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Mucus unplugged
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.
, 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.
, 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.
, 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.
How to remain apolitical with patients
It is assumed that psychiatrists in general, but particularly in academia, are progressive liberals. There is evidence to support this idea, with a survey finding that more than three-quarters of U.S. psychiatrists are registered Democrats.1
Other corroborating factors to our field’s progressive tendency include the publication of pseudo-political books like “The Dangerous Case of Donald Trump: 27 Psychiatrists and Mental Health Experts Assess a President” – without a well-known equivalent on the other side.
Additionally, psychiatry has in the recent past, rightfully spent significant effort examining the disproportional trauma faced by patients with underprivileged backgrounds, which is often seen as a political position. The American Psychiatric Association has itself taken a stance on the national debate about abortion to warn against the psychiatric consequences of the Dobbs v. Jackson Supreme Court decision despite the clear political statement it makes.
We understand a likely rationale for psychiatry’s liberal tendency. Most psychiatrists support political objectives that provide resources for the treatment of the severely mentally ill. In general, the psychosocial consequences of mental illness place a downward economic pressure on our patients that leads to poverty and its associated traumas that then tend to feedback to worsen the severity of the illness itself. It is thus natural for psychiatry to promote political causes such as progressivism that focus on the needs of economically and socially struggling communities. If one posits a natural role for psychiatry in promoting the interests of patients, then it is a short leap to psychiatry promoting the political causes of the underprivileged, often in the form of endorsing the Democratic party.
As a result, a proportion of patients come into psychiatric treatment with expectations that their providers will negatively judge them and possibly punish their conservative beliefs or Republican political affiliation. Herein lies a question – “Is psychiatry willing to make 46.9% of Americans uncomfortable?” How should psychiatry address the 46.9% of Americans who voted Republican during the 2020 presidential election? In our desire to support the disadvantaged, how political are we willing to get and at what cost? While we cannot speak for the field as a whole, it is our concern that a vast percentage of Americans feel alienated from talking to us, which is particularly problematic in a field based on mutual trust and understanding.
This problem may be particularly palpable to us, as we are psychiatrists in a large metropolitan area of California who often treat specialty populations like veterans and law enforcement. In one study, law enforcement officers were found to be twice as likely to be Republicans as civilians.2 Michael McHale, the president of the National Association of Police Organizations, spoke at the 2020 Republican Party’s national convention as documented in an article titled “Union leader tells Republican convention why cops back Trump.”3 Similarly, about 60% of veterans identify as Republicans.4
Within the first few sessions, when patients are most vulnerable and sensitive to the perception of being judged, we commonly get asked questions to test our political beliefs. Some patients will display clothing that suggests a political affiliation; those wardrobe arrangements are, at times, an attempt at testing our knowledge of their in-group. While a bright-red cap with a reminder to keep the United States “great” in capital letters may be an overt invitation to address the topic, other patients may have a small symbol of a rattlesnake to test our ability to recognize the “Don’t Tread on Me” Gadsden flag.
Alternatively, other patients will ask our opinion, or bring up news topics, to share their concerns and/or examine our response and reactions. We remember, in particular, a patient who subtly asked if they needed to be vaccinated to attend therapy visits in person as a leading statement into their conservative political beliefs. It is a reminder that many patients fear how we will judge them or where we will draw the line – “Is there something I, the patient, can say that will make him dislike me?”
While the concept of making all patients comfortable may feel abstract or trivial to some, the consequences can be very real. We remember a patient with severe depression and occasional suicidality, who required many months of treatment for him to reveal that he owned a gun. His conservative beliefs made him very resistant to discuss gun ownership with someone who is presumably liberal and has the power to restrict such ownership. However, after a frank discussion that our concerns about his gun were not constitutional or political but medical, the patient agreed to relinquish his gun, at least temporarily, a likely more important intervention than many in psychiatry.
The ramifications are also wider than most imagine. In California, a particularly liberal state, many consistently and reliably liberal patients have some conservative beliefs. Those beliefs are often closeted: a Democratic mother who doesn’t think her 3-year-old daughter should wear a mask in school; a Democratic woman who questioned the veracity of Amber Heard during the Johnny Depp defamation trial and feels guilty about her prior dedication to the #MeToo movement.
Patients may feel torn about those beliefs and may be apprehensive to discuss them despite a nagging need to express or examine them in a place without judgment.
that we attempted to highlight in this article. In particular, a vast proportion of Americans may feel alienated from treatment or may refuse to divulge clinically relevant information, and a large number of patients may enter psychiatric treatment with concerns that they will be judged.
Psychiatry is founded on the honest exchange of thoughts and feelings between patients and providers without the fear of harsh judgment and intellectual retaliation. Psychiatrists would be wise to consider those factors and their repercussions when choosing to take political positions and setting a frame of care with their patients.
Dr. Lehman is a professor of psychiatry at the University of California, San Diego. He is codirector of all acute and intensive psychiatric treatment at the Veterans Affairs Medical Center in San Diego, where he practices clinical psychiatry. He has no conflicts of interest. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. He has no conflicts of interest.
References
1. Sanger-Katz M. Your surgeon is probably a Republican, your psychiatrist probably a Democrat. New York Times. 2016 Oct 6.
2. Ba B et al. Who are the police? Descriptive representation in the coercive arm of government. 2022 Mar 21.
3. Rainey J. Union leader tells Republican convention why cops back Trump. Los Angeles Times. 2020 Aug 26.
4. Igielnik R et al. Trump draws stronger support from veterans than from the public on leadership of U.S. military. Pew Research Center. 2019 July 10.
It is assumed that psychiatrists in general, but particularly in academia, are progressive liberals. There is evidence to support this idea, with a survey finding that more than three-quarters of U.S. psychiatrists are registered Democrats.1
Other corroborating factors to our field’s progressive tendency include the publication of pseudo-political books like “The Dangerous Case of Donald Trump: 27 Psychiatrists and Mental Health Experts Assess a President” – without a well-known equivalent on the other side.
Additionally, psychiatry has in the recent past, rightfully spent significant effort examining the disproportional trauma faced by patients with underprivileged backgrounds, which is often seen as a political position. The American Psychiatric Association has itself taken a stance on the national debate about abortion to warn against the psychiatric consequences of the Dobbs v. Jackson Supreme Court decision despite the clear political statement it makes.
We understand a likely rationale for psychiatry’s liberal tendency. Most psychiatrists support political objectives that provide resources for the treatment of the severely mentally ill. In general, the psychosocial consequences of mental illness place a downward economic pressure on our patients that leads to poverty and its associated traumas that then tend to feedback to worsen the severity of the illness itself. It is thus natural for psychiatry to promote political causes such as progressivism that focus on the needs of economically and socially struggling communities. If one posits a natural role for psychiatry in promoting the interests of patients, then it is a short leap to psychiatry promoting the political causes of the underprivileged, often in the form of endorsing the Democratic party.
As a result, a proportion of patients come into psychiatric treatment with expectations that their providers will negatively judge them and possibly punish their conservative beliefs or Republican political affiliation. Herein lies a question – “Is psychiatry willing to make 46.9% of Americans uncomfortable?” How should psychiatry address the 46.9% of Americans who voted Republican during the 2020 presidential election? In our desire to support the disadvantaged, how political are we willing to get and at what cost? While we cannot speak for the field as a whole, it is our concern that a vast percentage of Americans feel alienated from talking to us, which is particularly problematic in a field based on mutual trust and understanding.
This problem may be particularly palpable to us, as we are psychiatrists in a large metropolitan area of California who often treat specialty populations like veterans and law enforcement. In one study, law enforcement officers were found to be twice as likely to be Republicans as civilians.2 Michael McHale, the president of the National Association of Police Organizations, spoke at the 2020 Republican Party’s national convention as documented in an article titled “Union leader tells Republican convention why cops back Trump.”3 Similarly, about 60% of veterans identify as Republicans.4
Within the first few sessions, when patients are most vulnerable and sensitive to the perception of being judged, we commonly get asked questions to test our political beliefs. Some patients will display clothing that suggests a political affiliation; those wardrobe arrangements are, at times, an attempt at testing our knowledge of their in-group. While a bright-red cap with a reminder to keep the United States “great” in capital letters may be an overt invitation to address the topic, other patients may have a small symbol of a rattlesnake to test our ability to recognize the “Don’t Tread on Me” Gadsden flag.
Alternatively, other patients will ask our opinion, or bring up news topics, to share their concerns and/or examine our response and reactions. We remember, in particular, a patient who subtly asked if they needed to be vaccinated to attend therapy visits in person as a leading statement into their conservative political beliefs. It is a reminder that many patients fear how we will judge them or where we will draw the line – “Is there something I, the patient, can say that will make him dislike me?”
While the concept of making all patients comfortable may feel abstract or trivial to some, the consequences can be very real. We remember a patient with severe depression and occasional suicidality, who required many months of treatment for him to reveal that he owned a gun. His conservative beliefs made him very resistant to discuss gun ownership with someone who is presumably liberal and has the power to restrict such ownership. However, after a frank discussion that our concerns about his gun were not constitutional or political but medical, the patient agreed to relinquish his gun, at least temporarily, a likely more important intervention than many in psychiatry.
