.65 favoring CMS I-neb. Moreover, in contrast to data from the PROMIS II patients enrolled during the COVID pandemic, the other three sets of data were “remarkably consistent.”

If PROMIS II data collected from patients enrolled during COVID are compared with the other sets of data, they are “the clear outlier,” he asserted.

Many guidelines in Europe, including those from the European Respiratory Society and the British Thoracic Society, already recommend inhaled colistin in patients with bronchiectasis for the treatment of P. aeruginosa. Although Dr. Haworth believes that the preponderance of controlled data now argue that CMS I-neb is effective as well as safe (adverse events in the experimental and placebo arms of PROMIS I and II were similar), he is not sure what steps will be taken to confirm a benefit to regulatory authorities. According to Dr. Haworth, there are no approved inhaled antibiotics in the United States.

Referring to Zambon, which funded the trials and is developing CMS I-neb, Dr. Haworth said, “This will be a company decision. There are some logistical hurdles to doing another trial.”

Not least of these hurdles is that clinicians and patients already consider inhalational antibiotics in general and inhaled colistin specifically to be effective for several types of infections, including P. aeruginosa, according to Eva Polverino, MD, PhD, a pulmonologist associated with the Hospital Clinic of Barcelona. She said that these drugs are already a standard of care in her own country as well as in many other countries in Europe.

“There has been a loss of equipoise needed to conduct a randomized placebo-controlled trial,” Dr. Polverino said. In her opinion, the U.S. FDA “should start thinking of other pathways to approval.” She thinks that enrollment in a placebo-controlled trial is no longer appropriate.

Dr. Haworth and Dr. Polverino have disclosed no relevant financial relationships.

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

NEW YORK – When data were combined from two parallel phase 3 bronchiectasis treatment trials, inhaled colistimethate sodium failed to significantly reduce the rate of exacerbations associated with Pseudomonas aeruginosa infection, but the disparity in the findings from the two trials, presented at the 6th World Bronchiectasis & NTM Conference (WBC) 2023, strongly suggests that this therapy is effective after all.

“The totality of the evidence supports a consistent and clinically meaningful benefit [of this therapy] outside of pandemic conditions,” reported Charles Haworth, MD, director, Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, England.

The key phrase is “outside of pandemic conditions.” PROMIS I, which was fully enrolled before the COVID-19 pandemic descended, associated the inhaled therapy with highly significant benefits. PROMIS II, which was initiated later and enrolled 40% of its participants during the pandemic, did not.

The difference between these two trials, which were essentially identical, was the timing, according to Dr. Haworth. By starting later, PROMIS II caught the onset of the pandemic, which he believes introduced numerous problems that defeated the opportunity to show an advantage for the inhaled antibiotic.

Injectable colistimethate sodium, a decades-old formulation of colistin, is already approved in the United States for gram-negative infections and is considered helpful even in challenging diseases, such as cystic fibrosis. Positive results from a phase 2 trial with inhaled colistimethate sodium in bronchiectasis patients with P. aeruginosa infection provided the rationale for the phase 3 PROMIS program.

The key entry criterion of PROMIS I and PROMIS II, each with nearly 90 participating study sites, was a history of bronchiectasis and ≥ two P. aeruginosa infections requiring oral therapy or ≥ 1 infection requiring intravenous therapy in the prior 12 months. Patients were randomly assigned to receive colistimethate sodium delivered in the proprietary I-neb nebulizer (CMS I-neb) or a matching placebo.

On the primary endpoint of annualized rate of exacerbations, the figures per year were 0.58 for CMS I-neb and 0.95 for placebo in the PROMIS I trial. This produced a rate ratio of 0.65, signaling a significant 35% (P = .00101) reduction in risk. In PROMIS II, the annualized rates of exacerbation were essentially identical in the experimental and control arms (0.089 vs. 0.088; P = .97).

With “no signal of benefit” in the PROMIS II trial, the numerical advantage of CMS I-neb for the combined data did not reach statistical significance, Dr. Haworth reported.

Other endpoints told the same story. For example, the time to first exacerbation was reduced by 41% in PROMIS I (HR, 0.59; P = .0074) but was not reduced significantly (P = .603) in PROMIS II. In PROMIS I, there was a nearly 60% reduction in the risk of severe exacerbations associated with CMS I-neb, but the risk ratio of severe infections was slightly but not significantly higher on CMS I-neb in PROMIS II.

There were signals of benefit in PROMIS II. For example, the reductions in P. aeruginosa density were similar in the two studies (P < .00001 in both), and assessment with the Severe Exacerbations and Quality of Life (SQOL) tool associated CMS I-neb with end-of-study improvement in QOL for the experimental arm in both studies.

While Dr. Haworth acknowledged that he recognizes the “issues of post hoc analysis with any data,” he argued that there is compelling evidence that the pandemic “severely disrupted the conduct of the trial,” obscuring a benefit that would have been otherwise shown.

Besides the dramatic reduction in rates of hospitalization during the pandemic, an obstacle for showing differences in exacerbations, and other COVID-related factors with the potential to skew results, Dr. Haworth also provided several sets of objective data to make his point.

Most importantly, Dr. Haworth and his coinvestigators conducted a meta-analysis that combined data from the phase 2 trial, data from PROMIS I, and data from the patients enrolled in PROMIS II prior to the COVID pandemic. In this analysis the rate ratio for annualized exacerbations was a “pretty impressive” 0.65 favoring CMS I-neb. Moreover, in contrast to data from the PROMIS II patients enrolled during the COVID pandemic, the other three sets of data were “remarkably consistent.”

If PROMIS II data collected from patients enrolled during COVID are compared with the other sets of data, they are “the clear outlier,” he asserted.

Many guidelines in Europe, including those from the European Respiratory Society and the British Thoracic Society, already recommend inhaled colistin in patients with bronchiectasis for the treatment of P. aeruginosa. Although Dr. Haworth believes that the preponderance of controlled data now argue that CMS I-neb is effective as well as safe (adverse events in the experimental and placebo arms of PROMIS I and II were similar), he is not sure what steps will be taken to confirm a benefit to regulatory authorities. According to Dr. Haworth, there are no approved inhaled antibiotics in the United States.

Referring to Zambon, which funded the trials and is developing CMS I-neb, Dr. Haworth said, “This will be a company decision. There are some logistical hurdles to doing another trial.”

Not least of these hurdles is that clinicians and patients already consider inhalational antibiotics in general and inhaled colistin specifically to be effective for several types of infections, including P. aeruginosa, according to Eva Polverino, MD, PhD, a pulmonologist associated with the Hospital Clinic of Barcelona. She said that these drugs are already a standard of care in her own country as well as in many other countries in Europe.

“There has been a loss of equipoise needed to conduct a randomized placebo-controlled trial,” Dr. Polverino said. In her opinion, the U.S. FDA “should start thinking of other pathways to approval.” She thinks that enrollment in a placebo-controlled trial is no longer appropriate.

Dr. Haworth and Dr. Polverino have disclosed no relevant financial relationships.

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

NEW YORK – When data were combined from two parallel phase 3 bronchiectasis treatment trials, inhaled colistimethate sodium failed to significantly reduce the rate of exacerbations associated with Pseudomonas aeruginosa infection, but the disparity in the findings from the two trials, presented at the 6th World Bronchiectasis & NTM Conference (WBC) 2023, strongly suggests that this therapy is effective after all.

“The totality of the evidence supports a consistent and clinically meaningful benefit [of this therapy] outside of pandemic conditions,” reported Charles Haworth, MD, director, Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, England.

The key phrase is “outside of pandemic conditions.” PROMIS I, which was fully enrolled before the COVID-19 pandemic descended, associated the inhaled therapy with highly significant benefits. PROMIS II, which was initiated later and enrolled 40% of its participants during the pandemic, did not.

The difference between these two trials, which were essentially identical, was the timing, according to Dr. Haworth. By starting later, PROMIS II caught the onset of the pandemic, which he believes introduced numerous problems that defeated the opportunity to show an advantage for the inhaled antibiotic.

Injectable colistimethate sodium, a decades-old formulation of colistin, is already approved in the United States for gram-negative infections and is considered helpful even in challenging diseases, such as cystic fibrosis. Positive results from a phase 2 trial with inhaled colistimethate sodium in bronchiectasis patients with P. aeruginosa infection provided the rationale for the phase 3 PROMIS program.

The key entry criterion of PROMIS I and PROMIS II, each with nearly 90 participating study sites, was a history of bronchiectasis and ≥ two P. aeruginosa infections requiring oral therapy or ≥ 1 infection requiring intravenous therapy in the prior 12 months. Patients were randomly assigned to receive colistimethate sodium delivered in the proprietary I-neb nebulizer (CMS I-neb) or a matching placebo.

On the primary endpoint of annualized rate of exacerbations, the figures per year were 0.58 for CMS I-neb and 0.95 for placebo in the PROMIS I trial. This produced a rate ratio of 0.65, signaling a significant 35% (P = .00101) reduction in risk. In PROMIS II, the annualized rates of exacerbation were essentially identical in the experimental and control arms (0.089 vs. 0.088; P = .97).

With “no signal of benefit” in the PROMIS II trial, the numerical advantage of CMS I-neb for the combined data did not reach statistical significance, Dr. Haworth reported.

Other endpoints told the same story. For example, the time to first exacerbation was reduced by 41% in PROMIS I (HR, 0.59; P = .0074) but was not reduced significantly (P = .603) in PROMIS II. In PROMIS I, there was a nearly 60% reduction in the risk of severe exacerbations associated with CMS I-neb, but the risk ratio of severe infections was slightly but not significantly higher on CMS I-neb in PROMIS II.

There were signals of benefit in PROMIS II. For example, the reductions in P. aeruginosa density were similar in the two studies (P < .00001 in both), and assessment with the Severe Exacerbations and Quality of Life (SQOL) tool associated CMS I-neb with end-of-study improvement in QOL for the experimental arm in both studies.

While Dr. Haworth acknowledged that he recognizes the “issues of post hoc analysis with any data,” he argued that there is compelling evidence that the pandemic “severely disrupted the conduct of the trial,” obscuring a benefit that would have been otherwise shown.

Besides the dramatic reduction in rates of hospitalization during the pandemic, an obstacle for showing differences in exacerbations, and other COVID-related factors with the potential to skew results, Dr. Haworth also provided several sets of objective data to make his point.

Most importantly, Dr. Haworth and his coinvestigators conducted a meta-analysis that combined data from the phase 2 trial, data from PROMIS I, and data from the patients enrolled in PROMIS II prior to the COVID pandemic. In this analysis the rate ratio for annualized exacerbations was a “pretty impressive” 0.65 favoring CMS I-neb. Moreover, in contrast to data from the PROMIS II patients enrolled during the COVID pandemic, the other three sets of data were “remarkably consistent.”

If PROMIS II data collected from patients enrolled during COVID are compared with the other sets of data, they are “the clear outlier,” he asserted.

Many guidelines in Europe, including those from the European Respiratory Society and the British Thoracic Society, already recommend inhaled colistin in patients with bronchiectasis for the treatment of P. aeruginosa. Although Dr. Haworth believes that the preponderance of controlled data now argue that CMS I-neb is effective as well as safe (adverse events in the experimental and placebo arms of PROMIS I and II were similar), he is not sure what steps will be taken to confirm a benefit to regulatory authorities. According to Dr. Haworth, there are no approved inhaled antibiotics in the United States.

Referring to Zambon, which funded the trials and is developing CMS I-neb, Dr. Haworth said, “This will be a company decision. There are some logistical hurdles to doing another trial.”

Not least of these hurdles is that clinicians and patients already consider inhalational antibiotics in general and inhaled colistin specifically to be effective for several types of infections, including P. aeruginosa, according to Eva Polverino, MD, PhD, a pulmonologist associated with the Hospital Clinic of Barcelona. She said that these drugs are already a standard of care in her own country as well as in many other countries in Europe.

“There has been a loss of equipoise needed to conduct a randomized placebo-controlled trial,” Dr. Polverino said. In her opinion, the U.S. FDA “should start thinking of other pathways to approval.” She thinks that enrollment in a placebo-controlled trial is no longer appropriate.

Dr. Haworth and Dr. Polverino have disclosed no relevant financial relationships.

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

Optimism about new opportunities to treat alopecia areata can be derived not only from a recently approved Janus kinase (JAK) inhibitor in older children but promising results with the monoclonal antibody dupilumab alone or in combination with additional treatments, such as minoxidil or corticosteroids, in children with AA and concomitant atopy.

It was only a little over a year ago that the JAK inhibitor baricitinib became the first systemic therapy approved by the Food and Drug Administration for AA in adults. In June 2023, the JAK inhibitor ritlecitinib was approved for severe AA in patients as young as 12 years of age, but there is accumulating evidence that dupilumab, which binds to the interleukin-4 receptor, might be an option for even younger children with AA.

Of those who have worked with dupilumab for controlling AA in children, Brittany Craiglow, MD, an adjunct associate professor of dermatology at Yale University, New Haven, Conn., updated a case series at the recent MedscapeLive! Annual Women’s and Pediatric Dermatology Seminar in Baltimore. A series of six children with AA treated with dupilumab was published 2 years ago in JAAD Case Reports.

Even in 2021, her case series was not the first report of benefit from dupilumab in children with AA, but instead contributed to a “growing body of literature” supporting the potential benefit in the setting of concomitant atopy, Dr. Craiglow, one of the authors of the series, said in an interview.

Of the six patients in that series, five had improvement and four had complete regrowth with dupilumab, whether as a monotherapy or in combination with other agents. The children ranged in age from 7 to 12 years. The age range at the time of AA onset was 3-11 years. All had atopic dermatitis (AD) and most had additional atopic conditions, such as food allergies or asthma.

Since publication, Dr. Craiglow has successfully treated many more patients with dupilumab, either as monotherapy or in combination with oral minoxidil, corticosteroids, and/or a topical JAK inhibitor. Dupilumab, which is approved for the treatment of AD in children as young as 6 months of age, has been well tolerated.

“Oral minoxidil is often a great adjuvant treatment in patients with AA and should be used unless there are contraindications,” based on the initial and subsequent experience treating AA with dupilumab, said Dr. Craiglow.

“Topical steroids can be used in combination with dupilumab and minoxidil, but in general dupilumab should not be combined with an oral JAK inhibitor,” she added.

Now, with the approval of ritlecitinib, Dr. Craiglow said this JAK inhibitor will become a first-line therapy in children 12 years or older with severe, persistent AA, but she considers a trial of dupilumab reasonable in younger children, given the controlled studies of safety for atopic diseases.

“I would say that dupilumab could be considered in the following clinical scenarios: children under 12 with AA and concomitant atopy, such as atopic dermatitis, asthma, allergies, and/or elevated IgE; and children over the age of 12 with concomitant atopy who either have a contraindication to a JAK inhibitor or whose families have reservations about or are unwilling to take one,” Dr. Craiglow said.

In older children, she believes that dupilumab has “a much lower chance of being effective” than an oral JAK inhibitor like ritlecitinib, but it circumvents the potential safety issues of JAK inhibitors that have been observed in adults.

With ritlecitinib providing an on-label option for AA in older children, Dr. Craiglow suggested it might be easier to obtain third-party coverage for dupilumab as an alternative to a JAK inhibitor for AA in patients younger than 12, particularly when there is an indication for a concomitant atopic condition and a rationale, such as a concern about relative safety.

Two years ago, when Dr. Craiglow and her coinvestigator published their six-patient case series, a second case series was published about the same time by investigators at the University of Pennsylvania, Philadelphia, in the Journal of the American Academy of Dermatology. This series of 16 pediatric patients with AA on dupilumab was more heterogeneous, but four of six patients with active disease and more than 4 months of follow-up had improvement in AA, including total regrowth. The improvement was concentrated in patients with moderate to severe AD at the time of treatment.

Based on this series, the authors, led by Leslie Castelo-Soccio, MD, PhD, who is now an attending physician in the Dermatology Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md., concluded that dupilumab “may be a therapeutic option for AA” when traditional therapies have failed, “especially in patients with concurrent AD or asthma, for which the benefits of dupilumab are clear.”

When contacted about where this therapy might fit on the basis of her case series and the update on Dr. Craiglow’s experience, Dr. Castelo-Soccio, like Dr. Craiglow, stressed the importance of employing this therapy selectively.

“I do think that dupilumab is a reasonable option for AA in children with atopy and IgE levels greater than 200 IU/mL, especially if treatment is for atopic dermatitis or asthma as well,” she said.

Many clinicians, including Dr. Craiglow, have experience with oral JAK inhibitors in children younger than 12. Indeed, a recently published case study associated oral abrocitinib, a JAK inhibitor approved for moderate to severe AD in patients ages 12 and older, with hair regrowth in an 11-year-old child who had persistent AA for more than 6 years despite numerous conventional therapies.

However, the advantage of dupilumab in younger children is the greater evidence of safety, providing a level of reassurance for a treatment that is commonly used for severe atopic diseases but does not have a specific indication for AA, according to Dr. Craiglow.

Dr. Craiglow disclosed being a speaker for AbbVie and a speaker and consultant for Eli Lilly, Incyte, Pfizer, Regeneron, and Sanofi Genzyme. Dr. Castelo-Soccio had no disclosures.

Optimism about new opportunities to treat alopecia areata can be derived not only from a recently approved Janus kinase (JAK) inhibitor in older children but promising results with the monoclonal antibody dupilumab alone or in combination with additional treatments, such as minoxidil or corticosteroids, in children with AA and concomitant atopy.

It was only a little over a year ago that the JAK inhibitor baricitinib became the first systemic therapy approved by the Food and Drug Administration for AA in adults. In June 2023, the JAK inhibitor ritlecitinib was approved for severe AA in patients as young as 12 years of age, but there is accumulating evidence that dupilumab, which binds to the interleukin-4 receptor, might be an option for even younger children with AA.

