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Heart failure drug a new treatment option for alcoholism?
(AUD), new research suggests.
Researchers at the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and Yale University, New Haven, Conn., investigated the impact of spironolactone on AUD.
Initially, they studied rodents and found that spironolactone reduced binge drinking in mice and reduced self-administration of alcohol in rats without adversely affecting food or water intake or causing motor or coordination problems.
They also analyzed electronic health records of patients drawn from the United States Veterans Affairs health care system to explore potential changes in alcohol use after spironolactone treatment was initiated for other conditions and found a significant link between spironolactone treatment and reduction in self-reported alcohol consumption, with the largest effects observed among those who reported hazardous/heavy episodic alcohol use prior to starting spironolactone treatment.
“Combining findings across three species and different types of research studies, and then seeing similarities in these data, gives us confidence that we are onto something potentially important scientifically and clinically,” senior coauthor Lorenzo Leggio, MD, PhD, senior investigator in the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint NIDA and NIAAA laboratory, said in a news release.
The study was published online in Molecular Psychiatry.
There is a “critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD,” the authors note, adding that neuroendocrine systems involved in alcohol craving and drinking “offer promising pharmacologic targets in this regard.”
“Both our team and others have observed that patients with AUD often present with changes in peripheral hormones, including aldosterone, which plays a key role in regulating blood pressure and electrolytes,” Dr. Leggio said in an interview.
Spironolactone is a nonselective mineralocorticoid receptor (MT) antagonist. In studies in animal models, investigators said they found “an inverse correlation between alcohol drinking and the expression of the MR in the amygdala, a key brain region in the development and maintenance of AUD and addiction in general.”
Taken together, this led them to hypothesize that blocking the MR, which is the mechanism of action of spironolactone, “could be a novel pharmacotherapeutic approach for AUD,” he said.
Previous research by the same group of researchers suggested spironolactone “may be a potential new medication to treat patients with AUD.” The present study expanded on those findings and consisted of a three-part investigation.
In the current study, the investigators tested different dosages of spironolactone on binge-like alcohol consumption in male and female mice and assessed food and water intake, blood alcohol levels, motor coordination, and spontaneous locomotion.
They then tested the effects of different dosages of spironolactone injections on operant alcohol self-administration in alcohol-dependent and nondependent male and female rats, also testing blood alcohol levels and motor coordination.
Finally, they analyzed health records of veterans to examine the association between at least 60 continuous days of spironolactone treatment and self-reported alcohol consumption (measured by the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]).
Each of the spironolactone-exposed patients was matched using propensity scores with up to five unexposed patients who had reported alcohol consumption in the 2 years prior to the index date.
The final analysis included a matched cohort of 10,726 spironolactone-exposed individuals who were matched to 34,461 unexposed individuals.
New targets
Spironolactone reduced alcohol intake in mice drinking a sweetened alcohol solution; a 2-way ANOVA revealed a main effect of dose (F 4,52 = 9.09; P < .0001) and sex, with female mice drinking more alcohol, compared to male mice (F 1,13 = 6.05; P = .02).
Post hoc comparisons showed that spironolactone at doses of 50, 100, and 200 mg/kg significantly reduced alcohol intake (P values = .007, .002, and .0001, respectively).
In mice drinking an unsweetened alcohol solution, the 2-way repeated measures ANOVA similarly found a main effect of dose (F 4,52 = 5.77; P = .0006), but not of sex (F 1,13 = 1.41; P = .25).
Spironolactone had no effect on the mice’s intake of a sweet solution without alcohol and had no impact on the consumption of food and water or on locomotion and coordination.
In rats, a 2-way ANOVA revealed a significant spironolactone effect of dose (F 3,66 = 43.95; P < .001), with a post hoc test indicating that spironolactone at 25, 50, and 75 mg/kg reduced alcohol self-administration in alcohol-dependent and nondependent rats (all P values = .0001).
In humans, among the exposed individuals in the matched cohort, 25%, 57%, and 18% received daily doses of spironolactone of less than 25 mg/day, 25-49 mg/day, and 50 mg/day or higher, respectively, with a median follow-up time of 542 (interquartile range, 337-730) days.
The AUDIT-C scores decreased during the study period in both treatment groups, with a larger decrease in average AUDIT-C scores among the exposed vs. unexposed individuals.
“These are very exciting times because, thanks to the progress in the addiction biomedical research field, we are increasing our understanding of the mechanisms how some people develop AUD; hence we can use this knowledge to identify new targets.” The current study “is an example of these ongoing efforts,” said Dr. Leggio.
“It is important to note that [these results] are important but preliminary.” At this juncture, “it would be too premature to think about prescribing spironolactone to treat AUD,” he added.
Exciting findings
Commenting on the study, Joyce Besheer, PhD, professor, department of psychiatry and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, called the study an “elegant demonstration of translational science.”
“While clinical trials will be needed to determine whether this medication is effective at reducing drinking in patients with AUD, these findings are exciting as they suggest that spironolactone may be a promising compound and new treatment options for AUD are much needed,” said Dr. Besheer, who was not involved with the current study.
Dr. Leggio agreed. “We now need prospective, placebo-controlled studies to assess the potential safety and efficacy of spironolactone in people with AUD,” he said.
This work was supported by the National Institutes of Health and the NIAAA. Dr. Leggio, study coauthors, and Dr. Besheer declare no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(AUD), new research suggests.
Researchers at the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and Yale University, New Haven, Conn., investigated the impact of spironolactone on AUD.
Initially, they studied rodents and found that spironolactone reduced binge drinking in mice and reduced self-administration of alcohol in rats without adversely affecting food or water intake or causing motor or coordination problems.
They also analyzed electronic health records of patients drawn from the United States Veterans Affairs health care system to explore potential changes in alcohol use after spironolactone treatment was initiated for other conditions and found a significant link between spironolactone treatment and reduction in self-reported alcohol consumption, with the largest effects observed among those who reported hazardous/heavy episodic alcohol use prior to starting spironolactone treatment.
“Combining findings across three species and different types of research studies, and then seeing similarities in these data, gives us confidence that we are onto something potentially important scientifically and clinically,” senior coauthor Lorenzo Leggio, MD, PhD, senior investigator in the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint NIDA and NIAAA laboratory, said in a news release.
The study was published online in Molecular Psychiatry.
There is a “critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD,” the authors note, adding that neuroendocrine systems involved in alcohol craving and drinking “offer promising pharmacologic targets in this regard.”
“Both our team and others have observed that patients with AUD often present with changes in peripheral hormones, including aldosterone, which plays a key role in regulating blood pressure and electrolytes,” Dr. Leggio said in an interview.
Spironolactone is a nonselective mineralocorticoid receptor (MT) antagonist. In studies in animal models, investigators said they found “an inverse correlation between alcohol drinking and the expression of the MR in the amygdala, a key brain region in the development and maintenance of AUD and addiction in general.”
Taken together, this led them to hypothesize that blocking the MR, which is the mechanism of action of spironolactone, “could be a novel pharmacotherapeutic approach for AUD,” he said.
Previous research by the same group of researchers suggested spironolactone “may be a potential new medication to treat patients with AUD.” The present study expanded on those findings and consisted of a three-part investigation.
In the current study, the investigators tested different dosages of spironolactone on binge-like alcohol consumption in male and female mice and assessed food and water intake, blood alcohol levels, motor coordination, and spontaneous locomotion.
They then tested the effects of different dosages of spironolactone injections on operant alcohol self-administration in alcohol-dependent and nondependent male and female rats, also testing blood alcohol levels and motor coordination.
Finally, they analyzed health records of veterans to examine the association between at least 60 continuous days of spironolactone treatment and self-reported alcohol consumption (measured by the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]).
Each of the spironolactone-exposed patients was matched using propensity scores with up to five unexposed patients who had reported alcohol consumption in the 2 years prior to the index date.
The final analysis included a matched cohort of 10,726 spironolactone-exposed individuals who were matched to 34,461 unexposed individuals.
New targets
Spironolactone reduced alcohol intake in mice drinking a sweetened alcohol solution; a 2-way ANOVA revealed a main effect of dose (F 4,52 = 9.09; P < .0001) and sex, with female mice drinking more alcohol, compared to male mice (F 1,13 = 6.05; P = .02).
Post hoc comparisons showed that spironolactone at doses of 50, 100, and 200 mg/kg significantly reduced alcohol intake (P values = .007, .002, and .0001, respectively).
In mice drinking an unsweetened alcohol solution, the 2-way repeated measures ANOVA similarly found a main effect of dose (F 4,52 = 5.77; P = .0006), but not of sex (F 1,13 = 1.41; P = .25).
Spironolactone had no effect on the mice’s intake of a sweet solution without alcohol and had no impact on the consumption of food and water or on locomotion and coordination.
In rats, a 2-way ANOVA revealed a significant spironolactone effect of dose (F 3,66 = 43.95; P < .001), with a post hoc test indicating that spironolactone at 25, 50, and 75 mg/kg reduced alcohol self-administration in alcohol-dependent and nondependent rats (all P values = .0001).
In humans, among the exposed individuals in the matched cohort, 25%, 57%, and 18% received daily doses of spironolactone of less than 25 mg/day, 25-49 mg/day, and 50 mg/day or higher, respectively, with a median follow-up time of 542 (interquartile range, 337-730) days.
The AUDIT-C scores decreased during the study period in both treatment groups, with a larger decrease in average AUDIT-C scores among the exposed vs. unexposed individuals.
“These are very exciting times because, thanks to the progress in the addiction biomedical research field, we are increasing our understanding of the mechanisms how some people develop AUD; hence we can use this knowledge to identify new targets.” The current study “is an example of these ongoing efforts,” said Dr. Leggio.
“It is important to note that [these results] are important but preliminary.” At this juncture, “it would be too premature to think about prescribing spironolactone to treat AUD,” he added.
Exciting findings
Commenting on the study, Joyce Besheer, PhD, professor, department of psychiatry and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, called the study an “elegant demonstration of translational science.”
“While clinical trials will be needed to determine whether this medication is effective at reducing drinking in patients with AUD, these findings are exciting as they suggest that spironolactone may be a promising compound and new treatment options for AUD are much needed,” said Dr. Besheer, who was not involved with the current study.
Dr. Leggio agreed. “We now need prospective, placebo-controlled studies to assess the potential safety and efficacy of spironolactone in people with AUD,” he said.
This work was supported by the National Institutes of Health and the NIAAA. Dr. Leggio, study coauthors, and Dr. Besheer declare no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(AUD), new research suggests.
Researchers at the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and Yale University, New Haven, Conn., investigated the impact of spironolactone on AUD.
Initially, they studied rodents and found that spironolactone reduced binge drinking in mice and reduced self-administration of alcohol in rats without adversely affecting food or water intake or causing motor or coordination problems.
They also analyzed electronic health records of patients drawn from the United States Veterans Affairs health care system to explore potential changes in alcohol use after spironolactone treatment was initiated for other conditions and found a significant link between spironolactone treatment and reduction in self-reported alcohol consumption, with the largest effects observed among those who reported hazardous/heavy episodic alcohol use prior to starting spironolactone treatment.
“Combining findings across three species and different types of research studies, and then seeing similarities in these data, gives us confidence that we are onto something potentially important scientifically and clinically,” senior coauthor Lorenzo Leggio, MD, PhD, senior investigator in the Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, a joint NIDA and NIAAA laboratory, said in a news release.
The study was published online in Molecular Psychiatry.
There is a “critical need to increase the armamentarium of pharmacotherapies to treat individuals with AUD,” the authors note, adding that neuroendocrine systems involved in alcohol craving and drinking “offer promising pharmacologic targets in this regard.”
“Both our team and others have observed that patients with AUD often present with changes in peripheral hormones, including aldosterone, which plays a key role in regulating blood pressure and electrolytes,” Dr. Leggio said in an interview.
Spironolactone is a nonselective mineralocorticoid receptor (MT) antagonist. In studies in animal models, investigators said they found “an inverse correlation between alcohol drinking and the expression of the MR in the amygdala, a key brain region in the development and maintenance of AUD and addiction in general.”
Taken together, this led them to hypothesize that blocking the MR, which is the mechanism of action of spironolactone, “could be a novel pharmacotherapeutic approach for AUD,” he said.
Previous research by the same group of researchers suggested spironolactone “may be a potential new medication to treat patients with AUD.” The present study expanded on those findings and consisted of a three-part investigation.
In the current study, the investigators tested different dosages of spironolactone on binge-like alcohol consumption in male and female mice and assessed food and water intake, blood alcohol levels, motor coordination, and spontaneous locomotion.
They then tested the effects of different dosages of spironolactone injections on operant alcohol self-administration in alcohol-dependent and nondependent male and female rats, also testing blood alcohol levels and motor coordination.
Finally, they analyzed health records of veterans to examine the association between at least 60 continuous days of spironolactone treatment and self-reported alcohol consumption (measured by the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]).
Each of the spironolactone-exposed patients was matched using propensity scores with up to five unexposed patients who had reported alcohol consumption in the 2 years prior to the index date.
The final analysis included a matched cohort of 10,726 spironolactone-exposed individuals who were matched to 34,461 unexposed individuals.
New targets
Spironolactone reduced alcohol intake in mice drinking a sweetened alcohol solution; a 2-way ANOVA revealed a main effect of dose (F 4,52 = 9.09; P < .0001) and sex, with female mice drinking more alcohol, compared to male mice (F 1,13 = 6.05; P = .02).
Post hoc comparisons showed that spironolactone at doses of 50, 100, and 200 mg/kg significantly reduced alcohol intake (P values = .007, .002, and .0001, respectively).
In mice drinking an unsweetened alcohol solution, the 2-way repeated measures ANOVA similarly found a main effect of dose (F 4,52 = 5.77; P = .0006), but not of sex (F 1,13 = 1.41; P = .25).
Spironolactone had no effect on the mice’s intake of a sweet solution without alcohol and had no impact on the consumption of food and water or on locomotion and coordination.