The ramifications are also wider than most imagine. In California, a particularly liberal state, many consistently and reliably liberal patients have some conservative beliefs. Those beliefs are often closeted: a Democratic mother who doesn’t think her 3-year-old daughter should wear a mask in school; a Democratic woman who questioned the veracity of Amber Heard during the Johnny Depp defamation trial and feels guilty about her prior dedication to the #MeToo movement.
Patients may feel torn about those beliefs and may be apprehensive to discuss them despite a nagging need to express or examine them in a place without judgment.
that we attempted to highlight in this article. In particular, a vast proportion of Americans may feel alienated from treatment or may refuse to divulge clinically relevant information, and a large number of patients may enter psychiatric treatment with concerns that they will be judged.
Psychiatry is founded on the honest exchange of thoughts and feelings between patients and providers without the fear of harsh judgment and intellectual retaliation. Psychiatrists would be wise to consider those factors and their repercussions when choosing to take political positions and setting a frame of care with their patients.
Dr. Lehman is a professor of psychiatry at the University of California, San Diego. He is codirector of all acute and intensive psychiatric treatment at the Veterans Affairs Medical Center in San Diego, where he practices clinical psychiatry. He has no conflicts of interest. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. He has no conflicts of interest.
References
1. Sanger-Katz M. Your surgeon is probably a Republican, your psychiatrist probably a Democrat. New York Times. 2016 Oct 6.
2. Ba B et al. Who are the police? Descriptive representation in the coercive arm of government. 2022 Mar 21.
3. Rainey J. Union leader tells Republican convention why cops back Trump. Los Angeles Times. 2020 Aug 26.
4. Igielnik R et al. Trump draws stronger support from veterans than from the public on leadership of U.S. military. Pew Research Center. 2019 July 10.
It is assumed that psychiatrists in general, but particularly in academia, are progressive liberals. There is evidence to support this idea, with a survey finding that more than three-quarters of U.S. psychiatrists are registered Democrats.1
Other corroborating factors to our field’s progressive tendency include the publication of pseudo-political books like “The Dangerous Case of Donald Trump: 27 Psychiatrists and Mental Health Experts Assess a President” – without a well-known equivalent on the other side.
Additionally, psychiatry has in the recent past, rightfully spent significant effort examining the disproportional trauma faced by patients with underprivileged backgrounds, which is often seen as a political position. The American Psychiatric Association has itself taken a stance on the national debate about abortion to warn against the psychiatric consequences of the Dobbs v. Jackson Supreme Court decision despite the clear political statement it makes.
We understand a likely rationale for psychiatry’s liberal tendency. Most psychiatrists support political objectives that provide resources for the treatment of the severely mentally ill. In general, the psychosocial consequences of mental illness place a downward economic pressure on our patients that leads to poverty and its associated traumas that then tend to feedback to worsen the severity of the illness itself. It is thus natural for psychiatry to promote political causes such as progressivism that focus on the needs of economically and socially struggling communities. If one posits a natural role for psychiatry in promoting the interests of patients, then it is a short leap to psychiatry promoting the political causes of the underprivileged, often in the form of endorsing the Democratic party.
As a result, a proportion of patients come into psychiatric treatment with expectations that their providers will negatively judge them and possibly punish their conservative beliefs or Republican political affiliation. Herein lies a question – “Is psychiatry willing to make 46.9% of Americans uncomfortable?” How should psychiatry address the 46.9% of Americans who voted Republican during the 2020 presidential election? In our desire to support the disadvantaged, how political are we willing to get and at what cost? While we cannot speak for the field as a whole, it is our concern that a vast percentage of Americans feel alienated from talking to us, which is particularly problematic in a field based on mutual trust and understanding.
This problem may be particularly palpable to us, as we are psychiatrists in a large metropolitan area of California who often treat specialty populations like veterans and law enforcement. In one study, law enforcement officers were found to be twice as likely to be Republicans as civilians.2 Michael McHale, the president of the National Association of Police Organizations, spoke at the 2020 Republican Party’s national convention as documented in an article titled “Union leader tells Republican convention why cops back Trump.”3 Similarly, about 60% of veterans identify as Republicans.4
Within the first few sessions, when patients are most vulnerable and sensitive to the perception of being judged, we commonly get asked questions to test our political beliefs. Some patients will display clothing that suggests a political affiliation; those wardrobe arrangements are, at times, an attempt at testing our knowledge of their in-group. While a bright-red cap with a reminder to keep the United States “great” in capital letters may be an overt invitation to address the topic, other patients may have a small symbol of a rattlesnake to test our ability to recognize the “Don’t Tread on Me” Gadsden flag.
Alternatively, other patients will ask our opinion, or bring up news topics, to share their concerns and/or examine our response and reactions. We remember, in particular, a patient who subtly asked if they needed to be vaccinated to attend therapy visits in person as a leading statement into their conservative political beliefs. It is a reminder that many patients fear how we will judge them or where we will draw the line – “Is there something I, the patient, can say that will make him dislike me?”
While the concept of making all patients comfortable may feel abstract or trivial to some, the consequences can be very real. We remember a patient with severe depression and occasional suicidality, who required many months of treatment for him to reveal that he owned a gun. His conservative beliefs made him very resistant to discuss gun ownership with someone who is presumably liberal and has the power to restrict such ownership. However, after a frank discussion that our concerns about his gun were not constitutional or political but medical, the patient agreed to relinquish his gun, at least temporarily, a likely more important intervention than many in psychiatry.
The ramifications are also wider than most imagine. In California, a particularly liberal state, many consistently and reliably liberal patients have some conservative beliefs. Those beliefs are often closeted: a Democratic mother who doesn’t think her 3-year-old daughter should wear a mask in school; a Democratic woman who questioned the veracity of Amber Heard during the Johnny Depp defamation trial and feels guilty about her prior dedication to the #MeToo movement.
Patients may feel torn about those beliefs and may be apprehensive to discuss them despite a nagging need to express or examine them in a place without judgment.
that we attempted to highlight in this article. In particular, a vast proportion of Americans may feel alienated from treatment or may refuse to divulge clinically relevant information, and a large number of patients may enter psychiatric treatment with concerns that they will be judged.
Psychiatry is founded on the honest exchange of thoughts and feelings between patients and providers without the fear of harsh judgment and intellectual retaliation. Psychiatrists would be wise to consider those factors and their repercussions when choosing to take political positions and setting a frame of care with their patients.
Dr. Lehman is a professor of psychiatry at the University of California, San Diego. He is codirector of all acute and intensive psychiatric treatment at the Veterans Affairs Medical Center in San Diego, where he practices clinical psychiatry. He has no conflicts of interest. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. He has no conflicts of interest.
References
1. Sanger-Katz M. Your surgeon is probably a Republican, your psychiatrist probably a Democrat. New York Times. 2016 Oct 6.
2. Ba B et al. Who are the police? Descriptive representation in the coercive arm of government. 2022 Mar 21.
3. Rainey J. Union leader tells Republican convention why cops back Trump. Los Angeles Times. 2020 Aug 26.
4. Igielnik R et al. Trump draws stronger support from veterans than from the public on leadership of U.S. military. Pew Research Center. 2019 July 10.
Confirmed: ECT tops ketamine for major depression
in new findings that are in line with the KetECT study – the first head-to-head trial of ketamine and ECT.
The KetECT trial, which was published earlier this year, showed that ECT was more effective than IV ketamine for hospitalized patients with severe depression. ECT yielded higher remission rates and a greater reduction of symptoms.
Despite the apparent superiority of ECT over ketamine, the researchers of the current meta-analysis caution that treatment options for MDE “should still be individualized and patient-centered because ketamine’s faster antidepressant effects may still be desirable for certain patients with severe MDE who require quick recovery from the severity of depression.”
The study was published online in JAMA Psychiatry.
Confirmatory data
The review included six clinical trials with 340 patients with MDE. Of those patients, 162 were treated with ECT, and 178 were treated with ketamine. The mean age of the participants ranged from 37 to 52 years.
The primary efficacy outcome of interest was improvement of depressive symptoms.
ECT was superior to ketamine across different depressive symptom measures, reported Taeho Greg Rhee, PhD, of the University of Connecticut, Farmington, and colleagues.
The standardized mean difference (SMD) was –0.59 (95% confidence interval [CI], –0.85 to –0.33) on the Montgomery-Åsberg Depression Rating Scale.
The SMD was –0.83 (95% CI, –1.22 to –0.44] on the Hamilton Depression Rating Scale and –0.86 (95% CI, –1.50 to –0.22) on the Beck Depression Inventory.
The overall pooled SMD for ECT, when compared with ketamine, was –0.69 (95% CI, –0.89 to –0.48), indicating that ECT was more efficacious than ketamine.
The researchers did not find any moderating effects of various factors, including age, male sex, and presence of psychotic features.
For cognition and memory performance, one study reported that the ketamine group outperformed the ECT group in cognition, but the effect size was small to moderate.
A separate study that reported memory performance found no difference between ketamine and ECT, though this study was likely underpowered to detect such differences, with a total sample size of 32.
“Because of underpowered study designs, no firm conclusions regarding cognition and memory performance can be made in this meta-analysis. Future research should address this issue,” the investigators wrote.
Unique side effects
Ketamine and ECT had unique adverse effect profiles.
With ketamine, there was a lower risk of headache and muscle pain but a higher risk of transient dissociative or depersonalization symptoms. With ECT, there was a lower risk of blurred vision, vertigo, and diplopia/nystagmus.