Of those who have worked with dupilumab for controlling AA in children, Brittany Craiglow, MD, an adjunct associate professor of dermatology at Yale University, New Haven, Conn., updated a case series at the recent MedscapeLive! Annual Women’s and Pediatric Dermatology Seminar in Baltimore. A series of six children with AA treated with dupilumab was published 2 years ago in JAAD Case Reports.

Even in 2021, her case series was not the first report of benefit from dupilumab in children with AA, but instead contributed to a “growing body of literature” supporting the potential benefit in the setting of concomitant atopy, Dr. Craiglow, one of the authors of the series, said in an interview.

Of the six patients in that series, five had improvement and four had complete regrowth with dupilumab, whether as a monotherapy or in combination with other agents. The children ranged in age from 7 to 12 years. The age range at the time of AA onset was 3-11 years. All had atopic dermatitis (AD) and most had additional atopic conditions, such as food allergies or asthma.

Since publication, Dr. Craiglow has successfully treated many more patients with dupilumab, either as monotherapy or in combination with oral minoxidil, corticosteroids, and/or a topical JAK inhibitor. Dupilumab, which is approved for the treatment of AD in children as young as 6 months of age, has been well tolerated.

“Oral minoxidil is often a great adjuvant treatment in patients with AA and should be used unless there are contraindications,” based on the initial and subsequent experience treating AA with dupilumab, said Dr. Craiglow.

“Topical steroids can be used in combination with dupilumab and minoxidil, but in general dupilumab should not be combined with an oral JAK inhibitor,” she added.

Now, with the approval of ritlecitinib, Dr. Craiglow said this JAK inhibitor will become a first-line therapy in children 12 years or older with severe, persistent AA, but she considers a trial of dupilumab reasonable in younger children, given the controlled studies of safety for atopic diseases.

“I would say that dupilumab could be considered in the following clinical scenarios: children under 12 with AA and concomitant atopy, such as atopic dermatitis, asthma, allergies, and/or elevated IgE; and children over the age of 12 with concomitant atopy who either have a contraindication to a JAK inhibitor or whose families have reservations about or are unwilling to take one,” Dr. Craiglow said.

In older children, she believes that dupilumab has “a much lower chance of being effective” than an oral JAK inhibitor like ritlecitinib, but it circumvents the potential safety issues of JAK inhibitors that have been observed in adults.

With ritlecitinib providing an on-label option for AA in older children, Dr. Craiglow suggested it might be easier to obtain third-party coverage for dupilumab as an alternative to a JAK inhibitor for AA in patients younger than 12, particularly when there is an indication for a concomitant atopic condition and a rationale, such as a concern about relative safety.

Two years ago, when Dr. Craiglow and her coinvestigator published their six-patient case series, a second case series was published about the same time by investigators at the University of Pennsylvania, Philadelphia, in the Journal of the American Academy of Dermatology. This series of 16 pediatric patients with AA on dupilumab was more heterogeneous, but four of six patients with active disease and more than 4 months of follow-up had improvement in AA, including total regrowth. The improvement was concentrated in patients with moderate to severe AD at the time of treatment.

Based on this series, the authors, led by Leslie Castelo-Soccio, MD, PhD, who is now an attending physician in the Dermatology Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md., concluded that dupilumab “may be a therapeutic option for AA” when traditional therapies have failed, “especially in patients with concurrent AD or asthma, for which the benefits of dupilumab are clear.”

When contacted about where this therapy might fit on the basis of her case series and the update on Dr. Craiglow’s experience, Dr. Castelo-Soccio, like Dr. Craiglow, stressed the importance of employing this therapy selectively.

“I do think that dupilumab is a reasonable option for AA in children with atopy and IgE levels greater than 200 IU/mL, especially if treatment is for atopic dermatitis or asthma as well,” she said.

Many clinicians, including Dr. Craiglow, have experience with oral JAK inhibitors in children younger than 12. Indeed, a recently published case study associated oral abrocitinib, a JAK inhibitor approved for moderate to severe AD in patients ages 12 and older, with hair regrowth in an 11-year-old child who had persistent AA for more than 6 years despite numerous conventional therapies.

However, the advantage of dupilumab in younger children is the greater evidence of safety, providing a level of reassurance for a treatment that is commonly used for severe atopic diseases but does not have a specific indication for AA, according to Dr. Craiglow.

Dr. Craiglow disclosed being a speaker for AbbVie and a speaker and consultant for Eli Lilly, Incyte, Pfizer, Regeneron, and Sanofi Genzyme. Dr. Castelo-Soccio had no disclosures.

Optimism about new opportunities to treat alopecia areata can be derived not only from a recently approved Janus kinase (JAK) inhibitor in older children but promising results with the monoclonal antibody dupilumab alone or in combination with additional treatments, such as minoxidil or corticosteroids, in children with AA and concomitant atopy.

It was only a little over a year ago that the JAK inhibitor baricitinib became the first systemic therapy approved by the Food and Drug Administration for AA in adults. In June 2023, the JAK inhibitor ritlecitinib was approved for severe AA in patients as young as 12 years of age, but there is accumulating evidence that dupilumab, which binds to the interleukin-4 receptor, might be an option for even younger children with AA.

Of those who have worked with dupilumab for controlling AA in children, Brittany Craiglow, MD, an adjunct associate professor of dermatology at Yale University, New Haven, Conn., updated a case series at the recent MedscapeLive! Annual Women’s and Pediatric Dermatology Seminar in Baltimore. A series of six children with AA treated with dupilumab was published 2 years ago in JAAD Case Reports.

Even in 2021, her case series was not the first report of benefit from dupilumab in children with AA, but instead contributed to a “growing body of literature” supporting the potential benefit in the setting of concomitant atopy, Dr. Craiglow, one of the authors of the series, said in an interview.

Of the six patients in that series, five had improvement and four had complete regrowth with dupilumab, whether as a monotherapy or in combination with other agents. The children ranged in age from 7 to 12 years. The age range at the time of AA onset was 3-11 years. All had atopic dermatitis (AD) and most had additional atopic conditions, such as food allergies or asthma.

Since publication, Dr. Craiglow has successfully treated many more patients with dupilumab, either as monotherapy or in combination with oral minoxidil, corticosteroids, and/or a topical JAK inhibitor. Dupilumab, which is approved for the treatment of AD in children as young as 6 months of age, has been well tolerated.

“Oral minoxidil is often a great adjuvant treatment in patients with AA and should be used unless there are contraindications,” based on the initial and subsequent experience treating AA with dupilumab, said Dr. Craiglow.

“Topical steroids can be used in combination with dupilumab and minoxidil, but in general dupilumab should not be combined with an oral JAK inhibitor,” she added.

Now, with the approval of ritlecitinib, Dr. Craiglow said this JAK inhibitor will become a first-line therapy in children 12 years or older with severe, persistent AA, but she considers a trial of dupilumab reasonable in younger children, given the controlled studies of safety for atopic diseases.

“I would say that dupilumab could be considered in the following clinical scenarios: children under 12 with AA and concomitant atopy, such as atopic dermatitis, asthma, allergies, and/or elevated IgE; and children over the age of 12 with concomitant atopy who either have a contraindication to a JAK inhibitor or whose families have reservations about or are unwilling to take one,” Dr. Craiglow said.

In older children, she believes that dupilumab has “a much lower chance of being effective” than an oral JAK inhibitor like ritlecitinib, but it circumvents the potential safety issues of JAK inhibitors that have been observed in adults.

With ritlecitinib providing an on-label option for AA in older children, Dr. Craiglow suggested it might be easier to obtain third-party coverage for dupilumab as an alternative to a JAK inhibitor for AA in patients younger than 12, particularly when there is an indication for a concomitant atopic condition and a rationale, such as a concern about relative safety.

Two years ago, when Dr. Craiglow and her coinvestigator published their six-patient case series, a second case series was published about the same time by investigators at the University of Pennsylvania, Philadelphia, in the Journal of the American Academy of Dermatology. This series of 16 pediatric patients with AA on dupilumab was more heterogeneous, but four of six patients with active disease and more than 4 months of follow-up had improvement in AA, including total regrowth. The improvement was concentrated in patients with moderate to severe AD at the time of treatment.

Based on this series, the authors, led by Leslie Castelo-Soccio, MD, PhD, who is now an attending physician in the Dermatology Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Md., concluded that dupilumab “may be a therapeutic option for AA” when traditional therapies have failed, “especially in patients with concurrent AD or asthma, for which the benefits of dupilumab are clear.”

When contacted about where this therapy might fit on the basis of her case series and the update on Dr. Craiglow’s experience, Dr. Castelo-Soccio, like Dr. Craiglow, stressed the importance of employing this therapy selectively.

“I do think that dupilumab is a reasonable option for AA in children with atopy and IgE levels greater than 200 IU/mL, especially if treatment is for atopic dermatitis or asthma as well,” she said.

Many clinicians, including Dr. Craiglow, have experience with oral JAK inhibitors in children younger than 12. Indeed, a recently published case study associated oral abrocitinib, a JAK inhibitor approved for moderate to severe AD in patients ages 12 and older, with hair regrowth in an 11-year-old child who had persistent AA for more than 6 years despite numerous conventional therapies.

However, the advantage of dupilumab in younger children is the greater evidence of safety, providing a level of reassurance for a treatment that is commonly used for severe atopic diseases but does not have a specific indication for AA, according to Dr. Craiglow.

Dr. Craiglow disclosed being a speaker for AbbVie and a speaker and consultant for Eli Lilly, Incyte, Pfizer, Regeneron, and Sanofi Genzyme. Dr. Castelo-Soccio had no disclosures.

ASHEVILLE, N.C. – Epidermolysis bullosa (EB), a heterogeneous congenital condition of skin fragility, received its first U.S. Food and Drug Association–approved gene therapy only a few months ago, but accelerated progress across multiple treatment strategies predicts additional important and perhaps dramatic further progress, according to a prominent EB researcher.

Not only are recent developments in EB “exciting,” the progress on multiple fronts for control of disease or its symptoms suggests “we are on the cusp of a new era,” Jemima Mellerio, BSc, MD, a consultant dermatologist, St. John’s Institute of Dermatology, London, said at the annual meeting of the Society for Pediatric Dermatology.

Published clinical studies of cell therapies and gene therapies date back at least 15 years, according to a review by Dr. Mellerio on why developments are starting to move so quickly. The difference now is that many obstacles to routine use of these options are being resolved so that viable strategies have reached or are reaching phase 3 trials.

In addition to cell therapies and gene therapies, Dr. Mellerio discussed progress in three additional areas: gene editing, protein therapy, and drug repurposing.

Summarizing progress in each, she described improvement in levels of collagen VII, an important deficit in most types of EB, that were achieved with fibroblast injections that improved levels of collagen VII and anchoring fibrils in a study published in the Journal of Investigative Dermatology. Injection of mesenchymal stromal cells (MSC) have been associated with reduced pain and itch in a series of studies, one of the earliest of which was published in the New England Journal of Medicine.

Since that time, there have been several approaches using MSC.

Of these approaches, intravenous injection of ABCB5+ MSCs might be the first to gain regulatory approval. According to Dr. Mellerio, there is an ongoing phase 3 crossover trial evaluating this approach, which followed several earlier phase studies that demonstrated adequate safety and tolerability while reducing severity scores, relieving pain and itch, and improving wound closure in patients with EB.

In 2006, correction of junctional EB (JEB) was achieved by transplantation of genetically modified epidermal cells to replace the LAMB3 gene, thereby restoring production of laminin 332, which is an essential component of the dermal-epidermal junction, according to Dr. Mellerio, citing a study in Nature Medicine.

The next attempt with this approach did not take place until 2015, resurrected to save the life of a 7-year-old Syrian boy – to generate epidermal sheets that eventually covered 80% of his body. The success is supporting further work on this approach but has also been an inspiration to other gene therapies, including a topical gene therapy recently approved in the United States.

Topically applied beremagene geperpavec (Vyjuvek, formerly known as B-VEC) was approved by the FDA in May for treating wounds in patients 6 months of age and older, with recessive or dominant dystrophic EB, on the basis of a phase 3 trial published in the New England Journal of Medicine, but others are coming. Dr. Mellerio also described a recently completed phase 3 trial with introduction of ex vivo gene-corrected keratinocytes, which has been associated with long-term improvements among patients with recessive dystrophic EB (RDEB). The responses in early phase studies included wound healing and reduction in pain and itch.

Perhaps less advanced but still promising, protein therapy, gene editing, and repurposing of existing therapies are all approaches that are moving forward. Many are supported by at least some clinical data, according to Dr. Mellerio.

As an example of protein therapy, a completed phase I/II trial associated recombinant human collagen with wound healing and pain reduction in RDEB. This study provided proof of principle for a therapy that could be applied topically or intravenously. Further development is anticipated.

Multiple platforms for gene editing have been described with the goal of simply excising pathogenic mutations or antisense oligonucleotides for sustained or permanent control of EB expression. Clinical evidence is limited, but Dr. Mellerio suggested that the theoretical potential for eliminating the source of abnormal transcription is the restoration of functional proteins essential for reversing skin fragility.

In some cases, existing drugs have the same potential. Dr. Mellerio described efforts to use an aminoglycoside to circumvent nonsense mutations that produce messenger RNA decay and impaired production of the proteins that prevent EB. In a pilot study evaluating topical gentamicin in RDEB, there were substantial improvements at 1 month and 3 months in several measures of skin fragility and encouraged studies that are now ongoing in both RDEB and JEB.

More than promising, a multinational randomized phase 3 study with birch bark extract recently published in the British Journal of Dermatology, associated treatment with this topical gel, known as Oleogel-S10, with higher rates of complete wound closure at 45 days (41.3% vs. 28.9% in the control vehicle arm) and a low risk of adverse events.

“This therapy is now approved in Europe and the United Kingdom, although, unfortunately, it is not yet available in the United States,” Dr. Mellerio noted.

Importantly, none of these therapies are necessarily effective across subtypes of EB, which often have different underlying pathogenic mechanisms, she said. However, the growing sophistication with which the pathophysiology of these subtypes is understood makes the numerous treatments in the pipeline “exciting.”

“We are at a point where we can really start to think of personalized medicine in EB,” Dr. Mellerio said. With the clinical advances already available and those expected, she suggested the recently approved treatment options are just the beginning. She expects the treatment landscape to evolve quickly over the next few years.

This does not appear to be a personal opinion. Another prominent researcher in EB, M. Peter Marinkovich, MD, director of the Stanford Bullous Disease and Psoriasis Clinics at Stanford (Calif.) University, is seeing the same real-world promise of therapies that have been in gestation for a decade or more.

“Dr. Mellerio is right. This is an exciting time for EB patients,” Dr. Marinkovich said in an interview. While the approval of B-VEC, the first gene therapy for EB, is the proof, Dr. Marinkovich, the lead author of the NEJM paper on B-VEC, noted that “many other potential EB therapies are being studied right now.” Based on promise in earlier clinical studies with many of these agents, he, like Dr. Mellerio, expects progress in real-world treatments for EB to accelerate.

Dr. Mellerio reported financial relationships with Amryt Pharma and Krystal Biotech. Dr. Marinkovich receives research support from Abeona Therapeutics, Castle Creek Pharmaceuticals, Krystal Biotech, Phoenix Tissue Repair, and WINGS Therapeutics.

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

ASHEVILLE, N.C. – Epidermolysis bullosa (EB), a heterogeneous congenital condition of skin fragility, received its first U.S. Food and Drug Association–approved gene therapy only a few months ago, but accelerated progress across multiple treatment strategies predicts additional important and perhaps dramatic further progress, according to a prominent EB researcher.

Not only are recent developments in EB “exciting,” the progress on multiple fronts for control of disease or its symptoms suggests “we are on the cusp of a new era,” Jemima Mellerio, BSc, MD, a consultant dermatologist, St. John’s Institute of Dermatology, London, said at the annual meeting of the Society for Pediatric Dermatology.

Published clinical studies of cell therapies and gene therapies date back at least 15 years, according to a review by Dr. Mellerio on why developments are starting to move so quickly. The difference now is that many obstacles to routine use of these options are being resolved so that viable strategies have reached or are reaching phase 3 trials.

In addition to cell therapies and gene therapies, Dr. Mellerio discussed progress in three additional areas: gene editing, protein therapy, and drug repurposing.

Summarizing progress in each, she described improvement in levels of collagen VII, an important deficit in most types of EB, that were achieved with fibroblast injections that improved levels of collagen VII and anchoring fibrils in a study published in the Journal of Investigative Dermatology. Injection of mesenchymal stromal cells (MSC) have been associated with reduced pain and itch in a series of studies, one of the earliest of which was published in the New England Journal of Medicine.

Since that time, there have been several approaches using MSC.

Of these approaches, intravenous injection of ABCB5+ MSCs might be the first to gain regulatory approval. According to Dr. Mellerio, there is an ongoing phase 3 crossover trial evaluating this approach, which followed several earlier phase studies that demonstrated adequate safety and tolerability while reducing severity scores, relieving pain and itch, and improving wound closure in patients with EB.

In 2006, correction of junctional EB (JEB) was achieved by transplantation of genetically modified epidermal cells to replace the LAMB3 gene, thereby restoring production of laminin 332, which is an essential component of the dermal-epidermal junction, according to Dr. Mellerio, citing a study in Nature Medicine.

The next attempt with this approach did not take place until 2015, resurrected to save the life of a 7-year-old Syrian boy – to generate epidermal sheets that eventually covered 80% of his body. The success is supporting further work on this approach but has also been an inspiration to other gene therapies, including a topical gene therapy recently approved in the United States.

Topically applied beremagene geperpavec (Vyjuvek, formerly known as B-VEC) was approved by the FDA in May for treating wounds in patients 6 months of age and older, with recessive or dominant dystrophic EB, on the basis of a phase 3 trial published in the New England Journal of Medicine, but others are coming. Dr. Mellerio also described a recently completed phase 3 trial with introduction of ex vivo gene-corrected keratinocytes, which has been associated with long-term improvements among patients with recessive dystrophic EB (RDEB). The responses in early phase studies included wound healing and reduction in pain and itch.

