People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.

Kmatta/Moment/Getty Images

“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”

Study results

The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).

The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.

The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
 

Expert commentary

This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”

The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.

“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”

The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.

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

People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.

Kmatta/Moment/Getty Images

“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”

Study results

The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).

The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.

The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
 

Expert commentary

This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”

The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.

“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”

The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.

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

People taking methotrexate for immunomodulatory diseases can skip one or two scheduled doses after they get an mRNA-based vaccine booster for COVID-19 and achieve a level of immunity against Omicron variants that’s comparable to people who aren’t immunosuppressed, a small observational cohort study from Germany reported.

Kmatta/Moment/Getty Images

“In general, the data suggest that pausing methotrexate is feasible, and it’s sufficient if the last dose occurs 1-3 days before the vaccination,” study coauthor Gerd Burmester, MD, a senior professor of rheumatology and immunology at the University of Medicine Berlin, told this news organization. “In pragmatic terms: pausing the methotrexate injection just twice after the vaccine is finished and, interestingly, not prior to the vaccination.”

Study results

The study found that serum neutralizing activity against the Omicron BA.1 variant, measured as geometric mean 50% inhibitory serum dilution (ID50s), wasn’t significantly different between the methotrexate and the nonimmunosuppressed groups before getting their mRNA booster (P = .657). However, 4 weeks after getting the booster, the nonimmunosuppressed group had a 68-fold increase in antibody activity versus a 20-fold increase in the methotrexate patients. After 12 weeks, ID50s in both groups decreased by about half (P = .001).

The methotrexate patients who continued therapy after the booster had significantly lower neutralization against Omicron BA.1 at both 4 weeks and 12 weeks than did their counterparts who paused therapy, as well as control patients.

The results were very similar in the same group comparisons of the serum neutralizing activity against the Omicron BA.2 variant at 4 and 12 weeks after booster vaccination.
 

Expert commentary

This study is noteworthy because it used SARS-CoV-2 pseudovirus neutralization assays to evaluate antibody levels, Kevin Winthrop, MD, MPH, professor of infectious disease and public health at Oregon Health & Science University, Portland, who was not involved in the study, said. “A lot of studies don’t look at neutralizing antibody titers, and that’s really what we care about,” Dr. Winthrop said. “What we want are functional antibodies that are doing something, and the only way to do that is to test them.”

The study is “confirmatory” of other studies that call for pausing methotrexate after vaccination, Dr. Winthrop said, including a study he coauthored, and which the German researchers cited, that found pausing methotrexate for a week or so after the influenza vaccination in RA patients improved vaccine immunogenicity. He added that the findings with the early Omicron variants are important because the newest boosters target the later Omicron variants, BA.4 and BA.5.

“The bottom line is that when someone comes in for a COVID-19 vaccination, tell them to be off of methotrexate for 7-10 days,” Dr. Winthrop said. “This is for the booster, but it raises the question: If you go out to three, four, or five vaccinations, does this matter anymore? With the flu vaccine, most people are out to 10 or 15 boosters, and we haven’t seen any significant increase in disease flares.”

The study received funding from Medac, Gilead/Galapagos, and Friends and Sponsors of Berlin Charity. Dr. Burmester reported no relevant disclosures. Dr. Winthrop is a research consultant to Pfizer.

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

The road to hell is paved with good intentions – especially true in clinical research. A Food and Drug Administration press release notes, “Historically, children were not included in clinical trials because of a misperception that excluding them from research was in fact protecting them. This resulted in many FDA-approved, licensed, cleared, or authorized drugs, biological products, and medical devices lacking pediatric-specific labeling information.” In an effort to improve on this situation, the FDA published in September 2022 a proposed new draft guidance on performing research with children that is open for public comment for 3 months.

Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].

The road to hell is paved with good intentions – especially true in clinical research. A Food and Drug Administration press release notes, “Historically, children were not included in clinical trials because of a misperception that excluding them from research was in fact protecting them. This resulted in many FDA-approved, licensed, cleared, or authorized drugs, biological products, and medical devices lacking pediatric-specific labeling information.” In an effort to improve on this situation, the FDA published in September 2022 a proposed new draft guidance on performing research with children that is open for public comment for 3 months.

Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].

The road to hell is paved with good intentions – especially true in clinical research. A Food and Drug Administration press release notes, “Historically, children were not included in clinical trials because of a misperception that excluding them from research was in fact protecting them. This resulted in many FDA-approved, licensed, cleared, or authorized drugs, biological products, and medical devices lacking pediatric-specific labeling information.” In an effort to improve on this situation, the FDA published in September 2022 a proposed new draft guidance on performing research with children that is open for public comment for 3 months.

Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

One of the more baffling decisions the CDC made during this pandemic was when they reduced the duration of isolation after a positive COVID test from 10 days to 5 days and did not require a negative antigen test to end isolation.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. He disclosed no relevant financial relationships.

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

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

One of the more baffling decisions the CDC made during this pandemic was when they reduced the duration of isolation after a positive COVID test from 10 days to 5 days and did not require a negative antigen test to end isolation.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. He disclosed no relevant financial relationships.

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

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr. F. Perry Wilson of the Yale School of Medicine.

One of the more baffling decisions the CDC made during this pandemic was when they reduced the duration of isolation after a positive COVID test from 10 days to 5 days and did not require a negative antigen test to end isolation.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. He disclosed no relevant financial relationships.

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

CINCINNATI – Cerebral palsy affects about 3 in every 1,000 children, but there is usually little sign of the condition at birth. Instead, it usually shows clinical manifestation between ages 2 and 5, and a diagnosis can trigger early interventions that can improve long-term outcomes.

Physicians and patients would benefit from a screening method for cerebral palsy at birth, but that has so far eluded researchers.

At the 2022 annual meeting of the Child Neurology Society, researchers presented evidence that respiratory rate measured in the last 24 hours of residence in the neonate intensive care unit (NICU) predicts later onset of cerebral palsy, with higher variability associated with increased cerebral palsy risk.

The study results were promising, according to Marc Patterson, MD, who comoderated the session. “It gives us more confidence in predicting the children at risk and making sure that they’re going to be followed closely to get the interventions they need to help them,” said Dr. Patterson, who is a professor of neurology, pediatrics, and medical genetics at Mayo Medical School in Rochester, Minn.

“By the time a child is 5 or 6, the symptoms are usually very obvious, but you really want to intervene as soon as possible before their brain’s plasticity decreases over time, so the earlier you can intervene in general, the better your results are going to be,” said Dr. Patterson.

There are tools available to diagnose cerebral palsy at an earlier age, including the Prechtl General Movements Assessment (GMA), which can be done up to 5 months of corrected age. It has 97% sensitivity and 89% specificity for cerebral palsy. The Hammersmith Infant Neurological Examination (HINE), which can be used in the same age range, and has 72-91% sensitivity and 100% specificity.

Both of the available tools are resource intensive and require trained clinicians, and may be unavailable in many areas. Despite these tools, early diagnosis of cerebral palsy is still underemployed, according to Arohi Saxena, a third-year medical student at Washington University in St. Louis, who presented the study results.
 

Respiratory rate variability may indicate increased risk

The researchers set out to identify objective metrics that correlated with HINE and GMA scores. They looked at kinematic data from practical assessments carried out by their physical therapists, as well as vital sign instability obtained at NICU discharge, which was based on suggestions that hemodynamic instability may be linked to later risk of cerebral palsy, according to Ms. Saxena.

They analyzed data from 31 infants with a corrected age of 8-25 weeks at a tertiary NICU follow-up clinic. Of these, 18 displayed fidgety movements on their Prechtl assessment, and 13 did not.

They used DeepLabCut software to analyze data from videos of the Prechtl assessment, with a focus on range and variance of hand and foot movements normalized to nose-to-umbilicus distance. They also analyzed pulse and respiratory data from the final 24 hours before NICU discharge.

They found that infants without fidgety movements had decreased hand and foot movement ranges (P = .04). There was no significant difference between the two groups with respect to pulse measurements. However, the respiratory rate range and variance was significantly higher in infants without fidgety movements. “Infants who are at higher risk for developing cerebral palsy had more respiratory instability early on in life,” said Ms. Saxena during her talk.

When they compared values to HINE scores, they found a correlation with less foot movement and a predisposition to develop cerebral palsy, but no correlation with hand movement. A lower HINE sore also correlated to larger respiratory rate range and variance (P < .01 for both).

“Our hypothesis to explain this link is that respiratory rate variability is likely driven by neonatal injury in the brainstem, where the respiratory centers are located. In some infants, this may correlate with more extensive cerebral injury that could predict the development of cerebral palsy,” said Ms. Saxena.

The group plans to increase its sample size as well as to conduct long-term follow-up on the infants to see how many receive formal diagnoses of cerebral palsy.

After her talk, asked by a moderator why motor assessments were not a reliable predictor in their study, Ms. Saxena pointed to the inexperience of assessors at the institution, where Prechtl testing had only recently begun.

“I think a lot of it is to do with the more subjective nature of the motor assessment. We definitely saw kind of a trend where in the earlier data that was collected, right when our institutions started doing these Prechtls, it was even less of a reliable effect. So I think possibly as clinicians continue to get more familiar with this assessment and there’s more like a validated and robust scoring system, maybe we’ll see a stronger correlation,” she said.

Ms. Saxena had no relevant disclosures. Coauthor Boomah Aravamuthan, MD, DPhil, is a consultant for Neurocrine Biosciences and has received royalties from UpToDate and funding from the National Institute of Neurological Disorders and Stroke.

CINCINNATI – Cerebral palsy affects about 3 in every 1,000 children, but there is usually little sign of the condition at birth. Instead, it usually shows clinical manifestation between ages 2 and 5, and a diagnosis can trigger early interventions that can improve long-term outcomes.

Physicians and patients would benefit from a screening method for cerebral palsy at birth, but that has so far eluded researchers.

At the 2022 annual meeting of the Child Neurology Society, researchers presented evidence that respiratory rate measured in the last 24 hours of residence in the neonate intensive care unit (NICU) predicts later onset of cerebral palsy, with higher variability associated with increased cerebral palsy risk.

The study results were promising, according to Marc Patterson, MD, who comoderated the session. “It gives us more confidence in predicting the children at risk and making sure that they’re going to be followed closely to get the interventions they need to help them,” said Dr. Patterson, who is a professor of neurology, pediatrics, and medical genetics at Mayo Medical School in Rochester, Minn.

“By the time a child is 5 or 6, the symptoms are usually very obvious, but you really want to intervene as soon as possible before their brain’s plasticity decreases over time, so the earlier you can intervene in general, the better your results are going to be,” said Dr. Patterson.

There are tools available to diagnose cerebral palsy at an earlier age, including the Prechtl General Movements Assessment (GMA), which can be done up to 5 months of corrected age. It has 97% sensitivity and 89% specificity for cerebral palsy. The Hammersmith Infant Neurological Examination (HINE), which can be used in the same age range, and has 72-91% sensitivity and 100% specificity.

Both of the available tools are resource intensive and require trained clinicians, and may be unavailable in many areas. Despite these tools, early diagnosis of cerebral palsy is still underemployed, according to Arohi Saxena, a third-year medical student at Washington University in St. Louis, who presented the study results.
 

Respiratory rate variability may indicate increased risk

The researchers set out to identify objective metrics that correlated with HINE and GMA scores. They looked at kinematic data from practical assessments carried out by their physical therapists, as well as vital sign instability obtained at NICU discharge, which was based on suggestions that hemodynamic instability may be linked to later risk of cerebral palsy, according to Ms. Saxena.

They analyzed data from 31 infants with a corrected age of 8-25 weeks at a tertiary NICU follow-up clinic. Of these, 18 displayed fidgety movements on their Prechtl assessment, and 13 did not.