Only one study reported suicide attempts and suicide deaths, for which there was no marked difference between ECT and ketamine.
A limitation of the meta-analysis is the low to moderate methodologic quality of the studies that were included, as well as the use of different ketamine and/or ECT treatment protocols, which could have influenced efficacy and safety outcomes.
The researchers noted that more research is needed to optimize long-term treatment outcomes for both ketamine and ECT to prevent relapse, “which is of key importance for clinical practice.”
The study had no specific funding. Dr. Rhee currently serves as a co–editor-in-chief of Mental Health Science and will receive honorarium payments annually from the publisher, John Wiley & Sons. A complete list of the authors’ relevant financial relationships is available with the original article.
A version of this article first appeared on Medscape.com.
in new findings that are in line with the KetECT study – the first head-to-head trial of ketamine and ECT.
The KetECT trial, which was published earlier this year, showed that ECT was more effective than IV ketamine for hospitalized patients with severe depression. ECT yielded higher remission rates and a greater reduction of symptoms.
Despite the apparent superiority of ECT over ketamine, the researchers of the current meta-analysis caution that treatment options for MDE “should still be individualized and patient-centered because ketamine’s faster antidepressant effects may still be desirable for certain patients with severe MDE who require quick recovery from the severity of depression.”
The study was published online in JAMA Psychiatry.
Confirmatory data
The review included six clinical trials with 340 patients with MDE. Of those patients, 162 were treated with ECT, and 178 were treated with ketamine. The mean age of the participants ranged from 37 to 52 years.
The primary efficacy outcome of interest was improvement of depressive symptoms.
ECT was superior to ketamine across different depressive symptom measures, reported Taeho Greg Rhee, PhD, of the University of Connecticut, Farmington, and colleagues.
The standardized mean difference (SMD) was –0.59 (95% confidence interval [CI], –0.85 to –0.33) on the Montgomery-Åsberg Depression Rating Scale.
The SMD was –0.83 (95% CI, –1.22 to –0.44] on the Hamilton Depression Rating Scale and –0.86 (95% CI, –1.50 to –0.22) on the Beck Depression Inventory.
The overall pooled SMD for ECT, when compared with ketamine, was –0.69 (95% CI, –0.89 to –0.48), indicating that ECT was more efficacious than ketamine.
The researchers did not find any moderating effects of various factors, including age, male sex, and presence of psychotic features.
For cognition and memory performance, one study reported that the ketamine group outperformed the ECT group in cognition, but the effect size was small to moderate.
A separate study that reported memory performance found no difference between ketamine and ECT, though this study was likely underpowered to detect such differences, with a total sample size of 32.
“Because of underpowered study designs, no firm conclusions regarding cognition and memory performance can be made in this meta-analysis. Future research should address this issue,” the investigators wrote.
Unique side effects
Ketamine and ECT had unique adverse effect profiles.
With ketamine, there was a lower risk of headache and muscle pain but a higher risk of transient dissociative or depersonalization symptoms. With ECT, there was a lower risk of blurred vision, vertigo, and diplopia/nystagmus.
Only one study reported suicide attempts and suicide deaths, for which there was no marked difference between ECT and ketamine.
A limitation of the meta-analysis is the low to moderate methodologic quality of the studies that were included, as well as the use of different ketamine and/or ECT treatment protocols, which could have influenced efficacy and safety outcomes.
The researchers noted that more research is needed to optimize long-term treatment outcomes for both ketamine and ECT to prevent relapse, “which is of key importance for clinical practice.”
The study had no specific funding. Dr. Rhee currently serves as a co–editor-in-chief of Mental Health Science and will receive honorarium payments annually from the publisher, John Wiley & Sons. A complete list of the authors’ relevant financial relationships is available with the original article.
A version of this article first appeared on Medscape.com.
in new findings that are in line with the KetECT study – the first head-to-head trial of ketamine and ECT.
The KetECT trial, which was published earlier this year, showed that ECT was more effective than IV ketamine for hospitalized patients with severe depression. ECT yielded higher remission rates and a greater reduction of symptoms.
Despite the apparent superiority of ECT over ketamine, the researchers of the current meta-analysis caution that treatment options for MDE “should still be individualized and patient-centered because ketamine’s faster antidepressant effects may still be desirable for certain patients with severe MDE who require quick recovery from the severity of depression.”
The study was published online in JAMA Psychiatry.
Confirmatory data
The review included six clinical trials with 340 patients with MDE. Of those patients, 162 were treated with ECT, and 178 were treated with ketamine. The mean age of the participants ranged from 37 to 52 years.
The primary efficacy outcome of interest was improvement of depressive symptoms.
ECT was superior to ketamine across different depressive symptom measures, reported Taeho Greg Rhee, PhD, of the University of Connecticut, Farmington, and colleagues.
The standardized mean difference (SMD) was –0.59 (95% confidence interval [CI], –0.85 to –0.33) on the Montgomery-Åsberg Depression Rating Scale.
The SMD was –0.83 (95% CI, –1.22 to –0.44] on the Hamilton Depression Rating Scale and –0.86 (95% CI, –1.50 to –0.22) on the Beck Depression Inventory.
The overall pooled SMD for ECT, when compared with ketamine, was –0.69 (95% CI, –0.89 to –0.48), indicating that ECT was more efficacious than ketamine.
The researchers did not find any moderating effects of various factors, including age, male sex, and presence of psychotic features.
For cognition and memory performance, one study reported that the ketamine group outperformed the ECT group in cognition, but the effect size was small to moderate.
A separate study that reported memory performance found no difference between ketamine and ECT, though this study was likely underpowered to detect such differences, with a total sample size of 32.
“Because of underpowered study designs, no firm conclusions regarding cognition and memory performance can be made in this meta-analysis. Future research should address this issue,” the investigators wrote.
Unique side effects
Ketamine and ECT had unique adverse effect profiles.
With ketamine, there was a lower risk of headache and muscle pain but a higher risk of transient dissociative or depersonalization symptoms. With ECT, there was a lower risk of blurred vision, vertigo, and diplopia/nystagmus.
Only one study reported suicide attempts and suicide deaths, for which there was no marked difference between ECT and ketamine.
A limitation of the meta-analysis is the low to moderate methodologic quality of the studies that were included, as well as the use of different ketamine and/or ECT treatment protocols, which could have influenced efficacy and safety outcomes.
The researchers noted that more research is needed to optimize long-term treatment outcomes for both ketamine and ECT to prevent relapse, “which is of key importance for clinical practice.”
The study had no specific funding. Dr. Rhee currently serves as a co–editor-in-chief of Mental Health Science and will receive honorarium payments annually from the publisher, John Wiley & Sons. A complete list of the authors’ relevant financial relationships is available with the original article.
A version of this article first appeared on Medscape.com.
FROM JAMA PSYCHIATRY
JAK inhibitors show no excess cardiovascular safety signal in French nationwide cohort
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
Janus kinase inhibitors tofacitinib (Xeljanz) and baricitinib (Olumiant) may pose no greater risk than does adalimumab (Humira and biosimilars) for major adverse cardiovascular events (MACEs) or venous thromboembolism (VTE) on the basis of a nationwide cohort study.
The French data, which included almost 16,000 patients with rheumatoid arthritis, revealed similar safety across subgroups, including older patients with at least one preexisting cardiovascular risk factor, reported lead author Léa Hoisnard, MD, of Henri Mondor Hospital, Paris, and colleagues.
These findings arrive 1 year after the U.S. Food and Drug Administration imposed class-wide boxed warnings on three Janus kinase (JAK) inhibitors, citing increased risks for both cancer and serious cardiac events detected by the open-label, randomized ORAL Surveillance postmarketing trial, which compared tofacitinib against adalimumab and etanercept.
More recently, the observational STAR-RA study, relying upon private insurance and Medicare claims in the United States, found no significant increase in cardiovascular events among patients taking tofacitinib, adding some uncertainty to the conversation.
“In this context, observational studies of unselected populations outside of North America are still needed to assess other JAK inhibitor agents,” Dr. Hoisnard and colleagues write in Annals of the Rheumatic Diseases.
Their retrospective study included 8,481 patients who received baricitinib or tofacitinib, and 7,354 patients who received adalimumab. Almost all patients in the tofacitinib group received 5 mg twice daily instead of 10 mg twice daily (99.4% vs. 0.6%), so cardiovascular safety was assessed only for the 5-mg dose. Baricitinib was prescribed at 4-mg and 2-mg doses (79.5% vs. 20.5%), allowing inclusion of both dose levels. The investigators accounted for a range of covariates, including concurrent therapy, comorbidities, and other patient characteristics.
Median follow-up durations were 440 days in the JAK inhibitor group and 344 days in the adalimumab group. The JAK inhibitor group had numerically more MACEs than did the adalimumab group, but the difference in risk was not statistically significant (54 vs. 35 MACEs; weighted hazard ratio, 1.0; 95% confidence interval, 0.7-1.5; P = .99). Similarly, more patients taking JAK inhibitors had VTEs, but relative risk was, again, not significant (75 vs. 32 VTEs; HRw, 1.1; 95% CI, 0.7-1.6; P = .63).
These findings were consistent for all subgroups, including patients aged 50 years or older and patients aged 65 years or older, although the investigators noted that statistical power was lacking for subgroup analyses.