Perhaps less advanced but still promising, protein therapy, gene editing, and repurposing of existing therapies are all approaches that are moving forward. Many are supported by at least some clinical data, according to Dr. Mellerio.

As an example of protein therapy, a completed phase I/II trial associated recombinant human collagen with wound healing and pain reduction in RDEB. This study provided proof of principle for a therapy that could be applied topically or intravenously. Further development is anticipated.

Multiple platforms for gene editing have been described with the goal of simply excising pathogenic mutations or antisense oligonucleotides for sustained or permanent control of EB expression. Clinical evidence is limited, but Dr. Mellerio suggested that the theoretical potential for eliminating the source of abnormal transcription is the restoration of functional proteins essential for reversing skin fragility.

In some cases, existing drugs have the same potential. Dr. Mellerio described efforts to use an aminoglycoside to circumvent nonsense mutations that produce messenger RNA decay and impaired production of the proteins that prevent EB. In a pilot study evaluating topical gentamicin in RDEB, there were substantial improvements at 1 month and 3 months in several measures of skin fragility and encouraged studies that are now ongoing in both RDEB and JEB.

More than promising, a multinational randomized phase 3 study with birch bark extract recently published in the British Journal of Dermatology, associated treatment with this topical gel, known as Oleogel-S10, with higher rates of complete wound closure at 45 days (41.3% vs. 28.9% in the control vehicle arm) and a low risk of adverse events.

“This therapy is now approved in Europe and the United Kingdom, although, unfortunately, it is not yet available in the United States,” Dr. Mellerio noted.

Importantly, none of these therapies are necessarily effective across subtypes of EB, which often have different underlying pathogenic mechanisms, she said. However, the growing sophistication with which the pathophysiology of these subtypes is understood makes the numerous treatments in the pipeline “exciting.”

“We are at a point where we can really start to think of personalized medicine in EB,” Dr. Mellerio said. With the clinical advances already available and those expected, she suggested the recently approved treatment options are just the beginning. She expects the treatment landscape to evolve quickly over the next few years.

This does not appear to be a personal opinion. Another prominent researcher in EB, M. Peter Marinkovich, MD, director of the Stanford Bullous Disease and Psoriasis Clinics at Stanford (Calif.) University, is seeing the same real-world promise of therapies that have been in gestation for a decade or more.

“Dr. Mellerio is right. This is an exciting time for EB patients,” Dr. Marinkovich said in an interview. While the approval of B-VEC, the first gene therapy for EB, is the proof, Dr. Marinkovich, the lead author of the NEJM paper on B-VEC, noted that “many other potential EB therapies are being studied right now.” Based on promise in earlier clinical studies with many of these agents, he, like Dr. Mellerio, expects progress in real-world treatments for EB to accelerate.

Dr. Mellerio reported financial relationships with Amryt Pharma and Krystal Biotech. Dr. Marinkovich receives research support from Abeona Therapeutics, Castle Creek Pharmaceuticals, Krystal Biotech, Phoenix Tissue Repair, and WINGS Therapeutics.

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

ASHEVILLE, N.C. – Epidermolysis bullosa (EB), a heterogeneous congenital condition of skin fragility, received its first U.S. Food and Drug Association–approved gene therapy only a few months ago, but accelerated progress across multiple treatment strategies predicts additional important and perhaps dramatic further progress, according to a prominent EB researcher.

Not only are recent developments in EB “exciting,” the progress on multiple fronts for control of disease or its symptoms suggests “we are on the cusp of a new era,” Jemima Mellerio, BSc, MD, a consultant dermatologist, St. John’s Institute of Dermatology, London, said at the annual meeting of the Society for Pediatric Dermatology.

Published clinical studies of cell therapies and gene therapies date back at least 15 years, according to a review by Dr. Mellerio on why developments are starting to move so quickly. The difference now is that many obstacles to routine use of these options are being resolved so that viable strategies have reached or are reaching phase 3 trials.

In addition to cell therapies and gene therapies, Dr. Mellerio discussed progress in three additional areas: gene editing, protein therapy, and drug repurposing.

Summarizing progress in each, she described improvement in levels of collagen VII, an important deficit in most types of EB, that were achieved with fibroblast injections that improved levels of collagen VII and anchoring fibrils in a study published in the Journal of Investigative Dermatology. Injection of mesenchymal stromal cells (MSC) have been associated with reduced pain and itch in a series of studies, one of the earliest of which was published in the New England Journal of Medicine.

Since that time, there have been several approaches using MSC.

Of these approaches, intravenous injection of ABCB5+ MSCs might be the first to gain regulatory approval. According to Dr. Mellerio, there is an ongoing phase 3 crossover trial evaluating this approach, which followed several earlier phase studies that demonstrated adequate safety and tolerability while reducing severity scores, relieving pain and itch, and improving wound closure in patients with EB.

In 2006, correction of junctional EB (JEB) was achieved by transplantation of genetically modified epidermal cells to replace the LAMB3 gene, thereby restoring production of laminin 332, which is an essential component of the dermal-epidermal junction, according to Dr. Mellerio, citing a study in Nature Medicine.

The next attempt with this approach did not take place until 2015, resurrected to save the life of a 7-year-old Syrian boy – to generate epidermal sheets that eventually covered 80% of his body. The success is supporting further work on this approach but has also been an inspiration to other gene therapies, including a topical gene therapy recently approved in the United States.

Topically applied beremagene geperpavec (Vyjuvek, formerly known as B-VEC) was approved by the FDA in May for treating wounds in patients 6 months of age and older, with recessive or dominant dystrophic EB, on the basis of a phase 3 trial published in the New England Journal of Medicine, but others are coming. Dr. Mellerio also described a recently completed phase 3 trial with introduction of ex vivo gene-corrected keratinocytes, which has been associated with long-term improvements among patients with recessive dystrophic EB (RDEB). The responses in early phase studies included wound healing and reduction in pain and itch.

Perhaps less advanced but still promising, protein therapy, gene editing, and repurposing of existing therapies are all approaches that are moving forward. Many are supported by at least some clinical data, according to Dr. Mellerio.

As an example of protein therapy, a completed phase I/II trial associated recombinant human collagen with wound healing and pain reduction in RDEB. This study provided proof of principle for a therapy that could be applied topically or intravenously. Further development is anticipated.

Multiple platforms for gene editing have been described with the goal of simply excising pathogenic mutations or antisense oligonucleotides for sustained or permanent control of EB expression. Clinical evidence is limited, but Dr. Mellerio suggested that the theoretical potential for eliminating the source of abnormal transcription is the restoration of functional proteins essential for reversing skin fragility.

In some cases, existing drugs have the same potential. Dr. Mellerio described efforts to use an aminoglycoside to circumvent nonsense mutations that produce messenger RNA decay and impaired production of the proteins that prevent EB. In a pilot study evaluating topical gentamicin in RDEB, there were substantial improvements at 1 month and 3 months in several measures of skin fragility and encouraged studies that are now ongoing in both RDEB and JEB.

More than promising, a multinational randomized phase 3 study with birch bark extract recently published in the British Journal of Dermatology, associated treatment with this topical gel, known as Oleogel-S10, with higher rates of complete wound closure at 45 days (41.3% vs. 28.9% in the control vehicle arm) and a low risk of adverse events.

“This therapy is now approved in Europe and the United Kingdom, although, unfortunately, it is not yet available in the United States,” Dr. Mellerio noted.

Importantly, none of these therapies are necessarily effective across subtypes of EB, which often have different underlying pathogenic mechanisms, she said. However, the growing sophistication with which the pathophysiology of these subtypes is understood makes the numerous treatments in the pipeline “exciting.”

“We are at a point where we can really start to think of personalized medicine in EB,” Dr. Mellerio said. With the clinical advances already available and those expected, she suggested the recently approved treatment options are just the beginning. She expects the treatment landscape to evolve quickly over the next few years.

This does not appear to be a personal opinion. Another prominent researcher in EB, M. Peter Marinkovich, MD, director of the Stanford Bullous Disease and Psoriasis Clinics at Stanford (Calif.) University, is seeing the same real-world promise of therapies that have been in gestation for a decade or more.

“Dr. Mellerio is right. This is an exciting time for EB patients,” Dr. Marinkovich said in an interview. While the approval of B-VEC, the first gene therapy for EB, is the proof, Dr. Marinkovich, the lead author of the NEJM paper on B-VEC, noted that “many other potential EB therapies are being studied right now.” Based on promise in earlier clinical studies with many of these agents, he, like Dr. Mellerio, expects progress in real-world treatments for EB to accelerate.

Dr. Mellerio reported financial relationships with Amryt Pharma and Krystal Biotech. Dr. Marinkovich receives research support from Abeona Therapeutics, Castle Creek Pharmaceuticals, Krystal Biotech, Phoenix Tissue Repair, and WINGS Therapeutics.

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

ASHEVILLE, N.C. – TikTok, typical of several forms of social media, has been intentionally repositioned to rival Google as a primary source of information, meaning that health care professionals, including those who provide dermatologic care to children, should be thinking about how to get on board to counter myths, erroneous facts, and fake news, warned an expert at the annual meeting of the Society for Pediatric Dermatology.

“If we don’t get involved, we are basically letting misinformation win. We need to be there,” said Angelo Landriscina, MD, director of dermatology at a Mount Sinai Doctors Clinic in New York.

Most of the content currently available on medical topics, including dermatology and pediatric dermatology, is not created by health care professionals, Dr. Landriscina noted. Not surprisingly, given that much of the content is based on personal opinion from individuals who have no expertise in medical care, he described the information as being of “low quality” when not fully erroneous.

Dr. Landriscina has been active on social media, including TikTok, for several years. Most of his posts involve responses to misinformation. When he sets the record straight on the basis of existing evidence, he often supports his counterargument with references.

He acknowledged that when he became involved in social media he faced criticism from colleagues about participating on an entertainment platform that many considered unworthy of providing objective information. If that was ever true, he argued, it is no longer the case.

“TikTok has adopted a new strategy. The goal is to unseat Google as a search tool, and it’s working,” he said. He explained that many people now use TikTok and other social media sites as their primary source of information on essentially every topic, from where to eat to whether to be screened for cancer.

The particular problem with TikTok – one of the most popular social media outlets – is that there is no mechanism for vetting the source of information. YouTube, by contrast, now requires some sort of validation for anyone who claims to have a medical degree or any other verifiable qualification, according to Dr. Landriscina. TikTok, like many other platforms, has no such requirement.

“Anyone can buy a pair of scrubs [implying expertise] and then post a video,” Dr. Landriscina said.

Even if information from one content provider is more valid than information from others, the TikTok algorithm is specifically designed to emphasize content that has the potential for going viral, which means it favors videos that are provocative over those that are not.

“The algorithm favors any content that is more controversial, more surprising, and keeps viewers engaged,” Dr. Landriscina pointed out.

This does not mean that objective and factual information is ignored, but the algorithm is indifferent to the validity of information, meaning that it allows videos to be posted without regard to whether the content is true, untrue, purposefully misleading, or utter nonsense. For that reason, it is often easier to attract attention by responding to a post that has already gone viral. Information that is clear and digestible can attract viewers and therefore is distributed more widely with the TikTok algorithm.
 

Parents are on Tiktok too

There is a misperception that the TikTok audience is younger, according to Dr. Landriscina. While peak use in the United States fell among people between the ages of 25 and 34 years in 2022, he said the number of users falls off relatively slowly with subsequent 10-year increments in age. In 2022, there were nearly 20 million users in the peak 10-year age range, but 7.5 million users were 55 years of age or older.

“Pediatric dermatologists should recognize that it is not just kids who are looking for information about their skin diseases, but also their parents,” Dr. Landriscina said.

The top three dermatology topics searched on TikTok in a recent period were acne, alopecia, and cysts. But top searches are very fluid and are extremely hard to quantify, because the basis of the algorithm, which is a proprietary secret, is not only unknown but produces different results for every user.

“The second you touch the app, it changes,” Dr. Landriscina said. He explained that an inquiry about any subject, including those that are medically related, yields content that is different, or at least ordered differently, “depending on how you behaved on the app in the past.”

The phenomenon that drives social media predates this technology. Dr. Landriscina cited a study in 1956 that described the “parasocial interaction theory.” The theory was based on the observation that those who consume media, such as television, which was relatively new in 1956, believed that they had a personal relationship with media figures.

“The users begin to trust influencers as a source, like a friend providing them advice,” Dr. Landriscina said. As an example, he suggested that a fan of the television show Friends who follows actor Jennifer Aniston on social media platforms may begin to think of her as a trusted source of information on any topic, including those for which she may not have expertise.

The reason that he urges medical professionals to become active on TikTok and other social media platforms is that they have a potentially critical role in responding to information that is not just wrong but harmful.

On TikTok and other social media platforms, “there is a lot of interest in content about dermatologic conditions in children. There is a real need for accurate information,” he said,

In the question-and-answer session following his presentation, Dr. Landriscina’s message was not uniformly embraced. One risk, according to an audience member, is that medical professionals will begin to express their own personal opinions rather than rely on evidence, with the result that they will “just add to the sea of misinformation.”

However, this opinion appeared to be the minority view. Most of those who commented took a “that-ship-has-sailed” stance, recognizing the irreversible ascendancy of social media.

“Whether you like it or not, social media is here to stay. We cannot fight it. Rather, we need to embrace it in a responsible way,” said Dakara R. Wright, MD, a dermatologist at the Mid-Atlantic Kaiser Permanente Group, Halethorpe, Md. She, like others, reported that she has come to recognize that social media is a major source of medical information for her patients.

“We need to be a presence on these platforms for the benefit of our patients and their parents,” she said. She acknowledged that she has not been active in posting on social media in the past but said that she has been speaking with administrators in her organization about how to become involved in a responsible way that can be useful to patients.

Candrice R. Heath, MD, assistant professor of dermatology at Temple University, Philadelphia, has been active on social media for several years, posting content on her own account, which is not related to her academic affiliation. She posts for many reasons, not least of which is drawing attention to her expertise.

Like Dr. Landriscina, she recognizes that users of these platforms are guided by the content to make decisions about health care. She also agreed that physicians should not ignore this phenomenon.

Tips on providing content

Given the fact that the algorithm is intended to produce posts that go viral, Dr. Landriscina urged clinicians to make their content easy to watch. He said it is not necessary to overthink content beyond providing accurate information, but he advised that videos be made with attention to adequate lighting and other simple factors to promote visual quality. He said that accurate information is not necessarily dull.

“Some facts can actually be surprising to patients,” he said. He noted that a calm, coherent video can be particularly effective in attracting an audience when it is in reaction to information that has gone viral but is misleading or patently incorrect.

Dr. Landriscina has been an influencer associated with multiple social media platforms, including TikTok. He has in the past been paid for consulting work for TikTok. Dr. Wright and Dr. Heath reported no potential conflicts of interest.

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

ASHEVILLE, N.C. – TikTok, typical of several forms of social media, has been intentionally repositioned to rival Google as a primary source of information, meaning that health care professionals, including those who provide dermatologic care to children, should be thinking about how to get on board to counter myths, erroneous facts, and fake news, warned an expert at the annual meeting of the Society for Pediatric Dermatology.

“If we don’t get involved, we are basically letting misinformation win. We need to be there,” said Angelo Landriscina, MD, director of dermatology at a Mount Sinai Doctors Clinic in New York.

Most of the content currently available on medical topics, including dermatology and pediatric dermatology, is not created by health care professionals, Dr. Landriscina noted. Not surprisingly, given that much of the content is based on personal opinion from individuals who have no expertise in medical care, he described the information as being of “low quality” when not fully erroneous.

Dr. Landriscina has been active on social media, including TikTok, for several years. Most of his posts involve responses to misinformation. When he sets the record straight on the basis of existing evidence, he often supports his counterargument with references.

He acknowledged that when he became involved in social media he faced criticism from colleagues about participating on an entertainment platform that many considered unworthy of providing objective information. If that was ever true, he argued, it is no longer the case.

“TikTok has adopted a new strategy. The goal is to unseat Google as a search tool, and it’s working,” he said. He explained that many people now use TikTok and other social media sites as their primary source of information on essentially every topic, from where to eat to whether to be screened for cancer.

The particular problem with TikTok – one of the most popular social media outlets – is that there is no mechanism for vetting the source of information. YouTube, by contrast, now requires some sort of validation for anyone who claims to have a medical degree or any other verifiable qualification, according to Dr. Landriscina. TikTok, like many other platforms, has no such requirement.

“Anyone can buy a pair of scrubs [implying expertise] and then post a video,” Dr. Landriscina said.

Even if information from one content provider is more valid than information from others, the TikTok algorithm is specifically designed to emphasize content that has the potential for going viral, which means it favors videos that are provocative over those that are not.

“The algorithm favors any content that is more controversial, more surprising, and keeps viewers engaged,” Dr. Landriscina pointed out.

This does not mean that objective and factual information is ignored, but the algorithm is indifferent to the validity of information, meaning that it allows videos to be posted without regard to whether the content is true, untrue, purposefully misleading, or utter nonsense. For that reason, it is often easier to attract attention by responding to a post that has already gone viral. Information that is clear and digestible can attract viewers and therefore is distributed more widely with the TikTok algorithm.
 

Parents are on Tiktok too

There is a misperception that the TikTok audience is younger, according to Dr. Landriscina. While peak use in the United States fell among people between the ages of 25 and 34 years in 2022, he said the number of users falls off relatively slowly with subsequent 10-year increments in age. In 2022, there were nearly 20 million users in the peak 10-year age range, but 7.5 million users were 55 years of age or older.

“Pediatric dermatologists should recognize that it is not just kids who are looking for information about their skin diseases, but also their parents,” Dr. Landriscina said.