In rats, a 2-way ANOVA revealed a significant spironolactone effect of dose (F 3,66 = 43.95; P < .001), with a post hoc test indicating that spironolactone at 25, 50, and 75 mg/kg reduced alcohol self-administration in alcohol-dependent and nondependent rats (all P values = .0001).
In humans, among the exposed individuals in the matched cohort, 25%, 57%, and 18% received daily doses of spironolactone of less than 25 mg/day, 25-49 mg/day, and 50 mg/day or higher, respectively, with a median follow-up time of 542 (interquartile range, 337-730) days.
The AUDIT-C scores decreased during the study period in both treatment groups, with a larger decrease in average AUDIT-C scores among the exposed vs. unexposed individuals.
“These are very exciting times because, thanks to the progress in the addiction biomedical research field, we are increasing our understanding of the mechanisms how some people develop AUD; hence we can use this knowledge to identify new targets.” The current study “is an example of these ongoing efforts,” said Dr. Leggio.
“It is important to note that [these results] are important but preliminary.” At this juncture, “it would be too premature to think about prescribing spironolactone to treat AUD,” he added.
Exciting findings
Commenting on the study, Joyce Besheer, PhD, professor, department of psychiatry and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, called the study an “elegant demonstration of translational science.”
“While clinical trials will be needed to determine whether this medication is effective at reducing drinking in patients with AUD, these findings are exciting as they suggest that spironolactone may be a promising compound and new treatment options for AUD are much needed,” said Dr. Besheer, who was not involved with the current study.
Dr. Leggio agreed. “We now need prospective, placebo-controlled studies to assess the potential safety and efficacy of spironolactone in people with AUD,” he said.
This work was supported by the National Institutes of Health and the NIAAA. Dr. Leggio, study coauthors, and Dr. Besheer declare no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM MOLECULAR PSYCHIATRY
Coffee linked to reduced cardiovascular disease and mortality risk
Drinking two to three daily cups of – ground, instant, or decaffeinated – is associated with significant reductions in new cardiovascular disease (CVD) and mortality risk, compared with avoiding coffee, a new analysis of the prospective UK Biobank suggests.
Ground and instant coffee, but not decaffeinated coffee, also was associated with reduced risk of new-onset arrhythmia, including atrial fibrillation.
“Our study is the first to look at differences in coffee subtypes to tease out important differences which may explain some of the mechanisms through which coffee works,” Peter M. Kistler, MD, of the Alfred Hospital and Baker Heart and Diabetes Institute, Melbourne, Australia, told this news organization.
“Daily coffee intake should not be discouraged by physicians but rather considered part of a healthy diet,” Dr. Kistler said.
“This study supports that coffee is safe and even potentially beneficial, which is consistent with most of the prior evidence,” Carl “Chip” Lavie, MD, who wasn’t involved in the study, told this news organization.
“We do not prescribe coffee to patients, but for the majority who like coffee, they can be encouraged it is fine to take a few cups daily,” said Dr. Lavie, with the Ochsner Heart and Vascular Institute in New Orleans.
The study was published online in the European Journal of Preventive Cardiology.
Clear cardiovascular benefits
A total of 449,563 UK Biobank participants (median age 58 years; 55% women), who were free of arrhythmias or other CVD at baseline, reported in questionnaires their level of daily coffee intake and preferred type of coffee.
During more than 12.5 years of follow-up, 27,809 participants (6.2%) died.
Drinking one to five cups per day of ground or instant coffee (but not decaffeinated coffee) was associated with a significant reduction in incident arrhythmia. The lowest risk was with four to five cups per day for ground coffee (hazard ratio [HR] 0.83; 95% confidence interval [CI], 0.76-0.91; P < .0001) and two to three cups per day for instant coffee (HR, 0.88; 95% CI, 0.85-0.92; P < .0001).
Habitual coffee drinking of up to five cups perday was also associated with significant reductions in the risk of incident CVD, when compared with nondrinkers.
Significant reductions in the risk of incident coronary heart disease (CHD) were associated with habitual coffee intake of up to five cups per day, with the lowest risk for CHD observed in those who consumed two to three cups per day (HR 0.89; 95% CI, 0.86-0.91; P < .0001).
Coffee consumption at all levels was linked to significant reduction in the risk of congestive cardiac failure (CCF) and ischemic stroke. The lowest risks were observed in those who consumed two to three cups per day, with HR, 0.83 (95% CI, 0.79-0.87; P < .0001) for CCF and HR, 0.84 (95% CI, 0.78-0.90; P < .0001) for ischemic stroke.
Death from any cause was significantly reduced for all coffee subtypes, with the greatest risk reduction seen with two to three cups per day for decaffeinated (HR, 0.86; 95% CI, 0.81-0.91; P < .0001); ground (HR, 0.73; 95% CI, 0.69-0.78; P < .0001); and instant coffee (HR, 0.89; 95% CI, 0.86-0.93; P < .0001).
“Coffee consumption is associated with cardiovascular benefits and should not empirically be discontinued in those with underlying heart rhythm disorders or cardiovascular disease,” Dr. Kistler told this news organization.
Plausible mechanisms
There are a number of proposed mechanisms to explain the benefits of coffee on CVD.
“Caffeine has antiarrhythmic properties through adenosine A1 and A2A receptor inhibition, hence the difference in effects of decaf vs. full-strength coffee on heart rhythm disorders,” Dr. Kistler explained.
Coffee has vasodilatory effects and coffee also contains antioxidant polyphenols, which reduce oxidative stress and modulate metabolism.
“The explanation for improved survival with habitual coffee consumption remains unclear,” Dr. Kistler said.
“Putative mechanisms include improved endothelial function, circulating antioxidants, improved insulin sensitivity, and reduced inflammation. Another potential mechanism includes the beneficial effects of coffee on metabolic syndrome,” he said.
“Caffeine has a role in weight loss through inhibition of gut fatty acid absorption and increase in basal metabolic rate. Furthermore, coffee has been associated with a significantly lower incidence of type 2 diabetes mellitus,” Dr. Kistler added.
Direction of relationship unclear
Charlotte Mills, PhD, University of Reading, England, said this study “adds to the body of evidence from observational trials associating moderate coffee consumption with cardioprotection, which looks promising.”
However, with the observational design, it’s unclear “which direction the relationship goes – for example, does coffee make you healthy or do inherently healthier people consume coffee? Randomized controlled trials are needed to fully understand the relationship between coffee and health before recommendations can be made,” Dr. Mills told the UK nonprofit Science Media Centre.
Annette Creedon, PhD, nutrition scientist with the British Nutrition Foundation, said it’s possible that respondents over- or underestimated the amount of coffee that they were consuming at the start of the study when they self-reported their intake.
“It is therefore difficult to determine whether the outcomes can be directly associated with the behaviors in coffee consumption reported at the start of the study,” she told the Science Media Centre.
The study had no funding. Dr. Kistler has received funding from Abbott Medical for consultancy and speaking engagements and fellowship support from Biosense Webster. Dr. Lavie has no relevant disclosures. Dr. Mills has worked in collaboration with Nestle on research relating to coffee and health funded by UKRI. Dr. Creedon has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Drinking two to three daily cups of – ground, instant, or decaffeinated – is associated with significant reductions in new cardiovascular disease (CVD) and mortality risk, compared with avoiding coffee, a new analysis of the prospective UK Biobank suggests.
Ground and instant coffee, but not decaffeinated coffee, also was associated with reduced risk of new-onset arrhythmia, including atrial fibrillation.
“Our study is the first to look at differences in coffee subtypes to tease out important differences which may explain some of the mechanisms through which coffee works,” Peter M. Kistler, MD, of the Alfred Hospital and Baker Heart and Diabetes Institute, Melbourne, Australia, told this news organization.
“Daily coffee intake should not be discouraged by physicians but rather considered part of a healthy diet,” Dr. Kistler said.
“This study supports that coffee is safe and even potentially beneficial, which is consistent with most of the prior evidence,” Carl “Chip” Lavie, MD, who wasn’t involved in the study, told this news organization.
“We do not prescribe coffee to patients, but for the majority who like coffee, they can be encouraged it is fine to take a few cups daily,” said Dr. Lavie, with the Ochsner Heart and Vascular Institute in New Orleans.
The study was published online in the European Journal of Preventive Cardiology.
Clear cardiovascular benefits
A total of 449,563 UK Biobank participants (median age 58 years; 55% women), who were free of arrhythmias or other CVD at baseline, reported in questionnaires their level of daily coffee intake and preferred type of coffee.
During more than 12.5 years of follow-up, 27,809 participants (6.2%) died.
Drinking one to five cups per day of ground or instant coffee (but not decaffeinated coffee) was associated with a significant reduction in incident arrhythmia. The lowest risk was with four to five cups per day for ground coffee (hazard ratio [HR] 0.83; 95% confidence interval [CI], 0.76-0.91; P < .0001) and two to three cups per day for instant coffee (HR, 0.88; 95% CI, 0.85-0.92; P < .0001).
Habitual coffee drinking of up to five cups perday was also associated with significant reductions in the risk of incident CVD, when compared with nondrinkers.
Significant reductions in the risk of incident coronary heart disease (CHD) were associated with habitual coffee intake of up to five cups per day, with the lowest risk for CHD observed in those who consumed two to three cups per day (HR 0.89; 95% CI, 0.86-0.91; P < .0001).
Coffee consumption at all levels was linked to significant reduction in the risk of congestive cardiac failure (CCF) and ischemic stroke. The lowest risks were observed in those who consumed two to three cups per day, with HR, 0.83 (95% CI, 0.79-0.87; P < .0001) for CCF and HR, 0.84 (95% CI, 0.78-0.90; P < .0001) for ischemic stroke.
Death from any cause was significantly reduced for all coffee subtypes, with the greatest risk reduction seen with two to three cups per day for decaffeinated (HR, 0.86; 95% CI, 0.81-0.91; P < .0001); ground (HR, 0.73; 95% CI, 0.69-0.78; P < .0001); and instant coffee (HR, 0.89; 95% CI, 0.86-0.93; P < .0001).
“Coffee consumption is associated with cardiovascular benefits and should not empirically be discontinued in those with underlying heart rhythm disorders or cardiovascular disease,” Dr. Kistler told this news organization.
Plausible mechanisms
There are a number of proposed mechanisms to explain the benefits of coffee on CVD.
“Caffeine has antiarrhythmic properties through adenosine A1 and A2A receptor inhibition, hence the difference in effects of decaf vs. full-strength coffee on heart rhythm disorders,” Dr. Kistler explained.
Coffee has vasodilatory effects and coffee also contains antioxidant polyphenols, which reduce oxidative stress and modulate metabolism.
“The explanation for improved survival with habitual coffee consumption remains unclear,” Dr. Kistler said.
“Putative mechanisms include improved endothelial function, circulating antioxidants, improved insulin sensitivity, and reduced inflammation. Another potential mechanism includes the beneficial effects of coffee on metabolic syndrome,” he said.
“Caffeine has a role in weight loss through inhibition of gut fatty acid absorption and increase in basal metabolic rate. Furthermore, coffee has been associated with a significantly lower incidence of type 2 diabetes mellitus,” Dr. Kistler added.
Direction of relationship unclear
Charlotte Mills, PhD, University of Reading, England, said this study “adds to the body of evidence from observational trials associating moderate coffee consumption with cardioprotection, which looks promising.”
However, with the observational design, it’s unclear “which direction the relationship goes – for example, does coffee make you healthy or do inherently healthier people consume coffee? Randomized controlled trials are needed to fully understand the relationship between coffee and health before recommendations can be made,” Dr. Mills told the UK nonprofit Science Media Centre.
Annette Creedon, PhD, nutrition scientist with the British Nutrition Foundation, said it’s possible that respondents over- or underestimated the amount of coffee that they were consuming at the start of the study when they self-reported their intake.
“It is therefore difficult to determine whether the outcomes can be directly associated with the behaviors in coffee consumption reported at the start of the study,” she told the Science Media Centre.
The study had no funding. Dr. Kistler has received funding from Abbott Medical for consultancy and speaking engagements and fellowship support from Biosense Webster. Dr. Lavie has no relevant disclosures. Dr. Mills has worked in collaboration with Nestle on research relating to coffee and health funded by UKRI. Dr. Creedon has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Drinking two to three daily cups of – ground, instant, or decaffeinated – is associated with significant reductions in new cardiovascular disease (CVD) and mortality risk, compared with avoiding coffee, a new analysis of the prospective UK Biobank suggests.
Ground and instant coffee, but not decaffeinated coffee, also was associated with reduced risk of new-onset arrhythmia, including atrial fibrillation.
“Our study is the first to look at differences in coffee subtypes to tease out important differences which may explain some of the mechanisms through which coffee works,” Peter M. Kistler, MD, of the Alfred Hospital and Baker Heart and Diabetes Institute, Melbourne, Australia, told this news organization.
“Daily coffee intake should not be discouraged by physicians but rather considered part of a healthy diet,” Dr. Kistler said.
“This study supports that coffee is safe and even potentially beneficial, which is consistent with most of the prior evidence,” Carl “Chip” Lavie, MD, who wasn’t involved in the study, told this news organization.
“We do not prescribe coffee to patients, but for the majority who like coffee, they can be encouraged it is fine to take a few cups daily,” said Dr. Lavie, with the Ochsner Heart and Vascular Institute in New Orleans.
The study was published online in the European Journal of Preventive Cardiology.
Clear cardiovascular benefits
A total of 449,563 UK Biobank participants (median age 58 years; 55% women), who were free of arrhythmias or other CVD at baseline, reported in questionnaires their level of daily coffee intake and preferred type of coffee.
During more than 12.5 years of follow-up, 27,809 participants (6.2%) died.