Findings from Echo ORAL Surveillance
“I think the baricitinib data are important,” Kevin Winthrop, MD, MPH, professor of infectious diseases and epidemiology at Oregon Health & Science University, Portland, told this news organization. “There’s no difference between 2 mg and 4 mg [dose levels] in this analysis. And there doesn’t really seem to be a difference between baricitinib and tofacitinib. Most of the results are pretty consistent with ORAL Surveillance, which was a randomized, controlled trial.”
Dr. Winthrop, who has been active in JAK inhibitor clinical trials, recently coauthored an article in Nature Reviews Rheumatology encouraging clinicians to remember that the cardiovascular risks of JAK inhibitors are relative to adalimumab, and safety should be framed within the context of risk-to-benefit ratios.
He and his coauthor also called into question the FDA’s “better to be safe than sorry” approach, which resulted in boxed warnings across all JAK inhibitors, despite differences in target specificity.
“There are pros and cons of taking that approach,” Dr. Winthrop said in an interview. “The FDA might ultimately be right. Certainly, these drugs appear similar for some types of events, like herpes zoster, for example. But whether they’re similar with regard to malignancy or cardiovascular events, I don’t think we know.”
Dr. Winthrop noted that deucravacitinib was recently approved for psoriasis sans boxed warning, suggesting inconsistency in the FDA’s approach. The agent headlines as a “TYK2 inhibitor,” but TYK2 is a member of the JAK family.
“I don’t know why the FDA decided to treat them differently,” Dr. Winthrop said.
Boxed warnings encourage caution, lock treatment sequence
Michael Thakor, MD, of Arthritis & Rheumatology Clinic of Northern Colorado, Fort Collins, supports the boxed warnings because they encourage caution and transparency.
“It forces you to have that discussion with your patient, which may take some time, but it’s actually a very good thing,” Dr. Thakor said in an interview. “Some patients will say, ‘Oh my gosh, I don’t want to take that drug.’ But most patients, considering the level of risk that you’re talking about, are actually okay going ahead with the medication.”
If these risks aren’t discussed, he noted, patient trust may falter.
“They’re going to go online, and they’re going to be reading about it,” Dr. Thakor said. “And then they tend to get more spooked. They also may question your advice from then on, if you’re not telling them the possible risk.”
Reflecting on the present study, Dr. Thakor said that the findings initially appeared reassuring, but he became concerned about the lack of power and how adverse events trended higher in the JAK inhibitor group, particularly for VTEs, most of which occurred with baricitinib. This latter finding is challenging to interpret, however, because the 4-mg dose is not used in the United States, he added.
Dr. Thakor described how JAK inhibitors once seemed poised to assume a frontline role in RA until the boxed warnings came out. These safety concerns don’t take JAK inhibitors off the table, he said, but they do keep the class further down the treatment sequence, and the present data don’t alter this picture in daily practice.
“If I had a patient who was over the age of 50 with at least one cardiovascular risk factor, I might have a little bit of concern, but if they need their RA treated, I would definitely discuss the possibility of using a JAK inhibitor,” Dr. Thakor said. “If the patient is comfortable with it, then I would feel comfortable going ahead.”
The investigators disclosed no outside funding or conflicts of interest. Dr. Winthrop disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, and others. Dr. Thakor disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF THE RHEUMATIC DISEASES
Iron deficiency may protect against bacterial pneumonia
Patients with iron deficiency anemia who developed bacterial pneumonia showed improved outcomes compared to those without iron deficiency anemia, based on data from more than 450,000 individuals in the National Inpatient Sample.
Iron deficiency is the most common nutritional deficiency worldwide, and can lead to anemia, but iron also has been identified as essential to the survival and growth of pathogenic organisms, Mubarak Yusuf, MD, said in a presentation at the annual meeting of the American College of Chest Physicians (CHEST).
However, the specific impact of iron deficiency anemia (IDA) on outcomes in patients hospitalized with acute bacterial infections has not been explored, said Dr. Yusuf, a third-year internal medicine resident at Lincoln Medical Center in New York.
In the study, Dr. Yusuf and colleagues reviewed data from the Nationwide Inpatient Sample (NIS) Database for 2016-2019. They identified 452,040 adults aged 18 or older with a primary diagnosis of bacterial pneumonia based on ICD-10 codes. Patients with a principal diagnosis other than bacterial pneumonia were excluded.
Of these, 5.5% had a secondary diagnosis of IDA. The mean age of the study population was similar between the IDA and non-IDA groups (68 years) and racial distribution was similar, with a White majority of approximately 77%. Slightly more patients in the IDA group were women (58.5% vs. 51.6%) and this difference was statistically significant (P < .00001). Most of the patients (94.6%) in the IDA group had at least three comorbidities, as did 78.1% of the non-IDA group.
The primary outcome was mortality, and the overall mortality in the study population was 2.89%. Although the mortality percentage was higher in the IDA group compared to the non-IDA group (3.25% vs. 2.87%), “when we adjusted for confounders, we noticed a decreased odds of mortality in the IDA group” with an adjusted odds ratio of 0.74 (P = .001), Dr. Yusuf said.
In addition, secondary outcomes of septic shock, acute respiratory failure, and cardiac arrest were lower in the IDA group in a regression analysis, with adjusted odds ratios of 0.71, 0.78, and 0.57, respectively.
The mean length of stay was 0.3 days higher in the IDA group, and the researchers found a nonsignificant increase in total hospital costs of $402.5 for IDA patients compared to those without IDA, said Dr. Yusuf.
The take-home message from the study is actually a question to the clinician, Dr. Yusuf said. “Should you consider a delay in treatment [of iron deficiency anemia] if the patient is not symptomatic?” he asked.
More research is needed to investigate the improved outcomes in the iron deficient population, but the large sample size supports an association that is worth exploring, he concluded.
“The findings of this research may suggest a protective effect of iron deficiency in acute bacterial pneumonia,” Dr. Yusuf said in a press release accompanying the meeting presentation. “More research is needed to elucidate the improved outcomes found in this population, but this research may lead clinicians to consider a delay in treatment of nonsymptomatic iron deficiency in acute bacterial infection,” he added.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Patients with iron deficiency anemia who developed bacterial pneumonia showed improved outcomes compared to those without iron deficiency anemia, based on data from more than 450,000 individuals in the National Inpatient Sample.
Iron deficiency is the most common nutritional deficiency worldwide, and can lead to anemia, but iron also has been identified as essential to the survival and growth of pathogenic organisms, Mubarak Yusuf, MD, said in a presentation at the annual meeting of the American College of Chest Physicians (CHEST).
However, the specific impact of iron deficiency anemia (IDA) on outcomes in patients hospitalized with acute bacterial infections has not been explored, said Dr. Yusuf, a third-year internal medicine resident at Lincoln Medical Center in New York.
In the study, Dr. Yusuf and colleagues reviewed data from the Nationwide Inpatient Sample (NIS) Database for 2016-2019. They identified 452,040 adults aged 18 or older with a primary diagnosis of bacterial pneumonia based on ICD-10 codes. Patients with a principal diagnosis other than bacterial pneumonia were excluded.
Of these, 5.5% had a secondary diagnosis of IDA. The mean age of the study population was similar between the IDA and non-IDA groups (68 years) and racial distribution was similar, with a White majority of approximately 77%. Slightly more patients in the IDA group were women (58.5% vs. 51.6%) and this difference was statistically significant (P < .00001). Most of the patients (94.6%) in the IDA group had at least three comorbidities, as did 78.1% of the non-IDA group.
The primary outcome was mortality, and the overall mortality in the study population was 2.89%. Although the mortality percentage was higher in the IDA group compared to the non-IDA group (3.25% vs. 2.87%), “when we adjusted for confounders, we noticed a decreased odds of mortality in the IDA group” with an adjusted odds ratio of 0.74 (P = .001), Dr. Yusuf said.
In addition, secondary outcomes of septic shock, acute respiratory failure, and cardiac arrest were lower in the IDA group in a regression analysis, with adjusted odds ratios of 0.71, 0.78, and 0.57, respectively.
The mean length of stay was 0.3 days higher in the IDA group, and the researchers found a nonsignificant increase in total hospital costs of $402.5 for IDA patients compared to those without IDA, said Dr. Yusuf.
The take-home message from the study is actually a question to the clinician, Dr. Yusuf said. “Should you consider a delay in treatment [of iron deficiency anemia] if the patient is not symptomatic?” he asked.
More research is needed to investigate the improved outcomes in the iron deficient population, but the large sample size supports an association that is worth exploring, he concluded.
“The findings of this research may suggest a protective effect of iron deficiency in acute bacterial pneumonia,” Dr. Yusuf said in a press release accompanying the meeting presentation. “More research is needed to elucidate the improved outcomes found in this population, but this research may lead clinicians to consider a delay in treatment of nonsymptomatic iron deficiency in acute bacterial infection,” he added.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Patients with iron deficiency anemia who developed bacterial pneumonia showed improved outcomes compared to those without iron deficiency anemia, based on data from more than 450,000 individuals in the National Inpatient Sample.
Iron deficiency is the most common nutritional deficiency worldwide, and can lead to anemia, but iron also has been identified as essential to the survival and growth of pathogenic organisms, Mubarak Yusuf, MD, said in a presentation at the annual meeting of the American College of Chest Physicians (CHEST).