They used DeepLabCut software to analyze data from videos of the Prechtl assessment, with a focus on range and variance of hand and foot movements normalized to nose-to-umbilicus distance. They also analyzed pulse and respiratory data from the final 24 hours before NICU discharge.

They found that infants without fidgety movements had decreased hand and foot movement ranges (P = .04). There was no significant difference between the two groups with respect to pulse measurements. However, the respiratory rate range and variance was significantly higher in infants without fidgety movements. “Infants who are at higher risk for developing cerebral palsy had more respiratory instability early on in life,” said Ms. Saxena during her talk.

When they compared values to HINE scores, they found a correlation with less foot movement and a predisposition to develop cerebral palsy, but no correlation with hand movement. A lower HINE sore also correlated to larger respiratory rate range and variance (P < .01 for both).

“Our hypothesis to explain this link is that respiratory rate variability is likely driven by neonatal injury in the brainstem, where the respiratory centers are located. In some infants, this may correlate with more extensive cerebral injury that could predict the development of cerebral palsy,” said Ms. Saxena.

The group plans to increase its sample size as well as to conduct long-term follow-up on the infants to see how many receive formal diagnoses of cerebral palsy.

After her talk, asked by a moderator why motor assessments were not a reliable predictor in their study, Ms. Saxena pointed to the inexperience of assessors at the institution, where Prechtl testing had only recently begun.

“I think a lot of it is to do with the more subjective nature of the motor assessment. We definitely saw kind of a trend where in the earlier data that was collected, right when our institutions started doing these Prechtls, it was even less of a reliable effect. So I think possibly as clinicians continue to get more familiar with this assessment and there’s more like a validated and robust scoring system, maybe we’ll see a stronger correlation,” she said.

Ms. Saxena had no relevant disclosures. Coauthor Boomah Aravamuthan, MD, DPhil, is a consultant for Neurocrine Biosciences and has received royalties from UpToDate and funding from the National Institute of Neurological Disorders and Stroke.

CINCINNATI – Cerebral palsy affects about 3 in every 1,000 children, but there is usually little sign of the condition at birth. Instead, it usually shows clinical manifestation between ages 2 and 5, and a diagnosis can trigger early interventions that can improve long-term outcomes.

Physicians and patients would benefit from a screening method for cerebral palsy at birth, but that has so far eluded researchers.

At the 2022 annual meeting of the Child Neurology Society, researchers presented evidence that respiratory rate measured in the last 24 hours of residence in the neonate intensive care unit (NICU) predicts later onset of cerebral palsy, with higher variability associated with increased cerebral palsy risk.

The study results were promising, according to Marc Patterson, MD, who comoderated the session. “It gives us more confidence in predicting the children at risk and making sure that they’re going to be followed closely to get the interventions they need to help them,” said Dr. Patterson, who is a professor of neurology, pediatrics, and medical genetics at Mayo Medical School in Rochester, Minn.

“By the time a child is 5 or 6, the symptoms are usually very obvious, but you really want to intervene as soon as possible before their brain’s plasticity decreases over time, so the earlier you can intervene in general, the better your results are going to be,” said Dr. Patterson.

There are tools available to diagnose cerebral palsy at an earlier age, including the Prechtl General Movements Assessment (GMA), which can be done up to 5 months of corrected age. It has 97% sensitivity and 89% specificity for cerebral palsy. The Hammersmith Infant Neurological Examination (HINE), which can be used in the same age range, and has 72-91% sensitivity and 100% specificity.

Both of the available tools are resource intensive and require trained clinicians, and may be unavailable in many areas. Despite these tools, early diagnosis of cerebral palsy is still underemployed, according to Arohi Saxena, a third-year medical student at Washington University in St. Louis, who presented the study results.
 

Respiratory rate variability may indicate increased risk

The researchers set out to identify objective metrics that correlated with HINE and GMA scores. They looked at kinematic data from practical assessments carried out by their physical therapists, as well as vital sign instability obtained at NICU discharge, which was based on suggestions that hemodynamic instability may be linked to later risk of cerebral palsy, according to Ms. Saxena.

They analyzed data from 31 infants with a corrected age of 8-25 weeks at a tertiary NICU follow-up clinic. Of these, 18 displayed fidgety movements on their Prechtl assessment, and 13 did not.

They used DeepLabCut software to analyze data from videos of the Prechtl assessment, with a focus on range and variance of hand and foot movements normalized to nose-to-umbilicus distance. They also analyzed pulse and respiratory data from the final 24 hours before NICU discharge.

They found that infants without fidgety movements had decreased hand and foot movement ranges (P = .04). There was no significant difference between the two groups with respect to pulse measurements. However, the respiratory rate range and variance was significantly higher in infants without fidgety movements. “Infants who are at higher risk for developing cerebral palsy had more respiratory instability early on in life,” said Ms. Saxena during her talk.

When they compared values to HINE scores, they found a correlation with less foot movement and a predisposition to develop cerebral palsy, but no correlation with hand movement. A lower HINE sore also correlated to larger respiratory rate range and variance (P < .01 for both).

“Our hypothesis to explain this link is that respiratory rate variability is likely driven by neonatal injury in the brainstem, where the respiratory centers are located. In some infants, this may correlate with more extensive cerebral injury that could predict the development of cerebral palsy,” said Ms. Saxena.

The group plans to increase its sample size as well as to conduct long-term follow-up on the infants to see how many receive formal diagnoses of cerebral palsy.

After her talk, asked by a moderator why motor assessments were not a reliable predictor in their study, Ms. Saxena pointed to the inexperience of assessors at the institution, where Prechtl testing had only recently begun.

“I think a lot of it is to do with the more subjective nature of the motor assessment. We definitely saw kind of a trend where in the earlier data that was collected, right when our institutions started doing these Prechtls, it was even less of a reliable effect. So I think possibly as clinicians continue to get more familiar with this assessment and there’s more like a validated and robust scoring system, maybe we’ll see a stronger correlation,” she said.

Ms. Saxena had no relevant disclosures. Coauthor Boomah Aravamuthan, MD, DPhil, is a consultant for Neurocrine Biosciences and has received royalties from UpToDate and funding from the National Institute of Neurological Disorders and Stroke.

Visits to the emergency department for asthma increase more than a year before a failed inspection by the U.S. Department of Housing and Urban Development (HUD), according to a new study presented at the annual meeting of the American College of Emergency Physicians.

While links between asthma and low-quality housing prone to harboring allergens have been well-documented, the current study takes the extra step of looking at housing down to the level of individual land parcels and suggests that asthma hospital visits can be used to identify hazardous housing earlier.

“Emergency department visits for asthma provide a leading indicator that can be used by health departments or housing authorities to direct housing inspections and remediation of poor housing conditions, track improvements in housing quality, measure housing department performance, support resident grievances, and inform funding allocation decisions,” said the study’s lead researcher, Elizabeth Samuels, MD, who is assistant professor of epidemiology and emergency medicine at Brown University, Providence, R.I.

Researchers retrospectively looked at cases of children and adults in the Greater New Haven area of Connecticut seen at the Yale New Haven Hospital ED for asthma-related problems between March 2013 and August 2017. The region has the fifth-highest prevalence of asthma in the United States, the researchers point out, due to its air quality, pollens, and quality of its housing. More than half of residences were built before 1,940, compared with about 13% nationally. Patient addresses were matched with HUD inspection records.

The review encompassed 11,429 ED visits by 6,366 individuals; 54% were insured by Medicaid, and 42% were Black. Controlling for patient and neighborhood data, researchers found that increased asthma ED visits at the parcel level were associated with decreased HUD inspection scores to a highly significant degree (P < .001).

They also found that there was a relationship in terms of timing between asthma ED visits and inspection scores: asthma ED visits increased more than 1 year before a failed HUD inspection. They also found that asthma ED visits were not elevated at housing units that passed inspection. Using asthma ED visits to predict failed housing inspections produced a specificity rate of 92.3% in an adjusted model, Dr. Samuels noted.

“This approach represents a novel method of early identification of dangerous housing conditions, which could aid in the prevention of asthma-related morbidity and mortality,” Dr. Samuels said.

The investigators noted that, of the parcels with the top three incidence rates of asthma ED visits, “all of them have been closed or demolished.”

In addition to limiting exposure of patients with asthma to the allergens of mold, mice and rats, and cockroaches, improving poor-quality housing earlier could help asthma by reducing stress, she said.

“There is also an increasing evidence base that psychosocial stress increases the risk of asthma attacks, and it’s therefore possible that living in poor housing conditions – often highly stressful situations – drives exacerbation risk via this pathway,” she said. “Synergistic effects between these pathways are also possible or even likely.”

Neeta Thakur, MD, associate professor of medicine at the University of California, San Francisco, who researches asthma, said the findings could lead to a strategy for improving poor-quality housing more quickly. As it is, inspections are too infrequent, often prompted by resident complaints.

“Once the complaints get to a certain threshold, then there might be an inspection that happens, and if there is a periodic review of the buildings, they often happen few and far between,” she said. “We could actually use some of the information that we’re already getting from something like ED visits and see if there is a pattern.”

An important follow-up would be to see whether asthma outcomes improve after housing deficiencies are addressed and whether the predictive capacity of ED visits occurs in other places.

“Would you then see a decline in the ED visit rates from individuals living in those buildings?” Dr. Thakur said. “It’s important to find a leading indicator, but you want to be sure that that leading indicator is useful as something that can be intervened upon.”

Dr. Samuels and Dr. Thakur have reported no relevant financial relationships.

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

Visits to the emergency department for asthma increase more than a year before a failed inspection by the U.S. Department of Housing and Urban Development (HUD), according to a new study presented at the annual meeting of the American College of Emergency Physicians.

While links between asthma and low-quality housing prone to harboring allergens have been well-documented, the current study takes the extra step of looking at housing down to the level of individual land parcels and suggests that asthma hospital visits can be used to identify hazardous housing earlier.

“Emergency department visits for asthma provide a leading indicator that can be used by health departments or housing authorities to direct housing inspections and remediation of poor housing conditions, track improvements in housing quality, measure housing department performance, support resident grievances, and inform funding allocation decisions,” said the study’s lead researcher, Elizabeth Samuels, MD, who is assistant professor of epidemiology and emergency medicine at Brown University, Providence, R.I.

Researchers retrospectively looked at cases of children and adults in the Greater New Haven area of Connecticut seen at the Yale New Haven Hospital ED for asthma-related problems between March 2013 and August 2017. The region has the fifth-highest prevalence of asthma in the United States, the researchers point out, due to its air quality, pollens, and quality of its housing. More than half of residences were built before 1,940, compared with about 13% nationally. Patient addresses were matched with HUD inspection records.

The review encompassed 11,429 ED visits by 6,366 individuals; 54% were insured by Medicaid, and 42% were Black. Controlling for patient and neighborhood data, researchers found that increased asthma ED visits at the parcel level were associated with decreased HUD inspection scores to a highly significant degree (P < .001).

They also found that there was a relationship in terms of timing between asthma ED visits and inspection scores: asthma ED visits increased more than 1 year before a failed HUD inspection. They also found that asthma ED visits were not elevated at housing units that passed inspection. Using asthma ED visits to predict failed housing inspections produced a specificity rate of 92.3% in an adjusted model, Dr. Samuels noted.

“This approach represents a novel method of early identification of dangerous housing conditions, which could aid in the prevention of asthma-related morbidity and mortality,” Dr. Samuels said.

The investigators noted that, of the parcels with the top three incidence rates of asthma ED visits, “all of them have been closed or demolished.”

In addition to limiting exposure of patients with asthma to the allergens of mold, mice and rats, and cockroaches, improving poor-quality housing earlier could help asthma by reducing stress, she said.

“There is also an increasing evidence base that psychosocial stress increases the risk of asthma attacks, and it’s therefore possible that living in poor housing conditions – often highly stressful situations – drives exacerbation risk via this pathway,” she said. “Synergistic effects between these pathways are also possible or even likely.”