Drinking one to five cups per day of ground or instant coffee (but not decaffeinated coffee) was associated with a significant reduction in incident arrhythmia. The lowest risk was with four to five cups per day for ground coffee (hazard ratio [HR] 0.83; 95% confidence interval [CI], 0.76-0.91; P < .0001) and two to three cups per day for instant coffee (HR, 0.88; 95% CI, 0.85-0.92; P < .0001).
Habitual coffee drinking of up to five cups perday was also associated with significant reductions in the risk of incident CVD, when compared with nondrinkers.
Significant reductions in the risk of incident coronary heart disease (CHD) were associated with habitual coffee intake of up to five cups per day, with the lowest risk for CHD observed in those who consumed two to three cups per day (HR 0.89; 95% CI, 0.86-0.91; P < .0001).
Coffee consumption at all levels was linked to significant reduction in the risk of congestive cardiac failure (CCF) and ischemic stroke. The lowest risks were observed in those who consumed two to three cups per day, with HR, 0.83 (95% CI, 0.79-0.87; P < .0001) for CCF and HR, 0.84 (95% CI, 0.78-0.90; P < .0001) for ischemic stroke.
Death from any cause was significantly reduced for all coffee subtypes, with the greatest risk reduction seen with two to three cups per day for decaffeinated (HR, 0.86; 95% CI, 0.81-0.91; P < .0001); ground (HR, 0.73; 95% CI, 0.69-0.78; P < .0001); and instant coffee (HR, 0.89; 95% CI, 0.86-0.93; P < .0001).
“Coffee consumption is associated with cardiovascular benefits and should not empirically be discontinued in those with underlying heart rhythm disorders or cardiovascular disease,” Dr. Kistler told this news organization.
Plausible mechanisms
There are a number of proposed mechanisms to explain the benefits of coffee on CVD.
“Caffeine has antiarrhythmic properties through adenosine A1 and A2A receptor inhibition, hence the difference in effects of decaf vs. full-strength coffee on heart rhythm disorders,” Dr. Kistler explained.
Coffee has vasodilatory effects and coffee also contains antioxidant polyphenols, which reduce oxidative stress and modulate metabolism.
“The explanation for improved survival with habitual coffee consumption remains unclear,” Dr. Kistler said.
“Putative mechanisms include improved endothelial function, circulating antioxidants, improved insulin sensitivity, and reduced inflammation. Another potential mechanism includes the beneficial effects of coffee on metabolic syndrome,” he said.
“Caffeine has a role in weight loss through inhibition of gut fatty acid absorption and increase in basal metabolic rate. Furthermore, coffee has been associated with a significantly lower incidence of type 2 diabetes mellitus,” Dr. Kistler added.
Direction of relationship unclear
Charlotte Mills, PhD, University of Reading, England, said this study “adds to the body of evidence from observational trials associating moderate coffee consumption with cardioprotection, which looks promising.”
However, with the observational design, it’s unclear “which direction the relationship goes – for example, does coffee make you healthy or do inherently healthier people consume coffee? Randomized controlled trials are needed to fully understand the relationship between coffee and health before recommendations can be made,” Dr. Mills told the UK nonprofit Science Media Centre.
Annette Creedon, PhD, nutrition scientist with the British Nutrition Foundation, said it’s possible that respondents over- or underestimated the amount of coffee that they were consuming at the start of the study when they self-reported their intake.
“It is therefore difficult to determine whether the outcomes can be directly associated with the behaviors in coffee consumption reported at the start of the study,” she told the Science Media Centre.
The study had no funding. Dr. Kistler has received funding from Abbott Medical for consultancy and speaking engagements and fellowship support from Biosense Webster. Dr. Lavie has no relevant disclosures. Dr. Mills has worked in collaboration with Nestle on research relating to coffee and health funded by UKRI. Dr. Creedon has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY
Newer 3D lung models starting to remake research
Pulmonologist-scientist Veena B. Antony, MD, professor of medicine at the University of Alabama in Birmingham, grows “pulmospheres” in her lab. The tiny spheres, about 1 mL in diameter, contain cells representing all of the cell types in a lung struck with pulmonary fibrosis.
They are a three-dimensional model of idiopathic pulmonary fibrosis (IPF) that can be used to study the behavior of invasive myofibroblasts and to predict in vivo responsiveness to antifibrotic drugs; 
“The utility is extensive, including looking at the impact of early-life exposures on mid-life lung disease. We can ask all kinds of questions and answer them much faster, and with more accuracy, than with any 2D model,” said Dr. Antony, also professor of environmental health sciences and director of UAB’s program for environmental and translational medicine.
“The future of 3D modeling of the lung will happen step by step ... but we’re right at the edge of a prime explosion of information coming from these models, in all kinds of lung diseases,” she said.
Two-dimensional model systems – mainly monolayer cell cultures where cells adhere to and grow on a plate – cannot approximate the variety of cell types and architecture found in tissue, nor can they recapitulate cell-cell communication, biochemical cues, and other factors that are key to lung development and the pathogenesis of disease.
Dr. Antony’s pulmospheres resemble what have come to be known as organoids – 3D tissue cultures emanating from induced pluripotent stem cells (iPSC) or adult stem cells, in which multiple cell types self-organize, usually while suspended in natural or synthetic extracellular matrix (with or without a scaffold of some kind).
Lung-on-a-chip
In lung-on-a-chip (LOC) models, multiple cell types are seeded into miniature chambers, or “chips,” that contain networks of microfabricated channels designed to deliver and remove fluids, chemical cues, oxygen, and biomechanical forces. LOCs and other organs-on-chips – also called tissues-on-chips – can be continuously perfused and are highly structured and precisely controlled.
It’s the organs-on-chip model – or potential fusions of the organoid and organs-on-chip models – that will likely impact drug development. Almost 9 out of 10 investigational drugs fail in clinical trials – approximately 60% because of lack of efficacy and 30% because of toxicity. More reliable and predictive preclinical investigation is key, said Danilo A. Tagle, PhD, director of the Office of Special Initiatives in the National Center for Advancing Translational Sciences, of the National Institutes of Health.
“We have so many candidate drugs that go through preclinical safety testing, and that do relatively well in animal studies of efficacy, but then fail in clinical trials,” Dr. Tagle said. “We need better preclinical models.”
In its 10 years of life, the Tissue Chip for Drug Screening Program led by the NCATS – and funded by the NIH and Defense Advanced Research Projects Agency – has shown that organs-on-chips can be used to model disease and to predict both the safety and efficacy of clinical compounds, he said.
Lung organoids
Dr. Antony’s pulmospheres emanate not from stem cells but from primary tissue obtained from diseased lung. “We reconstitute the lung cells in single-cell suspensions, and then we allow them to come back together to form lung tissue,” she said. The pulmospheres take about 3 days to grow.
In a study published 5 years ago of pulmospheres of 20 patients with IPF and 9 control subjects, Dr. Antony and colleagues quantitated invasiveness and found “remarkable” differences in the invasiveness of IPF pulmospheres following exposure to the Food and Drug Administration–approved antifibrotic drugs nintedanib and pirfenidone. Some pulmospheres responded to one or the other drug, some to both, and two to neither – findings that Dr. Antony said offer hope for the goals of personalizing therapy and assessing new drugs.
Moreover, clinical disease progression correlated with invasiveness of the pulmospheres, showing that the organoid-like structures “do give us a model that [reflects] what’s happening in the clinical setting,” she said. (Lung tissue for the study was obtained via video-assisted thoracic surgery biopsy of IPF patients and from failed donor lung explants, but bronchoscopic forceps biopsies have become a useful method for obtaining tissue.)
The pulmospheres are not yet in clinical use, Dr. Antony said, but her lab is testing other fibrosis modifiers and continuing to use the model as a research tool.
One state to the east, at Vanderbilt University, Nashville, Tenn., Amanda Linkous, PhD, grows “branching lung organoids” and brain organoids to study the biology of small cell lung cancer (SCLC).
“We want to understand how [SCLC] cells change in the primary organ site, compared with metastatic sites like the brain. ... Are different transcription factors expressed [for instance] depending on where the tumor is growing?” said Dr. Linkous, scientific center manager of the National Cancer Institute’s Center for Systems Biology of SCLC at Vanderbilt. “Then we hope to start drug screening within the next year.”
Her lung organoids take shape from either human embryonic stem cells or iPSCs. Within commercially available media, the cells mature through several stages of differentiation, forming definitive endoderm, anterior foregut endoderm, and then circular lung bud structures – the latter of which are then placed into droplets of Matrigel, an extracellular matrix gel.
“In the Matrigel droplets, the lung bud cells will develop proximal and distal-like branching structures that express things like EPCAM, MUC1, SOX2, SOX9, and NKX2.1 – key markers that you should see in a more mature lung microenvironment,” she said. Tumor cells from established SCLC cell lines will then easily invade the branching lung organoid.
Dr. Linkous said she has found her organoid models highly reproducible and values their long-lasting nature – especially for future drug screening. “We can keep organoids going for months at a time,” said Dr. Linkous, a research associate professor in Vanderbilt’s department of biochemistry.
Like Dr. Antony, she envisions personalizing treatment in the future. “SCLC is a very heterogeneous tumor with many different cell types, so what works for one patient may not work well at all for another patient,” she said.
As recently as 5 years ago, “many in the cancer field would have been resistant to moving away from mouse models,” Dr. Linkous noted. “But preclinical studies in mice often don’t pan out in the clinic ... so we’re moving toward a human microenvironment to study human disease.”
The greatest challenge, Dr. Linkous and Dr. Antony said, lies in integrating both vascular blood flow and air into these models. “We just don’t have that combination as of yet,” Dr. Antony said.
LOC models
One of the first LOC models – and a galvanizing event for organs-on-chips more broadly – was a 1- to 2-cm–long model of the alveolar-capillary interface developed at the Wyss Institute for Biologically Inspired Engineering at Harvard Medical School, Boston.
Microchannels ran alongside a porous membrane coated with extracellular matrix, with alveolar cells seeded on one side and lung endothelial cells on the other side. When a vacuum was applied rhythmically to the channels, the cell-lined membrane stretched and relaxed, mimicking breathing movements.
Lead investigator Dongeun (Dan) Huh, PhD, then a postdoctoral student working with Donald E. Ingber, MD, PhD, founding director of the institute, ran tests showing that the model could reproduce organ-level responses to bacteria and inflammatory cytokines, as well as to silica nanoparticles. The widely cited paper was published in 2010 (Science. 2010;328[5986]:1662-8), and was followed by another study published in 2012 (Sci Transl Med. 2012;4[159]:159ra147) that used the LOC device to reproduce drug toxicity–induced pulmonary edema. “Here we were demonstrating for the first time that we could use the lung-on-chip to model human lung disease,” said Dr. Huh, who started his own lab at the University of Pennsylvania, Philadelphia, in 2013.
Since then, “as a field we’ve come a long way in modeling the complexity of human lung tissues ... with more advanced devices that can be used to mimic different parts of the lung and different processes, like immune responses in asthma and viral infections,” said Dr. Huh, “and with several studies using primary human cells taken from lung disease patients.”
Among Dr. Huh’s latest devices, built with NIH funding, is an asthma-on-a-chip device. Lung cells isolated from asthma patients are grown in a microfabricated device to create multilayered airway tissue, with airspace, that contains a fully differentiated epithelium and a vascularized stroma. “We can compress the entire engineered area of asthmatic human tissue in a lateral direction to mimic bronchoconstriction that happens during an asthma attack,” he said.
A paper soon to be published will describe how “abnormal pathophysiologic compressive forces due to bronchoconstriction in asthmatic lungs can make the lungs fibrotic, and how those mechanical forces also can induce increased vascularity,” said Dr. Huh, associate professor in the university’s department of bioengineering. “The increased vascular density can also change the phenotype of blood vessels in asthmatic airways.”
Dr. Huh also has an $8.3 million contract with the government’s Biomedical Advanced Research and Development Authority to study how chlorine gas damages lung tissues and identify biomarkers of chlorine gas–induced lung injury, with the goal of developing therapeutics.
Dr. Ingber and associates have developed a device modeling cystic fibrosis (CF). The chip is lined with primary human CF bronchial epithelial cells grown under an air-liquid interface and interfaced with primary lung microvascular endothelium that are exposed to fluid flow.
The chip reproduced, “with high fidelity, many of the structural, biochemical, and pathophysiological features of the human CF lung airway and its response to pathogens and circulating immune cells in vitro,” Dr. Ingber and colleagues reported (J Cyst Fibros. 2022;21:605-15).
Government investment in tissue chips
Efforts to commercialize organs-on-chip platforms and translate them for nonengineers have also picked in recent years. Several companies in the United States (including Emulate, a Wyss start-up) and in Europe now offer microengineered lung tissue models that can be used for research and drug testing. And some large pharmaceutical companies, said Dr. Tagle, have begun integrating tissue chip technology into their drug development programs.
The FDA, meanwhile, “has come to embrace the technology and see its promise,” Dr. Tagle said. An FDA pilot program announced in 2021 – called ISTAND (Innovative Science and Technology Approaches for New Drugs) – allows for tissue chip data to be submitted, as standalone data, for some drug applications.
The first 5 years of the government’s Tissue Chip for Drug Screening Program focused on safety and toxicity, and it “was successful in that model organ systems were able to capture the human response that [had been missed in] animal models,” he said.
For example, when a liver-tissue model was used to test several compounds that had passed animal testing for toxicity/safety but then failed in human clinical trials – killing some of the participants – the model showed a 100% sensitivity and a 87% specificity in predicting the human response, said Dr. Tagle, who recently coauthored a review on the future of organs-on-chips (Nature Reviews I Drug Discovery. 2021;20:345-61).
The second 5 years of the program, currently winding down, have focused on efficacy – the ability of organs-on-chip models to recreate the pathophysiology of chronic obstructive pulmonary disease, influenza, and other diseases, so that potential drugs can be assessed. In 2020, with extra support from the Coronavirus Aid, Relief, and Economic Security Act, NCATS funded academic labs to use organs-on-chip technology to evaluate SARS-CoV-2 and potential therapeutics.