However, the specific impact of iron deficiency anemia (IDA) on outcomes in patients hospitalized with acute bacterial infections has not been explored, said Dr. Yusuf, a third-year internal medicine resident at Lincoln Medical Center in New York.
In the study, Dr. Yusuf and colleagues reviewed data from the Nationwide Inpatient Sample (NIS) Database for 2016-2019. They identified 452,040 adults aged 18 or older with a primary diagnosis of bacterial pneumonia based on ICD-10 codes. Patients with a principal diagnosis other than bacterial pneumonia were excluded.
Of these, 5.5% had a secondary diagnosis of IDA. The mean age of the study population was similar between the IDA and non-IDA groups (68 years) and racial distribution was similar, with a White majority of approximately 77%. Slightly more patients in the IDA group were women (58.5% vs. 51.6%) and this difference was statistically significant (P < .00001). Most of the patients (94.6%) in the IDA group had at least three comorbidities, as did 78.1% of the non-IDA group.
The primary outcome was mortality, and the overall mortality in the study population was 2.89%. Although the mortality percentage was higher in the IDA group compared to the non-IDA group (3.25% vs. 2.87%), “when we adjusted for confounders, we noticed a decreased odds of mortality in the IDA group” with an adjusted odds ratio of 0.74 (P = .001), Dr. Yusuf said.
In addition, secondary outcomes of septic shock, acute respiratory failure, and cardiac arrest were lower in the IDA group in a regression analysis, with adjusted odds ratios of 0.71, 0.78, and 0.57, respectively.
The mean length of stay was 0.3 days higher in the IDA group, and the researchers found a nonsignificant increase in total hospital costs of $402.5 for IDA patients compared to those without IDA, said Dr. Yusuf.
The take-home message from the study is actually a question to the clinician, Dr. Yusuf said. “Should you consider a delay in treatment [of iron deficiency anemia] if the patient is not symptomatic?” he asked.
More research is needed to investigate the improved outcomes in the iron deficient population, but the large sample size supports an association that is worth exploring, he concluded.
“The findings of this research may suggest a protective effect of iron deficiency in acute bacterial pneumonia,” Dr. Yusuf said in a press release accompanying the meeting presentation. “More research is needed to elucidate the improved outcomes found in this population, but this research may lead clinicians to consider a delay in treatment of nonsymptomatic iron deficiency in acute bacterial infection,” he added.
The study received no outside funding. The researchers had no financial conflicts to disclose.
FROM CHEST 2022
Doctor removes 23 contact lenses from woman’s eye
In a video posted on Instagram, ophthalmologist Katerina Kurteeva, MD, is shown removing contact lenses from a woman’s eye.
“Don’t sleep in your contact lenses!” she warned.
“They were essentially glued together after sitting under the eyelid for a month,” Dr. Kurteeva said in the post.
The patient is doing fine and wants to continue wearing contact lenses, the doctor told the Los Angeles ABC News affiliate, noting that the patient didn’t know how she could have forgotten to take her lenses out.
About 45 million Americans wear contact lenses, according to the Centers for Disease Control and Prevention. Contact lens usage increases the risk of infections such as microbial keratitis. In severe cases, microbial keratitis can cause blindness or require corneal transplant.
Dr. Kurteeva told the Los Angeles TV station that the cornea becomes desensitized after years of contact lens wear.
“This is essentially a protective feature, because otherwise you’d be really bothered by everyday contact lens wear. After all, it is a foreign body in your eye,” she said. “So when the cornea loses sensitivity, it’s sort of an adjustment, but at the same time, you don’t feel when something is really wrong as acutely.”
A version of this article first appeared on WebMD.com.
In a video posted on Instagram, ophthalmologist Katerina Kurteeva, MD, is shown removing contact lenses from a woman’s eye.
“Don’t sleep in your contact lenses!” she warned.
“They were essentially glued together after sitting under the eyelid for a month,” Dr. Kurteeva said in the post.
The patient is doing fine and wants to continue wearing contact lenses, the doctor told the Los Angeles ABC News affiliate, noting that the patient didn’t know how she could have forgotten to take her lenses out.
About 45 million Americans wear contact lenses, according to the Centers for Disease Control and Prevention. Contact lens usage increases the risk of infections such as microbial keratitis. In severe cases, microbial keratitis can cause blindness or require corneal transplant.
Dr. Kurteeva told the Los Angeles TV station that the cornea becomes desensitized after years of contact lens wear.
“This is essentially a protective feature, because otherwise you’d be really bothered by everyday contact lens wear. After all, it is a foreign body in your eye,” she said. “So when the cornea loses sensitivity, it’s sort of an adjustment, but at the same time, you don’t feel when something is really wrong as acutely.”
A version of this article first appeared on WebMD.com.
In a video posted on Instagram, ophthalmologist Katerina Kurteeva, MD, is shown removing contact lenses from a woman’s eye.
“Don’t sleep in your contact lenses!” she warned.
“They were essentially glued together after sitting under the eyelid for a month,” Dr. Kurteeva said in the post.
The patient is doing fine and wants to continue wearing contact lenses, the doctor told the Los Angeles ABC News affiliate, noting that the patient didn’t know how she could have forgotten to take her lenses out.
About 45 million Americans wear contact lenses, according to the Centers for Disease Control and Prevention. Contact lens usage increases the risk of infections such as microbial keratitis. In severe cases, microbial keratitis can cause blindness or require corneal transplant.
Dr. Kurteeva told the Los Angeles TV station that the cornea becomes desensitized after years of contact lens wear.
“This is essentially a protective feature, because otherwise you’d be really bothered by everyday contact lens wear. After all, it is a foreign body in your eye,” she said. “So when the cornea loses sensitivity, it’s sort of an adjustment, but at the same time, you don’t feel when something is really wrong as acutely.”
A version of this article first appeared on WebMD.com.
Reminder that COVID-19 and cancer can be a deadly combo
A new study underscores the importance of COVID-19 and regular COVID-19 testing among adults with a recent cancer diagnosis.
The Indiana statewide study, conducted at the beginning of the pandemic, found that
“This analysis provides additional empirical evidence on the magnitude of risk to patients with cancer whose immune systems are often weakened either by the disease or treatment,” the study team wrote.
The study was published online in JMIR Cancer.
Although evidence has consistently revealed similar findings, the risk of death among unvaccinated people with cancer and COVID-19 has not been nearly as high in previous studies, lead author Brian E. Dixon, PhD, MBA, with Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, said in a statement. Previous studies from China, for instance, reported a two- to threefold greater risk of all-cause mortality among unvaccinated adults with cancer and COVID-19.
A potential reason for this discrepancy, Dr. Dixon noted, is that earlier studies were “generally smaller and made calculations based on data from a single cancer center or health system.”
Another reason is testing for COVID-19 early in the pandemic was limited to symptomatic individuals who may have had more severe infections, possibly leading to an overestimate of the association between SARS-CoV-2 infection, cancer, and all-cause mortality.
In the current analysis, researchers used electronic health records linked to Indiana’s statewide SARS-CoV-2 testing database and state vital records to evaluate the association between SARS-CoV-2 infection and all-cause mortality among 41,924 adults newly diagnosed with cancer between Jan. 1, 2019, and Dec. 31, 2020.
Most people with cancer were White (78.4%) and about half were male. At the time of diagnosis, 17% had one comorbid condition and about 10% had two or more. Most patients had breast cancer (14%), prostate cancer (13%), or melanoma (13%).
During the study period, 2,894 patients (7%) tested positive for SARS-CoV-2.
In multivariate adjusted analysis, the risk of death among those newly diagnosed with cancer increased by 91% (adjusted hazard ratio, 1.91) during the first year of the pandemic before vaccines were available, compared with the year before (January 2019 to Jan. 14, 2020).
During the pandemic period, the risk of death was roughly threefold higher among adults 65 years old and older, compared with adults 18-44 years old (aHR, 3.35).
When looking at the time from a cancer diagnosis to SARS-CoV-2 infection, infection was associated with an almost sevenfold increase in all-cause mortality (aHR, 6.91). Adults 65 years old and older had an almost threefold increased risk of dying, compared with their younger peers (aHR, 2.74).
Dr. Dixon and colleagues also observed an increased risk of death in men with cancer and COVID, compared with women (aHR, 1.23) and those with at least two comorbid conditions versus none (aHR, 2.12). In addition, the risk of dying was 9% higher among Indiana’s rural population than urban dwellers.
Compared with other cancer types, individuals with lung cancer and other digestive cancers had the highest risk of death after SARS-CoV-2 infection (aHR, 1.45 and 1.80, respectively).
“Our findings highlight the increased risk of death for adult cancer patients who test positive for COVID and underscore the importance to cancer patients – including those in remission – of vaccinations, boosters, and regular COVID testing,” Dr. Dixon commented.
“Our results should encourage individuals diagnosed with cancer not only to take preventive action, but also to expeditiously seek out treatments available in the marketplace should they test positive for COVID,” he added.
Support for the study was provided by Indiana University Simon Cancer Center and the Centers for Disease Control and Prevention. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new study underscores the importance of COVID-19 and regular COVID-19 testing among adults with a recent cancer diagnosis.
The Indiana statewide study, conducted at the beginning of the pandemic, found that
“This analysis provides additional empirical evidence on the magnitude of risk to patients with cancer whose immune systems are often weakened either by the disease or treatment,” the study team wrote.
The study was published online in JMIR Cancer.