Neeta Thakur, MD, associate professor of medicine at the University of California, San Francisco, who researches asthma, said the findings could lead to a strategy for improving poor-quality housing more quickly. As it is, inspections are too infrequent, often prompted by resident complaints.

“Once the complaints get to a certain threshold, then there might be an inspection that happens, and if there is a periodic review of the buildings, they often happen few and far between,” she said. “We could actually use some of the information that we’re already getting from something like ED visits and see if there is a pattern.”

An important follow-up would be to see whether asthma outcomes improve after housing deficiencies are addressed and whether the predictive capacity of ED visits occurs in other places.

“Would you then see a decline in the ED visit rates from individuals living in those buildings?” Dr. Thakur said. “It’s important to find a leading indicator, but you want to be sure that that leading indicator is useful as something that can be intervened upon.”

Dr. Samuels and Dr. Thakur have reported no relevant financial relationships.

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

Visits to the emergency department for asthma increase more than a year before a failed inspection by the U.S. Department of Housing and Urban Development (HUD), according to a new study presented at the annual meeting of the American College of Emergency Physicians.

While links between asthma and low-quality housing prone to harboring allergens have been well-documented, the current study takes the extra step of looking at housing down to the level of individual land parcels and suggests that asthma hospital visits can be used to identify hazardous housing earlier.

“Emergency department visits for asthma provide a leading indicator that can be used by health departments or housing authorities to direct housing inspections and remediation of poor housing conditions, track improvements in housing quality, measure housing department performance, support resident grievances, and inform funding allocation decisions,” said the study’s lead researcher, Elizabeth Samuels, MD, who is assistant professor of epidemiology and emergency medicine at Brown University, Providence, R.I.

Researchers retrospectively looked at cases of children and adults in the Greater New Haven area of Connecticut seen at the Yale New Haven Hospital ED for asthma-related problems between March 2013 and August 2017. The region has the fifth-highest prevalence of asthma in the United States, the researchers point out, due to its air quality, pollens, and quality of its housing. More than half of residences were built before 1,940, compared with about 13% nationally. Patient addresses were matched with HUD inspection records.

The review encompassed 11,429 ED visits by 6,366 individuals; 54% were insured by Medicaid, and 42% were Black. Controlling for patient and neighborhood data, researchers found that increased asthma ED visits at the parcel level were associated with decreased HUD inspection scores to a highly significant degree (P < .001).

They also found that there was a relationship in terms of timing between asthma ED visits and inspection scores: asthma ED visits increased more than 1 year before a failed HUD inspection. They also found that asthma ED visits were not elevated at housing units that passed inspection. Using asthma ED visits to predict failed housing inspections produced a specificity rate of 92.3% in an adjusted model, Dr. Samuels noted.

“This approach represents a novel method of early identification of dangerous housing conditions, which could aid in the prevention of asthma-related morbidity and mortality,” Dr. Samuels said.

The investigators noted that, of the parcels with the top three incidence rates of asthma ED visits, “all of them have been closed or demolished.”

In addition to limiting exposure of patients with asthma to the allergens of mold, mice and rats, and cockroaches, improving poor-quality housing earlier could help asthma by reducing stress, she said.

“There is also an increasing evidence base that psychosocial stress increases the risk of asthma attacks, and it’s therefore possible that living in poor housing conditions – often highly stressful situations – drives exacerbation risk via this pathway,” she said. “Synergistic effects between these pathways are also possible or even likely.”

Neeta Thakur, MD, associate professor of medicine at the University of California, San Francisco, who researches asthma, said the findings could lead to a strategy for improving poor-quality housing more quickly. As it is, inspections are too infrequent, often prompted by resident complaints.

“Once the complaints get to a certain threshold, then there might be an inspection that happens, and if there is a periodic review of the buildings, they often happen few and far between,” she said. “We could actually use some of the information that we’re already getting from something like ED visits and see if there is a pattern.”

An important follow-up would be to see whether asthma outcomes improve after housing deficiencies are addressed and whether the predictive capacity of ED visits occurs in other places.

“Would you then see a decline in the ED visit rates from individuals living in those buildings?” Dr. Thakur said. “It’s important to find a leading indicator, but you want to be sure that that leading indicator is useful as something that can be intervened upon.”

Dr. Samuels and Dr. Thakur have reported no relevant financial relationships.

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

“I’m not getting the vaccine. Nobody knows the long-term effects, and I heard that people are getting clots.”

We were screening patients at a low-cost clinic in Philadelphia for concerns surrounding social determinants of health. During one patient visit, in addition to concerns including housing, medication affordability, and transportation, we found that she had not received the COVID-19 vaccine, and we asked if she was interested in being immunized.

News reports have endlessly covered antivaccine sentiment, but this personal encounter hit home. From simple face masks to groundbreaking vaccines, we failed as physicians to encourage widespread uptake of health-protective measures despite strong scientific backing.

Large swaths of the public deny these tools’ importance or question their safety. This is ultimately rooted in the inability of community leaders and health care professionals to communicate with the public.

Science communication is inherently difficult. Scientists use complex language, and it is hard to evaluate the lay public’s baseline knowledge. Moreover, we are trained to speak with qualifications, encourage doubt, and accept change and evolution of fact. These qualities contrast the definitive messaging necessary in public settings. COVID-19 highlighted these gaps, where regardless of novel scientific solutions, poor communication led to a resistance to accept the tested scientific solution, which ultimately was the rate-limiting factor for overcoming the virus.

As directors of Physician Executive Leadership, an organization that trains future physicians at Thomas Jefferson University to tackle emerging health care issues, we hosted Paul Offit, MD, a national media figure and vaccine advocate. Dr. Offit shared his personal growth during the pandemic, from being abruptly thrown into the spotlight to eventually honing his communication skills. Dr. Offit discussed the challenges of sharing medical knowledge with laypeople and adaptations that are necessary. We found this transformative, realizing the importance of science communication training early in medical education.

Emphasizing the humanities and building soft skills will improve outcomes and benefit broader society by producing physician-leaders in public health and policy. We hope to improve our own communication skills and work in medical education to incorporate similar training into education paradigms for future students.

As seen in our patient interaction, strong science alone will not drive patient adherence; instead, we must work at personal and system levels to induce change. Physicians have a unique opportunity to generate trust and guide evidence-based policy. We must communicate, whether one-on-one with patients, or to millions of viewers via media or policymaker settings. We hope to not only be doctors, but to be advocates, leaders, and trusted advisers for the public.

Mr. Kieran and Mr. Shah are second-year medical students at Sidney Kimmel Medical College, Philadelphia. Neither disclosed any relevant conflicts of interest. A version of this article first appeared on Medscape.com.

“I’m not getting the vaccine. Nobody knows the long-term effects, and I heard that people are getting clots.”

We were screening patients at a low-cost clinic in Philadelphia for concerns surrounding social determinants of health. During one patient visit, in addition to concerns including housing, medication affordability, and transportation, we found that she had not received the COVID-19 vaccine, and we asked if she was interested in being immunized.

News reports have endlessly covered antivaccine sentiment, but this personal encounter hit home. From simple face masks to groundbreaking vaccines, we failed as physicians to encourage widespread uptake of health-protective measures despite strong scientific backing.

Large swaths of the public deny these tools’ importance or question their safety. This is ultimately rooted in the inability of community leaders and health care professionals to communicate with the public.

Science communication is inherently difficult. Scientists use complex language, and it is hard to evaluate the lay public’s baseline knowledge. Moreover, we are trained to speak with qualifications, encourage doubt, and accept change and evolution of fact. These qualities contrast the definitive messaging necessary in public settings. COVID-19 highlighted these gaps, where regardless of novel scientific solutions, poor communication led to a resistance to accept the tested scientific solution, which ultimately was the rate-limiting factor for overcoming the virus.

As directors of Physician Executive Leadership, an organization that trains future physicians at Thomas Jefferson University to tackle emerging health care issues, we hosted Paul Offit, MD, a national media figure and vaccine advocate. Dr. Offit shared his personal growth during the pandemic, from being abruptly thrown into the spotlight to eventually honing his communication skills. Dr. Offit discussed the challenges of sharing medical knowledge with laypeople and adaptations that are necessary. We found this transformative, realizing the importance of science communication training early in medical education.

Emphasizing the humanities and building soft skills will improve outcomes and benefit broader society by producing physician-leaders in public health and policy. We hope to improve our own communication skills and work in medical education to incorporate similar training into education paradigms for future students.

As seen in our patient interaction, strong science alone will not drive patient adherence; instead, we must work at personal and system levels to induce change. Physicians have a unique opportunity to generate trust and guide evidence-based policy. We must communicate, whether one-on-one with patients, or to millions of viewers via media or policymaker settings. We hope to not only be doctors, but to be advocates, leaders, and trusted advisers for the public.

Mr. Kieran and Mr. Shah are second-year medical students at Sidney Kimmel Medical College, Philadelphia. Neither disclosed any relevant conflicts of interest. A version of this article first appeared on Medscape.com.

“I’m not getting the vaccine. Nobody knows the long-term effects, and I heard that people are getting clots.”

We were screening patients at a low-cost clinic in Philadelphia for concerns surrounding social determinants of health. During one patient visit, in addition to concerns including housing, medication affordability, and transportation, we found that she had not received the COVID-19 vaccine, and we asked if she was interested in being immunized.

News reports have endlessly covered antivaccine sentiment, but this personal encounter hit home. From simple face masks to groundbreaking vaccines, we failed as physicians to encourage widespread uptake of health-protective measures despite strong scientific backing.

Large swaths of the public deny these tools’ importance or question their safety. This is ultimately rooted in the inability of community leaders and health care professionals to communicate with the public.

Science communication is inherently difficult. Scientists use complex language, and it is hard to evaluate the lay public’s baseline knowledge. Moreover, we are trained to speak with qualifications, encourage doubt, and accept change and evolution of fact. These qualities contrast the definitive messaging necessary in public settings. COVID-19 highlighted these gaps, where regardless of novel scientific solutions, poor communication led to a resistance to accept the tested scientific solution, which ultimately was the rate-limiting factor for overcoming the virus.

As directors of Physician Executive Leadership, an organization that trains future physicians at Thomas Jefferson University to tackle emerging health care issues, we hosted Paul Offit, MD, a national media figure and vaccine advocate. Dr. Offit shared his personal growth during the pandemic, from being abruptly thrown into the spotlight to eventually honing his communication skills. Dr. Offit discussed the challenges of sharing medical knowledge with laypeople and adaptations that are necessary. We found this transformative, realizing the importance of science communication training early in medical education.

Emphasizing the humanities and building soft skills will improve outcomes and benefit broader society by producing physician-leaders in public health and policy. We hope to improve our own communication skills and work in medical education to incorporate similar training into education paradigms for future students.

As seen in our patient interaction, strong science alone will not drive patient adherence; instead, we must work at personal and system levels to induce change. Physicians have a unique opportunity to generate trust and guide evidence-based policy. We must communicate, whether one-on-one with patients, or to millions of viewers via media or policymaker settings. We hope to not only be doctors, but to be advocates, leaders, and trusted advisers for the public.

Mr. Kieran and Mr. Shah are second-year medical students at Sidney Kimmel Medical College, Philadelphia. Neither disclosed any relevant conflicts of interest. A version of this article first appeared on Medscape.com.

NASHVILLE, TENN. – In a growing number of states, pulmonologists face serious legal consequences for advising women who have an underlying medical condition that places them at risk for life-threatening complications from pregnancy or childbirth, according to a panel of experts assembled for a special session at the annual meeting of the American College of Chest Physicians.

Following the June 24 decision by the U.S. Supreme Court to overturn Roe v. Wade, several states were swift to enact tight restrictions on abortion. These restrictions include bans on elective abortions for almost any reason. Worded in various ways, the new laws typically include exceptions when the health of the mother is threatened, but these exceptions must be navigated carefully.