Dr. Ingbar was one of the grantees. His team screened a number of FDA-approved drugs for potential repurposing using a bronchial-airway-on-a-chip and compared results with 2D model systems (Nat Biomed Eng. 2021;5:815-29). Amodiaquine inhibited infection in the 3D model and is now in phase 2 COVID trials. Several other drugs showed effectiveness in a 2D model but not in the chip.
Now, in a next phase of study at NCATS, coined Clinical Trials on a Chip, the center has awarded $35.5 million for investigators to test candidate therapies, often in parallel to ongoing clinical trials. The hope is that organs-on-chips can improve clinical trial design, from enrollment criteria and patient stratification to endpoints and the use of biomarkers. And in his lab, Dr. Huh is now engineering a shift to “organoids-on-a-chip” that combines the best features of each approach. “The idea,” he said, “is to grow organoids, and maintain the organoids in the microengineered systems where we can control their environment better ... and apply cues to allow them to develop into even more realistic tissues.”
Drs. Antony, Linkous, and Tagle reported no relevant disclosures. Dr. Huh is a co-founder of Vivodyne Inc, and owns shares in Vivodyne Inc. and Emulate Inc.
Pulmonologist-scientist Veena B. Antony, MD, professor of medicine at the University of Alabama in Birmingham, grows “pulmospheres” in her lab. The tiny spheres, about 1 mL in diameter, contain cells representing all of the cell types in a lung struck with pulmonary fibrosis.
They are a three-dimensional model of idiopathic pulmonary fibrosis (IPF) that can be used to study the behavior of invasive myofibroblasts and to predict in vivo responsiveness to antifibrotic drugs;
“The utility is extensive, including looking at the impact of early-life exposures on mid-life lung disease. We can ask all kinds of questions and answer them much faster, and with more accuracy, than with any 2D model,” said Dr. Antony, also professor of environmental health sciences and director of UAB’s program for environmental and translational medicine.
“The future of 3D modeling of the lung will happen step by step ... but we’re right at the edge of a prime explosion of information coming from these models, in all kinds of lung diseases,” she said.
Two-dimensional model systems – mainly monolayer cell cultures where cells adhere to and grow on a plate – cannot approximate the variety of cell types and architecture found in tissue, nor can they recapitulate cell-cell communication, biochemical cues, and other factors that are key to lung development and the pathogenesis of disease.
Dr. Antony’s pulmospheres resemble what have come to be known as organoids – 3D tissue cultures emanating from induced pluripotent stem cells (iPSC) or adult stem cells, in which multiple cell types self-organize, usually while suspended in natural or synthetic extracellular matrix (with or without a scaffold of some kind).
Lung-on-a-chip
In lung-on-a-chip (LOC) models, multiple cell types are seeded into miniature chambers, or “chips,” that contain networks of microfabricated channels designed to deliver and remove fluids, chemical cues, oxygen, and biomechanical forces. LOCs and other organs-on-chips – also called tissues-on-chips – can be continuously perfused and are highly structured and precisely controlled.
It’s the organs-on-chip model – or potential fusions of the organoid and organs-on-chip models – that will likely impact drug development. Almost 9 out of 10 investigational drugs fail in clinical trials – approximately 60% because of lack of efficacy and 30% because of toxicity. More reliable and predictive preclinical investigation is key, said Danilo A. Tagle, PhD, director of the Office of Special Initiatives in the National Center for Advancing Translational Sciences, of the National Institutes of Health.
“We have so many candidate drugs that go through preclinical safety testing, and that do relatively well in animal studies of efficacy, but then fail in clinical trials,” Dr. Tagle said. “We need better preclinical models.”
In its 10 years of life, the Tissue Chip for Drug Screening Program led by the NCATS – and funded by the NIH and Defense Advanced Research Projects Agency – has shown that organs-on-chips can be used to model disease and to predict both the safety and efficacy of clinical compounds, he said.
Lung organoids
Dr. Antony’s pulmospheres emanate not from stem cells but from primary tissue obtained from diseased lung. “We reconstitute the lung cells in single-cell suspensions, and then we allow them to come back together to form lung tissue,” she said. The pulmospheres take about 3 days to grow.
In a study published 5 years ago of pulmospheres of 20 patients with IPF and 9 control subjects, Dr. Antony and colleagues quantitated invasiveness and found “remarkable” differences in the invasiveness of IPF pulmospheres following exposure to the Food and Drug Administration–approved antifibrotic drugs nintedanib and pirfenidone. Some pulmospheres responded to one or the other drug, some to both, and two to neither – findings that Dr. Antony said offer hope for the goals of personalizing therapy and assessing new drugs.
Moreover, clinical disease progression correlated with invasiveness of the pulmospheres, showing that the organoid-like structures “do give us a model that [reflects] what’s happening in the clinical setting,” she said. (Lung tissue for the study was obtained via video-assisted thoracic surgery biopsy of IPF patients and from failed donor lung explants, but bronchoscopic forceps biopsies have become a useful method for obtaining tissue.)
The pulmospheres are not yet in clinical use, Dr. Antony said, but her lab is testing other fibrosis modifiers and continuing to use the model as a research tool.
One state to the east, at Vanderbilt University, Nashville, Tenn., Amanda Linkous, PhD, grows “branching lung organoids” and brain organoids to study the biology of small cell lung cancer (SCLC).
“We want to understand how [SCLC] cells change in the primary organ site, compared with metastatic sites like the brain. ... Are different transcription factors expressed [for instance] depending on where the tumor is growing?” said Dr. Linkous, scientific center manager of the National Cancer Institute’s Center for Systems Biology of SCLC at Vanderbilt. “Then we hope to start drug screening within the next year.”
Her lung organoids take shape from either human embryonic stem cells or iPSCs. Within commercially available media, the cells mature through several stages of differentiation, forming definitive endoderm, anterior foregut endoderm, and then circular lung bud structures – the latter of which are then placed into droplets of Matrigel, an extracellular matrix gel.
“In the Matrigel droplets, the lung bud cells will develop proximal and distal-like branching structures that express things like EPCAM, MUC1, SOX2, SOX9, and NKX2.1 – key markers that you should see in a more mature lung microenvironment,” she said. Tumor cells from established SCLC cell lines will then easily invade the branching lung organoid.
Dr. Linkous said she has found her organoid models highly reproducible and values their long-lasting nature – especially for future drug screening. “We can keep organoids going for months at a time,” said Dr. Linkous, a research associate professor in Vanderbilt’s department of biochemistry.
Like Dr. Antony, she envisions personalizing treatment in the future. “SCLC is a very heterogeneous tumor with many different cell types, so what works for one patient may not work well at all for another patient,” she said.
As recently as 5 years ago, “many in the cancer field would have been resistant to moving away from mouse models,” Dr. Linkous noted. “But preclinical studies in mice often don’t pan out in the clinic ... so we’re moving toward a human microenvironment to study human disease.”
The greatest challenge, Dr. Linkous and Dr. Antony said, lies in integrating both vascular blood flow and air into these models. “We just don’t have that combination as of yet,” Dr. Antony said.
LOC models
One of the first LOC models – and a galvanizing event for organs-on-chips more broadly – was a 1- to 2-cm–long model of the alveolar-capillary interface developed at the Wyss Institute for Biologically Inspired Engineering at Harvard Medical School, Boston.
Microchannels ran alongside a porous membrane coated with extracellular matrix, with alveolar cells seeded on one side and lung endothelial cells on the other side. When a vacuum was applied rhythmically to the channels, the cell-lined membrane stretched and relaxed, mimicking breathing movements.
Lead investigator Dongeun (Dan) Huh, PhD, then a postdoctoral student working with Donald E. Ingber, MD, PhD, founding director of the institute, ran tests showing that the model could reproduce organ-level responses to bacteria and inflammatory cytokines, as well as to silica nanoparticles. The widely cited paper was published in 2010 (Science. 2010;328[5986]:1662-8), and was followed by another study published in 2012 (Sci Transl Med. 2012;4[159]:159ra147) that used the LOC device to reproduce drug toxicity–induced pulmonary edema. “Here we were demonstrating for the first time that we could use the lung-on-chip to model human lung disease,” said Dr. Huh, who started his own lab at the University of Pennsylvania, Philadelphia, in 2013.
Since then, “as a field we’ve come a long way in modeling the complexity of human lung tissues ... with more advanced devices that can be used to mimic different parts of the lung and different processes, like immune responses in asthma and viral infections,” said Dr. Huh, “and with several studies using primary human cells taken from lung disease patients.”
Among Dr. Huh’s latest devices, built with NIH funding, is an asthma-on-a-chip device. Lung cells isolated from asthma patients are grown in a microfabricated device to create multilayered airway tissue, with airspace, that contains a fully differentiated epithelium and a vascularized stroma. “We can compress the entire engineered area of asthmatic human tissue in a lateral direction to mimic bronchoconstriction that happens during an asthma attack,” he said.
A paper soon to be published will describe how “abnormal pathophysiologic compressive forces due to bronchoconstriction in asthmatic lungs can make the lungs fibrotic, and how those mechanical forces also can induce increased vascularity,” said Dr. Huh, associate professor in the university’s department of bioengineering. “The increased vascular density can also change the phenotype of blood vessels in asthmatic airways.”
Dr. Huh also has an $8.3 million contract with the government’s Biomedical Advanced Research and Development Authority to study how chlorine gas damages lung tissues and identify biomarkers of chlorine gas–induced lung injury, with the goal of developing therapeutics.
Dr. Ingber and associates have developed a device modeling cystic fibrosis (CF). The chip is lined with primary human CF bronchial epithelial cells grown under an air-liquid interface and interfaced with primary lung microvascular endothelium that are exposed to fluid flow.
The chip reproduced, “with high fidelity, many of the structural, biochemical, and pathophysiological features of the human CF lung airway and its response to pathogens and circulating immune cells in vitro,” Dr. Ingber and colleagues reported (J Cyst Fibros. 2022;21:605-15).
Government investment in tissue chips
Efforts to commercialize organs-on-chip platforms and translate them for nonengineers have also picked in recent years. Several companies in the United States (including Emulate, a Wyss start-up) and in Europe now offer microengineered lung tissue models that can be used for research and drug testing. And some large pharmaceutical companies, said Dr. Tagle, have begun integrating tissue chip technology into their drug development programs.
The FDA, meanwhile, “has come to embrace the technology and see its promise,” Dr. Tagle said. An FDA pilot program announced in 2021 – called ISTAND (Innovative Science and Technology Approaches for New Drugs) – allows for tissue chip data to be submitted, as standalone data, for some drug applications.
The first 5 years of the government’s Tissue Chip for Drug Screening Program focused on safety and toxicity, and it “was successful in that model organ systems were able to capture the human response that [had been missed in] animal models,” he said.
For example, when a liver-tissue model was used to test several compounds that had passed animal testing for toxicity/safety but then failed in human clinical trials – killing some of the participants – the model showed a 100% sensitivity and a 87% specificity in predicting the human response, said Dr. Tagle, who recently coauthored a review on the future of organs-on-chips (Nature Reviews I Drug Discovery. 2021;20:345-61).
The second 5 years of the program, currently winding down, have focused on efficacy – the ability of organs-on-chip models to recreate the pathophysiology of chronic obstructive pulmonary disease, influenza, and other diseases, so that potential drugs can be assessed. In 2020, with extra support from the Coronavirus Aid, Relief, and Economic Security Act, NCATS funded academic labs to use organs-on-chip technology to evaluate SARS-CoV-2 and potential therapeutics.
Dr. Ingbar was one of the grantees. His team screened a number of FDA-approved drugs for potential repurposing using a bronchial-airway-on-a-chip and compared results with 2D model systems (Nat Biomed Eng. 2021;5:815-29). Amodiaquine inhibited infection in the 3D model and is now in phase 2 COVID trials. Several other drugs showed effectiveness in a 2D model but not in the chip.
Now, in a next phase of study at NCATS, coined Clinical Trials on a Chip, the center has awarded $35.5 million for investigators to test candidate therapies, often in parallel to ongoing clinical trials. The hope is that organs-on-chips can improve clinical trial design, from enrollment criteria and patient stratification to endpoints and the use of biomarkers. And in his lab, Dr. Huh is now engineering a shift to “organoids-on-a-chip” that combines the best features of each approach. “The idea,” he said, “is to grow organoids, and maintain the organoids in the microengineered systems where we can control their environment better ... and apply cues to allow them to develop into even more realistic tissues.”
Drs. Antony, Linkous, and Tagle reported no relevant disclosures. Dr. Huh is a co-founder of Vivodyne Inc, and owns shares in Vivodyne Inc. and Emulate Inc.
Pulmonologist-scientist Veena B. Antony, MD, professor of medicine at the University of Alabama in Birmingham, grows “pulmospheres” in her lab. The tiny spheres, about 1 mL in diameter, contain cells representing all of the cell types in a lung struck with pulmonary fibrosis.
They are a three-dimensional model of idiopathic pulmonary fibrosis (IPF) that can be used to study the behavior of invasive myofibroblasts and to predict in vivo responsiveness to antifibrotic drugs;
“The utility is extensive, including looking at the impact of early-life exposures on mid-life lung disease. We can ask all kinds of questions and answer them much faster, and with more accuracy, than with any 2D model,” said Dr. Antony, also professor of environmental health sciences and director of UAB’s program for environmental and translational medicine.
“The future of 3D modeling of the lung will happen step by step ... but we’re right at the edge of a prime explosion of information coming from these models, in all kinds of lung diseases,” she said.
Two-dimensional model systems – mainly monolayer cell cultures where cells adhere to and grow on a plate – cannot approximate the variety of cell types and architecture found in tissue, nor can they recapitulate cell-cell communication, biochemical cues, and other factors that are key to lung development and the pathogenesis of disease.