Although evidence has consistently revealed similar findings, the risk of death among unvaccinated people with cancer and COVID-19 has not been nearly as high in previous studies, lead author Brian E. Dixon, PhD, MBA, with Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, said in a statement. Previous studies from China, for instance, reported a two- to threefold greater risk of all-cause mortality among unvaccinated adults with cancer and COVID-19.
A potential reason for this discrepancy, Dr. Dixon noted, is that earlier studies were “generally smaller and made calculations based on data from a single cancer center or health system.”
Another reason is testing for COVID-19 early in the pandemic was limited to symptomatic individuals who may have had more severe infections, possibly leading to an overestimate of the association between SARS-CoV-2 infection, cancer, and all-cause mortality.
In the current analysis, researchers used electronic health records linked to Indiana’s statewide SARS-CoV-2 testing database and state vital records to evaluate the association between SARS-CoV-2 infection and all-cause mortality among 41,924 adults newly diagnosed with cancer between Jan. 1, 2019, and Dec. 31, 2020.
Most people with cancer were White (78.4%) and about half were male. At the time of diagnosis, 17% had one comorbid condition and about 10% had two or more. Most patients had breast cancer (14%), prostate cancer (13%), or melanoma (13%).
During the study period, 2,894 patients (7%) tested positive for SARS-CoV-2.
In multivariate adjusted analysis, the risk of death among those newly diagnosed with cancer increased by 91% (adjusted hazard ratio, 1.91) during the first year of the pandemic before vaccines were available, compared with the year before (January 2019 to Jan. 14, 2020).
During the pandemic period, the risk of death was roughly threefold higher among adults 65 years old and older, compared with adults 18-44 years old (aHR, 3.35).
When looking at the time from a cancer diagnosis to SARS-CoV-2 infection, infection was associated with an almost sevenfold increase in all-cause mortality (aHR, 6.91). Adults 65 years old and older had an almost threefold increased risk of dying, compared with their younger peers (aHR, 2.74).
Dr. Dixon and colleagues also observed an increased risk of death in men with cancer and COVID, compared with women (aHR, 1.23) and those with at least two comorbid conditions versus none (aHR, 2.12). In addition, the risk of dying was 9% higher among Indiana’s rural population than urban dwellers.
Compared with other cancer types, individuals with lung cancer and other digestive cancers had the highest risk of death after SARS-CoV-2 infection (aHR, 1.45 and 1.80, respectively).
“Our findings highlight the increased risk of death for adult cancer patients who test positive for COVID and underscore the importance to cancer patients – including those in remission – of vaccinations, boosters, and regular COVID testing,” Dr. Dixon commented.
“Our results should encourage individuals diagnosed with cancer not only to take preventive action, but also to expeditiously seek out treatments available in the marketplace should they test positive for COVID,” he added.
Support for the study was provided by Indiana University Simon Cancer Center and the Centers for Disease Control and Prevention. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new study underscores the importance of COVID-19 and regular COVID-19 testing among adults with a recent cancer diagnosis.
The Indiana statewide study, conducted at the beginning of the pandemic, found that
“This analysis provides additional empirical evidence on the magnitude of risk to patients with cancer whose immune systems are often weakened either by the disease or treatment,” the study team wrote.
The study was published online in JMIR Cancer.
Although evidence has consistently revealed similar findings, the risk of death among unvaccinated people with cancer and COVID-19 has not been nearly as high in previous studies, lead author Brian E. Dixon, PhD, MBA, with Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, said in a statement. Previous studies from China, for instance, reported a two- to threefold greater risk of all-cause mortality among unvaccinated adults with cancer and COVID-19.
A potential reason for this discrepancy, Dr. Dixon noted, is that earlier studies were “generally smaller and made calculations based on data from a single cancer center or health system.”
Another reason is testing for COVID-19 early in the pandemic was limited to symptomatic individuals who may have had more severe infections, possibly leading to an overestimate of the association between SARS-CoV-2 infection, cancer, and all-cause mortality.
In the current analysis, researchers used electronic health records linked to Indiana’s statewide SARS-CoV-2 testing database and state vital records to evaluate the association between SARS-CoV-2 infection and all-cause mortality among 41,924 adults newly diagnosed with cancer between Jan. 1, 2019, and Dec. 31, 2020.
Most people with cancer were White (78.4%) and about half were male. At the time of diagnosis, 17% had one comorbid condition and about 10% had two or more. Most patients had breast cancer (14%), prostate cancer (13%), or melanoma (13%).
During the study period, 2,894 patients (7%) tested positive for SARS-CoV-2.
In multivariate adjusted analysis, the risk of death among those newly diagnosed with cancer increased by 91% (adjusted hazard ratio, 1.91) during the first year of the pandemic before vaccines were available, compared with the year before (January 2019 to Jan. 14, 2020).
During the pandemic period, the risk of death was roughly threefold higher among adults 65 years old and older, compared with adults 18-44 years old (aHR, 3.35).
When looking at the time from a cancer diagnosis to SARS-CoV-2 infection, infection was associated with an almost sevenfold increase in all-cause mortality (aHR, 6.91). Adults 65 years old and older had an almost threefold increased risk of dying, compared with their younger peers (aHR, 2.74).
Dr. Dixon and colleagues also observed an increased risk of death in men with cancer and COVID, compared with women (aHR, 1.23) and those with at least two comorbid conditions versus none (aHR, 2.12). In addition, the risk of dying was 9% higher among Indiana’s rural population than urban dwellers.
Compared with other cancer types, individuals with lung cancer and other digestive cancers had the highest risk of death after SARS-CoV-2 infection (aHR, 1.45 and 1.80, respectively).
“Our findings highlight the increased risk of death for adult cancer patients who test positive for COVID and underscore the importance to cancer patients – including those in remission – of vaccinations, boosters, and regular COVID testing,” Dr. Dixon commented.
“Our results should encourage individuals diagnosed with cancer not only to take preventive action, but also to expeditiously seek out treatments available in the marketplace should they test positive for COVID,” he added.
Support for the study was provided by Indiana University Simon Cancer Center and the Centers for Disease Control and Prevention. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JMIR CANCER
Phase 3 topline results ‘disappointing’ for novel antidepressant as monotherapy
The negative monotherapy data come on the heels of earlier phase 2 data showing a benefit of REL-1017 when used as add-on therapy for adults with major depressive disorder (MDD).
Despite the monotherapy results, Relmada reported in a release that it is continuing to enroll patients in two other phase 3 trials. However, RELIANCE I and RELIANCE II are assessing the drug only as adjunctive therapy.
“While these RELIANCE III results are disappointing for patients, the need for new, safe, and effective treatments for MDD continues to exist,” Maurizio Fava, MD, psychiatrist in chief at Massachusetts General Hospital, Boston, said in the release.
“We look forward to the data from the ongoing RELIANCE I and II trials of REL-1017, a potential new therapy for the adjunctive treatment of MDD,” Dr. Fava added.
REL-1017 is a novel N-methyl-D-aspartate receptor channel blocker that preferentially targets hyperactive channels while maintaining physiologic glutamatergic neurotransmission. RELIANCE III tested REL-1017 against placebo for 28 days in 232 adults with MDD.
The study did not achieve its primary endpoint, which was a statistically significant improvement in symptoms of depression compared with placebo, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) on day 28.
At that time point, the REL-1017 treatment group showed a reduction in MADRS scores of 14.8 points, vs. 13.9 points for the placebo arm.
The placebo response was “higher than expected” – placebo “dramatically” outperformed REL-1017 at some study sites, Relmada said in the release.
The company added that it is “investigating the nature of these results.”
A version of this article first appeared on Medscape.com.
The negative monotherapy data come on the heels of earlier phase 2 data showing a benefit of REL-1017 when used as add-on therapy for adults with major depressive disorder (MDD).
Despite the monotherapy results, Relmada reported in a release that it is continuing to enroll patients in two other phase 3 trials. However, RELIANCE I and RELIANCE II are assessing the drug only as adjunctive therapy.
“While these RELIANCE III results are disappointing for patients, the need for new, safe, and effective treatments for MDD continues to exist,” Maurizio Fava, MD, psychiatrist in chief at Massachusetts General Hospital, Boston, said in the release.
“We look forward to the data from the ongoing RELIANCE I and II trials of REL-1017, a potential new therapy for the adjunctive treatment of MDD,” Dr. Fava added.
REL-1017 is a novel N-methyl-D-aspartate receptor channel blocker that preferentially targets hyperactive channels while maintaining physiologic glutamatergic neurotransmission. RELIANCE III tested REL-1017 against placebo for 28 days in 232 adults with MDD.
The study did not achieve its primary endpoint, which was a statistically significant improvement in symptoms of depression compared with placebo, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) on day 28.
At that time point, the REL-1017 treatment group showed a reduction in MADRS scores of 14.8 points, vs. 13.9 points for the placebo arm.
The placebo response was “higher than expected” – placebo “dramatically” outperformed REL-1017 at some study sites, Relmada said in the release.
The company added that it is “investigating the nature of these results.”
A version of this article first appeared on Medscape.com.
The negative monotherapy data come on the heels of earlier phase 2 data showing a benefit of REL-1017 when used as add-on therapy for adults with major depressive disorder (MDD).
Despite the monotherapy results, Relmada reported in a release that it is continuing to enroll patients in two other phase 3 trials. However, RELIANCE I and RELIANCE II are assessing the drug only as adjunctive therapy.