As a general rule, “there is no clear and specific definition of when the mother’s life is at risk. These laws are vague on purpose,” said Rebecca Cohen, MD, division chief, Complex Family Planning, University of Colorado at Denver, Aurora.

The remarks were relevant to any clinician who advises women regarding pregnancy termination, but Dr. Cohen’s advice was tailored to pulmonologists. Advances have reduced the proportion of women with severe lung diseases, such as pulmonary arterial hypertension or interstitial lung disease, that make pregnancy untenable, but serious risks persist.

Clinicians need to assume a defensive posture, and the first step is to understand the laws, according to Dr. Cohen. For this, she recommended the nongovernmental Guttmacher Institute as a resource. With a focus on sexual and reproductive health, this research institute maintains a state-by-state summary of laws that govern pregnancy termination. The laws are being reconsidered across the country, and Dr. Cohen said the website updates its summaries accordingly.

In states with the most rigorous restrictions, the risks to physicians are substantial. Pulmonologists need to recognize that they might face legal consequences from merely advising a patient to terminate her pregnancy if the medical need is ambiguous or unclear, according to Dr. Cohen.

“If the advice is interpreted as aiding and abetting an elective abortion, it is a felony offense in some states,” Dr. Cohen said.

In states with restrictive laws, pregnancy prevention is the safest approach for women of childbearing age who face life-threatening complications in the event of pregnancy, according to Dr. Cohen. This might reasonably include a step beyond standard contraception. Dr. Cohen mentioned such approaches as period tracking to double down.

In addition, for women of childbearing age with health problems that might result in complications in the event of a pregnancy, it is appropriate to establish this fact in the medical record. This history could prove useful for maximizing options when making decisions in the best interest of the mother’s health in the event of contraception failure.

In addition, pulmonologists who counsel women about the potential for pregnancy termination should consider establishing a relationship with the legal department at the institution where they work, according to Dr. Cohen. In specific cases in which termination is recommended, she further advised building documentation with participation from additional medical specialists, such as an obstetrician who manages high-risk pregnancies.

“There is no guarantee that any given documentation is adequate,” Dr. Cohen warned. She indicated that consensus from multiple clinicians can strengthen the legal defense if one is necessary.

For some serious lung conditions that are incompatible with pregnancy, the threat to the mother’s life can occur early, according to Deborah Jo Levine, MD, a clinical instructor in the division of pulmonary, allergy, and critical care medicine, Stanford (Calif.) University.

As a result, “you need to identify at-risk patients early and develop a plan promptly,” said Dr. Levine, who joined Dr. Cohen on the special panel at the CHEST 2022 meeting. Even when termination is medically appropriate, restrictive laws are making these services harder to find.

In the case of a pregnancy likely to pose a high risk of complications owing to the patient’s having lung disease, “it is important to involve a high-risk ob quickly,” Dr. Levine warned. “In some cases, termination poses less risk if performed early.”

Sunjay R. Devarajan, MD, assistant professor of pulmonary medicine and critical care, Baylor College of Medicine, Houston, has faced this issue in a state that has some of the most restrictive laws. Even when there is no debate about the necessity of a medically indicated abortion, he cautioned that abortion services are becoming harder to find.

“A recent patient who had a complicated unintentional pregnancy on our service had to go out of state for pregnancy termination,” Dr. Devarajan said. He noted that this option is not available to all women, particularly in states such as his own in which most bordering states also now have highly restrictive abortion laws.

On the basis of this experience, he is thinking more defensively. Now that clinicians can be drawn into legal proceedings even when pregnancy termination is indicated, he agreed that clinicians must become familiar with the local laws.

“We are doing better in managing pregnancies in women with serious lung diseases, but termination is still the prudent approach in some cases,” Dr. Devarajan said. He indicated that he considered the advice offered by Dr. Cohen helpful in avoiding complications for the patient and the physician.

Dr. Cohen, Dr. Levine, and Dr. Devarajan have disclosed no relevant financial relationships.

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

NASHVILLE, TENN. – In a growing number of states, pulmonologists face serious legal consequences for advising women who have an underlying medical condition that places them at risk for life-threatening complications from pregnancy or childbirth, according to a panel of experts assembled for a special session at the annual meeting of the American College of Chest Physicians.

Following the June 24 decision by the U.S. Supreme Court to overturn Roe v. Wade, several states were swift to enact tight restrictions on abortion. These restrictions include bans on elective abortions for almost any reason. Worded in various ways, the new laws typically include exceptions when the health of the mother is threatened, but these exceptions must be navigated carefully.

As a general rule, “there is no clear and specific definition of when the mother’s life is at risk. These laws are vague on purpose,” said Rebecca Cohen, MD, division chief, Complex Family Planning, University of Colorado at Denver, Aurora.

The remarks were relevant to any clinician who advises women regarding pregnancy termination, but Dr. Cohen’s advice was tailored to pulmonologists. Advances have reduced the proportion of women with severe lung diseases, such as pulmonary arterial hypertension or interstitial lung disease, that make pregnancy untenable, but serious risks persist.

Clinicians need to assume a defensive posture, and the first step is to understand the laws, according to Dr. Cohen. For this, she recommended the nongovernmental Guttmacher Institute as a resource. With a focus on sexual and reproductive health, this research institute maintains a state-by-state summary of laws that govern pregnancy termination. The laws are being reconsidered across the country, and Dr. Cohen said the website updates its summaries accordingly.

In states with the most rigorous restrictions, the risks to physicians are substantial. Pulmonologists need to recognize that they might face legal consequences from merely advising a patient to terminate her pregnancy if the medical need is ambiguous or unclear, according to Dr. Cohen.

“If the advice is interpreted as aiding and abetting an elective abortion, it is a felony offense in some states,” Dr. Cohen said.

In states with restrictive laws, pregnancy prevention is the safest approach for women of childbearing age who face life-threatening complications in the event of pregnancy, according to Dr. Cohen. This might reasonably include a step beyond standard contraception. Dr. Cohen mentioned such approaches as period tracking to double down.

In addition, for women of childbearing age with health problems that might result in complications in the event of a pregnancy, it is appropriate to establish this fact in the medical record. This history could prove useful for maximizing options when making decisions in the best interest of the mother’s health in the event of contraception failure.

In addition, pulmonologists who counsel women about the potential for pregnancy termination should consider establishing a relationship with the legal department at the institution where they work, according to Dr. Cohen. In specific cases in which termination is recommended, she further advised building documentation with participation from additional medical specialists, such as an obstetrician who manages high-risk pregnancies.

“There is no guarantee that any given documentation is adequate,” Dr. Cohen warned. She indicated that consensus from multiple clinicians can strengthen the legal defense if one is necessary.

For some serious lung conditions that are incompatible with pregnancy, the threat to the mother’s life can occur early, according to Deborah Jo Levine, MD, a clinical instructor in the division of pulmonary, allergy, and critical care medicine, Stanford (Calif.) University.

As a result, “you need to identify at-risk patients early and develop a plan promptly,” said Dr. Levine, who joined Dr. Cohen on the special panel at the CHEST 2022 meeting. Even when termination is medically appropriate, restrictive laws are making these services harder to find.

In the case of a pregnancy likely to pose a high risk of complications owing to the patient’s having lung disease, “it is important to involve a high-risk ob quickly,” Dr. Levine warned. “In some cases, termination poses less risk if performed early.”

Sunjay R. Devarajan, MD, assistant professor of pulmonary medicine and critical care, Baylor College of Medicine, Houston, has faced this issue in a state that has some of the most restrictive laws. Even when there is no debate about the necessity of a medically indicated abortion, he cautioned that abortion services are becoming harder to find.

“A recent patient who had a complicated unintentional pregnancy on our service had to go out of state for pregnancy termination,” Dr. Devarajan said. He noted that this option is not available to all women, particularly in states such as his own in which most bordering states also now have highly restrictive abortion laws.

On the basis of this experience, he is thinking more defensively. Now that clinicians can be drawn into legal proceedings even when pregnancy termination is indicated, he agreed that clinicians must become familiar with the local laws.

“We are doing better in managing pregnancies in women with serious lung diseases, but termination is still the prudent approach in some cases,” Dr. Devarajan said. He indicated that he considered the advice offered by Dr. Cohen helpful in avoiding complications for the patient and the physician.

Dr. Cohen, Dr. Levine, and Dr. Devarajan have disclosed no relevant financial relationships.

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

NASHVILLE, TENN. – In a growing number of states, pulmonologists face serious legal consequences for advising women who have an underlying medical condition that places them at risk for life-threatening complications from pregnancy or childbirth, according to a panel of experts assembled for a special session at the annual meeting of the American College of Chest Physicians.

Following the June 24 decision by the U.S. Supreme Court to overturn Roe v. Wade, several states were swift to enact tight restrictions on abortion. These restrictions include bans on elective abortions for almost any reason. Worded in various ways, the new laws typically include exceptions when the health of the mother is threatened, but these exceptions must be navigated carefully.

As a general rule, “there is no clear and specific definition of when the mother’s life is at risk. These laws are vague on purpose,” said Rebecca Cohen, MD, division chief, Complex Family Planning, University of Colorado at Denver, Aurora.

The remarks were relevant to any clinician who advises women regarding pregnancy termination, but Dr. Cohen’s advice was tailored to pulmonologists. Advances have reduced the proportion of women with severe lung diseases, such as pulmonary arterial hypertension or interstitial lung disease, that make pregnancy untenable, but serious risks persist.

Clinicians need to assume a defensive posture, and the first step is to understand the laws, according to Dr. Cohen. For this, she recommended the nongovernmental Guttmacher Institute as a resource. With a focus on sexual and reproductive health, this research institute maintains a state-by-state summary of laws that govern pregnancy termination. The laws are being reconsidered across the country, and Dr. Cohen said the website updates its summaries accordingly.

In states with the most rigorous restrictions, the risks to physicians are substantial. Pulmonologists need to recognize that they might face legal consequences from merely advising a patient to terminate her pregnancy if the medical need is ambiguous or unclear, according to Dr. Cohen.

“If the advice is interpreted as aiding and abetting an elective abortion, it is a felony offense in some states,” Dr. Cohen said.

In states with restrictive laws, pregnancy prevention is the safest approach for women of childbearing age who face life-threatening complications in the event of pregnancy, according to Dr. Cohen. This might reasonably include a step beyond standard contraception. Dr. Cohen mentioned such approaches as period tracking to double down.

In addition, for women of childbearing age with health problems that might result in complications in the event of a pregnancy, it is appropriate to establish this fact in the medical record. This history could prove useful for maximizing options when making decisions in the best interest of the mother’s health in the event of contraception failure.

In addition, pulmonologists who counsel women about the potential for pregnancy termination should consider establishing a relationship with the legal department at the institution where they work, according to Dr. Cohen. In specific cases in which termination is recommended, she further advised building documentation with participation from additional medical specialists, such as an obstetrician who manages high-risk pregnancies.

“There is no guarantee that any given documentation is adequate,” Dr. Cohen warned. She indicated that consensus from multiple clinicians can strengthen the legal defense if one is necessary.

For some serious lung conditions that are incompatible with pregnancy, the threat to the mother’s life can occur early, according to Deborah Jo Levine, MD, a clinical instructor in the division of pulmonary, allergy, and critical care medicine, Stanford (Calif.) University.

As a result, “you need to identify at-risk patients early and develop a plan promptly,” said Dr. Levine, who joined Dr. Cohen on the special panel at the CHEST 2022 meeting. Even when termination is medically appropriate, restrictive laws are making these services harder to find.

In the case of a pregnancy likely to pose a high risk of complications owing to the patient’s having lung disease, “it is important to involve a high-risk ob quickly,” Dr. Levine warned. “In some cases, termination poses less risk if performed early.”