The top three dermatology topics searched on TikTok in a recent period were acne, alopecia, and cysts. But top searches are very fluid and are extremely hard to quantify, because the basis of the algorithm, which is a proprietary secret, is not only unknown but produces different results for every user.

“The second you touch the app, it changes,” Dr. Landriscina said. He explained that an inquiry about any subject, including those that are medically related, yields content that is different, or at least ordered differently, “depending on how you behaved on the app in the past.”

The phenomenon that drives social media predates this technology. Dr. Landriscina cited a study in 1956 that described the “parasocial interaction theory.” The theory was based on the observation that those who consume media, such as television, which was relatively new in 1956, believed that they had a personal relationship with media figures.

“The users begin to trust influencers as a source, like a friend providing them advice,” Dr. Landriscina said. As an example, he suggested that a fan of the television show Friends who follows actor Jennifer Aniston on social media platforms may begin to think of her as a trusted source of information on any topic, including those for which she may not have expertise.

The reason that he urges medical professionals to become active on TikTok and other social media platforms is that they have a potentially critical role in responding to information that is not just wrong but harmful.

On TikTok and other social media platforms, “there is a lot of interest in content about dermatologic conditions in children. There is a real need for accurate information,” he said,

In the question-and-answer session following his presentation, Dr. Landriscina’s message was not uniformly embraced. One risk, according to an audience member, is that medical professionals will begin to express their own personal opinions rather than rely on evidence, with the result that they will “just add to the sea of misinformation.”

However, this opinion appeared to be the minority view. Most of those who commented took a “that-ship-has-sailed” stance, recognizing the irreversible ascendancy of social media.

“Whether you like it or not, social media is here to stay. We cannot fight it. Rather, we need to embrace it in a responsible way,” said Dakara R. Wright, MD, a dermatologist at the Mid-Atlantic Kaiser Permanente Group, Halethorpe, Md. She, like others, reported that she has come to recognize that social media is a major source of medical information for her patients.

“We need to be a presence on these platforms for the benefit of our patients and their parents,” she said. She acknowledged that she has not been active in posting on social media in the past but said that she has been speaking with administrators in her organization about how to become involved in a responsible way that can be useful to patients.

Candrice R. Heath, MD, assistant professor of dermatology at Temple University, Philadelphia, has been active on social media for several years, posting content on her own account, which is not related to her academic affiliation. She posts for many reasons, not least of which is drawing attention to her expertise.

Like Dr. Landriscina, she recognizes that users of these platforms are guided by the content to make decisions about health care. She also agreed that physicians should not ignore this phenomenon.

Tips on providing content

Given the fact that the algorithm is intended to produce posts that go viral, Dr. Landriscina urged clinicians to make their content easy to watch. He said it is not necessary to overthink content beyond providing accurate information, but he advised that videos be made with attention to adequate lighting and other simple factors to promote visual quality. He said that accurate information is not necessarily dull.

“Some facts can actually be surprising to patients,” he said. He noted that a calm, coherent video can be particularly effective in attracting an audience when it is in reaction to information that has gone viral but is misleading or patently incorrect.

Dr. Landriscina has been an influencer associated with multiple social media platforms, including TikTok. He has in the past been paid for consulting work for TikTok. Dr. Wright and Dr. Heath reported no potential conflicts of interest.

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

ASHEVILLE, N.C. – TikTok, typical of several forms of social media, has been intentionally repositioned to rival Google as a primary source of information, meaning that health care professionals, including those who provide dermatologic care to children, should be thinking about how to get on board to counter myths, erroneous facts, and fake news, warned an expert at the annual meeting of the Society for Pediatric Dermatology.

“If we don’t get involved, we are basically letting misinformation win. We need to be there,” said Angelo Landriscina, MD, director of dermatology at a Mount Sinai Doctors Clinic in New York.

Most of the content currently available on medical topics, including dermatology and pediatric dermatology, is not created by health care professionals, Dr. Landriscina noted. Not surprisingly, given that much of the content is based on personal opinion from individuals who have no expertise in medical care, he described the information as being of “low quality” when not fully erroneous.

Dr. Landriscina has been active on social media, including TikTok, for several years. Most of his posts involve responses to misinformation. When he sets the record straight on the basis of existing evidence, he often supports his counterargument with references.

He acknowledged that when he became involved in social media he faced criticism from colleagues about participating on an entertainment platform that many considered unworthy of providing objective information. If that was ever true, he argued, it is no longer the case.

“TikTok has adopted a new strategy. The goal is to unseat Google as a search tool, and it’s working,” he said. He explained that many people now use TikTok and other social media sites as their primary source of information on essentially every topic, from where to eat to whether to be screened for cancer.

The particular problem with TikTok – one of the most popular social media outlets – is that there is no mechanism for vetting the source of information. YouTube, by contrast, now requires some sort of validation for anyone who claims to have a medical degree or any other verifiable qualification, according to Dr. Landriscina. TikTok, like many other platforms, has no such requirement.

“Anyone can buy a pair of scrubs [implying expertise] and then post a video,” Dr. Landriscina said.

Even if information from one content provider is more valid than information from others, the TikTok algorithm is specifically designed to emphasize content that has the potential for going viral, which means it favors videos that are provocative over those that are not.

“The algorithm favors any content that is more controversial, more surprising, and keeps viewers engaged,” Dr. Landriscina pointed out.

This does not mean that objective and factual information is ignored, but the algorithm is indifferent to the validity of information, meaning that it allows videos to be posted without regard to whether the content is true, untrue, purposefully misleading, or utter nonsense. For that reason, it is often easier to attract attention by responding to a post that has already gone viral. Information that is clear and digestible can attract viewers and therefore is distributed more widely with the TikTok algorithm.
 

Parents are on Tiktok too

There is a misperception that the TikTok audience is younger, according to Dr. Landriscina. While peak use in the United States fell among people between the ages of 25 and 34 years in 2022, he said the number of users falls off relatively slowly with subsequent 10-year increments in age. In 2022, there were nearly 20 million users in the peak 10-year age range, but 7.5 million users were 55 years of age or older.

“Pediatric dermatologists should recognize that it is not just kids who are looking for information about their skin diseases, but also their parents,” Dr. Landriscina said.

The top three dermatology topics searched on TikTok in a recent period were acne, alopecia, and cysts. But top searches are very fluid and are extremely hard to quantify, because the basis of the algorithm, which is a proprietary secret, is not only unknown but produces different results for every user.

“The second you touch the app, it changes,” Dr. Landriscina said. He explained that an inquiry about any subject, including those that are medically related, yields content that is different, or at least ordered differently, “depending on how you behaved on the app in the past.”

The phenomenon that drives social media predates this technology. Dr. Landriscina cited a study in 1956 that described the “parasocial interaction theory.” The theory was based on the observation that those who consume media, such as television, which was relatively new in 1956, believed that they had a personal relationship with media figures.

“The users begin to trust influencers as a source, like a friend providing them advice,” Dr. Landriscina said. As an example, he suggested that a fan of the television show Friends who follows actor Jennifer Aniston on social media platforms may begin to think of her as a trusted source of information on any topic, including those for which she may not have expertise.

The reason that he urges medical professionals to become active on TikTok and other social media platforms is that they have a potentially critical role in responding to information that is not just wrong but harmful.

On TikTok and other social media platforms, “there is a lot of interest in content about dermatologic conditions in children. There is a real need for accurate information,” he said,

In the question-and-answer session following his presentation, Dr. Landriscina’s message was not uniformly embraced. One risk, according to an audience member, is that medical professionals will begin to express their own personal opinions rather than rely on evidence, with the result that they will “just add to the sea of misinformation.”

However, this opinion appeared to be the minority view. Most of those who commented took a “that-ship-has-sailed” stance, recognizing the irreversible ascendancy of social media.

“Whether you like it or not, social media is here to stay. We cannot fight it. Rather, we need to embrace it in a responsible way,” said Dakara R. Wright, MD, a dermatologist at the Mid-Atlantic Kaiser Permanente Group, Halethorpe, Md. She, like others, reported that she has come to recognize that social media is a major source of medical information for her patients.

“We need to be a presence on these platforms for the benefit of our patients and their parents,” she said. She acknowledged that she has not been active in posting on social media in the past but said that she has been speaking with administrators in her organization about how to become involved in a responsible way that can be useful to patients.

Candrice R. Heath, MD, assistant professor of dermatology at Temple University, Philadelphia, has been active on social media for several years, posting content on her own account, which is not related to her academic affiliation. She posts for many reasons, not least of which is drawing attention to her expertise.

Like Dr. Landriscina, she recognizes that users of these platforms are guided by the content to make decisions about health care. She also agreed that physicians should not ignore this phenomenon.

Tips on providing content

Given the fact that the algorithm is intended to produce posts that go viral, Dr. Landriscina urged clinicians to make their content easy to watch. He said it is not necessary to overthink content beyond providing accurate information, but he advised that videos be made with attention to adequate lighting and other simple factors to promote visual quality. He said that accurate information is not necessarily dull.

“Some facts can actually be surprising to patients,” he said. He noted that a calm, coherent video can be particularly effective in attracting an audience when it is in reaction to information that has gone viral but is misleading or patently incorrect.

Dr. Landriscina has been an influencer associated with multiple social media platforms, including TikTok. He has in the past been paid for consulting work for TikTok. Dr. Wright and Dr. Heath reported no potential conflicts of interest.

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

ASHEVILLE, N.C. – Treating atopic dermatitis (AD) in most children­ – and working with parents – might be less dependent on the next, even better therapy than considering facets of poor response and dissatisfaction with treatment, according to a three-member expert panel mulling over strategies at the annual meeting of the Society for Pediatric Dermatology.

In introductory remarks, the three panelists briefly addressed different aspects for controlling AD, including drugs in the pipeline, the potential value of alternative therapies, and whom to blame when compliance is poor.

Northwestern Feinberg School of Medicine

Wake Forest University School of Medicine

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

ASHEVILLE, N.C. – Treating atopic dermatitis (AD) in most children­ – and working with parents – might be less dependent on the next, even better therapy than considering facets of poor response and dissatisfaction with treatment, according to a three-member expert panel mulling over strategies at the annual meeting of the Society for Pediatric Dermatology.

In introductory remarks, the three panelists briefly addressed different aspects for controlling AD, including drugs in the pipeline, the potential value of alternative therapies, and whom to blame when compliance is poor.

Northwestern Feinberg School of Medicine

Wake Forest University School of Medicine

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

ASHEVILLE, N.C. – Treating atopic dermatitis (AD) in most children­ – and working with parents – might be less dependent on the next, even better therapy than considering facets of poor response and dissatisfaction with treatment, according to a three-member expert panel mulling over strategies at the annual meeting of the Society for Pediatric Dermatology.

In introductory remarks, the three panelists briefly addressed different aspects for controlling AD, including drugs in the pipeline, the potential value of alternative therapies, and whom to blame when compliance is poor.

Northwestern Feinberg School of Medicine

Wake Forest University School of Medicine

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

The presence of a positive fungal culture in patients with bronchiectasis does not appear to correlate with disease severity or any increased risk of an adverse outcome, according to data pulled from the Bronchiectasis and NTM Registry and presented at the 6th World Bronchiectasis & NTM Conference.

“The question we were asking is whether there is some signal that suggests we need to take care of these patients differently, and the answer is no,” reported Pamela J. McShane, MD, a pulmonologist on the faculty at the University of Texas Health Science Center at Tyler.

When compared for outcome over time, those with a positive fungal culture at initial evaluation did not have more exacerbations, more hospitalizations, or other signs of a more severe disease or more complex course than did those without a positive fungal culture.

When fungal infections are detected in an initial microbiologic evaluation of patients with bronchiectasis or other lung diseases, first-line clinicians generally assume that coverage is needed. Dr. McShane noted that many of the patients referred to her with bronchiectasis and a positive fungal culture were already on an antifungal.

These data are not supportive of treatment in the absence of fungal-related complications. Dr. McShane suggested they even raise questions about the value of culturing beyond bacterial pathogens in the absence of suspicion that fungal organisms are playing a role in symptoms. She cautioned, however, that more studies specifically studying this possibility are needed.
 

Study details

The data were drawn in December 2022 from the U.S.-based Bronchiectasis and NTM Registry, which at that time had 22 participating sites. Of the more than 5,000 patients enrolled, the study looked at 2,230 after several exclusions, such as a diagnosis of allergic bronchopulmonary aspergillosis (ABPA).

Of these 2,230 patients, 949 had a fungal infection at the time of diagnosis and 1,281 did not. Those with a fungal infection were further subdivided into those with an aspergillosis (331 patients) and those with a nonaspergillosis fungal infection (751 patients). The total of these two numbers is greater than the total number of fungal infections because these were not mutually exclusive.

At enrollment into the registry, there were no statistical differences between groups for age. Some statistical differences were observed among groups stratified by race, but Dr. McShane doubted that these were clinically significant with the exception of a potential disparity among Asians that might deserve further analysis.
 

Infection results

Of clinical features evaluated for their association with fungal infection, there was no correlation with either body mass index or history of asthma. Eosinophilia was associated significantly with positive fungal cultures.

Baseline FEV₁ was slightly lower among those with a positive fungal culture even if the difference was highly significant (P = .0006). Again, Dr. McShane questioned the clinical significance of values that varied by only a few percentage points, even though she was willing to acknowledge that higher is always preferable to a lower FEV₁.

In the context of other pathogens, “generally speaking, those with a positive bacterial culture were more likely to have a fungal infection,” Dr. McShane reported, although there was some variation when looking at pathogenicity of the bacteria and other variables.

“Whether this [higher rate of fungal infection] just involves the environment or our antibiotics are driving the opportunity to permit the fungi to exist, we do not have the answer,” she added.

Nontuberculosis mycobacteria (NTM) infection was similarly represented in those with or without a fungal infection, according to Dr. McShane. Noting the high use of antibiotics in an NTM population, Dr. McShane conceded that this challenges the theory that antibiotic use is driving the risk of fungal infection, but these are what the data say.  

Steroid use was associated with a statistically significant risk of fungal infection, but Dr. McShane said it is unclear whether steroid use drives the risk or is an epiphenomenon.

“We looked at this a lot of different ways: oral vs. inhaled and oral vs. inhaled and oral, and it did not make much difference. Generally speaking, the fungal cultures were more likely to be positive in patients on any kind of steroid,” she said.

Finally, with the exception of the slightly lower FEV₁ in patients with fungal infections, Dr. McShane said that there was no discernible relationship between the presence of a fungal infection and severity of bronchiectasis.

Because of this evidence, Dr. McShane concluded that the presence of fungus in the culture of patients with bronchiectasis does not appear to correlate with outcome or severity. Since completing the study, she said she is now using these data to reassure patients who have a positive fungal culture.

While these data do not affect the need to diagnosis fungal infections in patients who are not responding typically to therapy or otherwise have an abnormal course of bronchiectasis, raising suspicion that fungal infection is participating in the disease course, the data provide a basis for questioning whether routine cultures are needed, according to the discussion that followed Dr. McShane’s presentation.
 

Expert opinion

Several of the experts at the presentation provided an opinion. Some reported that they would continue to order fungal cultures on a routine basis, while others said that they now, on the basis of these data, plan to order cultures only at the first visit or when fungal infection is suspected of exacerbating the disease.

Of this latter group, which seemed to be dominant, Juzar Ali, MD, professor of medicine, Louisiana State University, New Orleans, said that he has not been ordering fungal cultures on every visit. Rather, he has been doing so selectively. Examples include those who are on steroids or those with an unusual pattern of exacerbations.

“The value of these data is that they have now provided some data to support this approach,” Dr. Ali said in an interview. Noting that this is the first large study to address this question in a systematic way, he considers this to be a valuable contribution for approaching a common clinical issue.

Dr. McShane reports no relevant financial relationships. Dr. Ali reports a financial relationship with Insmed.
 

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

The presence of a positive fungal culture in patients with bronchiectasis does not appear to correlate with disease severity or any increased risk of an adverse outcome, according to data pulled from the Bronchiectasis and NTM Registry and presented at the 6th World Bronchiectasis & NTM Conference.

“The question we were asking is whether there is some signal that suggests we need to take care of these patients differently, and the answer is no,” reported Pamela J. McShane, MD, a pulmonologist on the faculty at the University of Texas Health Science Center at Tyler.

When compared for outcome over time, those with a positive fungal culture at initial evaluation did not have more exacerbations, more hospitalizations, or other signs of a more severe disease or more complex course than did those without a positive fungal culture.

When fungal infections are detected in an initial microbiologic evaluation of patients with bronchiectasis or other lung diseases, first-line clinicians generally assume that coverage is needed. Dr. McShane noted that many of the patients referred to her with bronchiectasis and a positive fungal culture were already on an antifungal.

These data are not supportive of treatment in the absence of fungal-related complications. Dr. McShane suggested they even raise questions about the value of culturing beyond bacterial pathogens in the absence of suspicion that fungal organisms are playing a role in symptoms. She cautioned, however, that more studies specifically studying this possibility are needed.
 

Study details

The data were drawn in December 2022 from the U.S.-based Bronchiectasis and NTM Registry, which at that time had 22 participating sites. Of the more than 5,000 patients enrolled, the study looked at 2,230 after several exclusions, such as a diagnosis of allergic bronchopulmonary aspergillosis (ABPA).

Of these 2,230 patients, 949 had a fungal infection at the time of diagnosis and 1,281 did not. Those with a fungal infection were further subdivided into those with an aspergillosis (331 patients) and those with a nonaspergillosis fungal infection (751 patients). The total of these two numbers is greater than the total number of fungal infections because these were not mutually exclusive.

At enrollment into the registry, there were no statistical differences between groups for age. Some statistical differences were observed among groups stratified by race, but Dr. McShane doubted that these were clinically significant with the exception of a potential disparity among Asians that might deserve further analysis.
 