“While these RELIANCE III results are disappointing for patients, the need for new, safe, and effective treatments for MDD continues to exist,” Maurizio Fava, MD, psychiatrist in chief at Massachusetts General Hospital, Boston, said in the release.
“We look forward to the data from the ongoing RELIANCE I and II trials of REL-1017, a potential new therapy for the adjunctive treatment of MDD,” Dr. Fava added.
REL-1017 is a novel N-methyl-D-aspartate receptor channel blocker that preferentially targets hyperactive channels while maintaining physiologic glutamatergic neurotransmission. RELIANCE III tested REL-1017 against placebo for 28 days in 232 adults with MDD.
The study did not achieve its primary endpoint, which was a statistically significant improvement in symptoms of depression compared with placebo, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) on day 28.
At that time point, the REL-1017 treatment group showed a reduction in MADRS scores of 14.8 points, vs. 13.9 points for the placebo arm.
The placebo response was “higher than expected” – placebo “dramatically” outperformed REL-1017 at some study sites, Relmada said in the release.
The company added that it is “investigating the nature of these results.”
A version of this article first appeared on Medscape.com.
COVID tied to spike in deaths in chronic liver disease with diabetes
The COVID-19 pandemic fueled a sharp uptick in deaths related to chronic liver disease and cirrhosis among people with diabetes, largely owing to nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), new data show.
“Our observations confirm that COVID-19 had a higher likelihood of impacting vulnerable populations with pre-existing chronic liver diseases and diabetes, with a death rate as high as 10% in individuals with co-existing chronic liver disease and diabetes,” write the authors.
“The inability to attend regular outpatient clinics for close monitoring and treatment accompanied by diversion of health care resources to COVID-19 care may have resulted in the suboptimal or delayed clinical care of individuals with diabetes and chronic liver disease during the COVID-19 pandemic,” they add.
Donghee Kim, MD, PhD, with the Division of Gastroenterology and Hepatology, Stanford (Calif.) University School of Medicine, and colleagues report their findings in the journal Digestive and Liver Disease.
Vulnerable group
The researchers used U.S. national mortality data (2017-2020) to estimate chronic liver disease–related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.
Before the pandemic, the quarterly mortality for chronic liver disease remained stable (quarterly percentage change, 0.6%) but then sharply increased during the pandemic (QPC, 8.6%).
A similar trend was seen with cirrhosis-related mortality (QPC, 0.3% before the pandemic vs. 8.4% during the pandemic).
NAFLD and ALD mortality among individuals with diabetes was steadily increasing before the pandemic (QPC, 4.2% and 3.5%, respectively) but showed a more rapid increase during the pandemic (QPC, 9.6% and 7.7%, respectively).
ALD-related mortality in men was more than threefold higher than in women, while NAFLD-related mortality in women was more than twofold higher than in men.
Mortality for hepatitis C virus infection declined before the pandemic (QPC, −3.3%) and remained stable during the pandemic.
COVID-19–related mortality among adults with chronic liver disease and diabetes also rose sharply during the pandemic – from 0.4% in the first quarter of 2020 to 12.9% in the last quarter of 2020 – with no considerable difference between men and women.
Blame it on lockdowns?
Dr. Kim and colleagues say research is needed to better understand the direct and indirect influence of COVID-19 on coexisting chronic liver disease and diabetes.
“It is plausible that psychosocial stress and a higher predisposition to psychiatric disorders during the COVID-19 pandemic can increase the risk of alcohol use disorder and ALD,” they write.
“Furthermore, it is prudent to suspect that COVID-19–related lockdowns may increase the risk of obesity, leading to a higher risk of insulin resistance and metabolic complications, including diabetes and NAFLD. Future studies are needed to improve our understanding of these possible pathogenetic links. More importantly, emergency preparedness or contingency plans must be in place to continue and provide uninterrupted care for chronic ailments during times of disaster,” they add.
The study had no specific funding. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The COVID-19 pandemic fueled a sharp uptick in deaths related to chronic liver disease and cirrhosis among people with diabetes, largely owing to nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), new data show.
“Our observations confirm that COVID-19 had a higher likelihood of impacting vulnerable populations with pre-existing chronic liver diseases and diabetes, with a death rate as high as 10% in individuals with co-existing chronic liver disease and diabetes,” write the authors.
“The inability to attend regular outpatient clinics for close monitoring and treatment accompanied by diversion of health care resources to COVID-19 care may have resulted in the suboptimal or delayed clinical care of individuals with diabetes and chronic liver disease during the COVID-19 pandemic,” they add.
Donghee Kim, MD, PhD, with the Division of Gastroenterology and Hepatology, Stanford (Calif.) University School of Medicine, and colleagues report their findings in the journal Digestive and Liver Disease.
Vulnerable group
The researchers used U.S. national mortality data (2017-2020) to estimate chronic liver disease–related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.
Before the pandemic, the quarterly mortality for chronic liver disease remained stable (quarterly percentage change, 0.6%) but then sharply increased during the pandemic (QPC, 8.6%).
A similar trend was seen with cirrhosis-related mortality (QPC, 0.3% before the pandemic vs. 8.4% during the pandemic).
NAFLD and ALD mortality among individuals with diabetes was steadily increasing before the pandemic (QPC, 4.2% and 3.5%, respectively) but showed a more rapid increase during the pandemic (QPC, 9.6% and 7.7%, respectively).
ALD-related mortality in men was more than threefold higher than in women, while NAFLD-related mortality in women was more than twofold higher than in men.
Mortality for hepatitis C virus infection declined before the pandemic (QPC, −3.3%) and remained stable during the pandemic.
COVID-19–related mortality among adults with chronic liver disease and diabetes also rose sharply during the pandemic – from 0.4% in the first quarter of 2020 to 12.9% in the last quarter of 2020 – with no considerable difference between men and women.
Blame it on lockdowns?
Dr. Kim and colleagues say research is needed to better understand the direct and indirect influence of COVID-19 on coexisting chronic liver disease and diabetes.
“It is plausible that psychosocial stress and a higher predisposition to psychiatric disorders during the COVID-19 pandemic can increase the risk of alcohol use disorder and ALD,” they write.
“Furthermore, it is prudent to suspect that COVID-19–related lockdowns may increase the risk of obesity, leading to a higher risk of insulin resistance and metabolic complications, including diabetes and NAFLD. Future studies are needed to improve our understanding of these possible pathogenetic links. More importantly, emergency preparedness or contingency plans must be in place to continue and provide uninterrupted care for chronic ailments during times of disaster,” they add.
The study had no specific funding. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The COVID-19 pandemic fueled a sharp uptick in deaths related to chronic liver disease and cirrhosis among people with diabetes, largely owing to nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), new data show.
“Our observations confirm that COVID-19 had a higher likelihood of impacting vulnerable populations with pre-existing chronic liver diseases and diabetes, with a death rate as high as 10% in individuals with co-existing chronic liver disease and diabetes,” write the authors.
“The inability to attend regular outpatient clinics for close monitoring and treatment accompanied by diversion of health care resources to COVID-19 care may have resulted in the suboptimal or delayed clinical care of individuals with diabetes and chronic liver disease during the COVID-19 pandemic,” they add.
Donghee Kim, MD, PhD, with the Division of Gastroenterology and Hepatology, Stanford (Calif.) University School of Medicine, and colleagues report their findings in the journal Digestive and Liver Disease.
Vulnerable group
The researchers used U.S. national mortality data (2017-2020) to estimate chronic liver disease–related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.
Before the pandemic, the quarterly mortality for chronic liver disease remained stable (quarterly percentage change, 0.6%) but then sharply increased during the pandemic (QPC, 8.6%).
A similar trend was seen with cirrhosis-related mortality (QPC, 0.3% before the pandemic vs. 8.4% during the pandemic).
NAFLD and ALD mortality among individuals with diabetes was steadily increasing before the pandemic (QPC, 4.2% and 3.5%, respectively) but showed a more rapid increase during the pandemic (QPC, 9.6% and 7.7%, respectively).
ALD-related mortality in men was more than threefold higher than in women, while NAFLD-related mortality in women was more than twofold higher than in men.
Mortality for hepatitis C virus infection declined before the pandemic (QPC, −3.3%) and remained stable during the pandemic.
COVID-19–related mortality among adults with chronic liver disease and diabetes also rose sharply during the pandemic – from 0.4% in the first quarter of 2020 to 12.9% in the last quarter of 2020 – with no considerable difference between men and women.
Blame it on lockdowns?
Dr. Kim and colleagues say research is needed to better understand the direct and indirect influence of COVID-19 on coexisting chronic liver disease and diabetes.
“It is plausible that psychosocial stress and a higher predisposition to psychiatric disorders during the COVID-19 pandemic can increase the risk of alcohol use disorder and ALD,” they write.
“Furthermore, it is prudent to suspect that COVID-19–related lockdowns may increase the risk of obesity, leading to a higher risk of insulin resistance and metabolic complications, including diabetes and NAFLD. Future studies are needed to improve our understanding of these possible pathogenetic links. More importantly, emergency preparedness or contingency plans must be in place to continue and provide uninterrupted care for chronic ailments during times of disaster,” they add.
The study had no specific funding. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Complaints of foot pain
This patient's physical findings are consistent with a diagnosis of claw toe, which can be caused by diabetes-related peripheral neuropathy.