Sunjay R. Devarajan, MD, assistant professor of pulmonary medicine and critical care, Baylor College of Medicine, Houston, has faced this issue in a state that has some of the most restrictive laws. Even when there is no debate about the necessity of a medically indicated abortion, he cautioned that abortion services are becoming harder to find.

“A recent patient who had a complicated unintentional pregnancy on our service had to go out of state for pregnancy termination,” Dr. Devarajan said. He noted that this option is not available to all women, particularly in states such as his own in which most bordering states also now have highly restrictive abortion laws.

On the basis of this experience, he is thinking more defensively. Now that clinicians can be drawn into legal proceedings even when pregnancy termination is indicated, he agreed that clinicians must become familiar with the local laws.

“We are doing better in managing pregnancies in women with serious lung diseases, but termination is still the prudent approach in some cases,” Dr. Devarajan said. He indicated that he considered the advice offered by Dr. Cohen helpful in avoiding complications for the patient and the physician.

Dr. Cohen, Dr. Levine, and Dr. Devarajan have disclosed no relevant financial relationships.

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

There does not appear to be a definitive clinical link between new-onset parkinsonism and SARS-CoV-2 (COVID-19) infection, a multinational team of researchers reported at the International Congress of Parkinson’s Disease and Movement Disorders.

SARS-CoV-2 led to numerous discussions about a potential post–COVID-19 emergence of new-onset parkinsonism in susceptible individuals, often referred to in the literature as a “perfect storm” or a “wave” of parkinsonism, according to lead study author Iro Boura, MD.
 

Postviral precedence

“Although pathogens have been associated both with parkinsonism cases and Parkinson’s disease pathogenesis, the main concern of a potential connection between COVID-19 and new-onset parkinsonism arose from the historically documented parkinsonism cases appearing with encephalitis lethargica,” said Dr. Boura, a PhD candidate with the University of Crete in Greece and ex-fellow at King’s College London.

Encephalitis lethargica appeared between 1916 and 1930 and has been epidemiologically related to the Spanish influenza pandemic, “although this link has been strongly debated by other researchers,” she added.

Because the connection of COVID-19 and parkinsonism seemed highly speculative, Dr. Boura and movement disorder specialist Kallol Ray Chaudhuri DSc, FRCP, MD, decided to search for any data supporting this notion. “Such a possibility would have a significant impact on everyday practice, including long follow-up neurological assessments of COVID-19 patients, along with greater vigilance in recognizing potential symptoms,” said Dr. Boura.  

They found no organized research exploring this link, aside from published case reports.
 

Scant evidence of a parkinsonism wave

The investigators conducted a review of the literature up to February 2022 to identify and analyze published cases of new-onset parkinsonism following a confirmed SARS-CoV-2 infection in otherwise healthy individuals. They ended up with 20 such cases.

Although some cases presented during or shortly after a COVID-19 infection, “the numbers are currently quite low to draw safe conclusions and generalize these findings as a risk of parkinsonism for the general population,” said Dr. Boura. Overall, parkinsonism appeared in the context of encephalopathy in 11 patients. Four patients developed postinfectious parkinsonism without encephalopathy. Another four had phenotypic similarities to idiopathic Parkinson’s disease. 

Nine patients were responsive to levodopa, while four required immunomodulatory treatment.

Although cases have already been reported, current data do not yet justify the concept of a post–COVID-19 parkinsonism wave. However, long-term surveillance is crucial to ensure that reports of further cases are carefully documented and analyzed.

Dr. Chaudhuri’s research team recently wrote a book exploring the numerous aspects of COVID-19 and parkinsonism, including Parkinson’s disease, said Dr. Boura.

“Moreover, the COVID-19 Clinical Neuroscience Study (COVID-CNS), with serial follow-up visits for COVID-19 patients, including imaging, is currently running in the United Kingdom with the active participation of Prof Chaudhuri’s team, aiming at revealing any potential parkinsonism cases after a COVID-19 infection,” she said.

There does not appear to be a definitive clinical link between new-onset parkinsonism and SARS-CoV-2 (COVID-19) infection, a multinational team of researchers reported at the International Congress of Parkinson’s Disease and Movement Disorders.

SARS-CoV-2 led to numerous discussions about a potential post–COVID-19 emergence of new-onset parkinsonism in susceptible individuals, often referred to in the literature as a “perfect storm” or a “wave” of parkinsonism, according to lead study author Iro Boura, MD.
 

Postviral precedence

“Although pathogens have been associated both with parkinsonism cases and Parkinson’s disease pathogenesis, the main concern of a potential connection between COVID-19 and new-onset parkinsonism arose from the historically documented parkinsonism cases appearing with encephalitis lethargica,” said Dr. Boura, a PhD candidate with the University of Crete in Greece and ex-fellow at King’s College London.

Encephalitis lethargica appeared between 1916 and 1930 and has been epidemiologically related to the Spanish influenza pandemic, “although this link has been strongly debated by other researchers,” she added.

Because the connection of COVID-19 and parkinsonism seemed highly speculative, Dr. Boura and movement disorder specialist Kallol Ray Chaudhuri DSc, FRCP, MD, decided to search for any data supporting this notion. “Such a possibility would have a significant impact on everyday practice, including long follow-up neurological assessments of COVID-19 patients, along with greater vigilance in recognizing potential symptoms,” said Dr. Boura.  

They found no organized research exploring this link, aside from published case reports.
 

Scant evidence of a parkinsonism wave

The investigators conducted a review of the literature up to February 2022 to identify and analyze published cases of new-onset parkinsonism following a confirmed SARS-CoV-2 infection in otherwise healthy individuals. They ended up with 20 such cases.

Although some cases presented during or shortly after a COVID-19 infection, “the numbers are currently quite low to draw safe conclusions and generalize these findings as a risk of parkinsonism for the general population,” said Dr. Boura. Overall, parkinsonism appeared in the context of encephalopathy in 11 patients. Four patients developed postinfectious parkinsonism without encephalopathy. Another four had phenotypic similarities to idiopathic Parkinson’s disease. 

Nine patients were responsive to levodopa, while four required immunomodulatory treatment.

Although cases have already been reported, current data do not yet justify the concept of a post–COVID-19 parkinsonism wave. However, long-term surveillance is crucial to ensure that reports of further cases are carefully documented and analyzed.

Dr. Chaudhuri’s research team recently wrote a book exploring the numerous aspects of COVID-19 and parkinsonism, including Parkinson’s disease, said Dr. Boura.

“Moreover, the COVID-19 Clinical Neuroscience Study (COVID-CNS), with serial follow-up visits for COVID-19 patients, including imaging, is currently running in the United Kingdom with the active participation of Prof Chaudhuri’s team, aiming at revealing any potential parkinsonism cases after a COVID-19 infection,” she said.

There does not appear to be a definitive clinical link between new-onset parkinsonism and SARS-CoV-2 (COVID-19) infection, a multinational team of researchers reported at the International Congress of Parkinson’s Disease and Movement Disorders.

SARS-CoV-2 led to numerous discussions about a potential post–COVID-19 emergence of new-onset parkinsonism in susceptible individuals, often referred to in the literature as a “perfect storm” or a “wave” of parkinsonism, according to lead study author Iro Boura, MD.
 

Postviral precedence

“Although pathogens have been associated both with parkinsonism cases and Parkinson’s disease pathogenesis, the main concern of a potential connection between COVID-19 and new-onset parkinsonism arose from the historically documented parkinsonism cases appearing with encephalitis lethargica,” said Dr. Boura, a PhD candidate with the University of Crete in Greece and ex-fellow at King’s College London.

Encephalitis lethargica appeared between 1916 and 1930 and has been epidemiologically related to the Spanish influenza pandemic, “although this link has been strongly debated by other researchers,” she added.

Because the connection of COVID-19 and parkinsonism seemed highly speculative, Dr. Boura and movement disorder specialist Kallol Ray Chaudhuri DSc, FRCP, MD, decided to search for any data supporting this notion. “Such a possibility would have a significant impact on everyday practice, including long follow-up neurological assessments of COVID-19 patients, along with greater vigilance in recognizing potential symptoms,” said Dr. Boura.  

They found no organized research exploring this link, aside from published case reports.
 

Scant evidence of a parkinsonism wave

The investigators conducted a review of the literature up to February 2022 to identify and analyze published cases of new-onset parkinsonism following a confirmed SARS-CoV-2 infection in otherwise healthy individuals. They ended up with 20 such cases.

Although some cases presented during or shortly after a COVID-19 infection, “the numbers are currently quite low to draw safe conclusions and generalize these findings as a risk of parkinsonism for the general population,” said Dr. Boura. Overall, parkinsonism appeared in the context of encephalopathy in 11 patients. Four patients developed postinfectious parkinsonism without encephalopathy. Another four had phenotypic similarities to idiopathic Parkinson’s disease. 

Nine patients were responsive to levodopa, while four required immunomodulatory treatment.

Although cases have already been reported, current data do not yet justify the concept of a post–COVID-19 parkinsonism wave. However, long-term surveillance is crucial to ensure that reports of further cases are carefully documented and analyzed.

Dr. Chaudhuri’s research team recently wrote a book exploring the numerous aspects of COVID-19 and parkinsonism, including Parkinson’s disease, said Dr. Boura.

“Moreover, the COVID-19 Clinical Neuroscience Study (COVID-CNS), with serial follow-up visits for COVID-19 patients, including imaging, is currently running in the United Kingdom with the active participation of Prof Chaudhuri’s team, aiming at revealing any potential parkinsonism cases after a COVID-19 infection,” she said.

Researchers have developed a computer program to identify drugs for other diseases that might be repurposed to treat type 2 diabetes and/or obesity by targeting genetic pathways for these two conditions.

The scientists identified four pathways with known drug targets for type 2 diabetes and five with known drug targets for obesity.

Their findings suggest that:

• Palbociclib (used to treat breast cancer) and cardiac glycosides (used to treat heart failure and heart rhythm disorders) might be repurposed to treat type 2 diabetes.
• Baclofen (a muscle relaxant) and carfilzomib (a chemotherapy) could potentially be used to treat obesity.
• Fostamatinib (used to treat thrombocytopenia), sucralfate (used to treat stomach ulcers), and regorafenib (used to treat cancer) might be used to treat type 2 diabetes and obesity.
• Baclofen and sucralfate would have favorable safety profiles as repurposed treatments.

Sahar El Shair, a PhD student at the Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia, presented the research during an oral session at the International Congress on Obesity, the biennial congress of the World Obesity Federation, in Melbourne.

“New treatments with higher activity and specificity are urgently needed to tackle a pandemic of chronic illness associated with type 2 diabetes and obesity,” senior coauthor Murray Cairns, PhD, said in a press release from the ICO.   

“Our technology harnesses genetically informed precision medicine to identify and target new treatments for these complex disorders,” said Dr. Cairns, from the school of biomedical sciences and pharmacy at the University of Newcastle.

Matchmaking between individual, their genetic traits, and drugs

Dr. Cairns and senior coauthor William Reay, PhD, also from the school of biomedical sciences and pharmacy, have cofounded a company called PolygenRx.

The company website explains that they have developed a propriety platform termed the pharmagenic enrichment score (PES), which is “essentially a matchmaking service between patients and drugs, allowing treatment to be optimized for each individual using their unique combination of genetic risk factors.”

It is important to note the genetic risk from complex traits, such as type 2 diabetes and obesity, “are quite different [from] the rare genetic disorders caused mostly by a devastating mutation in a single gene,” Dr. Cairns explained in an email.

“Complex traits,” he noted, “are associated with thousands of [genetic] variants that are common in people and have a cumulative effect.”

For this specific research, the investigators obtained genetic data from genome-wide association studies of obesity and type 2 diabetes.

“By using very large cohorts (hundreds of thousands of individuals) and comparing the frequency of millions of genetic variants in subjects with these conditions with controls, these studies have revealed regions of the genome and genes associated with the condition,” Dr. Cairns noted.