Infection results

Of clinical features evaluated for their association with fungal infection, there was no correlation with either body mass index or history of asthma. Eosinophilia was associated significantly with positive fungal cultures.

Baseline FEV₁ was slightly lower among those with a positive fungal culture even if the difference was highly significant (P = .0006). Again, Dr. McShane questioned the clinical significance of values that varied by only a few percentage points, even though she was willing to acknowledge that higher is always preferable to a lower FEV₁.

In the context of other pathogens, “generally speaking, those with a positive bacterial culture were more likely to have a fungal infection,” Dr. McShane reported, although there was some variation when looking at pathogenicity of the bacteria and other variables.

“Whether this [higher rate of fungal infection] just involves the environment or our antibiotics are driving the opportunity to permit the fungi to exist, we do not have the answer,” she added.

Nontuberculosis mycobacteria (NTM) infection was similarly represented in those with or without a fungal infection, according to Dr. McShane. Noting the high use of antibiotics in an NTM population, Dr. McShane conceded that this challenges the theory that antibiotic use is driving the risk of fungal infection, but these are what the data say.  

Steroid use was associated with a statistically significant risk of fungal infection, but Dr. McShane said it is unclear whether steroid use drives the risk or is an epiphenomenon.

“We looked at this a lot of different ways: oral vs. inhaled and oral vs. inhaled and oral, and it did not make much difference. Generally speaking, the fungal cultures were more likely to be positive in patients on any kind of steroid,” she said.

Finally, with the exception of the slightly lower FEV₁ in patients with fungal infections, Dr. McShane said that there was no discernible relationship between the presence of a fungal infection and severity of bronchiectasis.

Because of this evidence, Dr. McShane concluded that the presence of fungus in the culture of patients with bronchiectasis does not appear to correlate with outcome or severity. Since completing the study, she said she is now using these data to reassure patients who have a positive fungal culture.

While these data do not affect the need to diagnosis fungal infections in patients who are not responding typically to therapy or otherwise have an abnormal course of bronchiectasis, raising suspicion that fungal infection is participating in the disease course, the data provide a basis for questioning whether routine cultures are needed, according to the discussion that followed Dr. McShane’s presentation.
 

Expert opinion

Several of the experts at the presentation provided an opinion. Some reported that they would continue to order fungal cultures on a routine basis, while others said that they now, on the basis of these data, plan to order cultures only at the first visit or when fungal infection is suspected of exacerbating the disease.

Of this latter group, which seemed to be dominant, Juzar Ali, MD, professor of medicine, Louisiana State University, New Orleans, said that he has not been ordering fungal cultures on every visit. Rather, he has been doing so selectively. Examples include those who are on steroids or those with an unusual pattern of exacerbations.

“The value of these data is that they have now provided some data to support this approach,” Dr. Ali said in an interview. Noting that this is the first large study to address this question in a systematic way, he considers this to be a valuable contribution for approaching a common clinical issue.

Dr. McShane reports no relevant financial relationships. Dr. Ali reports a financial relationship with Insmed.
 

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

The presence of a positive fungal culture in patients with bronchiectasis does not appear to correlate with disease severity or any increased risk of an adverse outcome, according to data pulled from the Bronchiectasis and NTM Registry and presented at the 6th World Bronchiectasis & NTM Conference.

“The question we were asking is whether there is some signal that suggests we need to take care of these patients differently, and the answer is no,” reported Pamela J. McShane, MD, a pulmonologist on the faculty at the University of Texas Health Science Center at Tyler.

When compared for outcome over time, those with a positive fungal culture at initial evaluation did not have more exacerbations, more hospitalizations, or other signs of a more severe disease or more complex course than did those without a positive fungal culture.

When fungal infections are detected in an initial microbiologic evaluation of patients with bronchiectasis or other lung diseases, first-line clinicians generally assume that coverage is needed. Dr. McShane noted that many of the patients referred to her with bronchiectasis and a positive fungal culture were already on an antifungal.

These data are not supportive of treatment in the absence of fungal-related complications. Dr. McShane suggested they even raise questions about the value of culturing beyond bacterial pathogens in the absence of suspicion that fungal organisms are playing a role in symptoms. She cautioned, however, that more studies specifically studying this possibility are needed.
 

Study details

The data were drawn in December 2022 from the U.S.-based Bronchiectasis and NTM Registry, which at that time had 22 participating sites. Of the more than 5,000 patients enrolled, the study looked at 2,230 after several exclusions, such as a diagnosis of allergic bronchopulmonary aspergillosis (ABPA).

Of these 2,230 patients, 949 had a fungal infection at the time of diagnosis and 1,281 did not. Those with a fungal infection were further subdivided into those with an aspergillosis (331 patients) and those with a nonaspergillosis fungal infection (751 patients). The total of these two numbers is greater than the total number of fungal infections because these were not mutually exclusive.

At enrollment into the registry, there were no statistical differences between groups for age. Some statistical differences were observed among groups stratified by race, but Dr. McShane doubted that these were clinically significant with the exception of a potential disparity among Asians that might deserve further analysis.
 

Infection results

Of clinical features evaluated for their association with fungal infection, there was no correlation with either body mass index or history of asthma. Eosinophilia was associated significantly with positive fungal cultures.

Baseline FEV₁ was slightly lower among those with a positive fungal culture even if the difference was highly significant (P = .0006). Again, Dr. McShane questioned the clinical significance of values that varied by only a few percentage points, even though she was willing to acknowledge that higher is always preferable to a lower FEV₁.

In the context of other pathogens, “generally speaking, those with a positive bacterial culture were more likely to have a fungal infection,” Dr. McShane reported, although there was some variation when looking at pathogenicity of the bacteria and other variables.

“Whether this [higher rate of fungal infection] just involves the environment or our antibiotics are driving the opportunity to permit the fungi to exist, we do not have the answer,” she added.

Nontuberculosis mycobacteria (NTM) infection was similarly represented in those with or without a fungal infection, according to Dr. McShane. Noting the high use of antibiotics in an NTM population, Dr. McShane conceded that this challenges the theory that antibiotic use is driving the risk of fungal infection, but these are what the data say.  

Steroid use was associated with a statistically significant risk of fungal infection, but Dr. McShane said it is unclear whether steroid use drives the risk or is an epiphenomenon.

“We looked at this a lot of different ways: oral vs. inhaled and oral vs. inhaled and oral, and it did not make much difference. Generally speaking, the fungal cultures were more likely to be positive in patients on any kind of steroid,” she said.

Finally, with the exception of the slightly lower FEV₁ in patients with fungal infections, Dr. McShane said that there was no discernible relationship between the presence of a fungal infection and severity of bronchiectasis.

Because of this evidence, Dr. McShane concluded that the presence of fungus in the culture of patients with bronchiectasis does not appear to correlate with outcome or severity. Since completing the study, she said she is now using these data to reassure patients who have a positive fungal culture.

While these data do not affect the need to diagnosis fungal infections in patients who are not responding typically to therapy or otherwise have an abnormal course of bronchiectasis, raising suspicion that fungal infection is participating in the disease course, the data provide a basis for questioning whether routine cultures are needed, according to the discussion that followed Dr. McShane’s presentation.
 

Expert opinion

Several of the experts at the presentation provided an opinion. Some reported that they would continue to order fungal cultures on a routine basis, while others said that they now, on the basis of these data, plan to order cultures only at the first visit or when fungal infection is suspected of exacerbating the disease.

Of this latter group, which seemed to be dominant, Juzar Ali, MD, professor of medicine, Louisiana State University, New Orleans, said that he has not been ordering fungal cultures on every visit. Rather, he has been doing so selectively. Examples include those who are on steroids or those with an unusual pattern of exacerbations.

“The value of these data is that they have now provided some data to support this approach,” Dr. Ali said in an interview. Noting that this is the first large study to address this question in a systematic way, he considers this to be a valuable contribution for approaching a common clinical issue.

Dr. McShane reports no relevant financial relationships. Dr. Ali reports a financial relationship with Insmed.
 

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

ASHEVILLE, N.C. – The relative absorption of topical corticosteroids, which can induce cataracts and glaucoma, is 300-fold greater across the eyelids than plantar skin, but pediatric dermatologists need not dwell on this ratio when employing steroids near the eye, according to one of several clinical messages from a pediatric ophthalmologist who spoke at the annual meeting of the Society for Pediatric Dermatology.  

“There is a lot of steroid fear out there, which you can argue is actually harmful in itself, because not treating periorbital eczema is related to a lot of eye problems, including chronic discomfort and the eye rubbing that can cause corneal abrasions and keratoconus,” said Sara Grace, MD, a pediatric ophthalmologist who is on the clinical staff at Duke University, Durham, N.C. She maintains a practice at North Carolina Eye, Ear, Nose, and Throat in Durham.

Although the risks of periorbital steroid absorption are real, a limited course of low potency topical steroids is generally adequate for common periorbital indications, and these appear to be safe.

“There is insufficient evidence to link weak periocular topical corticosteroids such as desonide or hydrocortisone with ocular complications,” said Dr. Grace, suggesting that pediatric dermatologists can be reassured when using these medications at low concentrations.

“Potent periocular steroids have been associated with ocular complications, but this has typically involved exposures over months to years,” Dr. Grace specified.

When topical corticosteroids are applied at high concentrations on the face away from the periorbital area, glaucoma and other feared ophthalmic complications cannot be entirely ruled out, but, again, the risk is low in the absence of “very large quantities” of potent topical agents applied for lengthy periods of time, according to Dr. Grace, basing this observation on case studies.

In children, as in adults, the potential exception is a child with existing ocular disease. In such cases, or in children with risk factors for ocular disease, Dr. Grace recommends referral to an ophthalmologist for a baseline examination prior to a course of topical corticosteroids with the potential of periocular absorption. With a baseline assessment, adverse effects are more easily documented if exposure is prolonged.

The message, although not identical, is similar for use of dupilumab (Dupixent) or other biologics that target the interleukin-13 (IL-13) pathway. The potential for complications cannot be ignored but these are often time-limited and the benefit is likely to exceed the risk in children who have severe atopic dermatitis or other skin conditions for which these treatments are effective.

There are several potential mechanisms by which biologics targeting IL-13 might increase risk of ocular complications, one of which is the role that IL-13 plays in ocular mucus production, regulation of conjunctival goblet cells, and tear production, according to several published reports.

“Up to 30% of children will get some type of eye complication but, fortunately, most of them will not have to stop therapy,” Dr. Grace said. These side effects include conjunctivitis, blepharitis, keratitis, dry eye, and itching, but they are typically manageable. Topical steroids or calcineurin inhibitors can be offered if needed, but many of these conditions will self-resolve. Dr. Grace estimated that less than 1% of patients need to stop treatment because of ophthalmic side effects.

Lesions that obstruct vision

Dr. Grace urged pediatric dermatologists to be aware of the risk for amblyopia in young children with lesions that obstruct vision in one eye. In early development, prolonged obstruction of vision in one eye can alter neural communication with the brain, producing permanent vision impairment.

She explained that clearing the obstructed vision, whether from a capillary hemangioma or any periorbital growth, should be considered urgent to avoid irreversible damage.

Similarly, periorbital port-wine stains associated with Sturge-Weber syndrome, which is primarily a vascular disorder that predisposes children to glaucoma, represents a condition that requires prompt attention. Sturge-Weber syndrome is often but not always identified at birth, but it is a condition for which evaluation and treatment should involve the participation of an ophthalmologist.

Meibomian gland disease is another disorder that is often seen first by a pediatric dermatologist but also requires collaborative management. The challenge is sorting out the underlying cause or causes and initiating a therapy that unclogs the gland without having to resort to incision and drainage.

“Drainage is hard to do and is not necessarily effective,” explained Dr. Grace. While scrubs, warmth, and massage frequently are adequate to unclog the gland – which secretes meibum, a complex of lipids that perform several functions in protecting the eye – therapies specific to the cause, such as Demodex-related blepharitis, chalazions, and styes, might be needed.

Dr. Grace indicated that patience is often needed. The process of unclogging these glands often takes time, but she emphasized that a first-line conservative approach is always appropriate to avoid the difficulty and potential problems of incisions.

In general, these messages are not novel, but they provide a refresher for pediatric dermatologists who do not regularly confront complications that involve the eyes. According to session moderator, Elizabeth Neiman, MD, assistant professor of pediatric dermatology, University of North Carolina at Chapel Hill, the messages regarding topical steroids on the face and the eyes are “important” and worth emphasizing.

“It’s useful to reinforce the point that corticosteroids should be used when needed in the periorbital area [to control skin diseases] if they are used in low concentrations,” Dr. Neiman told this news organization.

Similarly, conjunctivitis and other ocular complications of dupilumab are a source of concern for parents as well as dermatologists. Dr. Neiman indicated that a review of the benefit-to-risk ratio is important when considering these treatments in patients with indications for severe skin disorders.

Dr. Grace and Dr. Nieman have no potential financial conflicts related to this topic.

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

ASHEVILLE, N.C. – The relative absorption of topical corticosteroids, which can induce cataracts and glaucoma, is 300-fold greater across the eyelids than plantar skin, but pediatric dermatologists need not dwell on this ratio when employing steroids near the eye, according to one of several clinical messages from a pediatric ophthalmologist who spoke at the annual meeting of the Society for Pediatric Dermatology.  

“There is a lot of steroid fear out there, which you can argue is actually harmful in itself, because not treating periorbital eczema is related to a lot of eye problems, including chronic discomfort and the eye rubbing that can cause corneal abrasions and keratoconus,” said Sara Grace, MD, a pediatric ophthalmologist who is on the clinical staff at Duke University, Durham, N.C. She maintains a practice at North Carolina Eye, Ear, Nose, and Throat in Durham.

Although the risks of periorbital steroid absorption are real, a limited course of low potency topical steroids is generally adequate for common periorbital indications, and these appear to be safe.

“There is insufficient evidence to link weak periocular topical corticosteroids such as desonide or hydrocortisone with ocular complications,” said Dr. Grace, suggesting that pediatric dermatologists can be reassured when using these medications at low concentrations.

“Potent periocular steroids have been associated with ocular complications, but this has typically involved exposures over months to years,” Dr. Grace specified.

When topical corticosteroids are applied at high concentrations on the face away from the periorbital area, glaucoma and other feared ophthalmic complications cannot be entirely ruled out, but, again, the risk is low in the absence of “very large quantities” of potent topical agents applied for lengthy periods of time, according to Dr. Grace, basing this observation on case studies.

In children, as in adults, the potential exception is a child with existing ocular disease. In such cases, or in children with risk factors for ocular disease, Dr. Grace recommends referral to an ophthalmologist for a baseline examination prior to a course of topical corticosteroids with the potential of periocular absorption. With a baseline assessment, adverse effects are more easily documented if exposure is prolonged.

The message, although not identical, is similar for use of dupilumab (Dupixent) or other biologics that target the interleukin-13 (IL-13) pathway. The potential for complications cannot be ignored but these are often time-limited and the benefit is likely to exceed the risk in children who have severe atopic dermatitis or other skin conditions for which these treatments are effective.

There are several potential mechanisms by which biologics targeting IL-13 might increase risk of ocular complications, one of which is the role that IL-13 plays in ocular mucus production, regulation of conjunctival goblet cells, and tear production, according to several published reports.

“Up to 30% of children will get some type of eye complication but, fortunately, most of them will not have to stop therapy,” Dr. Grace said. These side effects include conjunctivitis, blepharitis, keratitis, dry eye, and itching, but they are typically manageable. Topical steroids or calcineurin inhibitors can be offered if needed, but many of these conditions will self-resolve. Dr. Grace estimated that less than 1% of patients need to stop treatment because of ophthalmic side effects.

Lesions that obstruct vision

Dr. Grace urged pediatric dermatologists to be aware of the risk for amblyopia in young children with lesions that obstruct vision in one eye. In early development, prolonged obstruction of vision in one eye can alter neural communication with the brain, producing permanent vision impairment.

She explained that clearing the obstructed vision, whether from a capillary hemangioma or any periorbital growth, should be considered urgent to avoid irreversible damage.

Similarly, periorbital port-wine stains associated with Sturge-Weber syndrome, which is primarily a vascular disorder that predisposes children to glaucoma, represents a condition that requires prompt attention. Sturge-Weber syndrome is often but not always identified at birth, but it is a condition for which evaluation and treatment should involve the participation of an ophthalmologist.

Meibomian gland disease is another disorder that is often seen first by a pediatric dermatologist but also requires collaborative management. The challenge is sorting out the underlying cause or causes and initiating a therapy that unclogs the gland without having to resort to incision and drainage.

“Drainage is hard to do and is not necessarily effective,” explained Dr. Grace. While scrubs, warmth, and massage frequently are adequate to unclog the gland – which secretes meibum, a complex of lipids that perform several functions in protecting the eye – therapies specific to the cause, such as Demodex-related blepharitis, chalazions, and styes, might be needed.

Dr. Grace indicated that patience is often needed. The process of unclogging these glands often takes time, but she emphasized that a first-line conservative approach is always appropriate to avoid the difficulty and potential problems of incisions.

In general, these messages are not novel, but they provide a refresher for pediatric dermatologists who do not regularly confront complications that involve the eyes. According to session moderator, Elizabeth Neiman, MD, assistant professor of pediatric dermatology, University of North Carolina at Chapel Hill, the messages regarding topical steroids on the face and the eyes are “important” and worth emphasizing.

“It’s useful to reinforce the point that corticosteroids should be used when needed in the periorbital area [to control skin diseases] if they are used in low concentrations,” Dr. Neiman told this news organization.

Similarly, conjunctivitis and other ocular complications of dupilumab are a source of concern for parents as well as dermatologists. Dr. Neiman indicated that a review of the benefit-to-risk ratio is important when considering these treatments in patients with indications for severe skin disorders.

Dr. Grace and Dr. Nieman have no potential financial conflicts related to this topic.