According to the International Diabetes Federation, diabetes currently affects approximately 537 million adults worldwide. The number of individuals living with diabetes is expected to exceed 640 million by 2030 and 780 million by 2045. In the United States, more than 37 million people are living with diabetes.
Foot complications related to diabetes represent a significant economic and social burden and can profoundly affect a patient's quality of life and medical outcomes. Common diabetes-related foot complications include foot deformity and peripheral neuropathy, both of which increase the risk for ulceration and amputation. The most common deformity is at the metatarsophalangeal joint (MTPJ). As many as 85% of patients with a history of ulcers and amputation have an MTPJ deformity such as claw toe or hammertoe.
Although they are often grouped together, claw toe and hammertoe have distinct features. Extended MTPJ, flexed proximal interphalangeal joint (PIPJ), and flexed distal interphalangeal joint (DIPJ) are characteristic of claw toe. While hammertoe also has extended MTPJ and flexed PIPJ, the DIPJ is extended rather than flexed. In both cases, the area of high pressure at risk for skin breakdown and ulceration is at the metatarsal head as a result of MTPJ hyperextension deformity.
Prompt detection and care of diabetes-related foot complications can minimize progression and negative consequences on patients' health and quality of life. According to the American Diabetes Association, all patients with diabetes should undergo a comprehensive foot evaluation at least annually to identify risk factors for ulceration and amputation, which include foot deformities, poor glycemic control, peripheral neuropathy, cigarette smoking, preulcerative callus or corn, peripheral artery disease, chronic kidney disease, visual impairment, and a history of ulceration or amputation. When patients present with a history of ulceration or amputation, a foot inspection should be conducted at each visit.
A comprehensive foot evaluation should include inspection of the skin, evaluation of any foot deformities, a neurologic assessment (10-g monofilament testing with at least one other assessment: pinprick, temperature, vibration), and a vascular assessment, including pulses in the legs and feet.
Patients should be educated on risk factors and appropriate management of foot-related complications, including the importance of effective glycemic control and daily monitoring of feet. Treatment may be medical, surgical, or both, as indicated by the individual patient's presentation. Conservative treatment approaches include footwear that is extra wide or deep, avoiding high-heeled and narrow-toed shoes, use of a metatarsal bar or pad, cushioning sleeves or stocking caps with silicon linings, and a longitudinal pad beneath the toes.
Complete recommendations on achieving glycemic control in T2D can be found in the 2022 American Diabetes Association Standards of Medical Care. Guidelines on foot care are also available.
Romesh K. Khardori, MD, PhD, Professor, Department of Internal Medicine, Division of Diabetes, Endocrine, and Metabolic Disorders, Eastern Virginia Medical School; EVMS Medical Group, Norfolk, Virginia
Romesh K. Khardori, MD, PhD, has disclosed no relevant financial relationships.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
This patient's physical findings are consistent with a diagnosis of claw toe, which can be caused by diabetes-related peripheral neuropathy.
According to the International Diabetes Federation, diabetes currently affects approximately 537 million adults worldwide. The number of individuals living with diabetes is expected to exceed 640 million by 2030 and 780 million by 2045. In the United States, more than 37 million people are living with diabetes.
Foot complications related to diabetes represent a significant economic and social burden and can profoundly affect a patient's quality of life and medical outcomes. Common diabetes-related foot complications include foot deformity and peripheral neuropathy, both of which increase the risk for ulceration and amputation. The most common deformity is at the metatarsophalangeal joint (MTPJ). As many as 85% of patients with a history of ulcers and amputation have an MTPJ deformity such as claw toe or hammertoe.
Although they are often grouped together, claw toe and hammertoe have distinct features. Extended MTPJ, flexed proximal interphalangeal joint (PIPJ), and flexed distal interphalangeal joint (DIPJ) are characteristic of claw toe. While hammertoe also has extended MTPJ and flexed PIPJ, the DIPJ is extended rather than flexed. In both cases, the area of high pressure at risk for skin breakdown and ulceration is at the metatarsal head as a result of MTPJ hyperextension deformity.
Prompt detection and care of diabetes-related foot complications can minimize progression and negative consequences on patients' health and quality of life. According to the American Diabetes Association, all patients with diabetes should undergo a comprehensive foot evaluation at least annually to identify risk factors for ulceration and amputation, which include foot deformities, poor glycemic control, peripheral neuropathy, cigarette smoking, preulcerative callus or corn, peripheral artery disease, chronic kidney disease, visual impairment, and a history of ulceration or amputation. When patients present with a history of ulceration or amputation, a foot inspection should be conducted at each visit.
A comprehensive foot evaluation should include inspection of the skin, evaluation of any foot deformities, a neurologic assessment (10-g monofilament testing with at least one other assessment: pinprick, temperature, vibration), and a vascular assessment, including pulses in the legs and feet.
Patients should be educated on risk factors and appropriate management of foot-related complications, including the importance of effective glycemic control and daily monitoring of feet. Treatment may be medical, surgical, or both, as indicated by the individual patient's presentation. Conservative treatment approaches include footwear that is extra wide or deep, avoiding high-heeled and narrow-toed shoes, use of a metatarsal bar or pad, cushioning sleeves or stocking caps with silicon linings, and a longitudinal pad beneath the toes.
Complete recommendations on achieving glycemic control in T2D can be found in the 2022 American Diabetes Association Standards of Medical Care. Guidelines on foot care are also available.
Romesh K. Khardori, MD, PhD, Professor, Department of Internal Medicine, Division of Diabetes, Endocrine, and Metabolic Disorders, Eastern Virginia Medical School; EVMS Medical Group, Norfolk, Virginia
Romesh K. Khardori, MD, PhD, has disclosed no relevant financial relationships.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
This patient's physical findings are consistent with a diagnosis of claw toe, which can be caused by diabetes-related peripheral neuropathy.
According to the International Diabetes Federation, diabetes currently affects approximately 537 million adults worldwide. The number of individuals living with diabetes is expected to exceed 640 million by 2030 and 780 million by 2045. In the United States, more than 37 million people are living with diabetes.
Foot complications related to diabetes represent a significant economic and social burden and can profoundly affect a patient's quality of life and medical outcomes. Common diabetes-related foot complications include foot deformity and peripheral neuropathy, both of which increase the risk for ulceration and amputation. The most common deformity is at the metatarsophalangeal joint (MTPJ). As many as 85% of patients with a history of ulcers and amputation have an MTPJ deformity such as claw toe or hammertoe.
Although they are often grouped together, claw toe and hammertoe have distinct features. Extended MTPJ, flexed proximal interphalangeal joint (PIPJ), and flexed distal interphalangeal joint (DIPJ) are characteristic of claw toe. While hammertoe also has extended MTPJ and flexed PIPJ, the DIPJ is extended rather than flexed. In both cases, the area of high pressure at risk for skin breakdown and ulceration is at the metatarsal head as a result of MTPJ hyperextension deformity.
Prompt detection and care of diabetes-related foot complications can minimize progression and negative consequences on patients' health and quality of life. According to the American Diabetes Association, all patients with diabetes should undergo a comprehensive foot evaluation at least annually to identify risk factors for ulceration and amputation, which include foot deformities, poor glycemic control, peripheral neuropathy, cigarette smoking, preulcerative callus or corn, peripheral artery disease, chronic kidney disease, visual impairment, and a history of ulceration or amputation. When patients present with a history of ulceration or amputation, a foot inspection should be conducted at each visit.
A comprehensive foot evaluation should include inspection of the skin, evaluation of any foot deformities, a neurologic assessment (10-g monofilament testing with at least one other assessment: pinprick, temperature, vibration), and a vascular assessment, including pulses in the legs and feet.
Patients should be educated on risk factors and appropriate management of foot-related complications, including the importance of effective glycemic control and daily monitoring of feet. Treatment may be medical, surgical, or both, as indicated by the individual patient's presentation. Conservative treatment approaches include footwear that is extra wide or deep, avoiding high-heeled and narrow-toed shoes, use of a metatarsal bar or pad, cushioning sleeves or stocking caps with silicon linings, and a longitudinal pad beneath the toes.
Complete recommendations on achieving glycemic control in T2D can be found in the 2022 American Diabetes Association Standards of Medical Care. Guidelines on foot care are also available.
Romesh K. Khardori, MD, PhD, Professor, Department of Internal Medicine, Division of Diabetes, Endocrine, and Metabolic Disorders, Eastern Virginia Medical School; EVMS Medical Group, Norfolk, Virginia
Romesh K. Khardori, MD, PhD, has disclosed no relevant financial relationships.
Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.
A 59-year-old woman newly diagnosed with type 2 diabetes (T2D) and hypercholesterolemia presents with complaints of foot pain, particularly while wearing shoes. Physical examination reveals an extended metatarsophalangeal joint, a flexed proximal interphalangeal joint, and flexed distal interphalangeal joint. Her toenails are discolored with a yellowish hue, and callus formation is noted over the metatarsal area. The patient reports pain at the tip of the toe from pressure against the point of the distal phalanx. She states that she has not experienced any numbness, tingling, or muscle weakness. Before her recent diabetes diagnosis, the patient had not been receiving regular medical care. The patient's current medications include metformin 500 mg/d, empagliflozin 10 mg/d, and rosuvastatin 10 mg/d.