The pharmagenic enrichment score integrates a person’s genetics with drug pharmacology to determine if a person would respond more readily to a certain drug.

“We are investigating the potential of thousands of drugs across a broad spectrum of complex traits (the list is almost endless),” Dr. Cairns explained.

From the PES score, “we have an estimate of each individual’s likelihood of a positive response to said drug,” he noted. “We all have variants that increase (and decrease) the risk of these conditions to various degrees as they are common (high frequency) genetic variants.”

With this research, “we can implement this precision medicine strategy to match the right [repurposed] drugs for individuals based on their specific burden of genetic risk” for obesity and type 2 diabetes.

“Drug repurposing can be a fast track to new medicines because there is existing knowledge about their safety and activity in humans,” he said.

Next steps: Raising funds for clinical trials

“We would like to progress some of these compounds to preclinical and clinical trials,” Dr. Cairns said, “but need to raise the funds for this expensive research. With limited government research funding opportunities, we have recently spun out a startup company to attract commercial investment in our platform and the development of new drug candidates.”

The authors have reported no relevant financial relationships. Dr. Reay and Dr. Cairns are cofounders of PolygenRx.

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

Researchers have developed a computer program to identify drugs for other diseases that might be repurposed to treat type 2 diabetes and/or obesity by targeting genetic pathways for these two conditions.

The scientists identified four pathways with known drug targets for type 2 diabetes and five with known drug targets for obesity.

Their findings suggest that:

• Palbociclib (used to treat breast cancer) and cardiac glycosides (used to treat heart failure and heart rhythm disorders) might be repurposed to treat type 2 diabetes.
• Baclofen (a muscle relaxant) and carfilzomib (a chemotherapy) could potentially be used to treat obesity.
• Fostamatinib (used to treat thrombocytopenia), sucralfate (used to treat stomach ulcers), and regorafenib (used to treat cancer) might be used to treat type 2 diabetes and obesity.
• Baclofen and sucralfate would have favorable safety profiles as repurposed treatments.

Sahar El Shair, a PhD student at the Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia, presented the research during an oral session at the International Congress on Obesity, the biennial congress of the World Obesity Federation, in Melbourne.

“New treatments with higher activity and specificity are urgently needed to tackle a pandemic of chronic illness associated with type 2 diabetes and obesity,” senior coauthor Murray Cairns, PhD, said in a press release from the ICO.   

“Our technology harnesses genetically informed precision medicine to identify and target new treatments for these complex disorders,” said Dr. Cairns, from the school of biomedical sciences and pharmacy at the University of Newcastle.

Matchmaking between individual, their genetic traits, and drugs

Dr. Cairns and senior coauthor William Reay, PhD, also from the school of biomedical sciences and pharmacy, have cofounded a company called PolygenRx.

The company website explains that they have developed a propriety platform termed the pharmagenic enrichment score (PES), which is “essentially a matchmaking service between patients and drugs, allowing treatment to be optimized for each individual using their unique combination of genetic risk factors.”

It is important to note the genetic risk from complex traits, such as type 2 diabetes and obesity, “are quite different [from] the rare genetic disorders caused mostly by a devastating mutation in a single gene,” Dr. Cairns explained in an email.

“Complex traits,” he noted, “are associated with thousands of [genetic] variants that are common in people and have a cumulative effect.”

For this specific research, the investigators obtained genetic data from genome-wide association studies of obesity and type 2 diabetes.

“By using very large cohorts (hundreds of thousands of individuals) and comparing the frequency of millions of genetic variants in subjects with these conditions with controls, these studies have revealed regions of the genome and genes associated with the condition,” Dr. Cairns noted.

The pharmagenic enrichment score integrates a person’s genetics with drug pharmacology to determine if a person would respond more readily to a certain drug.

“We are investigating the potential of thousands of drugs across a broad spectrum of complex traits (the list is almost endless),” Dr. Cairns explained.

From the PES score, “we have an estimate of each individual’s likelihood of a positive response to said drug,” he noted. “We all have variants that increase (and decrease) the risk of these conditions to various degrees as they are common (high frequency) genetic variants.”

With this research, “we can implement this precision medicine strategy to match the right [repurposed] drugs for individuals based on their specific burden of genetic risk” for obesity and type 2 diabetes.

“Drug repurposing can be a fast track to new medicines because there is existing knowledge about their safety and activity in humans,” he said.

Next steps: Raising funds for clinical trials

“We would like to progress some of these compounds to preclinical and clinical trials,” Dr. Cairns said, “but need to raise the funds for this expensive research. With limited government research funding opportunities, we have recently spun out a startup company to attract commercial investment in our platform and the development of new drug candidates.”

The authors have reported no relevant financial relationships. Dr. Reay and Dr. Cairns are cofounders of PolygenRx.

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

Researchers have developed a computer program to identify drugs for other diseases that might be repurposed to treat type 2 diabetes and/or obesity by targeting genetic pathways for these two conditions.

The scientists identified four pathways with known drug targets for type 2 diabetes and five with known drug targets for obesity.

Their findings suggest that:

• Palbociclib (used to treat breast cancer) and cardiac glycosides (used to treat heart failure and heart rhythm disorders) might be repurposed to treat type 2 diabetes.
• Baclofen (a muscle relaxant) and carfilzomib (a chemotherapy) could potentially be used to treat obesity.
• Fostamatinib (used to treat thrombocytopenia), sucralfate (used to treat stomach ulcers), and regorafenib (used to treat cancer) might be used to treat type 2 diabetes and obesity.
• Baclofen and sucralfate would have favorable safety profiles as repurposed treatments.

Sahar El Shair, a PhD student at the Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia, presented the research during an oral session at the International Congress on Obesity, the biennial congress of the World Obesity Federation, in Melbourne.

“New treatments with higher activity and specificity are urgently needed to tackle a pandemic of chronic illness associated with type 2 diabetes and obesity,” senior coauthor Murray Cairns, PhD, said in a press release from the ICO.   

“Our technology harnesses genetically informed precision medicine to identify and target new treatments for these complex disorders,” said Dr. Cairns, from the school of biomedical sciences and pharmacy at the University of Newcastle.

Matchmaking between individual, their genetic traits, and drugs

Dr. Cairns and senior coauthor William Reay, PhD, also from the school of biomedical sciences and pharmacy, have cofounded a company called PolygenRx.

The company website explains that they have developed a propriety platform termed the pharmagenic enrichment score (PES), which is “essentially a matchmaking service between patients and drugs, allowing treatment to be optimized for each individual using their unique combination of genetic risk factors.”

It is important to note the genetic risk from complex traits, such as type 2 diabetes and obesity, “are quite different [from] the rare genetic disorders caused mostly by a devastating mutation in a single gene,” Dr. Cairns explained in an email.

“Complex traits,” he noted, “are associated with thousands of [genetic] variants that are common in people and have a cumulative effect.”

For this specific research, the investigators obtained genetic data from genome-wide association studies of obesity and type 2 diabetes.

“By using very large cohorts (hundreds of thousands of individuals) and comparing the frequency of millions of genetic variants in subjects with these conditions with controls, these studies have revealed regions of the genome and genes associated with the condition,” Dr. Cairns noted.

The pharmagenic enrichment score integrates a person’s genetics with drug pharmacology to determine if a person would respond more readily to a certain drug.

“We are investigating the potential of thousands of drugs across a broad spectrum of complex traits (the list is almost endless),” Dr. Cairns explained.

From the PES score, “we have an estimate of each individual’s likelihood of a positive response to said drug,” he noted. “We all have variants that increase (and decrease) the risk of these conditions to various degrees as they are common (high frequency) genetic variants.”

With this research, “we can implement this precision medicine strategy to match the right [repurposed] drugs for individuals based on their specific burden of genetic risk” for obesity and type 2 diabetes.

“Drug repurposing can be a fast track to new medicines because there is existing knowledge about their safety and activity in humans,” he said.

Next steps: Raising funds for clinical trials

“We would like to progress some of these compounds to preclinical and clinical trials,” Dr. Cairns said, “but need to raise the funds for this expensive research. With limited government research funding opportunities, we have recently spun out a startup company to attract commercial investment in our platform and the development of new drug candidates.”

The authors have reported no relevant financial relationships. Dr. Reay and Dr. Cairns are cofounders of PolygenRx.

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

Just uttering the word “mucus” is often sufficient to elicit amusement from those within earshot, but to patients with chronic inflammatory airway diseases, mucus is no laughing matter.

Under normal conditions, mucus plays an important protective role, trapping airway irritants such as smoke, pollen, and particulate matter, which are then moved by cilia out of the airways for expulsion through coughing.

But in cystic fibrosis (CF), for example, mucus hypersecretion can be deadly. The underlying pathology of CF – a mutation in the CFTR gene, which codes for the protein CF transmembrane conductance regulator – leads to buildup in the lungs of abnormally viscous and sticky mucus, resulting in frequent, severe infections (particularly with Pseudomonas aeruginosa), progressive lung damage, and prior to the development of effective disease management, significantly premature death.

Mucus hypersecretion is also a feature of chronic obstructive pulmonary disease (COPD), noted Victor Kim, MD, from Temple University, Philadelphia, Christopher M. Evans, PhD, from the University of Colorado at Denver, Aurora, and Burton F. Dickey, MD, from the University of Texas MD Anderson Cancer Center, Houston.

In COPD, “mucus dysfunction arises from several mechanisms, including excess production due to inflammation, decreased elimination due to impaired ciliary clearance and reduced cough efficiency, and excessive concentration due to smoke-induced dysfunction of transepithelial anion transport resembling CF,” they wrote in an editorial published in the American Journal of Respiratory and Critical Care Medicine.

In patients with idiopathic pulmonary fibrosis, a polymorphism in the enhancer region of MUC5B, a gene that encodes for mucin glycoproteins, results in a 20-fold overexpression of the gene and prominent mucus production that has been shown to parallel lung inflammation and decline in forced vital capacity (FVC).

In patients with asthma, up-regulation of MUC5AC and stimulated mucus secretion conspire to obstruct airways, which can in extreme cases lead to death.
 

‘Short shrift’

Yet until recently, the role of mucus hypersecretion in diseases such as COPD has been largely overlooked, or as Dr. Kim and colleagues put it, “airway mucus often receives short shrift from clinicians.”

“It’s a pretty hot topic in pulmonary medicine today because it has been so neglected for so long,” Dr. Dickey said in an interview with CHEST Physician. “As clinicians we haven’t had a way to identify who needs treatment, which is ridiculous, because many of the people who expectorate a lot, like those with chronic bronchitis, don’t actually have small airway obstruction, and conversely, a lot of asthmatics, who have very serious small airway obstruction, don’t expectorate, so you can’t really tell from symptoms.”

What has changed in recent years is the use of chest CT to image muco-obstructive pathology, commonly called “mucus plugging” in the peripheral airways of patients with COPD and asthma.

“In the last decade or so, we’ve seen the emergence in obstructive lung diseases such as asthma and COPD the use of more objective measures on CT scans, including the problem of mucus plugging, which is unfortunately very common,” Dr. Kim said in an interview.

The discovery of the extent and severity of mucus in obstructive lung diseases has led to new strategies to combat mucus overconcentration, such as hydration, mucolytics, and an intriguing investigational approach to decrease calcium-induced hypersecretion with designer peptides.
 

Mighty mucins

Under normal physiologic conditions mucus is composed largely of water (97%) and salts (2%), with the remainder consisting of entrapped globular proteins (0.7%) and mucins (0.3%), Dr. Dickey explains.

Yet those meager mucins pack a real punch, with the ability to absorb 300 times their mass of water after secretion, creating mucus of optimal consistency and viscoelasticity.

“Personally, I’ve never understood – maybe I should have paid more attention in physics – how a compound can absorb 300-fold its mass, but it does,” he said.