Dr. Antony’s pulmospheres resemble what have come to be known as organoids – 3D tissue cultures emanating from induced pluripotent stem cells (iPSC) or adult stem cells, in which multiple cell types self-organize, usually while suspended in natural or synthetic extracellular matrix (with or without a scaffold of some kind).
Lung-on-a-chip
In lung-on-a-chip (LOC) models, multiple cell types are seeded into miniature chambers, or “chips,” that contain networks of microfabricated channels designed to deliver and remove fluids, chemical cues, oxygen, and biomechanical forces. LOCs and other organs-on-chips – also called tissues-on-chips – can be continuously perfused and are highly structured and precisely controlled.
It’s the organs-on-chip model – or potential fusions of the organoid and organs-on-chip models – that will likely impact drug development. Almost 9 out of 10 investigational drugs fail in clinical trials – approximately 60% because of lack of efficacy and 30% because of toxicity. More reliable and predictive preclinical investigation is key, said Danilo A. Tagle, PhD, director of the Office of Special Initiatives in the National Center for Advancing Translational Sciences, of the National Institutes of Health.
“We have so many candidate drugs that go through preclinical safety testing, and that do relatively well in animal studies of efficacy, but then fail in clinical trials,” Dr. Tagle said. “We need better preclinical models.”
In its 10 years of life, the Tissue Chip for Drug Screening Program led by the NCATS – and funded by the NIH and Defense Advanced Research Projects Agency – has shown that organs-on-chips can be used to model disease and to predict both the safety and efficacy of clinical compounds, he said.
Lung organoids
Dr. Antony’s pulmospheres emanate not from stem cells but from primary tissue obtained from diseased lung. “We reconstitute the lung cells in single-cell suspensions, and then we allow them to come back together to form lung tissue,” she said. The pulmospheres take about 3 days to grow.
In a study published 5 years ago of pulmospheres of 20 patients with IPF and 9 control subjects, Dr. Antony and colleagues quantitated invasiveness and found “remarkable” differences in the invasiveness of IPF pulmospheres following exposure to the Food and Drug Administration–approved antifibrotic drugs nintedanib and pirfenidone. Some pulmospheres responded to one or the other drug, some to both, and two to neither – findings that Dr. Antony said offer hope for the goals of personalizing therapy and assessing new drugs.
Moreover, clinical disease progression correlated with invasiveness of the pulmospheres, showing that the organoid-like structures “do give us a model that [reflects] what’s happening in the clinical setting,” she said. (Lung tissue for the study was obtained via video-assisted thoracic surgery biopsy of IPF patients and from failed donor lung explants, but bronchoscopic forceps biopsies have become a useful method for obtaining tissue.)
The pulmospheres are not yet in clinical use, Dr. Antony said, but her lab is testing other fibrosis modifiers and continuing to use the model as a research tool.
One state to the east, at Vanderbilt University, Nashville, Tenn., Amanda Linkous, PhD, grows “branching lung organoids” and brain organoids to study the biology of small cell lung cancer (SCLC).
“We want to understand how [SCLC] cells change in the primary organ site, compared with metastatic sites like the brain. ... Are different transcription factors expressed [for instance] depending on where the tumor is growing?” said Dr. Linkous, scientific center manager of the National Cancer Institute’s Center for Systems Biology of SCLC at Vanderbilt. “Then we hope to start drug screening within the next year.”
Her lung organoids take shape from either human embryonic stem cells or iPSCs. Within commercially available media, the cells mature through several stages of differentiation, forming definitive endoderm, anterior foregut endoderm, and then circular lung bud structures – the latter of which are then placed into droplets of Matrigel, an extracellular matrix gel.
“In the Matrigel droplets, the lung bud cells will develop proximal and distal-like branching structures that express things like EPCAM, MUC1, SOX2, SOX9, and NKX2.1 – key markers that you should see in a more mature lung microenvironment,” she said. Tumor cells from established SCLC cell lines will then easily invade the branching lung organoid.
Dr. Linkous said she has found her organoid models highly reproducible and values their long-lasting nature – especially for future drug screening. “We can keep organoids going for months at a time,” said Dr. Linkous, a research associate professor in Vanderbilt’s department of biochemistry.
Like Dr. Antony, she envisions personalizing treatment in the future. “SCLC is a very heterogeneous tumor with many different cell types, so what works for one patient may not work well at all for another patient,” she said.
As recently as 5 years ago, “many in the cancer field would have been resistant to moving away from mouse models,” Dr. Linkous noted. “But preclinical studies in mice often don’t pan out in the clinic ... so we’re moving toward a human microenvironment to study human disease.”
The greatest challenge, Dr. Linkous and Dr. Antony said, lies in integrating both vascular blood flow and air into these models. “We just don’t have that combination as of yet,” Dr. Antony said.
LOC models
One of the first LOC models – and a galvanizing event for organs-on-chips more broadly – was a 1- to 2-cm–long model of the alveolar-capillary interface developed at the Wyss Institute for Biologically Inspired Engineering at Harvard Medical School, Boston.
Microchannels ran alongside a porous membrane coated with extracellular matrix, with alveolar cells seeded on one side and lung endothelial cells on the other side. When a vacuum was applied rhythmically to the channels, the cell-lined membrane stretched and relaxed, mimicking breathing movements.
Lead investigator Dongeun (Dan) Huh, PhD, then a postdoctoral student working with Donald E. Ingber, MD, PhD, founding director of the institute, ran tests showing that the model could reproduce organ-level responses to bacteria and inflammatory cytokines, as well as to silica nanoparticles. The widely cited paper was published in 2010 (Science. 2010;328[5986]:1662-8), and was followed by another study published in 2012 (Sci Transl Med. 2012;4[159]:159ra147) that used the LOC device to reproduce drug toxicity–induced pulmonary edema. “Here we were demonstrating for the first time that we could use the lung-on-chip to model human lung disease,” said Dr. Huh, who started his own lab at the University of Pennsylvania, Philadelphia, in 2013.
Since then, “as a field we’ve come a long way in modeling the complexity of human lung tissues ... with more advanced devices that can be used to mimic different parts of the lung and different processes, like immune responses in asthma and viral infections,” said Dr. Huh, “and with several studies using primary human cells taken from lung disease patients.”
Among Dr. Huh’s latest devices, built with NIH funding, is an asthma-on-a-chip device. Lung cells isolated from asthma patients are grown in a microfabricated device to create multilayered airway tissue, with airspace, that contains a fully differentiated epithelium and a vascularized stroma. “We can compress the entire engineered area of asthmatic human tissue in a lateral direction to mimic bronchoconstriction that happens during an asthma attack,” he said.
A paper soon to be published will describe how “abnormal pathophysiologic compressive forces due to bronchoconstriction in asthmatic lungs can make the lungs fibrotic, and how those mechanical forces also can induce increased vascularity,” said Dr. Huh, associate professor in the university’s department of bioengineering. “The increased vascular density can also change the phenotype of blood vessels in asthmatic airways.”
Dr. Huh also has an $8.3 million contract with the government’s Biomedical Advanced Research and Development Authority to study how chlorine gas damages lung tissues and identify biomarkers of chlorine gas–induced lung injury, with the goal of developing therapeutics.
Dr. Ingber and associates have developed a device modeling cystic fibrosis (CF). The chip is lined with primary human CF bronchial epithelial cells grown under an air-liquid interface and interfaced with primary lung microvascular endothelium that are exposed to fluid flow.
The chip reproduced, “with high fidelity, many of the structural, biochemical, and pathophysiological features of the human CF lung airway and its response to pathogens and circulating immune cells in vitro,” Dr. Ingber and colleagues reported (J Cyst Fibros. 2022;21:605-15).
Government investment in tissue chips
Efforts to commercialize organs-on-chip platforms and translate them for nonengineers have also picked in recent years. Several companies in the United States (including Emulate, a Wyss start-up) and in Europe now offer microengineered lung tissue models that can be used for research and drug testing. And some large pharmaceutical companies, said Dr. Tagle, have begun integrating tissue chip technology into their drug development programs.
The FDA, meanwhile, “has come to embrace the technology and see its promise,” Dr. Tagle said. An FDA pilot program announced in 2021 – called ISTAND (Innovative Science and Technology Approaches for New Drugs) – allows for tissue chip data to be submitted, as standalone data, for some drug applications.
The first 5 years of the government’s Tissue Chip for Drug Screening Program focused on safety and toxicity, and it “was successful in that model organ systems were able to capture the human response that [had been missed in] animal models,” he said.
For example, when a liver-tissue model was used to test several compounds that had passed animal testing for toxicity/safety but then failed in human clinical trials – killing some of the participants – the model showed a 100% sensitivity and a 87% specificity in predicting the human response, said Dr. Tagle, who recently coauthored a review on the future of organs-on-chips (Nature Reviews I Drug Discovery. 2021;20:345-61).
The second 5 years of the program, currently winding down, have focused on efficacy – the ability of organs-on-chip models to recreate the pathophysiology of chronic obstructive pulmonary disease, influenza, and other diseases, so that potential drugs can be assessed. In 2020, with extra support from the Coronavirus Aid, Relief, and Economic Security Act, NCATS funded academic labs to use organs-on-chip technology to evaluate SARS-CoV-2 and potential therapeutics.
Dr. Ingbar was one of the grantees. His team screened a number of FDA-approved drugs for potential repurposing using a bronchial-airway-on-a-chip and compared results with 2D model systems (Nat Biomed Eng. 2021;5:815-29). Amodiaquine inhibited infection in the 3D model and is now in phase 2 COVID trials. Several other drugs showed effectiveness in a 2D model but not in the chip.
Now, in a next phase of study at NCATS, coined Clinical Trials on a Chip, the center has awarded $35.5 million for investigators to test candidate therapies, often in parallel to ongoing clinical trials. The hope is that organs-on-chips can improve clinical trial design, from enrollment criteria and patient stratification to endpoints and the use of biomarkers. And in his lab, Dr. Huh is now engineering a shift to “organoids-on-a-chip” that combines the best features of each approach. “The idea,” he said, “is to grow organoids, and maintain the organoids in the microengineered systems where we can control their environment better ... and apply cues to allow them to develop into even more realistic tissues.”
Drs. Antony, Linkous, and Tagle reported no relevant disclosures. Dr. Huh is a co-founder of Vivodyne Inc, and owns shares in Vivodyne Inc. and Emulate Inc.
Tender Nonhealing Lesion on the Leg
The Diagnosis: Calciphylaxis
Calciphylaxis is a rare life-threatening condition that most often is seen in patients with end-stage renal disease at a rate of 35 per 10,000 chronic dialysis patients.1 It less commonly has been described in nonuremic patients. The exact incidence of nonuremic calciphylaxis is unknown, but multiple risk factors have been identified, such as alcoholic liver disease, primary hyperparathyroidism, connective tissue diseases, and underlying malignancies. Other less common risk factors include type 2 diabetes mellitus, hypercoagulable disorders, obesity, hypoalbuminemia, and warfarin/ corticosteroid use.2 However, most often no obvious triggers are identified.1
Regardless of the etiology, calciphylaxis is characterized by the calcification of blood vessels and connective tissues, leading to vessel injury, intimal fibrosis, and thrombosis, followed by ischemic necrosis of the skin and soft tissue. It is postulated that microvascular calcification occurs as an active cell-mediated process that depends on the balance between the promoters and inhibitors of calcification.1 In our patient, liver disease likely predisposed formation of calcification through the creation of an environment susceptible to vascular injury via decreased synthesis of proteins C and S.3 Synthesis of fetuin-A, a protein that acts as a circulating inhibitor of vascular ossification/calcification, also is decreased in calcification. Another inhibitor of calcification, matrix Gla protein, is unable to undergo activation through vitamin K–dependent carboxylation secondary to liver disease–induced vitamin K deficiency.3 Microvascular calcification without calciphylaxis may occur in other conditions such as type 2 diabetes mellitus. Therefore, clinicopathologic correlation is important in determining the diagnosis.
Calciphylaxis has a variety of clinical presentations depending on the stage of disease. It begins as a fixed, indurated, livedo reticularis–like plaque. The lesions become increasingly violaceous with intermixed areas of light blanched skin secondary to ischemia and then develop retiform pupura.4 Eventually, affected sites can become bullous and ulcerate or form a necrotic eschar. Severe pain is a cardinal feature throughout all stages.4 Lesions in nonuremic calciphylaxis most commonly are located in the central and/or proximal areas of the body.2
Clinical suspicion is essential for diagnosis. Skin biopsy is the standard method for confirmation in unclear cases. The classic histologic features include intravascular and extravascular calcification, microthrombosis, and fibrointimal hyperplasia of the small dermal and subcutaneous arteries and arterioles, leading to ischemia and intense septal panniculitis.1 Von Kossa immunostaining is used to increase the detection of calcium deposits (Figure 1).1 In addition to the classic changes, our case demonstrated a rare histologic variant with pseudoxanthoma elasticum (PXE)–like changes (Figure 2), which are thought to occur secondary to pathologic elastin fibrogenesis or increased proteolytic activity resulting in abnormal remodeling of the extracellular matrix in the setting of increased calcification of elastin fibers.5 Detection of PXE-like changes may be a helpful clue when specimens lack other characteristic signs.