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

ASHEVILLE, N.C. – The relative absorption of topical corticosteroids, which can induce cataracts and glaucoma, is 300-fold greater across the eyelids than plantar skin, but pediatric dermatologists need not dwell on this ratio when employing steroids near the eye, according to one of several clinical messages from a pediatric ophthalmologist who spoke at the annual meeting of the Society for Pediatric Dermatology.  

“There is a lot of steroid fear out there, which you can argue is actually harmful in itself, because not treating periorbital eczema is related to a lot of eye problems, including chronic discomfort and the eye rubbing that can cause corneal abrasions and keratoconus,” said Sara Grace, MD, a pediatric ophthalmologist who is on the clinical staff at Duke University, Durham, N.C. She maintains a practice at North Carolina Eye, Ear, Nose, and Throat in Durham.

Although the risks of periorbital steroid absorption are real, a limited course of low potency topical steroids is generally adequate for common periorbital indications, and these appear to be safe.

“There is insufficient evidence to link weak periocular topical corticosteroids such as desonide or hydrocortisone with ocular complications,” said Dr. Grace, suggesting that pediatric dermatologists can be reassured when using these medications at low concentrations.

“Potent periocular steroids have been associated with ocular complications, but this has typically involved exposures over months to years,” Dr. Grace specified.

When topical corticosteroids are applied at high concentrations on the face away from the periorbital area, glaucoma and other feared ophthalmic complications cannot be entirely ruled out, but, again, the risk is low in the absence of “very large quantities” of potent topical agents applied for lengthy periods of time, according to Dr. Grace, basing this observation on case studies.

In children, as in adults, the potential exception is a child with existing ocular disease. In such cases, or in children with risk factors for ocular disease, Dr. Grace recommends referral to an ophthalmologist for a baseline examination prior to a course of topical corticosteroids with the potential of periocular absorption. With a baseline assessment, adverse effects are more easily documented if exposure is prolonged.

The message, although not identical, is similar for use of dupilumab (Dupixent) or other biologics that target the interleukin-13 (IL-13) pathway. The potential for complications cannot be ignored but these are often time-limited and the benefit is likely to exceed the risk in children who have severe atopic dermatitis or other skin conditions for which these treatments are effective.

There are several potential mechanisms by which biologics targeting IL-13 might increase risk of ocular complications, one of which is the role that IL-13 plays in ocular mucus production, regulation of conjunctival goblet cells, and tear production, according to several published reports.

“Up to 30% of children will get some type of eye complication but, fortunately, most of them will not have to stop therapy,” Dr. Grace said. These side effects include conjunctivitis, blepharitis, keratitis, dry eye, and itching, but they are typically manageable. Topical steroids or calcineurin inhibitors can be offered if needed, but many of these conditions will self-resolve. Dr. Grace estimated that less than 1% of patients need to stop treatment because of ophthalmic side effects.

Lesions that obstruct vision

Dr. Grace urged pediatric dermatologists to be aware of the risk for amblyopia in young children with lesions that obstruct vision in one eye. In early development, prolonged obstruction of vision in one eye can alter neural communication with the brain, producing permanent vision impairment.

She explained that clearing the obstructed vision, whether from a capillary hemangioma or any periorbital growth, should be considered urgent to avoid irreversible damage.

Similarly, periorbital port-wine stains associated with Sturge-Weber syndrome, which is primarily a vascular disorder that predisposes children to glaucoma, represents a condition that requires prompt attention. Sturge-Weber syndrome is often but not always identified at birth, but it is a condition for which evaluation and treatment should involve the participation of an ophthalmologist.

Meibomian gland disease is another disorder that is often seen first by a pediatric dermatologist but also requires collaborative management. The challenge is sorting out the underlying cause or causes and initiating a therapy that unclogs the gland without having to resort to incision and drainage.

“Drainage is hard to do and is not necessarily effective,” explained Dr. Grace. While scrubs, warmth, and massage frequently are adequate to unclog the gland – which secretes meibum, a complex of lipids that perform several functions in protecting the eye – therapies specific to the cause, such as Demodex-related blepharitis, chalazions, and styes, might be needed.

Dr. Grace indicated that patience is often needed. The process of unclogging these glands often takes time, but she emphasized that a first-line conservative approach is always appropriate to avoid the difficulty and potential problems of incisions.

In general, these messages are not novel, but they provide a refresher for pediatric dermatologists who do not regularly confront complications that involve the eyes. According to session moderator, Elizabeth Neiman, MD, assistant professor of pediatric dermatology, University of North Carolina at Chapel Hill, the messages regarding topical steroids on the face and the eyes are “important” and worth emphasizing.

“It’s useful to reinforce the point that corticosteroids should be used when needed in the periorbital area [to control skin diseases] if they are used in low concentrations,” Dr. Neiman told this news organization.

Similarly, conjunctivitis and other ocular complications of dupilumab are a source of concern for parents as well as dermatologists. Dr. Neiman indicated that a review of the benefit-to-risk ratio is important when considering these treatments in patients with indications for severe skin disorders.

Dr. Grace and Dr. Nieman have no potential financial conflicts related to this topic.

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

For understanding the evolution in child neurology over the past 30 years, it would make sense to start with the science, particularly genetics, that have led to treatments and even cures for numerous inherited diseases over that time. When John Bodensteiner, MD, a pillar in the field of child neurology, was asked, he started with something different.

Parent advocacy accelerates advances in rare pediatric diseases

For the progress in many of the rare diseases seen by child neurologists in the last few decades, Dr. Bodensteiner first acknowledged parent support. “The concept was simple initially. For so many of these relatively rare diseases, like the Rett and Sturge-Weber syndromes, parents were learning of them for the first time. The support groups helped parents understand they were not alone. But it then evolved,” recalled Dr. Bodensteiner, who has been a professor of pediatrics and neurology at numerous institutions, most recently the Mayo Clinic in Rochester, Minn.

Many of these support groups first formed, or at least gained momentum, in the 1990s. “As the support groups grew, the members expanded their role to support research, in addition to supporting each other. They ended up volunteering their own data, providing more information about the epidemiology and disease course. They offered tissue samples for experimental studies. They enrolled their children in trials. And they raised funds,” Dr. Bodensteiner explained.

The impact of this advocacy has been enormous, according to Dr. Bodensteiner. As an expert in neuromuscular diseases, he worked directly with several of these groups.

Although the growth in parent advocacy took place in parallel with major advances in genetics that were driving new insights into disease pathophysiology, Dr. Bodensteiner characterized parent advocates as important partners in accelerating the transition of new information to clinical utility. He suggested that there is little doubt about the importance of their role in moving the science forward by drawing attention to rare disorders that had few, if any, treatment options at the time the advocacy groups were formed.

Since the 1990s, the list of childhood neurologic diseases for which there has been meaningful progress is long. Dr. Bodensteiner selected several examples. For Rett syndrome, key molecular mechanisms have now been isolated, providing meaningful targets that show potential for treatment. For spinal muscular atrophy (SMA), therapies have become available, one of which involves gene replacement that appears to provide cure if initiated early in life. For tuberous sclerosis complex (TSC), gene targets are showing strong promise for controlling seizures and other TSC manifestations.

It has also to be acknowledged that much of the ongoing expansion in knowledge taking place across diseases in pediatric neurology would have taken place with or without parent support. Dr. Bodensteiner singled out seizure disorders only as an illustration. “In the various forms of epilepsy, we now understand mechanisms in much greater detail than we did even a decade ago, let alone 30 years ago,” Dr. Bodensteiner said. In the context of the seizure medicines once widely employed on an empirical basis, “we now often have a clearer picture of why one drug works and not another.”
 

Growing pains: Child neurology evolves from a subspecialty to a specialty

Until about 10 years ago, child neurology was a subspecialty, variably placed within the departments of pediatrics or neurology based on institution. The decision to elevate child neurology to its own specialty solved some issues but created others, according to Dr. Bodensteiner.

“The initial problem was there was no immediate funding mechanism of residency slots and training,” Dr. Bodensteiner explained. The issue was particularly acute at smaller centers that had been able to support a subspecialty within another department but struggled with a new autonomous unit.

So far, the training requirements for specializing in child neurology remain largely unchanged. Clinical training requires 2 years of straight pediatrics, 1 year of adult neurology, 1 year of basic neurological science,” and 1 year of child neurology, but Dr. Bodensteiner said it might be time to reconsider. He pointed out that neurologists in general and child neurologists specifically are becoming increasingly focused in one area of expertise, such as epilepsy, neuromuscular diseases, and neurodevelopmental delay.

“It can be argued that a few months spent in a dementia clinic during training might not be the best use of time for a child neurologist working in congenital neurological diseases,” he said.

One consequence of the increasing degree of specialization in neurology overall, not just child neurology, has been the changes in recertification, according to Dr. Bodensteiner. Following a model used in other specialties, recertification in child neurology was initially based on an every-10-year examination. Ultimately, this was recognized as inconsistent with the target of keeping clinicians up to date.

“In general, I think that a lot of people waited for 9.5 years before cramming for an examination that was not necessarily relevant to the area in which they were working,” Dr. Bodensteiner said.

The revised process, carried out on an every-3-year cycle, involves board-guided review of the medical literature in 10 topic areas. Child neurologists can elect an article in any of the topic areas, but to complete their recertification process they must read articles in eight of these areas. Dr. Bodensteiner said that this approach has been more popular and is presumably more useful for staying abreast of developments.
 

Increased specialization necessitates collaboration

The radical increase in specialization in child neurology, like neurology in general, has been a necessary consequence of an avalanche of new information as advances in the field accelerate, but Dr. Bodensteiner cautioned that it is important for those working in these specialized areas to collaborate with others outside of their field of expertise.

“We cannot recognize what we do not know,” Dr. Bodensteiner said. If subspecialization within neurology is critical to stay current with rapid advances in very different diseases, then it also means that clinicians at every level, including within the field of child neurology, need to know when to collaborate or refer to ensure early diagnosis in challenging cases.

“Epileptologists have been trying for years to make it widely known that patients resistant to standard medications deserve referral, but I think this is increasingly true across domains,” Dr. Bodensteiner said. Neurology and child neurology are not alone, but the window of opportunity for effective intervention in children with a progressive disease might be particularly limited.

“The point is that this is more of a risk than it was 20 years ago,” said Dr. Bodensteiner, referring to the growth in new therapies. He cited data suggesting that a causative gene mutation can be identified in about 60% of rare diseases, which is a relatively new phenomenon. Of advances to improve outcomes, faster triage is becoming one of the most important in this increasingly specialized world.

With the growth in knowledge, “there is really no way to be an expert across all diseases in child neurology,” Dr. Bodensteiner said. “As physicians become increasingly insulated in their areas of expertise, I think there needs to be a greater emphasis on communication and collaboration.”

To some degree, this type of specialization has always existed, but Dr. Bodensteiner said the intensification of this trend is among the ways the field has most evolved over the past few decades. In inherited diseases that affect early child development, working together for a prompt diagnosis has assumed a new level of urgency.

For understanding the evolution in child neurology over the past 30 years, it would make sense to start with the science, particularly genetics, that have led to treatments and even cures for numerous inherited diseases over that time. When John Bodensteiner, MD, a pillar in the field of child neurology, was asked, he started with something different.

Parent advocacy accelerates advances in rare pediatric diseases

For the progress in many of the rare diseases seen by child neurologists in the last few decades, Dr. Bodensteiner first acknowledged parent support. “The concept was simple initially. For so many of these relatively rare diseases, like the Rett and Sturge-Weber syndromes, parents were learning of them for the first time. The support groups helped parents understand they were not alone. But it then evolved,” recalled Dr. Bodensteiner, who has been a professor of pediatrics and neurology at numerous institutions, most recently the Mayo Clinic in Rochester, Minn.

Many of these support groups first formed, or at least gained momentum, in the 1990s. “As the support groups grew, the members expanded their role to support research, in addition to supporting each other. They ended up volunteering their own data, providing more information about the epidemiology and disease course. They offered tissue samples for experimental studies. They enrolled their children in trials. And they raised funds,” Dr. Bodensteiner explained.

The impact of this advocacy has been enormous, according to Dr. Bodensteiner. As an expert in neuromuscular diseases, he worked directly with several of these groups.

Although the growth in parent advocacy took place in parallel with major advances in genetics that were driving new insights into disease pathophysiology, Dr. Bodensteiner characterized parent advocates as important partners in accelerating the transition of new information to clinical utility. He suggested that there is little doubt about the importance of their role in moving the science forward by drawing attention to rare disorders that had few, if any, treatment options at the time the advocacy groups were formed.

Since the 1990s, the list of childhood neurologic diseases for which there has been meaningful progress is long. Dr. Bodensteiner selected several examples. For Rett syndrome, key molecular mechanisms have now been isolated, providing meaningful targets that show potential for treatment. For spinal muscular atrophy (SMA), therapies have become available, one of which involves gene replacement that appears to provide cure if initiated early in life. For tuberous sclerosis complex (TSC), gene targets are showing strong promise for controlling seizures and other TSC manifestations.

It has also to be acknowledged that much of the ongoing expansion in knowledge taking place across diseases in pediatric neurology would have taken place with or without parent support. Dr. Bodensteiner singled out seizure disorders only as an illustration. “In the various forms of epilepsy, we now understand mechanisms in much greater detail than we did even a decade ago, let alone 30 years ago,” Dr. Bodensteiner said. In the context of the seizure medicines once widely employed on an empirical basis, “we now often have a clearer picture of why one drug works and not another.”
 

Growing pains: Child neurology evolves from a subspecialty to a specialty

Until about 10 years ago, child neurology was a subspecialty, variably placed within the departments of pediatrics or neurology based on institution. The decision to elevate child neurology to its own specialty solved some issues but created others, according to Dr. Bodensteiner.

“The initial problem was there was no immediate funding mechanism of residency slots and training,” Dr. Bodensteiner explained. The issue was particularly acute at smaller centers that had been able to support a subspecialty within another department but struggled with a new autonomous unit.

So far, the training requirements for specializing in child neurology remain largely unchanged. Clinical training requires 2 years of straight pediatrics, 1 year of adult neurology, 1 year of basic neurological science,” and 1 year of child neurology, but Dr. Bodensteiner said it might be time to reconsider. He pointed out that neurologists in general and child neurologists specifically are becoming increasingly focused in one area of expertise, such as epilepsy, neuromuscular diseases, and neurodevelopmental delay.

“It can be argued that a few months spent in a dementia clinic during training might not be the best use of time for a child neurologist working in congenital neurological diseases,” he said.

One consequence of the increasing degree of specialization in neurology overall, not just child neurology, has been the changes in recertification, according to Dr. Bodensteiner. Following a model used in other specialties, recertification in child neurology was initially based on an every-10-year examination. Ultimately, this was recognized as inconsistent with the target of keeping clinicians up to date.

“In general, I think that a lot of people waited for 9.5 years before cramming for an examination that was not necessarily relevant to the area in which they were working,” Dr. Bodensteiner said.

The revised process, carried out on an every-3-year cycle, involves board-guided review of the medical literature in 10 topic areas. Child neurologists can elect an article in any of the topic areas, but to complete their recertification process they must read articles in eight of these areas. Dr. Bodensteiner said that this approach has been more popular and is presumably more useful for staying abreast of developments.
 

Increased specialization necessitates collaboration

The radical increase in specialization in child neurology, like neurology in general, has been a necessary consequence of an avalanche of new information as advances in the field accelerate, but Dr. Bodensteiner cautioned that it is important for those working in these specialized areas to collaborate with others outside of their field of expertise.

“We cannot recognize what we do not know,” Dr. Bodensteiner said. If subspecialization within neurology is critical to stay current with rapid advances in very different diseases, then it also means that clinicians at every level, including within the field of child neurology, need to know when to collaborate or refer to ensure early diagnosis in challenging cases.

“Epileptologists have been trying for years to make it widely known that patients resistant to standard medications deserve referral, but I think this is increasingly true across domains,” Dr. Bodensteiner said. Neurology and child neurology are not alone, but the window of opportunity for effective intervention in children with a progressive disease might be particularly limited.

“The point is that this is more of a risk than it was 20 years ago,” said Dr. Bodensteiner, referring to the growth in new therapies. He cited data suggesting that a causative gene mutation can be identified in about 60% of rare diseases, which is a relatively new phenomenon. Of advances to improve outcomes, faster triage is becoming one of the most important in this increasingly specialized world.

With the growth in knowledge, “there is really no way to be an expert across all diseases in child neurology,” Dr. Bodensteiner said. “As physicians become increasingly insulated in their areas of expertise, I think there needs to be a greater emphasis on communication and collaboration.”

To some degree, this type of specialization has always existed, but Dr. Bodensteiner said the intensification of this trend is among the ways the field has most evolved over the past few decades. In inherited diseases that affect early child development, working together for a prompt diagnosis has assumed a new level of urgency.

For understanding the evolution in child neurology over the past 30 years, it would make sense to start with the science, particularly genetics, that have led to treatments and even cures for numerous inherited diseases over that time. When John Bodensteiner, MD, a pillar in the field of child neurology, was asked, he started with something different.

Parent advocacy accelerates advances in rare pediatric diseases

For the progress in many of the rare diseases seen by child neurologists in the last few decades, Dr. Bodensteiner first acknowledged parent support. “The concept was simple initially. For so many of these relatively rare diseases, like the Rett and Sturge-Weber syndromes, parents were learning of them for the first time. The support groups helped parents understand they were not alone. But it then evolved,” recalled Dr. Bodensteiner, who has been a professor of pediatrics and neurology at numerous institutions, most recently the Mayo Clinic in Rochester, Minn.

Many of these support groups first formed, or at least gained momentum, in the 1990s. “As the support groups grew, the members expanded their role to support research, in addition to supporting each other. They ended up volunteering their own data, providing more information about the epidemiology and disease course. They offered tissue samples for experimental studies. They enrolled their children in trials. And they raised funds,” Dr. Bodensteiner explained.