In a recent review article in the journal Clinical and Translational Medicine, Dr. Dickey and colleagues described how good mucus can go bad.

“[H]igh levels of mucin production from inflammatory stimulation (termed ‘mucous metaplasia’), followed by rapid release (together, termed ‘mucus hypersecretion’), can plug airways due to mucus volume expansion. In addition, if available lumenal liquid is insufficient, concentrated mucus of excessive viscoelasticity and adhesivity can cause mucus stasis,” they wrote.
 

Therapeutic strategies

In patients with CF, CFTR modulator therapy has markedly reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. The manipulations can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

Unlike in CF, where treating the underlying genetic pathology can help to resolve the thick, sticky mucus problems and thereby significantly reduce risk of infections and progressive lung damage, treatment of mucus metaplasia or hypersecretion in other diseases is aimed at symptomatic relief; it is still unclear whether symptomatic improvement of mucus overproduction would correlate with other disease-related outcomes, Dr. Kim and Dr. Dickey noted.

Potential therapeutic strategies to reduce excess mucus in the lungs include the use of mucolytic agents to thin secretions for more effective expulsion, decreasing mucus production through the use of an interleukin-13 (IL-13) inhibitor such as the anti-asthma agent dupilumab (Dupixent), and a novel strategy, still in the experimental phase, aimed at “disrupting the fusion of mucin storage granules with the cell membrane, thereby blocking secretion,” wrote Irina Gitlin, PhD, and John Fahy, MD, from the University of California, San Francisco, in Nature.

They were referring to research by Dr. Dickey and colleagues described in the same issue of Nature focusing on the inhibition of calcium-triggered mucus secretion by the use of hydrocarbon-stapled peptides, short chains of amino acids stabilized with a chemical bridge to a hydrocarbon molecule.
 

Knocking secretion down, but not out

The work has centered on decreasing overproduction of mucins with a focus on the signals for mucin production, including IL-13 and interleukin-1 beta, and on the signals for rapid release of mucins, including adenosine 5’-triphosphate (ATP), best known as an intracellular energy-storage module.

“But ATP is also steadily released by ciliated cells in response to the shear stress of tidal breathing, and it tells the neighboring secretory cells to slowly and steadily release mucin. But if the ciliated cells get stressed by any of a number of mechanisms, it can release a lot of ATP, and then the secretory cell can explosively release essentially all of its mucin content,” Dr. Dickey explained.

Other important signals for rapid release of mucins are acetylcholine and histamine, and all three of these agonists – ATP, acetylcholine, and histamine – cause a rise in intracellular calcium, which triggers calcium sensors that then lead to calcium-triggered membrane fusion and secretion.

Working as a postdoc in the Dickey laboratory, Dr. Evans had previously shown that deleting MUC5B in mice led to early development of serious lung abnormalities, some of which were fatal, indicating that MUC5B, a gene that is highly preserved in evolution, is essential for respiratory health.

This observation was later supported by a study of a family with a pattern of hereditary mucin deficiency caused by a homozygous loss-of-function mutation in MUC5B. The main subject in this study was an adult woman with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infections. Her sibling, who also had the biallelic mutation, had extensive sinus disease with nasal polyps. Other siblings who were heterozygous for the mutation were asymptomatic but had mild functional lung impairment.

The trick for the investigators, then, was to figure out how to reduce stimulated release of stored mucins while still preserving normal release of mucins to allow for ciliary clearance of mucus, and Dr. Dickey and colleagues appear to have accomplished this, at least in mice.

They first validated as a potential therapeutic target a protein labeled synaptotagmin-2 (Syt2). Syt2 is a calcium sensor that is an essential part of the system that triggers calcium-triggered secretion. In a model for allergic asthma, mice with Syt2 deleted from airway epithelia had marked reductions in both stimulated mucin secretion and in mucus occlusion in airway lumens, but remained otherwise healthy with normal lung function.

Working with structural biologist Axel Brunger, PhD, from Stanford (Calif.) University, Dr. Dickey and coinvestigators developed and validated a peptide that could specifically inhibit Syt2, and found that it mimicked the action of the Syt2 deletion, preventing mucus occlusion in the allergic asthma model without adversely effecting normal production.
 

Not ready for prime time

Dr. Dickey and colleagues are now working to translate the therapy into a form that can be used in humans, most likely as an aerosol that could be used for acute treatment of patients with mucus plugging from asthma and COPD, and also as a therapy for patients with chronic disease.

“In the chronic situation, what we would hope to do is identify patients with muco-obstructive lung disease – asthma, COPD, cystic fibrosis – who have airway mucus obstruction and then use the inhaled peptide on a regular basis as one part of a program to try to prevent this chronic mucus occlusion,” Dr. Dickey said.

As Dr. Gitlin and Dr. Fahy wrote in their editorial, “by confirming that it is possible to block calcium-regulated mucin secretion, Lai and colleagues have shown the potential of such an approach as a new therapeutic strategy for lung illnesses associated with mucus pathology, including diseases such as asthma and COPD, for which there is a large unmet medical need.”

The study by Dr. Dickey and colleagues was supported by grants from the German Research Foundation, National Institutes of Health and the Cystic Fibrosis Foundation. Dr. Dickey disclosed consulting for Arrowhead Pharmaceuticals. Dr. Kim disclosed personal fees from Medscape and others. Dr. Evans reported no relevant disclosures. Dr. Fahy and Dr. Gitlin are named inventors on patents for mucolytic drugs, and shareholders in Aer Therapeutics.

Just uttering the word “mucus” is often sufficient to elicit amusement from those within earshot, but to patients with chronic inflammatory airway diseases, mucus is no laughing matter.

Under normal conditions, mucus plays an important protective role, trapping airway irritants such as smoke, pollen, and particulate matter, which are then moved by cilia out of the airways for expulsion through coughing.

But in cystic fibrosis (CF), for example, mucus hypersecretion can be deadly. The underlying pathology of CF – a mutation in the CFTR gene, which codes for the protein CF transmembrane conductance regulator – leads to buildup in the lungs of abnormally viscous and sticky mucus, resulting in frequent, severe infections (particularly with Pseudomonas aeruginosa), progressive lung damage, and prior to the development of effective disease management, significantly premature death.

Mucus hypersecretion is also a feature of chronic obstructive pulmonary disease (COPD), noted Victor Kim, MD, from Temple University, Philadelphia, Christopher M. Evans, PhD, from the University of Colorado at Denver, Aurora, and Burton F. Dickey, MD, from the University of Texas MD Anderson Cancer Center, Houston.

In COPD, “mucus dysfunction arises from several mechanisms, including excess production due to inflammation, decreased elimination due to impaired ciliary clearance and reduced cough efficiency, and excessive concentration due to smoke-induced dysfunction of transepithelial anion transport resembling CF,” they wrote in an editorial published in the American Journal of Respiratory and Critical Care Medicine.

In patients with idiopathic pulmonary fibrosis, a polymorphism in the enhancer region of MUC5B, a gene that encodes for mucin glycoproteins, results in a 20-fold overexpression of the gene and prominent mucus production that has been shown to parallel lung inflammation and decline in forced vital capacity (FVC).

In patients with asthma, up-regulation of MUC5AC and stimulated mucus secretion conspire to obstruct airways, which can in extreme cases lead to death.
 

‘Short shrift’

Yet until recently, the role of mucus hypersecretion in diseases such as COPD has been largely overlooked, or as Dr. Kim and colleagues put it, “airway mucus often receives short shrift from clinicians.”

“It’s a pretty hot topic in pulmonary medicine today because it has been so neglected for so long,” Dr. Dickey said in an interview with CHEST Physician. “As clinicians we haven’t had a way to identify who needs treatment, which is ridiculous, because many of the people who expectorate a lot, like those with chronic bronchitis, don’t actually have small airway obstruction, and conversely, a lot of asthmatics, who have very serious small airway obstruction, don’t expectorate, so you can’t really tell from symptoms.”

What has changed in recent years is the use of chest CT to image muco-obstructive pathology, commonly called “mucus plugging” in the peripheral airways of patients with COPD and asthma.

“In the last decade or so, we’ve seen the emergence in obstructive lung diseases such as asthma and COPD the use of more objective measures on CT scans, including the problem of mucus plugging, which is unfortunately very common,” Dr. Kim said in an interview.

The discovery of the extent and severity of mucus in obstructive lung diseases has led to new strategies to combat mucus overconcentration, such as hydration, mucolytics, and an intriguing investigational approach to decrease calcium-induced hypersecretion with designer peptides.
 

Mighty mucins

Under normal physiologic conditions mucus is composed largely of water (97%) and salts (2%), with the remainder consisting of entrapped globular proteins (0.7%) and mucins (0.3%), Dr. Dickey explains.

Yet those meager mucins pack a real punch, with the ability to absorb 300 times their mass of water after secretion, creating mucus of optimal consistency and viscoelasticity.

“Personally, I’ve never understood – maybe I should have paid more attention in physics – how a compound can absorb 300-fold its mass, but it does,” he said.

In a recent review article in the journal Clinical and Translational Medicine, Dr. Dickey and colleagues described how good mucus can go bad.

“[H]igh levels of mucin production from inflammatory stimulation (termed ‘mucous metaplasia’), followed by rapid release (together, termed ‘mucus hypersecretion’), can plug airways due to mucus volume expansion. In addition, if available lumenal liquid is insufficient, concentrated mucus of excessive viscoelasticity and adhesivity can cause mucus stasis,” they wrote.
 

Therapeutic strategies

In patients with CF, CFTR modulator therapy has markedly reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. The manipulations can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

Unlike in CF, where treating the underlying genetic pathology can help to resolve the thick, sticky mucus problems and thereby significantly reduce risk of infections and progressive lung damage, treatment of mucus metaplasia or hypersecretion in other diseases is aimed at symptomatic relief; it is still unclear whether symptomatic improvement of mucus overproduction would correlate with other disease-related outcomes, Dr. Kim and Dr. Dickey noted.

Potential therapeutic strategies to reduce excess mucus in the lungs include the use of mucolytic agents to thin secretions for more effective expulsion, decreasing mucus production through the use of an interleukin-13 (IL-13) inhibitor such as the anti-asthma agent dupilumab (Dupixent), and a novel strategy, still in the experimental phase, aimed at “disrupting the fusion of mucin storage granules with the cell membrane, thereby blocking secretion,” wrote Irina Gitlin, PhD, and John Fahy, MD, from the University of California, San Francisco, in Nature.

They were referring to research by Dr. Dickey and colleagues described in the same issue of Nature focusing on the inhibition of calcium-triggered mucus secretion by the use of hydrocarbon-stapled peptides, short chains of amino acids stabilized with a chemical bridge to a hydrocarbon molecule.
 

Knocking secretion down, but not out

The work has centered on decreasing overproduction of mucins with a focus on the signals for mucin production, including IL-13 and interleukin-1 beta, and on the signals for rapid release of mucins, including adenosine 5’-triphosphate (ATP), best known as an intracellular energy-storage module.

“But ATP is also steadily released by ciliated cells in response to the shear stress of tidal breathing, and it tells the neighboring secretory cells to slowly and steadily release mucin. But if the ciliated cells get stressed by any of a number of mechanisms, it can release a lot of ATP, and then the secretory cell can explosively release essentially all of its mucin content,” Dr. Dickey explained.

Other important signals for rapid release of mucins are acetylcholine and histamine, and all three of these agonists – ATP, acetylcholine, and histamine – cause a rise in intracellular calcium, which triggers calcium sensors that then lead to calcium-triggered membrane fusion and secretion.

Working as a postdoc in the Dickey laboratory, Dr. Evans had previously shown that deleting MUC5B in mice led to early development of serious lung abnormalities, some of which were fatal, indicating that MUC5B, a gene that is highly preserved in evolution, is essential for respiratory health.