Wound care, pain control, and addressing underlying causes are mainstays of therapy. Sodium thiosulfate, an antioxidant with vasodilatory properties that also inhibits adipocyte calcification and blocks the ability of adipocytes to induce calcification of vascular smooth-muscle cells, also is useful. Antibiotic prophylaxis is not indicated.1
Even with treatment, both uremic and nonuremic calciphylaxis have a dismal prognosis; 1-year mortality is approximately 50% to 60% and rises to 80% at 2 years.4 Lesion location affects prognosis, and more proximal lesions portend worse outcomes. In patients with both proximal and distal lesions, there is a 90% mortality rate within 1 year. Ulceration also portends worse outcomes, as the wounds often are resistant to healing and act as nidi for infection.4 Septicemia is the most common cause of death.1
Ecthyma gangrenosum is a cutaneous manifestation secondary to an infection most commonly associated with Pseudomonas aeruginosa.6 It often presents in immunocompromised patients with an underlying gramnegative septicemia.7 The clinical presentation initially begins with painless macules that rapidly progress into necrotic ulcers, usually accompanied by associated systemic symptoms such as fever, chills, and hypotension. Histopathology reveals numerous gram-negative rods around necrotic vessels.7
Idiopathic purpura fulminans is the rarest form of purpura fulminans. It is caused by autoantibody formation against protein S, resulting in protein S depletion and subsequent hypercoagulability.8 It usually occurs 7 to 10 days after the onset of a precipitating infection. Lesions begin as erythematous macules that progress within hours to painful, sharply defined areas of purpura and hemorrhagic cutaneous necrosis that may extend to deeper tissues.8 Secondary infection of gangrenous tissue may occur. Distribution usually is diffuse and signs of septic shock and disseminated intravascular coagulation usually are present.
Hughes syndrome, also known as antiphospholipid syndrome, is an acquired autoimmune disorder that manifests clinically as recurrent arterial or venous thrombosis.9 Cutaneous manifestations consist of livedo reticularis, arterial and venous ulcers, and superficial thrombophlebitis.10 Laboratory testing for antiphospholipid antibodies and obtaining a detailed history of the patient’s cardiovascular health are crucial for diagnosis.9
Necrotizing fasciitis typically begins as an inconspicuous superficial cutaneous infection that rapidly is transmitted to the fascia. Infection can spread along fascial planes for several days without affecting the overlying skin, leading to delayed diagnosis.11 The first signs to appear are disproportionate pain and a change in skin color to reddish-purple or bluish-gray. Next, the skin will become indurated, swollen, shiny, and more painful.11 Skin breakdown will begin in 3 to 5 days and is accompanied by bullae and cutaneous gangrene. The involved area becomes painless due to thrombosis of the small vessels that supply the superficial nerves.12 Septic shock ultimately will develop if untreated.
We present a rare case of nonuremic calciphylaxis. We encourage dermatologists to include calciphylaxis in the differential when evaluating any patient with a painful retiform rash or ulcerated eschar, even in the absence of renal disease.
- Nigwekar SU, Thadhani R, Brandenburg VM. Calciphylaxis. N Engl J Med. 2018;378:1704-1714.
- Nigwekar SU, Wolf M, Sterns RH, et al. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol. 2008;3:1139-1143.
- Sammour YM, Saleh HM, Gad MM, et al. Non-uremic calciphylaxis associated with alcoholic hepatitis: a case report. World J Hepatol. 2019;11:127-132.
- James WD, Elston DM, Treat J, et al, eds. Cutaneous vascular diseases. Andrews’ Diseases of the Skin: Clinical Dermatology. Elsevier; 2020:813-861.
- Nathoo RK, Harb JN, Auerbach J, et al. Pseudoxanthoma elasticum-like changes in nonuremic calciphylaxis: case series and brief review of a helpful diagnostic clue. J Cutan Pathol. 2017;44:1064-1069.
- Vaiman M, Lazarovitch T, Heller L, et al. Ecthyma gangrenosum and ecthyma-like lesions: review article. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2015;34:633-639.
- Greene SL, Su WP, Muller SA. Ecthyma gangrenosum: report of clinical, histopathologic, and bacteriologic aspects of eight cases. J Am Acad Dermatol. 1984;11(5 pt 1):781-787.
- Levin M, Eley BS, Louis J, et al. Postinfectious purpura fulminans caused by an autoantibody directed against protein S. J Pediatr. 1995;127:355-363.
- Hughes G. Hughes syndrome: the antiphospholipid syndrome—a clinical overview. Clin Rev Allergy Immunol. 2007;32:3-12.
- Chang Y, Dabiri G, Damstetter E, et al. Coagulation disorders and their cutaneous presentations: pathophysiology. J Am Acad Dermatol. 2016;74:783-792; quiz 793-794.
- Fais P, Viero A, Viel G, et al. Necrotizing fasciitis: case series and review of the literature on clinical and medico-legal diagnostic challenges. Int J Legal Med. 2018;132:1357-1366.
- Brook I. Microbiology and management of soft tissue and muscle infections. Int J Surg Lond Engl. 2008;6:328-338.
The Diagnosis: Calciphylaxis
Calciphylaxis is a rare life-threatening condition that most often is seen in patients with end-stage renal disease at a rate of 35 per 10,000 chronic dialysis patients.1 It less commonly has been described in nonuremic patients. The exact incidence of nonuremic calciphylaxis is unknown, but multiple risk factors have been identified, such as alcoholic liver disease, primary hyperparathyroidism, connective tissue diseases, and underlying malignancies. Other less common risk factors include type 2 diabetes mellitus, hypercoagulable disorders, obesity, hypoalbuminemia, and warfarin/ corticosteroid use.2 However, most often no obvious triggers are identified.1
Regardless of the etiology, calciphylaxis is characterized by the calcification of blood vessels and connective tissues, leading to vessel injury, intimal fibrosis, and thrombosis, followed by ischemic necrosis of the skin and soft tissue. It is postulated that microvascular calcification occurs as an active cell-mediated process that depends on the balance between the promoters and inhibitors of calcification.1 In our patient, liver disease likely predisposed formation of calcification through the creation of an environment susceptible to vascular injury via decreased synthesis of proteins C and S.3 Synthesis of fetuin-A, a protein that acts as a circulating inhibitor of vascular ossification/calcification, also is decreased in calcification. Another inhibitor of calcification, matrix Gla protein, is unable to undergo activation through vitamin K–dependent carboxylation secondary to liver disease–induced vitamin K deficiency.3 Microvascular calcification without calciphylaxis may occur in other conditions such as type 2 diabetes mellitus. Therefore, clinicopathologic correlation is important in determining the diagnosis.
Calciphylaxis has a variety of clinical presentations depending on the stage of disease. It begins as a fixed, indurated, livedo reticularis–like plaque. The lesions become increasingly violaceous with intermixed areas of light blanched skin secondary to ischemia and then develop retiform pupura.4 Eventually, affected sites can become bullous and ulcerate or form a necrotic eschar. Severe pain is a cardinal feature throughout all stages.4 Lesions in nonuremic calciphylaxis most commonly are located in the central and/or proximal areas of the body.2
Clinical suspicion is essential for diagnosis. Skin biopsy is the standard method for confirmation in unclear cases. The classic histologic features include intravascular and extravascular calcification, microthrombosis, and fibrointimal hyperplasia of the small dermal and subcutaneous arteries and arterioles, leading to ischemia and intense septal panniculitis.1 Von Kossa immunostaining is used to increase the detection of calcium deposits (Figure 1).1 In addition to the classic changes, our case demonstrated a rare histologic variant with pseudoxanthoma elasticum (PXE)–like changes (Figure 2), which are thought to occur secondary to pathologic elastin fibrogenesis or increased proteolytic activity resulting in abnormal remodeling of the extracellular matrix in the setting of increased calcification of elastin fibers.5 Detection of PXE-like changes may be a helpful clue when specimens lack other characteristic signs.
Wound care, pain control, and addressing underlying causes are mainstays of therapy. Sodium thiosulfate, an antioxidant with vasodilatory properties that also inhibits adipocyte calcification and blocks the ability of adipocytes to induce calcification of vascular smooth-muscle cells, also is useful. Antibiotic prophylaxis is not indicated.1
Even with treatment, both uremic and nonuremic calciphylaxis have a dismal prognosis; 1-year mortality is approximately 50% to 60% and rises to 80% at 2 years.4 Lesion location affects prognosis, and more proximal lesions portend worse outcomes. In patients with both proximal and distal lesions, there is a 90% mortality rate within 1 year. Ulceration also portends worse outcomes, as the wounds often are resistant to healing and act as nidi for infection.4 Septicemia is the most common cause of death.1
Ecthyma gangrenosum is a cutaneous manifestation secondary to an infection most commonly associated with Pseudomonas aeruginosa.6 It often presents in immunocompromised patients with an underlying gramnegative septicemia.7 The clinical presentation initially begins with painless macules that rapidly progress into necrotic ulcers, usually accompanied by associated systemic symptoms such as fever, chills, and hypotension. Histopathology reveals numerous gram-negative rods around necrotic vessels.7
Idiopathic purpura fulminans is the rarest form of purpura fulminans. It is caused by autoantibody formation against protein S, resulting in protein S depletion and subsequent hypercoagulability.8 It usually occurs 7 to 10 days after the onset of a precipitating infection. Lesions begin as erythematous macules that progress within hours to painful, sharply defined areas of purpura and hemorrhagic cutaneous necrosis that may extend to deeper tissues.8 Secondary infection of gangrenous tissue may occur. Distribution usually is diffuse and signs of septic shock and disseminated intravascular coagulation usually are present.
Hughes syndrome, also known as antiphospholipid syndrome, is an acquired autoimmune disorder that manifests clinically as recurrent arterial or venous thrombosis.9 Cutaneous manifestations consist of livedo reticularis, arterial and venous ulcers, and superficial thrombophlebitis.10 Laboratory testing for antiphospholipid antibodies and obtaining a detailed history of the patient’s cardiovascular health are crucial for diagnosis.9
Necrotizing fasciitis typically begins as an inconspicuous superficial cutaneous infection that rapidly is transmitted to the fascia. Infection can spread along fascial planes for several days without affecting the overlying skin, leading to delayed diagnosis.11 The first signs to appear are disproportionate pain and a change in skin color to reddish-purple or bluish-gray. Next, the skin will become indurated, swollen, shiny, and more painful.11 Skin breakdown will begin in 3 to 5 days and is accompanied by bullae and cutaneous gangrene. The involved area becomes painless due to thrombosis of the small vessels that supply the superficial nerves.12 Septic shock ultimately will develop if untreated.
We present a rare case of nonuremic calciphylaxis. We encourage dermatologists to include calciphylaxis in the differential when evaluating any patient with a painful retiform rash or ulcerated eschar, even in the absence of renal disease.
The Diagnosis: Calciphylaxis
Calciphylaxis is a rare life-threatening condition that most often is seen in patients with end-stage renal disease at a rate of 35 per 10,000 chronic dialysis patients.1 It less commonly has been described in nonuremic patients. The exact incidence of nonuremic calciphylaxis is unknown, but multiple risk factors have been identified, such as alcoholic liver disease, primary hyperparathyroidism, connective tissue diseases, and underlying malignancies. Other less common risk factors include type 2 diabetes mellitus, hypercoagulable disorders, obesity, hypoalbuminemia, and warfarin/ corticosteroid use.2 However, most often no obvious triggers are identified.1
Regardless of the etiology, calciphylaxis is characterized by the calcification of blood vessels and connective tissues, leading to vessel injury, intimal fibrosis, and thrombosis, followed by ischemic necrosis of the skin and soft tissue. It is postulated that microvascular calcification occurs as an active cell-mediated process that depends on the balance between the promoters and inhibitors of calcification.1 In our patient, liver disease likely predisposed formation of calcification through the creation of an environment susceptible to vascular injury via decreased synthesis of proteins C and S.3 Synthesis of fetuin-A, a protein that acts as a circulating inhibitor of vascular ossification/calcification, also is decreased in calcification. Another inhibitor of calcification, matrix Gla protein, is unable to undergo activation through vitamin K–dependent carboxylation secondary to liver disease–induced vitamin K deficiency.3 Microvascular calcification without calciphylaxis may occur in other conditions such as type 2 diabetes mellitus. Therefore, clinicopathologic correlation is important in determining the diagnosis.
Calciphylaxis has a variety of clinical presentations depending on the stage of disease. It begins as a fixed, indurated, livedo reticularis–like plaque. The lesions become increasingly violaceous with intermixed areas of light blanched skin secondary to ischemia and then develop retiform pupura.4 Eventually, affected sites can become bullous and ulcerate or form a necrotic eschar. Severe pain is a cardinal feature throughout all stages.4 Lesions in nonuremic calciphylaxis most commonly are located in the central and/or proximal areas of the body.2
Clinical suspicion is essential for diagnosis. Skin biopsy is the standard method for confirmation in unclear cases. The classic histologic features include intravascular and extravascular calcification, microthrombosis, and fibrointimal hyperplasia of the small dermal and subcutaneous arteries and arterioles, leading to ischemia and intense septal panniculitis.1 Von Kossa immunostaining is used to increase the detection of calcium deposits (Figure 1).1 In addition to the classic changes, our case demonstrated a rare histologic variant with pseudoxanthoma elasticum (PXE)–like changes (Figure 2), which are thought to occur secondary to pathologic elastin fibrogenesis or increased proteolytic activity resulting in abnormal remodeling of the extracellular matrix in the setting of increased calcification of elastin fibers.5 Detection of PXE-like changes may be a helpful clue when specimens lack other characteristic signs.
Wound care, pain control, and addressing underlying causes are mainstays of therapy. Sodium thiosulfate, an antioxidant with vasodilatory properties that also inhibits adipocyte calcification and blocks the ability of adipocytes to induce calcification of vascular smooth-muscle cells, also is useful. Antibiotic prophylaxis is not indicated.1
Even with treatment, both uremic and nonuremic calciphylaxis have a dismal prognosis; 1-year mortality is approximately 50% to 60% and rises to 80% at 2 years.4 Lesion location affects prognosis, and more proximal lesions portend worse outcomes. In patients with both proximal and distal lesions, there is a 90% mortality rate within 1 year. Ulceration also portends worse outcomes, as the wounds often are resistant to healing and act as nidi for infection.4 Septicemia is the most common cause of death.1
Ecthyma gangrenosum is a cutaneous manifestation secondary to an infection most commonly associated with Pseudomonas aeruginosa.6 It often presents in immunocompromised patients with an underlying gramnegative septicemia.7 The clinical presentation initially begins with painless macules that rapidly progress into necrotic ulcers, usually accompanied by associated systemic symptoms such as fever, chills, and hypotension. Histopathology reveals numerous gram-negative rods around necrotic vessels.7
Idiopathic purpura fulminans is the rarest form of purpura fulminans. It is caused by autoantibody formation against protein S, resulting in protein S depletion and subsequent hypercoagulability.8 It usually occurs 7 to 10 days after the onset of a precipitating infection. Lesions begin as erythematous macules that progress within hours to painful, sharply defined areas of purpura and hemorrhagic cutaneous necrosis that may extend to deeper tissues.8 Secondary infection of gangrenous tissue may occur. Distribution usually is diffuse and signs of septic shock and disseminated intravascular coagulation usually are present.