The impact of this advocacy has been enormous, according to Dr. Bodensteiner. As an expert in neuromuscular diseases, he worked directly with several of these groups.

Although the growth in parent advocacy took place in parallel with major advances in genetics that were driving new insights into disease pathophysiology, Dr. Bodensteiner characterized parent advocates as important partners in accelerating the transition of new information to clinical utility. He suggested that there is little doubt about the importance of their role in moving the science forward by drawing attention to rare disorders that had few, if any, treatment options at the time the advocacy groups were formed.

Since the 1990s, the list of childhood neurologic diseases for which there has been meaningful progress is long. Dr. Bodensteiner selected several examples. For Rett syndrome, key molecular mechanisms have now been isolated, providing meaningful targets that show potential for treatment. For spinal muscular atrophy (SMA), therapies have become available, one of which involves gene replacement that appears to provide cure if initiated early in life. For tuberous sclerosis complex (TSC), gene targets are showing strong promise for controlling seizures and other TSC manifestations.

It has also to be acknowledged that much of the ongoing expansion in knowledge taking place across diseases in pediatric neurology would have taken place with or without parent support. Dr. Bodensteiner singled out seizure disorders only as an illustration. “In the various forms of epilepsy, we now understand mechanisms in much greater detail than we did even a decade ago, let alone 30 years ago,” Dr. Bodensteiner said. In the context of the seizure medicines once widely employed on an empirical basis, “we now often have a clearer picture of why one drug works and not another.”
 

Growing pains: Child neurology evolves from a subspecialty to a specialty

Until about 10 years ago, child neurology was a subspecialty, variably placed within the departments of pediatrics or neurology based on institution. The decision to elevate child neurology to its own specialty solved some issues but created others, according to Dr. Bodensteiner.

“The initial problem was there was no immediate funding mechanism of residency slots and training,” Dr. Bodensteiner explained. The issue was particularly acute at smaller centers that had been able to support a subspecialty within another department but struggled with a new autonomous unit.

So far, the training requirements for specializing in child neurology remain largely unchanged. Clinical training requires 2 years of straight pediatrics, 1 year of adult neurology, 1 year of basic neurological science,” and 1 year of child neurology, but Dr. Bodensteiner said it might be time to reconsider. He pointed out that neurologists in general and child neurologists specifically are becoming increasingly focused in one area of expertise, such as epilepsy, neuromuscular diseases, and neurodevelopmental delay.

“It can be argued that a few months spent in a dementia clinic during training might not be the best use of time for a child neurologist working in congenital neurological diseases,” he said.

One consequence of the increasing degree of specialization in neurology overall, not just child neurology, has been the changes in recertification, according to Dr. Bodensteiner. Following a model used in other specialties, recertification in child neurology was initially based on an every-10-year examination. Ultimately, this was recognized as inconsistent with the target of keeping clinicians up to date.

“In general, I think that a lot of people waited for 9.5 years before cramming for an examination that was not necessarily relevant to the area in which they were working,” Dr. Bodensteiner said.

The revised process, carried out on an every-3-year cycle, involves board-guided review of the medical literature in 10 topic areas. Child neurologists can elect an article in any of the topic areas, but to complete their recertification process they must read articles in eight of these areas. Dr. Bodensteiner said that this approach has been more popular and is presumably more useful for staying abreast of developments.
 

Increased specialization necessitates collaboration

The radical increase in specialization in child neurology, like neurology in general, has been a necessary consequence of an avalanche of new information as advances in the field accelerate, but Dr. Bodensteiner cautioned that it is important for those working in these specialized areas to collaborate with others outside of their field of expertise.

“We cannot recognize what we do not know,” Dr. Bodensteiner said. If subspecialization within neurology is critical to stay current with rapid advances in very different diseases, then it also means that clinicians at every level, including within the field of child neurology, need to know when to collaborate or refer to ensure early diagnosis in challenging cases.

“Epileptologists have been trying for years to make it widely known that patients resistant to standard medications deserve referral, but I think this is increasingly true across domains,” Dr. Bodensteiner said. Neurology and child neurology are not alone, but the window of opportunity for effective intervention in children with a progressive disease might be particularly limited.

“The point is that this is more of a risk than it was 20 years ago,” said Dr. Bodensteiner, referring to the growth in new therapies. He cited data suggesting that a causative gene mutation can be identified in about 60% of rare diseases, which is a relatively new phenomenon. Of advances to improve outcomes, faster triage is becoming one of the most important in this increasingly specialized world.

With the growth in knowledge, “there is really no way to be an expert across all diseases in child neurology,” Dr. Bodensteiner said. “As physicians become increasingly insulated in their areas of expertise, I think there needs to be a greater emphasis on communication and collaboration.”

To some degree, this type of specialization has always existed, but Dr. Bodensteiner said the intensification of this trend is among the ways the field has most evolved over the past few decades. In inherited diseases that affect early child development, working together for a prompt diagnosis has assumed a new level of urgency.

In response to a randomized trial that associated elective revascularization for ischemia with an increase in noncardiac mortality versus medical therapy alone, a meta-analysis with a far larger dataset challenges this assertion, suggesting the initial conclusion is due to a type 1 error. 

With data from nearly 17,000 patients in 18 randomized trials, the meta-analysis showed no signal for increased noncardiac mortality in the revascularization group overall or across several sensitivity analyses, reports William Wijns, MD, PhD, professor of interventional cardiology, National University of Ireland, Galway.

The larger pool of data from the meta-analysis was considered compelling by several experts at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, where it was presented.

“I think these data will close once and forever this controversy,” said Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy). 

Evidence for an unexpected increased risk of noncardiac mortality was drawn from the ISCHEMIA-EXTEND study, which was published earlier this year. Numerous prior studies comparing percutaneous intervention (PCI) to medical therapy for relief of ischemia had shown no such safety signal. 

The ISCHEMIA-EXTEND study provided long-term follow up of patients enrolled in ISCHEMIA, a study that randomized patients with stable coronary disease and moderate or severe ischemia to PCI or a conservative approach. After 3.2 years of follow up, there was no reduction in risk of cardiovascular events or all-cause death. While this lack of benefit was a disappointing result from the perspective of interventional cardiology, there was also no increase in these risks. 

In ISCHEMIA-EXTEND, the more than 5,000 patients originally randomized were followed for an additional 2.5 years (total 5.7 years). During this extended period, the estimated 7-year risk of cardiovascular mortality was 22% lower in the group randomized to PCI (hazard ratio, 0.78; 95% confidence interval, 0.63-0.96) but the noncardiac mortality was increased by 44% (HR, 1.44; 95% CI, 1.08-1.91). Because of the counterbalancing effects on survival, all-cause mortality was similar in the two groups.

The newly completed meta-analysis was undertaken to address this surprising result not least because the increased rates of noncardiac death did not have a plausible explanation, according to Dr. Wijns. 

When the patients from the 18 randomized trials were compared, noncardiac death occurred in 4.68% of the 8,665 patients assigned to elective revascularization and in 4.17% of the 8,243 patients assigned to medical therapy alone at an average follow up of 5.7 years. 

This difference was not significant overall (HR, 1.09; 95% CI, 0.94-1.26; P = .26) or after sensitivity analyses. For example, there was no difference (P = .52) between an invasive or conservative approach after controlling for length of follow up. 

There was also no heterogeneity (I2 = 0%) among the studies when ISCHEMIA-EXTEND was excluded.
 

Absence of negative effect ‘is confirmed’

On the basis of a Bayesian meta-analysis designed to account for residual uncertainty (relative risk, 1.08, 95% CI, 0.90-1.30) and the consistency of results among all studies with the exception of ISCHEMIA-EXTEND (RR, 1.0; 95% CI, 0.84-1;18; P = .7), “the absence of a negative effect of revascularization on noncardiac death was confirmed,” Dr. Wijns reported. 

Based on the preponderance of evidence assembled in this meta-analysis, the “noncardiac mortality excess risk observed following revascularization relative to medical therapy was confined to a single large trial and is likely due to a type 1 error,” Dr. Wijns reported. He noted that this study is “the first large-scale meta-analysis study designed to systematically evaluate potential differences in noncardiac mortality between treatment strategies for chronic coronary syndromes.” 

Eliano P. Navarese, MD, PhD, an associate professor of interventional cardiology at Nicolaus Copernicus University, Bydgoszcz, Poland, was the lead author of this study and Dr. Wijns was a coinvestigator. The study was published simultaneously in the Journal of the American College of Cardiology at the time of the EuroPCR meeting.

In the late-breaking session where these data were presented, there was a general consensus among invited panelists that the data are convincing. For example, Michael Joner, MD, PhD, director of early clinical trials, German Heart Centre, Munich, agreed that these data “resolve the issue.” 

Bernard de Bruyne, MD, PhD, an interventional cardiologist associated with the Cardiovascular Center Aalst, Kraainem, Belgium, also agreed that these data argue convincingly against the concern raised by publication of ISCHEMIA-EXTEND, but he added that this controversy has raised an important issue.

“We should always be reporting all-cause mortality, not just cardiovascular mortality, in our clinical trials,” he said, emphasizing that extending all-cause survival, not just preventing cardiovascular-related events, should be recognized as the goal of invasive strategies.

In an editorial accompanying the publication, Dr. Harvey D. White, MD, Te Whatu Ora-Health New Zealand, Auckland, writes similarly that the current findings, “alert us to the importance of adjudicating causes of death in clinical trials. 

“The current trial-level meta-analysis may seem to dispel concerns about increases in noncardiac and cardiovascular deaths seen in some revascularization trials, but paradoxically, it has raised the need for more and careful analysis of causes of death,” Dr. White notes. He feels the signal of increased noncardiac or noncardiovascular death in ISCHEMIA EXTEND and the REVIVED trials is something “that we should pay attention to and explore the possibility that increased radiation doses with PCI may cause increased rates of cancer.” 

Further study, including longer follow-up, other datasets, and quality of life data including cognitive function and “patient-focused outcomes such as day alive out of hospital,” is needed, he concludes. 

Dr. Navarese has received research grants from Abbott and Amgen and lecture fees/honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron. Dr. Wijns reports financial relationships with Argonauts, Corrib Core Laboratory, and Rede Optimus Research. Dr. Capodanno reports financial relationships with Amgen, Daiichi Sankyo, and Sanofi. Dr. de Bruyne and Dr. Joner report financial relationships with multiple pharmaceutical and device manufacturers. Prof. White, as the John Neutze scholar, is supported by the Green Lane Research and Educational Fund. Prof. White has received grant support paid to the institution and fees for serving on steering committees of multiple trials sponsored by various companies.
 

In response to a randomized trial that associated elective revascularization for ischemia with an increase in noncardiac mortality versus medical therapy alone, a meta-analysis with a far larger dataset challenges this assertion, suggesting the initial conclusion is due to a type 1 error. 

With data from nearly 17,000 patients in 18 randomized trials, the meta-analysis showed no signal for increased noncardiac mortality in the revascularization group overall or across several sensitivity analyses, reports William Wijns, MD, PhD, professor of interventional cardiology, National University of Ireland, Galway.

The larger pool of data from the meta-analysis was considered compelling by several experts at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, where it was presented.

“I think these data will close once and forever this controversy,” said Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy). 

Evidence for an unexpected increased risk of noncardiac mortality was drawn from the ISCHEMIA-EXTEND study, which was published earlier this year. Numerous prior studies comparing percutaneous intervention (PCI) to medical therapy for relief of ischemia had shown no such safety signal. 

The ISCHEMIA-EXTEND study provided long-term follow up of patients enrolled in ISCHEMIA, a study that randomized patients with stable coronary disease and moderate or severe ischemia to PCI or a conservative approach. After 3.2 years of follow up, there was no reduction in risk of cardiovascular events or all-cause death. While this lack of benefit was a disappointing result from the perspective of interventional cardiology, there was also no increase in these risks. 

In ISCHEMIA-EXTEND, the more than 5,000 patients originally randomized were followed for an additional 2.5 years (total 5.7 years). During this extended period, the estimated 7-year risk of cardiovascular mortality was 22% lower in the group randomized to PCI (hazard ratio, 0.78; 95% confidence interval, 0.63-0.96) but the noncardiac mortality was increased by 44% (HR, 1.44; 95% CI, 1.08-1.91). Because of the counterbalancing effects on survival, all-cause mortality was similar in the two groups.

The newly completed meta-analysis was undertaken to address this surprising result not least because the increased rates of noncardiac death did not have a plausible explanation, according to Dr. Wijns. 

When the patients from the 18 randomized trials were compared, noncardiac death occurred in 4.68% of the 8,665 patients assigned to elective revascularization and in 4.17% of the 8,243 patients assigned to medical therapy alone at an average follow up of 5.7 years. 

This difference was not significant overall (HR, 1.09; 95% CI, 0.94-1.26; P = .26) or after sensitivity analyses. For example, there was no difference (P = .52) between an invasive or conservative approach after controlling for length of follow up. 

There was also no heterogeneity (I2 = 0%) among the studies when ISCHEMIA-EXTEND was excluded.
 

Absence of negative effect ‘is confirmed’

On the basis of a Bayesian meta-analysis designed to account for residual uncertainty (relative risk, 1.08, 95% CI, 0.90-1.30) and the consistency of results among all studies with the exception of ISCHEMIA-EXTEND (RR, 1.0; 95% CI, 0.84-1;18; P = .7), “the absence of a negative effect of revascularization on noncardiac death was confirmed,” Dr. Wijns reported. 

Based on the preponderance of evidence assembled in this meta-analysis, the “noncardiac mortality excess risk observed following revascularization relative to medical therapy was confined to a single large trial and is likely due to a type 1 error,” Dr. Wijns reported. He noted that this study is “the first large-scale meta-analysis study designed to systematically evaluate potential differences in noncardiac mortality between treatment strategies for chronic coronary syndromes.” 

Eliano P. Navarese, MD, PhD, an associate professor of interventional cardiology at Nicolaus Copernicus University, Bydgoszcz, Poland, was the lead author of this study and Dr. Wijns was a coinvestigator. The study was published simultaneously in the Journal of the American College of Cardiology at the time of the EuroPCR meeting.

In the late-breaking session where these data were presented, there was a general consensus among invited panelists that the data are convincing. For example, Michael Joner, MD, PhD, director of early clinical trials, German Heart Centre, Munich, agreed that these data “resolve the issue.” 

Bernard de Bruyne, MD, PhD, an interventional cardiologist associated with the Cardiovascular Center Aalst, Kraainem, Belgium, also agreed that these data argue convincingly against the concern raised by publication of ISCHEMIA-EXTEND, but he added that this controversy has raised an important issue.

“We should always be reporting all-cause mortality, not just cardiovascular mortality, in our clinical trials,” he said, emphasizing that extending all-cause survival, not just preventing cardiovascular-related events, should be recognized as the goal of invasive strategies.

In an editorial accompanying the publication, Dr. Harvey D. White, MD, Te Whatu Ora-Health New Zealand, Auckland, writes similarly that the current findings, “alert us to the importance of adjudicating causes of death in clinical trials. 

“The current trial-level meta-analysis may seem to dispel concerns about increases in noncardiac and cardiovascular deaths seen in some revascularization trials, but paradoxically, it has raised the need for more and careful analysis of causes of death,” Dr. White notes. He feels the signal of increased noncardiac or noncardiovascular death in ISCHEMIA EXTEND and the REVIVED trials is something “that we should pay attention to and explore the possibility that increased radiation doses with PCI may cause increased rates of cancer.” 

Further study, including longer follow-up, other datasets, and quality of life data including cognitive function and “patient-focused outcomes such as day alive out of hospital,” is needed, he concludes. 

Dr. Navarese has received research grants from Abbott and Amgen and lecture fees/honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron. Dr. Wijns reports financial relationships with Argonauts, Corrib Core Laboratory, and Rede Optimus Research. Dr. Capodanno reports financial relationships with Amgen, Daiichi Sankyo, and Sanofi. Dr. de Bruyne and Dr. Joner report financial relationships with multiple pharmaceutical and device manufacturers. Prof. White, as the John Neutze scholar, is supported by the Green Lane Research and Educational Fund. Prof. White has received grant support paid to the institution and fees for serving on steering committees of multiple trials sponsored by various companies.
 

In response to a randomized trial that associated elective revascularization for ischemia with an increase in noncardiac mortality versus medical therapy alone, a meta-analysis with a far larger dataset challenges this assertion, suggesting the initial conclusion is due to a type 1 error. 

With data from nearly 17,000 patients in 18 randomized trials, the meta-analysis showed no signal for increased noncardiac mortality in the revascularization group overall or across several sensitivity analyses, reports William Wijns, MD, PhD, professor of interventional cardiology, National University of Ireland, Galway.

The larger pool of data from the meta-analysis was considered compelling by several experts at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions, where it was presented.

“I think these data will close once and forever this controversy,” said Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy). 

Evidence for an unexpected increased risk of noncardiac mortality was drawn from the ISCHEMIA-EXTEND study, which was published earlier this year. Numerous prior studies comparing percutaneous intervention (PCI) to medical therapy for relief of ischemia had shown no such safety signal. 

The ISCHEMIA-EXTEND study provided long-term follow up of patients enrolled in ISCHEMIA, a study that randomized patients with stable coronary disease and moderate or severe ischemia to PCI or a conservative approach. After 3.2 years of follow up, there was no reduction in risk of cardiovascular events or all-cause death. While this lack of benefit was a disappointing result from the perspective of interventional cardiology, there was also no increase in these risks. 

In ISCHEMIA-EXTEND, the more than 5,000 patients originally randomized were followed for an additional 2.5 years (total 5.7 years). During this extended period, the estimated 7-year risk of cardiovascular mortality was 22% lower in the group randomized to PCI (hazard ratio, 0.78; 95% confidence interval, 0.63-0.96) but the noncardiac mortality was increased by 44% (HR, 1.44; 95% CI, 1.08-1.91). Because of the counterbalancing effects on survival, all-cause mortality was similar in the two groups.