This observation was later supported by a study of a family with a pattern of hereditary mucin deficiency caused by a homozygous loss-of-function mutation in MUC5B. The main subject in this study was an adult woman with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infections. Her sibling, who also had the biallelic mutation, had extensive sinus disease with nasal polyps. Other siblings who were heterozygous for the mutation were asymptomatic but had mild functional lung impairment.

The trick for the investigators, then, was to figure out how to reduce stimulated release of stored mucins while still preserving normal release of mucins to allow for ciliary clearance of mucus, and Dr. Dickey and colleagues appear to have accomplished this, at least in mice.

They first validated as a potential therapeutic target a protein labeled synaptotagmin-2 (Syt2). Syt2 is a calcium sensor that is an essential part of the system that triggers calcium-triggered secretion. In a model for allergic asthma, mice with Syt2 deleted from airway epithelia had marked reductions in both stimulated mucin secretion and in mucus occlusion in airway lumens, but remained otherwise healthy with normal lung function.

Working with structural biologist Axel Brunger, PhD, from Stanford (Calif.) University, Dr. Dickey and coinvestigators developed and validated a peptide that could specifically inhibit Syt2, and found that it mimicked the action of the Syt2 deletion, preventing mucus occlusion in the allergic asthma model without adversely effecting normal production.
 

Not ready for prime time

Dr. Dickey and colleagues are now working to translate the therapy into a form that can be used in humans, most likely as an aerosol that could be used for acute treatment of patients with mucus plugging from asthma and COPD, and also as a therapy for patients with chronic disease.

“In the chronic situation, what we would hope to do is identify patients with muco-obstructive lung disease – asthma, COPD, cystic fibrosis – who have airway mucus obstruction and then use the inhaled peptide on a regular basis as one part of a program to try to prevent this chronic mucus occlusion,” Dr. Dickey said.

As Dr. Gitlin and Dr. Fahy wrote in their editorial, “by confirming that it is possible to block calcium-regulated mucin secretion, Lai and colleagues have shown the potential of such an approach as a new therapeutic strategy for lung illnesses associated with mucus pathology, including diseases such as asthma and COPD, for which there is a large unmet medical need.”

The study by Dr. Dickey and colleagues was supported by grants from the German Research Foundation, National Institutes of Health and the Cystic Fibrosis Foundation. Dr. Dickey disclosed consulting for Arrowhead Pharmaceuticals. Dr. Kim disclosed personal fees from Medscape and others. Dr. Evans reported no relevant disclosures. Dr. Fahy and Dr. Gitlin are named inventors on patents for mucolytic drugs, and shareholders in Aer Therapeutics.

Just uttering the word “mucus” is often sufficient to elicit amusement from those within earshot, but to patients with chronic inflammatory airway diseases, mucus is no laughing matter.

Under normal conditions, mucus plays an important protective role, trapping airway irritants such as smoke, pollen, and particulate matter, which are then moved by cilia out of the airways for expulsion through coughing.

But in cystic fibrosis (CF), for example, mucus hypersecretion can be deadly. The underlying pathology of CF – a mutation in the CFTR gene, which codes for the protein CF transmembrane conductance regulator – leads to buildup in the lungs of abnormally viscous and sticky mucus, resulting in frequent, severe infections (particularly with Pseudomonas aeruginosa), progressive lung damage, and prior to the development of effective disease management, significantly premature death.

Mucus hypersecretion is also a feature of chronic obstructive pulmonary disease (COPD), noted Victor Kim, MD, from Temple University, Philadelphia, Christopher M. Evans, PhD, from the University of Colorado at Denver, Aurora, and Burton F. Dickey, MD, from the University of Texas MD Anderson Cancer Center, Houston.

In COPD, “mucus dysfunction arises from several mechanisms, including excess production due to inflammation, decreased elimination due to impaired ciliary clearance and reduced cough efficiency, and excessive concentration due to smoke-induced dysfunction of transepithelial anion transport resembling CF,” they wrote in an editorial published in the American Journal of Respiratory and Critical Care Medicine.

In patients with idiopathic pulmonary fibrosis, a polymorphism in the enhancer region of MUC5B, a gene that encodes for mucin glycoproteins, results in a 20-fold overexpression of the gene and prominent mucus production that has been shown to parallel lung inflammation and decline in forced vital capacity (FVC).

In patients with asthma, up-regulation of MUC5AC and stimulated mucus secretion conspire to obstruct airways, which can in extreme cases lead to death.
 

‘Short shrift’

Yet until recently, the role of mucus hypersecretion in diseases such as COPD has been largely overlooked, or as Dr. Kim and colleagues put it, “airway mucus often receives short shrift from clinicians.”

“It’s a pretty hot topic in pulmonary medicine today because it has been so neglected for so long,” Dr. Dickey said in an interview with CHEST Physician. “As clinicians we haven’t had a way to identify who needs treatment, which is ridiculous, because many of the people who expectorate a lot, like those with chronic bronchitis, don’t actually have small airway obstruction, and conversely, a lot of asthmatics, who have very serious small airway obstruction, don’t expectorate, so you can’t really tell from symptoms.”

What has changed in recent years is the use of chest CT to image muco-obstructive pathology, commonly called “mucus plugging” in the peripheral airways of patients with COPD and asthma.

“In the last decade or so, we’ve seen the emergence in obstructive lung diseases such as asthma and COPD the use of more objective measures on CT scans, including the problem of mucus plugging, which is unfortunately very common,” Dr. Kim said in an interview.

The discovery of the extent and severity of mucus in obstructive lung diseases has led to new strategies to combat mucus overconcentration, such as hydration, mucolytics, and an intriguing investigational approach to decrease calcium-induced hypersecretion with designer peptides.
 

Mighty mucins

Under normal physiologic conditions mucus is composed largely of water (97%) and salts (2%), with the remainder consisting of entrapped globular proteins (0.7%) and mucins (0.3%), Dr. Dickey explains.

Yet those meager mucins pack a real punch, with the ability to absorb 300 times their mass of water after secretion, creating mucus of optimal consistency and viscoelasticity.

“Personally, I’ve never understood – maybe I should have paid more attention in physics – how a compound can absorb 300-fold its mass, but it does,” he said.

In a recent review article in the journal Clinical and Translational Medicine, Dr. Dickey and colleagues described how good mucus can go bad.

“[H]igh levels of mucin production from inflammatory stimulation (termed ‘mucous metaplasia’), followed by rapid release (together, termed ‘mucus hypersecretion’), can plug airways due to mucus volume expansion. In addition, if available lumenal liquid is insufficient, concentrated mucus of excessive viscoelasticity and adhesivity can cause mucus stasis,” they wrote.
 

Therapeutic strategies

In patients with CF, CFTR modulator therapy has markedly reduced but not eliminated the need for some patients to have mucolytic therapy, which may include dornase alfa, a recombinant human deoxyribonuclease that reduces the viscosity of lung secretions, hypertonic saline inhaled twice daily (for patients 12 and older), mannitol, and physical manipulations to help patients clear mucus. The manipulations can include both manual percussion and the use of devices for high-frequency chest wall oscillation.

Unlike in CF, where treating the underlying genetic pathology can help to resolve the thick, sticky mucus problems and thereby significantly reduce risk of infections and progressive lung damage, treatment of mucus metaplasia or hypersecretion in other diseases is aimed at symptomatic relief; it is still unclear whether symptomatic improvement of mucus overproduction would correlate with other disease-related outcomes, Dr. Kim and Dr. Dickey noted.

Potential therapeutic strategies to reduce excess mucus in the lungs include the use of mucolytic agents to thin secretions for more effective expulsion, decreasing mucus production through the use of an interleukin-13 (IL-13) inhibitor such as the anti-asthma agent dupilumab (Dupixent), and a novel strategy, still in the experimental phase, aimed at “disrupting the fusion of mucin storage granules with the cell membrane, thereby blocking secretion,” wrote Irina Gitlin, PhD, and John Fahy, MD, from the University of California, San Francisco, in Nature.

They were referring to research by Dr. Dickey and colleagues described in the same issue of Nature focusing on the inhibition of calcium-triggered mucus secretion by the use of hydrocarbon-stapled peptides, short chains of amino acids stabilized with a chemical bridge to a hydrocarbon molecule.
 

Knocking secretion down, but not out

The work has centered on decreasing overproduction of mucins with a focus on the signals for mucin production, including IL-13 and interleukin-1 beta, and on the signals for rapid release of mucins, including adenosine 5’-triphosphate (ATP), best known as an intracellular energy-storage module.

“But ATP is also steadily released by ciliated cells in response to the shear stress of tidal breathing, and it tells the neighboring secretory cells to slowly and steadily release mucin. But if the ciliated cells get stressed by any of a number of mechanisms, it can release a lot of ATP, and then the secretory cell can explosively release essentially all of its mucin content,” Dr. Dickey explained.

Other important signals for rapid release of mucins are acetylcholine and histamine, and all three of these agonists – ATP, acetylcholine, and histamine – cause a rise in intracellular calcium, which triggers calcium sensors that then lead to calcium-triggered membrane fusion and secretion.

Working as a postdoc in the Dickey laboratory, Dr. Evans had previously shown that deleting MUC5B in mice led to early development of serious lung abnormalities, some of which were fatal, indicating that MUC5B, a gene that is highly preserved in evolution, is essential for respiratory health.

This observation was later supported by a study of a family with a pattern of hereditary mucin deficiency caused by a homozygous loss-of-function mutation in MUC5B. The main subject in this study was an adult woman with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infections. Her sibling, who also had the biallelic mutation, had extensive sinus disease with nasal polyps. Other siblings who were heterozygous for the mutation were asymptomatic but had mild functional lung impairment.

The trick for the investigators, then, was to figure out how to reduce stimulated release of stored mucins while still preserving normal release of mucins to allow for ciliary clearance of mucus, and Dr. Dickey and colleagues appear to have accomplished this, at least in mice.

They first validated as a potential therapeutic target a protein labeled synaptotagmin-2 (Syt2). Syt2 is a calcium sensor that is an essential part of the system that triggers calcium-triggered secretion. In a model for allergic asthma, mice with Syt2 deleted from airway epithelia had marked reductions in both stimulated mucin secretion and in mucus occlusion in airway lumens, but remained otherwise healthy with normal lung function.

Working with structural biologist Axel Brunger, PhD, from Stanford (Calif.) University, Dr. Dickey and coinvestigators developed and validated a peptide that could specifically inhibit Syt2, and found that it mimicked the action of the Syt2 deletion, preventing mucus occlusion in the allergic asthma model without adversely effecting normal production.
 

Not ready for prime time

Dr. Dickey and colleagues are now working to translate the therapy into a form that can be used in humans, most likely as an aerosol that could be used for acute treatment of patients with mucus plugging from asthma and COPD, and also as a therapy for patients with chronic disease.

“In the chronic situation, what we would hope to do is identify patients with muco-obstructive lung disease – asthma, COPD, cystic fibrosis – who have airway mucus obstruction and then use the inhaled peptide on a regular basis as one part of a program to try to prevent this chronic mucus occlusion,” Dr. Dickey said.

As Dr. Gitlin and Dr. Fahy wrote in their editorial, “by confirming that it is possible to block calcium-regulated mucin secretion, Lai and colleagues have shown the potential of such an approach as a new therapeutic strategy for lung illnesses associated with mucus pathology, including diseases such as asthma and COPD, for which there is a large unmet medical need.”

The study by Dr. Dickey and colleagues was supported by grants from the German Research Foundation, National Institutes of Health and the Cystic Fibrosis Foundation. Dr. Dickey disclosed consulting for Arrowhead Pharmaceuticals. Dr. Kim disclosed personal fees from Medscape and others. Dr. Evans reported no relevant disclosures. Dr. Fahy and Dr. Gitlin are named inventors on patents for mucolytic drugs, and shareholders in Aer Therapeutics.