Hughes syndrome, also known as antiphospholipid syndrome, is an acquired autoimmune disorder that manifests clinically as recurrent arterial or venous thrombosis.9 Cutaneous manifestations consist of livedo reticularis, arterial and venous ulcers, and superficial thrombophlebitis.10 Laboratory testing for antiphospholipid antibodies and obtaining a detailed history of the patient’s cardiovascular health are crucial for diagnosis.9
Necrotizing fasciitis typically begins as an inconspicuous superficial cutaneous infection that rapidly is transmitted to the fascia. Infection can spread along fascial planes for several days without affecting the overlying skin, leading to delayed diagnosis.11 The first signs to appear are disproportionate pain and a change in skin color to reddish-purple or bluish-gray. Next, the skin will become indurated, swollen, shiny, and more painful.11 Skin breakdown will begin in 3 to 5 days and is accompanied by bullae and cutaneous gangrene. The involved area becomes painless due to thrombosis of the small vessels that supply the superficial nerves.12 Septic shock ultimately will develop if untreated.
We present a rare case of nonuremic calciphylaxis. We encourage dermatologists to include calciphylaxis in the differential when evaluating any patient with a painful retiform rash or ulcerated eschar, even in the absence of renal disease.
- Nigwekar SU, Thadhani R, Brandenburg VM. Calciphylaxis. N Engl J Med. 2018;378:1704-1714.
- Nigwekar SU, Wolf M, Sterns RH, et al. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol. 2008;3:1139-1143.
- Sammour YM, Saleh HM, Gad MM, et al. Non-uremic calciphylaxis associated with alcoholic hepatitis: a case report. World J Hepatol. 2019;11:127-132.
- James WD, Elston DM, Treat J, et al, eds. Cutaneous vascular diseases. Andrews’ Diseases of the Skin: Clinical Dermatology. Elsevier; 2020:813-861.
- Nathoo RK, Harb JN, Auerbach J, et al. Pseudoxanthoma elasticum-like changes in nonuremic calciphylaxis: case series and brief review of a helpful diagnostic clue. J Cutan Pathol. 2017;44:1064-1069.
- Vaiman M, Lazarovitch T, Heller L, et al. Ecthyma gangrenosum and ecthyma-like lesions: review article. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2015;34:633-639.
- Greene SL, Su WP, Muller SA. Ecthyma gangrenosum: report of clinical, histopathologic, and bacteriologic aspects of eight cases. J Am Acad Dermatol. 1984;11(5 pt 1):781-787.
- Levin M, Eley BS, Louis J, et al. Postinfectious purpura fulminans caused by an autoantibody directed against protein S. J Pediatr. 1995;127:355-363.
- Hughes G. Hughes syndrome: the antiphospholipid syndrome—a clinical overview. Clin Rev Allergy Immunol. 2007;32:3-12.
- Chang Y, Dabiri G, Damstetter E, et al. Coagulation disorders and their cutaneous presentations: pathophysiology. J Am Acad Dermatol. 2016;74:783-792; quiz 793-794.
- Fais P, Viero A, Viel G, et al. Necrotizing fasciitis: case series and review of the literature on clinical and medico-legal diagnostic challenges. Int J Legal Med. 2018;132:1357-1366.
- Brook I. Microbiology and management of soft tissue and muscle infections. Int J Surg Lond Engl. 2008;6:328-338.
- Nigwekar SU, Thadhani R, Brandenburg VM. Calciphylaxis. N Engl J Med. 2018;378:1704-1714.
- Nigwekar SU, Wolf M, Sterns RH, et al. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol. 2008;3:1139-1143.
- Sammour YM, Saleh HM, Gad MM, et al. Non-uremic calciphylaxis associated with alcoholic hepatitis: a case report. World J Hepatol. 2019;11:127-132.
- James WD, Elston DM, Treat J, et al, eds. Cutaneous vascular diseases. Andrews’ Diseases of the Skin: Clinical Dermatology. Elsevier; 2020:813-861.
- Nathoo RK, Harb JN, Auerbach J, et al. Pseudoxanthoma elasticum-like changes in nonuremic calciphylaxis: case series and brief review of a helpful diagnostic clue. J Cutan Pathol. 2017;44:1064-1069.
- Vaiman M, Lazarovitch T, Heller L, et al. Ecthyma gangrenosum and ecthyma-like lesions: review article. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2015;34:633-639.
- Greene SL, Su WP, Muller SA. Ecthyma gangrenosum: report of clinical, histopathologic, and bacteriologic aspects of eight cases. J Am Acad Dermatol. 1984;11(5 pt 1):781-787.
- Levin M, Eley BS, Louis J, et al. Postinfectious purpura fulminans caused by an autoantibody directed against protein S. J Pediatr. 1995;127:355-363.
- Hughes G. Hughes syndrome: the antiphospholipid syndrome—a clinical overview. Clin Rev Allergy Immunol. 2007;32:3-12.
- Chang Y, Dabiri G, Damstetter E, et al. Coagulation disorders and their cutaneous presentations: pathophysiology. J Am Acad Dermatol. 2016;74:783-792; quiz 793-794.
- Fais P, Viero A, Viel G, et al. Necrotizing fasciitis: case series and review of the literature on clinical and medico-legal diagnostic challenges. Int J Legal Med. 2018;132:1357-1366.
- Brook I. Microbiology and management of soft tissue and muscle infections. Int J Surg Lond Engl. 2008;6:328-338.
A 50-year-old woman presented to our dermatology clinic with an exquisitely tender, nonhealing lesion on the left leg of 2 weeks’ duration that began as a small red-purplish spot. She applied a triple antibiotic ointment and wrapped the area with gauze daily but reported that it continued to enlarge and darken in color before forming a “scab.” She noted occasional seropurulent discharge and denied any trauma or new exposures to the area. She was seen at a local emergency department 3 days prior to presentation and was prescribed oral clindamycin for suspected cellulitis, but she denied any improvement with the initiation of antibiotics. Her medical history was notable for obesity, depression, hypothyroidism, and liver disease secondary to alcohol use disorder. She reported that she drank a pint of vodka daily. Her medications included pantoprazole, spironolactone, bumetanide, citalopram, levothyroxine, naltrexone, tramadol, and a multivitamin. Physical examination revealed violaceous mottling with areas of superficial erythema and ulceration with necrotic eschars on the proximal left thigh that were extremely painful. A biopsy was obtained for confirmation of diagnosis, but the patient died before the results were returned.
Increasing primary care doctors’ knowledge of IPF could speed up diagnoses, suggests white paper
The nonspecific nature of the symptoms of idiopathic pulmonary fibrosis (IPF) especially in early stages, and the relative rarity of IPF compared with other conditions that have similar symptoms, may contribute to a delay in diagnosis in the primary care setting, wrote Daniel F. Dilling, MD, of Loyola University Chicago, Maywood, Ill., and colleagues in Chest: Clinical Perspectives (Dilling et al. State of Practice: Factors Driving Diagnostic Delays in Idiopathic Pulmonary Fibrosis. Chest. 2022).
“We have learned over and over again through research, and also through talking with our own patients with IPF, that there is often a long lag between the first signs of the disease and a diagnosis of IPF,” corresponding author Dr. Dilling said in an interview.
“Even some pulmonary specialists can be uncertain about how to approach the diagnosis when a CT scan or other test first suggests the possibility; this can cost a patient precious time, as being on drug therapy earlier can result in preservation of lung function,” he said. “By sounding the alarm bell with this paper, we hope to promote awareness and education/training within the primary care community as well as the pulmonary community, and also to make all of them aware of the possibility of referral to specialty ILD [interstitial lung disease] centers when desired and possible,” he added.
The researchers conducted a pair of online surveys to inform the development of improving education on IPF among primary care providers.
In the white paper, which can be accessed online, the authors reported results of the surveys. One included 100 general pulmonologists and the other included 306 primary care physicians (156 practiced family physicians and 150 practiced general internal medicine). The data were collected between April 11, 2022, and May 16, 2022. Participants were asked to respond to a patient case scenario of a 55-year-old woman with nonspecific symptoms such as shortness of breath on moderate exertion, cough, exhaustion, and trouble sleeping.
The PCPs were most likely to evaluate the patient for a cardiac condition (46%), 25% would evaluate for chronic obstructive pulmonary disease (COPD), and 23% for asthma. More than half (58%) ranked progressive fibrosing ILD as one of their bottom two diagnoses.
A total of 87% of PCPs said they would begin a diagnostic workup to evaluate symptoms if the patient had no preexisting respiratory disease, compared with 61% for patients with a respiratory diagnosis.
Although 93% of PCPs cited a chest x-ray as part of the initial patient workup, fewer than half said they would order an echocardiogram, spirometry, or pulmonary function test (PFT), and 11% said they would include diffusion capacity testing in the initial workup.
In addition, PCPs were less likely to ask patients about issues that might prompt an IPF diagnosis, such as exposures to agents through work, hobbies, the environment, or comorbidities.
In the pulmonology survey, more than 75% of respondents cited patient history, high-resolution tomography scan, serologic testing, and review for autoimmune disease symptoms as first steps in a diagnostic response to patients with suspected IPF.
Differences between PCPs’ and pulmonolgists’ responses
Both PCPs and pulmonologists responded to several questions to assess knowledge and opinion gaps related to IPF. Overall, pulmonologists were more likely than PCPs to cite both imaging and testing issues and waiting 6-8 weeks after symptom onset before imaging as contributing factors to diagnostic delays.
PCPs more often expressed beliefs that delayed diagnosis had little impact on a patient with IPF, and that the treatments may be worse than the disease.
Dr. Dilling said he was not surprised by the survey findings, as similar clues about the underdiagnosis of IPF have surfaced in prior studies.
“We need to get the word out to primary care physicians, to pulmonary physicians, and even to the public, that idiopathic pulmonary fibrosis and other forms of interstitial lung disease are out there and prevalent, and that making the right diagnosis in a timely way can lead to better outcomes for patients,” he said.
The take-home message for primary care is to think outside the COPD box, said Dr. Dilling. “Just because someone has shortness of breath or cough and used to smoke does not automatically mean that they have COPD,” he emphasized. “Listen carefully for crackles (rales) on exam. Get spirometry or PFTs before you secure the diagnosis of COPD, or else you will be missing all of your cases of pulmonary fibrosis; think of pulmonary fibrosis and use imaging to help guide your diagnosis,” he said.
The authors suggested several education goals for PCPs, including establishing the importance of early evaluation, outlining the correct approach to a patient workup, encouraging prompt referral, and empowering PCPs as part of the team approach to IPF patients’ care. For pulmonologists, only 11% of those surveyed said they were aware of the latest developments in antifibrotic research, and education efforts might include information about drug pipelines and clinical trials, as well as technology.
Looking ahead, “We need to better understand how to find the pulmonary fibrosis in the community,” Dr. Dilling said. This understanding may come in part from greater education and awareness, he noted. However, eventually there may be ways to enhance the reading of PFTs and of CT scans through artificial intelligence technologies that would not only prompt clinicians to recognize what they are seeing, but would prompt them to refer and send the patient on the correct diagnostic path as soon as possible, he added.
Key message: Include ILD in differential diagnosis of patients with shortness of breath and/or cough
Advances in diagnostics and therapies for interstitial lung disease can take time to be absorbed and adopted, and patients with ILD and pulmonologists caring for ILD, specifically IPF, continue to report delays in diagnosis and therapy, said Krishna Thavarajah, MD, a pulmonologist at Henry Ford Hospital, Detroit, Mich., in an interview.
The current study findings of the time to diagnosis and the approach to patient workups echo her own clinical experience, Dr. Thavarajah said. “There is a delay in IPF diagnosis as physicians look to more common diagnoses, such as cardiac disease or chronic obstructive pulmonary disease, prior to pursuit of additional workup, and the attitude toward treatment has, in some ways, lagged behind advances in therapy, including timing and feasibility of therapy for IPF,” she said.
The key message for primary care physicians is to include ILD in the differential diagnosis of patients with shortness of breath and/or cough, especially if the initial cardiac and pulmonary test (meaning at least a chest x-ray and pulmonary function tests, including a diffusion capacity) are not pointing to an alternative cause within 3 months of presentation, Dr. Thavarajah said.
Once IPF is diagnosed, primary care clinicians should know that there are FDA-approved therapies that improve survival, said Dr. Thavarajah. “There are identifiable and treatable comorbid conditions,” she added. “The statement of ‘time lost is lung lost’ sums up the care of an IPF patient; partnerships between primary care clinicians, pulmonologists, and referral centers can provide the patient multiple levels of support with quality-of-life interventions, treatments, and also clinical trials, delivered by a team of providers,” she said.
In the wake of the current study, more research is needed with outcome studies regarding educational interventions targeting primary care and pulmonologists on appropriate workup, timing of workup, and current therapy for IPF patients, she added.
The white paper received no outside funding. The authors and Dr. Thavarajah had no financial conflicts to disclose.
The nonspecific nature of the symptoms of idiopathic pulmonary fibrosis (IPF) especially in early stages, and the relative rarity of IPF compared with other conditions that have similar symptoms, may contribute to a delay in diagnosis in the primary care setting, wrote Daniel F. Dilling, MD, of Loyola University Chicago, Maywood, Ill., and colleagues in Chest: Clinical Perspectives (Dilling et al. State of Practice: Factors Driving Diagnostic Delays in Idiopathic Pulmonary Fibrosis. Chest. 2022).