The newly completed meta-analysis was undertaken to address this surprising result not least because the increased rates of noncardiac death did not have a plausible explanation, according to Dr. Wijns. 

When the patients from the 18 randomized trials were compared, noncardiac death occurred in 4.68% of the 8,665 patients assigned to elective revascularization and in 4.17% of the 8,243 patients assigned to medical therapy alone at an average follow up of 5.7 years. 

This difference was not significant overall (HR, 1.09; 95% CI, 0.94-1.26; P = .26) or after sensitivity analyses. For example, there was no difference (P = .52) between an invasive or conservative approach after controlling for length of follow up. 

There was also no heterogeneity (I2 = 0%) among the studies when ISCHEMIA-EXTEND was excluded.
 

Absence of negative effect ‘is confirmed’

On the basis of a Bayesian meta-analysis designed to account for residual uncertainty (relative risk, 1.08, 95% CI, 0.90-1.30) and the consistency of results among all studies with the exception of ISCHEMIA-EXTEND (RR, 1.0; 95% CI, 0.84-1;18; P = .7), “the absence of a negative effect of revascularization on noncardiac death was confirmed,” Dr. Wijns reported. 

Based on the preponderance of evidence assembled in this meta-analysis, the “noncardiac mortality excess risk observed following revascularization relative to medical therapy was confined to a single large trial and is likely due to a type 1 error,” Dr. Wijns reported. He noted that this study is “the first large-scale meta-analysis study designed to systematically evaluate potential differences in noncardiac mortality between treatment strategies for chronic coronary syndromes.” 

Eliano P. Navarese, MD, PhD, an associate professor of interventional cardiology at Nicolaus Copernicus University, Bydgoszcz, Poland, was the lead author of this study and Dr. Wijns was a coinvestigator. The study was published simultaneously in the Journal of the American College of Cardiology at the time of the EuroPCR meeting.

In the late-breaking session where these data were presented, there was a general consensus among invited panelists that the data are convincing. For example, Michael Joner, MD, PhD, director of early clinical trials, German Heart Centre, Munich, agreed that these data “resolve the issue.” 

Bernard de Bruyne, MD, PhD, an interventional cardiologist associated with the Cardiovascular Center Aalst, Kraainem, Belgium, also agreed that these data argue convincingly against the concern raised by publication of ISCHEMIA-EXTEND, but he added that this controversy has raised an important issue.

“We should always be reporting all-cause mortality, not just cardiovascular mortality, in our clinical trials,” he said, emphasizing that extending all-cause survival, not just preventing cardiovascular-related events, should be recognized as the goal of invasive strategies.

In an editorial accompanying the publication, Dr. Harvey D. White, MD, Te Whatu Ora-Health New Zealand, Auckland, writes similarly that the current findings, “alert us to the importance of adjudicating causes of death in clinical trials. 

“The current trial-level meta-analysis may seem to dispel concerns about increases in noncardiac and cardiovascular deaths seen in some revascularization trials, but paradoxically, it has raised the need for more and careful analysis of causes of death,” Dr. White notes. He feels the signal of increased noncardiac or noncardiovascular death in ISCHEMIA EXTEND and the REVIVED trials is something “that we should pay attention to and explore the possibility that increased radiation doses with PCI may cause increased rates of cancer.” 

Further study, including longer follow-up, other datasets, and quality of life data including cognitive function and “patient-focused outcomes such as day alive out of hospital,” is needed, he concludes. 

Dr. Navarese has received research grants from Abbott and Amgen and lecture fees/honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron. Dr. Wijns reports financial relationships with Argonauts, Corrib Core Laboratory, and Rede Optimus Research. Dr. Capodanno reports financial relationships with Amgen, Daiichi Sankyo, and Sanofi. Dr. de Bruyne and Dr. Joner report financial relationships with multiple pharmaceutical and device manufacturers. Prof. White, as the John Neutze scholar, is supported by the Green Lane Research and Educational Fund. Prof. White has received grant support paid to the institution and fees for serving on steering committees of multiple trials sponsored by various companies.
 

At the time that it was halted, a multicenter randomized trial was associating venoarterial extracorporeal membrane oxygenation (VA-ECMO) with an intriguing signal of benefit for patients in cardiogenic shock undergoing percutaneous intervention (PCI) for acute myocardial infarction.

Stopped early because of the pandemic, the EURO SHOCK trial has data on only 35 patients, but all-cause mortality at 30 days was nearly 30% lower in the VA-ECMO arm than in the standard-therapy arm, reported Manel Sabate, MD, PhD, chief of the interventional cardiology unit, Clinic University Hospital, Barcelona.

When patients were followed out to 12 months, the numerical survival advantage appeared to persist.

Yet, because of the early trial termination, “there really are no definite conclusions to be drawn from these results,” acknowledged Dr. Sabate, who noted that less than 10% of the planned enrollment had been reached. In addition, the survival benefit in the VA-ECMO arm was achieved at the cost of a higher rate of complications.

Despite the small numbers, results from the halted trial were presented as a late-breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. They were also simultaneously published in EuroIntervention.

The interest is based on an important unmet need, said Dr. Sabate. Cardiogenic shock occurs in about 10% of acute MI patients. Of those that continue on to revascularization, the 30-day mortality can approach 50%.

Meanwhile, the potential of mechanical circulatory support to maintain perfusion during cardiogenic shock makes it one of the most attractive, if unproven, approaches for improving outcomes.
 

Major multicenter trial terminated

The EURO SHOCK trial had a planned enrollment of 428 patients when it was initiated; 15 centers in six European countries participated. Recruitment and the trial were brought to a halt by the COVID-19 pandemic.

When trial recruitment was stopped, 18 patients had been assigned to standard supportive care and 17 patients to VA-ECMO. The primary endpoint of the trial was all-cause mortality at 30 days. Mortality at 12 months along with bleeding complications, cerebrovascular events, and readmission for heart failure, were among secondary endpoints.

At 30 days, the mortality rate was 61.1% among patients randomized to standard care, versus 43.8% among patients randomized to VA ECMO (hazard ratio, 0.56; 95% confidence interval, 0.21-01.45; P = 0.22).

At 12 months, the numerical advantage of VA-ECMO persisted (81.5% vs. 51.8%) with a similar nonsignificant signal for potential benefit despite the small sample size (HR, 0.52; 95% CI, 0.21-1.26; P = 0.14).

There were also numerically lower rates of cardiovascular death, ischemic stroke, recurrent MI, and acute kidney injury among patients in the VA-ECMO group relative to those in the standard-care group, Dr. Sabate reported.

However, VA-ECMO was associated with more vascular complications (21.4% vs. 0%) and bleeding events (35.7% vs. 5.6%).

Furthermore, although quality of life data were limited, Dr. Sabate noted that about half of patients in the VA-ECMO group reported problems with mobility, self-care, or usual activities on the basis of the EQ-5D-3L questionnaire at 30 days. None of the patients in the standard-care group reported any such difficulties.

When standard care was compared with VA-ECMO, rates of readmission for heart failure over 12 months (8.0% vs. 6.9%) were not different.

To be enrolled in this study, patients being treated for MI had to be in cardiogenic shock for at least 30 minutes following primary PCI. The median time from onset of cardiogenic shock to VA-ECMO in the active treatment arm was 4.8 hours.
 

Patient enrollment was challenging

Even independent of the COVID-19 pandemic, enrolling patients proved to be difficult. The 35 patients enrolled represented about 10% of the 333 patients screened at the participating centers. Unwitnessed out-of-hospital cardiac arrest, cardiogenic shock from a cause other than MI, and recovery from cardiogenic shock after the PCI was performed were among reasons for the high rate of exclusions.

The difficulty of identifying and engaging appropriate candidates for VA-ECMO, along with a substantial crossover rate, should be among lessons for investigators planning the next trial, said Dr. Sabate, who pointed out that 5 of the 17 patients assigned to VA-ECMO were never treated due to complications or patient refusal.

“We cannot associate VA-ECMO with a favorable benefit-to-risk ratio on the basis of this study, but it sets the state for a larger randomized controlled trial to address this question,” Dr. Sabate said.

Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy), agreed.

“It was a good decision to publish these results,” he said. Noting that there were challenges in conducting the trial unrelated to COVID-19, Dr. Capodanno acknowledged the promise of mechanical ventilatory support for a relatively common and life-threatening complication.

“This study must be read for the lessons it will provide for future trials,” he said.

Dr. Sabate reported he has no potential conflicts of interest. Dr. Capodanno reported financial relationships with Amgen, Daiichi Sankyo, and Sanofi.

At the time that it was halted, a multicenter randomized trial was associating venoarterial extracorporeal membrane oxygenation (VA-ECMO) with an intriguing signal of benefit for patients in cardiogenic shock undergoing percutaneous intervention (PCI) for acute myocardial infarction.

Stopped early because of the pandemic, the EURO SHOCK trial has data on only 35 patients, but all-cause mortality at 30 days was nearly 30% lower in the VA-ECMO arm than in the standard-therapy arm, reported Manel Sabate, MD, PhD, chief of the interventional cardiology unit, Clinic University Hospital, Barcelona.

When patients were followed out to 12 months, the numerical survival advantage appeared to persist.

Yet, because of the early trial termination, “there really are no definite conclusions to be drawn from these results,” acknowledged Dr. Sabate, who noted that less than 10% of the planned enrollment had been reached. In addition, the survival benefit in the VA-ECMO arm was achieved at the cost of a higher rate of complications.

Despite the small numbers, results from the halted trial were presented as a late-breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. They were also simultaneously published in EuroIntervention.

The interest is based on an important unmet need, said Dr. Sabate. Cardiogenic shock occurs in about 10% of acute MI patients. Of those that continue on to revascularization, the 30-day mortality can approach 50%.

Meanwhile, the potential of mechanical circulatory support to maintain perfusion during cardiogenic shock makes it one of the most attractive, if unproven, approaches for improving outcomes.
 

Major multicenter trial terminated

The EURO SHOCK trial had a planned enrollment of 428 patients when it was initiated; 15 centers in six European countries participated. Recruitment and the trial were brought to a halt by the COVID-19 pandemic.

When trial recruitment was stopped, 18 patients had been assigned to standard supportive care and 17 patients to VA-ECMO. The primary endpoint of the trial was all-cause mortality at 30 days. Mortality at 12 months along with bleeding complications, cerebrovascular events, and readmission for heart failure, were among secondary endpoints.

At 30 days, the mortality rate was 61.1% among patients randomized to standard care, versus 43.8% among patients randomized to VA ECMO (hazard ratio, 0.56; 95% confidence interval, 0.21-01.45; P = 0.22).

At 12 months, the numerical advantage of VA-ECMO persisted (81.5% vs. 51.8%) with a similar nonsignificant signal for potential benefit despite the small sample size (HR, 0.52; 95% CI, 0.21-1.26; P = 0.14).

There were also numerically lower rates of cardiovascular death, ischemic stroke, recurrent MI, and acute kidney injury among patients in the VA-ECMO group relative to those in the standard-care group, Dr. Sabate reported.

However, VA-ECMO was associated with more vascular complications (21.4% vs. 0%) and bleeding events (35.7% vs. 5.6%).

Furthermore, although quality of life data were limited, Dr. Sabate noted that about half of patients in the VA-ECMO group reported problems with mobility, self-care, or usual activities on the basis of the EQ-5D-3L questionnaire at 30 days. None of the patients in the standard-care group reported any such difficulties.

When standard care was compared with VA-ECMO, rates of readmission for heart failure over 12 months (8.0% vs. 6.9%) were not different.

To be enrolled in this study, patients being treated for MI had to be in cardiogenic shock for at least 30 minutes following primary PCI. The median time from onset of cardiogenic shock to VA-ECMO in the active treatment arm was 4.8 hours.
 

Patient enrollment was challenging

Even independent of the COVID-19 pandemic, enrolling patients proved to be difficult. The 35 patients enrolled represented about 10% of the 333 patients screened at the participating centers. Unwitnessed out-of-hospital cardiac arrest, cardiogenic shock from a cause other than MI, and recovery from cardiogenic shock after the PCI was performed were among reasons for the high rate of exclusions.

The difficulty of identifying and engaging appropriate candidates for VA-ECMO, along with a substantial crossover rate, should be among lessons for investigators planning the next trial, said Dr. Sabate, who pointed out that 5 of the 17 patients assigned to VA-ECMO were never treated due to complications or patient refusal.

“We cannot associate VA-ECMO with a favorable benefit-to-risk ratio on the basis of this study, but it sets the state for a larger randomized controlled trial to address this question,” Dr. Sabate said.

Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy), agreed.

“It was a good decision to publish these results,” he said. Noting that there were challenges in conducting the trial unrelated to COVID-19, Dr. Capodanno acknowledged the promise of mechanical ventilatory support for a relatively common and life-threatening complication.

“This study must be read for the lessons it will provide for future trials,” he said.

Dr. Sabate reported he has no potential conflicts of interest. Dr. Capodanno reported financial relationships with Amgen, Daiichi Sankyo, and Sanofi.

At the time that it was halted, a multicenter randomized trial was associating venoarterial extracorporeal membrane oxygenation (VA-ECMO) with an intriguing signal of benefit for patients in cardiogenic shock undergoing percutaneous intervention (PCI) for acute myocardial infarction.

Stopped early because of the pandemic, the EURO SHOCK trial has data on only 35 patients, but all-cause mortality at 30 days was nearly 30% lower in the VA-ECMO arm than in the standard-therapy arm, reported Manel Sabate, MD, PhD, chief of the interventional cardiology unit, Clinic University Hospital, Barcelona.

When patients were followed out to 12 months, the numerical survival advantage appeared to persist.

Yet, because of the early trial termination, “there really are no definite conclusions to be drawn from these results,” acknowledged Dr. Sabate, who noted that less than 10% of the planned enrollment had been reached. In addition, the survival benefit in the VA-ECMO arm was achieved at the cost of a higher rate of complications.

Despite the small numbers, results from the halted trial were presented as a late-breaker at the annual meeting of the European Association of Percutaneous Cardiovascular Interventions. They were also simultaneously published in EuroIntervention.

The interest is based on an important unmet need, said Dr. Sabate. Cardiogenic shock occurs in about 10% of acute MI patients. Of those that continue on to revascularization, the 30-day mortality can approach 50%.

Meanwhile, the potential of mechanical circulatory support to maintain perfusion during cardiogenic shock makes it one of the most attractive, if unproven, approaches for improving outcomes.
 

Major multicenter trial terminated

The EURO SHOCK trial had a planned enrollment of 428 patients when it was initiated; 15 centers in six European countries participated. Recruitment and the trial were brought to a halt by the COVID-19 pandemic.

When trial recruitment was stopped, 18 patients had been assigned to standard supportive care and 17 patients to VA-ECMO. The primary endpoint of the trial was all-cause mortality at 30 days. Mortality at 12 months along with bleeding complications, cerebrovascular events, and readmission for heart failure, were among secondary endpoints.

At 30 days, the mortality rate was 61.1% among patients randomized to standard care, versus 43.8% among patients randomized to VA ECMO (hazard ratio, 0.56; 95% confidence interval, 0.21-01.45; P = 0.22).

At 12 months, the numerical advantage of VA-ECMO persisted (81.5% vs. 51.8%) with a similar nonsignificant signal for potential benefit despite the small sample size (HR, 0.52; 95% CI, 0.21-1.26; P = 0.14).

There were also numerically lower rates of cardiovascular death, ischemic stroke, recurrent MI, and acute kidney injury among patients in the VA-ECMO group relative to those in the standard-care group, Dr. Sabate reported.

However, VA-ECMO was associated with more vascular complications (21.4% vs. 0%) and bleeding events (35.7% vs. 5.6%).

Furthermore, although quality of life data were limited, Dr. Sabate noted that about half of patients in the VA-ECMO group reported problems with mobility, self-care, or usual activities on the basis of the EQ-5D-3L questionnaire at 30 days. None of the patients in the standard-care group reported any such difficulties.

When standard care was compared with VA-ECMO, rates of readmission for heart failure over 12 months (8.0% vs. 6.9%) were not different.

To be enrolled in this study, patients being treated for MI had to be in cardiogenic shock for at least 30 minutes following primary PCI. The median time from onset of cardiogenic shock to VA-ECMO in the active treatment arm was 4.8 hours.
 

Patient enrollment was challenging

Even independent of the COVID-19 pandemic, enrolling patients proved to be difficult. The 35 patients enrolled represented about 10% of the 333 patients screened at the participating centers. Unwitnessed out-of-hospital cardiac arrest, cardiogenic shock from a cause other than MI, and recovery from cardiogenic shock after the PCI was performed were among reasons for the high rate of exclusions.

The difficulty of identifying and engaging appropriate candidates for VA-ECMO, along with a substantial crossover rate, should be among lessons for investigators planning the next trial, said Dr. Sabate, who pointed out that 5 of the 17 patients assigned to VA-ECMO were never treated due to complications or patient refusal.

“We cannot associate VA-ECMO with a favorable benefit-to-risk ratio on the basis of this study, but it sets the state for a larger randomized controlled trial to address this question,” Dr. Sabate said.

Davide Capodanno, MD, PhD, a professor of cardiology and interventional cardiologist at the University of Catania (Italy), agreed.

“It was a good decision to publish these results,” he said. Noting that there were challenges in conducting the trial unrelated to COVID-19, Dr. Capodanno acknowledged the promise of mechanical ventilatory support for a relatively common and life-threatening complication.

“This study must be read for the lessons it will provide for future trials,” he said.

Dr. Sabate reported he has no potential conflicts of interest. Dr. Capodanno reported financial relationships with Amgen, Daiichi Sankyo, and Sanofi.