“We have learned over and over again through research, and also through talking with our own patients with IPF, that there is often a long lag between the first signs of the disease and a diagnosis of IPF,” corresponding author Dr. Dilling said in an interview.
“Even some pulmonary specialists can be uncertain about how to approach the diagnosis when a CT scan or other test first suggests the possibility; this can cost a patient precious time, as being on drug therapy earlier can result in preservation of lung function,” he said. “By sounding the alarm bell with this paper, we hope to promote awareness and education/training within the primary care community as well as the pulmonary community, and also to make all of them aware of the possibility of referral to specialty ILD [interstitial lung disease] centers when desired and possible,” he added.
The researchers conducted a pair of online surveys to inform the development of improving education on IPF among primary care providers.
In the white paper, which can be accessed online, the authors reported results of the surveys. One included 100 general pulmonologists and the other included 306 primary care physicians (156 practiced family physicians and 150 practiced general internal medicine). The data were collected between April 11, 2022, and May 16, 2022. Participants were asked to respond to a patient case scenario of a 55-year-old woman with nonspecific symptoms such as shortness of breath on moderate exertion, cough, exhaustion, and trouble sleeping.
The PCPs were most likely to evaluate the patient for a cardiac condition (46%), 25% would evaluate for chronic obstructive pulmonary disease (COPD), and 23% for asthma. More than half (58%) ranked progressive fibrosing ILD as one of their bottom two diagnoses.
A total of 87% of PCPs said they would begin a diagnostic workup to evaluate symptoms if the patient had no preexisting respiratory disease, compared with 61% for patients with a respiratory diagnosis.
Although 93% of PCPs cited a chest x-ray as part of the initial patient workup, fewer than half said they would order an echocardiogram, spirometry, or pulmonary function test (PFT), and 11% said they would include diffusion capacity testing in the initial workup.
In addition, PCPs were less likely to ask patients about issues that might prompt an IPF diagnosis, such as exposures to agents through work, hobbies, the environment, or comorbidities.
In the pulmonology survey, more than 75% of respondents cited patient history, high-resolution tomography scan, serologic testing, and review for autoimmune disease symptoms as first steps in a diagnostic response to patients with suspected IPF.
Differences between PCPs’ and pulmonolgists’ responses
Both PCPs and pulmonologists responded to several questions to assess knowledge and opinion gaps related to IPF. Overall, pulmonologists were more likely than PCPs to cite both imaging and testing issues and waiting 6-8 weeks after symptom onset before imaging as contributing factors to diagnostic delays.
PCPs more often expressed beliefs that delayed diagnosis had little impact on a patient with IPF, and that the treatments may be worse than the disease.
Dr. Dilling said he was not surprised by the survey findings, as similar clues about the underdiagnosis of IPF have surfaced in prior studies.
“We need to get the word out to primary care physicians, to pulmonary physicians, and even to the public, that idiopathic pulmonary fibrosis and other forms of interstitial lung disease are out there and prevalent, and that making the right diagnosis in a timely way can lead to better outcomes for patients,” he said.
The take-home message for primary care is to think outside the COPD box, said Dr. Dilling. “Just because someone has shortness of breath or cough and used to smoke does not automatically mean that they have COPD,” he emphasized. “Listen carefully for crackles (rales) on exam. Get spirometry or PFTs before you secure the diagnosis of COPD, or else you will be missing all of your cases of pulmonary fibrosis; think of pulmonary fibrosis and use imaging to help guide your diagnosis,” he said.
The authors suggested several education goals for PCPs, including establishing the importance of early evaluation, outlining the correct approach to a patient workup, encouraging prompt referral, and empowering PCPs as part of the team approach to IPF patients’ care. For pulmonologists, only 11% of those surveyed said they were aware of the latest developments in antifibrotic research, and education efforts might include information about drug pipelines and clinical trials, as well as technology.
Looking ahead, “We need to better understand how to find the pulmonary fibrosis in the community,” Dr. Dilling said. This understanding may come in part from greater education and awareness, he noted. However, eventually there may be ways to enhance the reading of PFTs and of CT scans through artificial intelligence technologies that would not only prompt clinicians to recognize what they are seeing, but would prompt them to refer and send the patient on the correct diagnostic path as soon as possible, he added.
Key message: Include ILD in differential diagnosis of patients with shortness of breath and/or cough
Advances in diagnostics and therapies for interstitial lung disease can take time to be absorbed and adopted, and patients with ILD and pulmonologists caring for ILD, specifically IPF, continue to report delays in diagnosis and therapy, said Krishna Thavarajah, MD, a pulmonologist at Henry Ford Hospital, Detroit, Mich., in an interview.
The current study findings of the time to diagnosis and the approach to patient workups echo her own clinical experience, Dr. Thavarajah said. “There is a delay in IPF diagnosis as physicians look to more common diagnoses, such as cardiac disease or chronic obstructive pulmonary disease, prior to pursuit of additional workup, and the attitude toward treatment has, in some ways, lagged behind advances in therapy, including timing and feasibility of therapy for IPF,” she said.
The key message for primary care physicians is to include ILD in the differential diagnosis of patients with shortness of breath and/or cough, especially if the initial cardiac and pulmonary test (meaning at least a chest x-ray and pulmonary function tests, including a diffusion capacity) are not pointing to an alternative cause within 3 months of presentation, Dr. Thavarajah said.
Once IPF is diagnosed, primary care clinicians should know that there are FDA-approved therapies that improve survival, said Dr. Thavarajah. “There are identifiable and treatable comorbid conditions,” she added. “The statement of ‘time lost is lung lost’ sums up the care of an IPF patient; partnerships between primary care clinicians, pulmonologists, and referral centers can provide the patient multiple levels of support with quality-of-life interventions, treatments, and also clinical trials, delivered by a team of providers,” she said.
In the wake of the current study, more research is needed with outcome studies regarding educational interventions targeting primary care and pulmonologists on appropriate workup, timing of workup, and current therapy for IPF patients, she added.
The white paper received no outside funding. The authors and Dr. Thavarajah had no financial conflicts to disclose.
The nonspecific nature of the symptoms of idiopathic pulmonary fibrosis (IPF) especially in early stages, and the relative rarity of IPF compared with other conditions that have similar symptoms, may contribute to a delay in diagnosis in the primary care setting, wrote Daniel F. Dilling, MD, of Loyola University Chicago, Maywood, Ill., and colleagues in Chest: Clinical Perspectives (Dilling et al. State of Practice: Factors Driving Diagnostic Delays in Idiopathic Pulmonary Fibrosis. Chest. 2022).
“We have learned over and over again through research, and also through talking with our own patients with IPF, that there is often a long lag between the first signs of the disease and a diagnosis of IPF,” corresponding author Dr. Dilling said in an interview.
“Even some pulmonary specialists can be uncertain about how to approach the diagnosis when a CT scan or other test first suggests the possibility; this can cost a patient precious time, as being on drug therapy earlier can result in preservation of lung function,” he said. “By sounding the alarm bell with this paper, we hope to promote awareness and education/training within the primary care community as well as the pulmonary community, and also to make all of them aware of the possibility of referral to specialty ILD [interstitial lung disease] centers when desired and possible,” he added.
The researchers conducted a pair of online surveys to inform the development of improving education on IPF among primary care providers.
In the white paper, which can be accessed online, the authors reported results of the surveys. One included 100 general pulmonologists and the other included 306 primary care physicians (156 practiced family physicians and 150 practiced general internal medicine). The data were collected between April 11, 2022, and May 16, 2022. Participants were asked to respond to a patient case scenario of a 55-year-old woman with nonspecific symptoms such as shortness of breath on moderate exertion, cough, exhaustion, and trouble sleeping.
The PCPs were most likely to evaluate the patient for a cardiac condition (46%), 25% would evaluate for chronic obstructive pulmonary disease (COPD), and 23% for asthma. More than half (58%) ranked progressive fibrosing ILD as one of their bottom two diagnoses.
A total of 87% of PCPs said they would begin a diagnostic workup to evaluate symptoms if the patient had no preexisting respiratory disease, compared with 61% for patients with a respiratory diagnosis.
Although 93% of PCPs cited a chest x-ray as part of the initial patient workup, fewer than half said they would order an echocardiogram, spirometry, or pulmonary function test (PFT), and 11% said they would include diffusion capacity testing in the initial workup.
In addition, PCPs were less likely to ask patients about issues that might prompt an IPF diagnosis, such as exposures to agents through work, hobbies, the environment, or comorbidities.
In the pulmonology survey, more than 75% of respondents cited patient history, high-resolution tomography scan, serologic testing, and review for autoimmune disease symptoms as first steps in a diagnostic response to patients with suspected IPF.
Differences between PCPs’ and pulmonolgists’ responses
Both PCPs and pulmonologists responded to several questions to assess knowledge and opinion gaps related to IPF. Overall, pulmonologists were more likely than PCPs to cite both imaging and testing issues and waiting 6-8 weeks after symptom onset before imaging as contributing factors to diagnostic delays.
PCPs more often expressed beliefs that delayed diagnosis had little impact on a patient with IPF, and that the treatments may be worse than the disease.
Dr. Dilling said he was not surprised by the survey findings, as similar clues about the underdiagnosis of IPF have surfaced in prior studies.
“We need to get the word out to primary care physicians, to pulmonary physicians, and even to the public, that idiopathic pulmonary fibrosis and other forms of interstitial lung disease are out there and prevalent, and that making the right diagnosis in a timely way can lead to better outcomes for patients,” he said.
The take-home message for primary care is to think outside the COPD box, said Dr. Dilling. “Just because someone has shortness of breath or cough and used to smoke does not automatically mean that they have COPD,” he emphasized. “Listen carefully for crackles (rales) on exam. Get spirometry or PFTs before you secure the diagnosis of COPD, or else you will be missing all of your cases of pulmonary fibrosis; think of pulmonary fibrosis and use imaging to help guide your diagnosis,” he said.
The authors suggested several education goals for PCPs, including establishing the importance of early evaluation, outlining the correct approach to a patient workup, encouraging prompt referral, and empowering PCPs as part of the team approach to IPF patients’ care. For pulmonologists, only 11% of those surveyed said they were aware of the latest developments in antifibrotic research, and education efforts might include information about drug pipelines and clinical trials, as well as technology.
Looking ahead, “We need to better understand how to find the pulmonary fibrosis in the community,” Dr. Dilling said. This understanding may come in part from greater education and awareness, he noted. However, eventually there may be ways to enhance the reading of PFTs and of CT scans through artificial intelligence technologies that would not only prompt clinicians to recognize what they are seeing, but would prompt them to refer and send the patient on the correct diagnostic path as soon as possible, he added.
Key message: Include ILD in differential diagnosis of patients with shortness of breath and/or cough
Advances in diagnostics and therapies for interstitial lung disease can take time to be absorbed and adopted, and patients with ILD and pulmonologists caring for ILD, specifically IPF, continue to report delays in diagnosis and therapy, said Krishna Thavarajah, MD, a pulmonologist at Henry Ford Hospital, Detroit, Mich., in an interview.
The current study findings of the time to diagnosis and the approach to patient workups echo her own clinical experience, Dr. Thavarajah said. “There is a delay in IPF diagnosis as physicians look to more common diagnoses, such as cardiac disease or chronic obstructive pulmonary disease, prior to pursuit of additional workup, and the attitude toward treatment has, in some ways, lagged behind advances in therapy, including timing and feasibility of therapy for IPF,” she said.
The key message for primary care physicians is to include ILD in the differential diagnosis of patients with shortness of breath and/or cough, especially if the initial cardiac and pulmonary test (meaning at least a chest x-ray and pulmonary function tests, including a diffusion capacity) are not pointing to an alternative cause within 3 months of presentation, Dr. Thavarajah said.
Once IPF is diagnosed, primary care clinicians should know that there are FDA-approved therapies that improve survival, said Dr. Thavarajah. “There are identifiable and treatable comorbid conditions,” she added. “The statement of ‘time lost is lung lost’ sums up the care of an IPF patient; partnerships between primary care clinicians, pulmonologists, and referral centers can provide the patient multiple levels of support with quality-of-life interventions, treatments, and also clinical trials, delivered by a team of providers,” she said.
In the wake of the current study, more research is needed with outcome studies regarding educational interventions targeting primary care and pulmonologists on appropriate workup, timing of workup, and current therapy for IPF patients, she added.
The white paper received no outside funding. The authors and Dr. Thavarajah had no financial conflicts to disclose.
FROM CHEST CLINICAL PERSPECTIVES
Fine-tuning HR-ARM for constipation diagnoses
Among patients with constipation, reduced rectoanal gradient found during high-resolution anorectal manometry (HR-ARM) is the strongest parameter for predicting how a patient is likely to perform on a rectal balloon expulsion test (BET). Findings of both reduced rectoanal gradient and abnormal BET should be considered diagnostic for a defecatory disorder.
Those are the findings of a study out of the Mayo Clinic in Rochester, Minn., which was published in Gastroenterology. The research could help streamline diagnosis of defecatory disorders: Currently there is a lack of consensus on what tests should be performed and in what order to achieve a reliable diagnosis, according to the authors.
The authors recommend that, in patients with a suggestive history, a prolonged time on BET or reduced rectoanal gradient individually indicate a probable defecatory disorder, while the presence of both could be considered diagnostic even in the absence of defecography.
The research should provide clarity about the findings from HR-ARM, which can be complex, according to Kyle Staller, MD, who was asked to comment on the study. “You get lots of different numbers, you get lots of different parameters [with HR-ARM], and figuring out which ones are really relevant is somewhat difficult. [This study] is really a tour de force that distills down many of these parameters into some that we might want to pay attention to more than others,” said Dr. Staller, who is director of the GI Motility Laboratory at Massachusetts General Hospital and a professor of medicine at Harvard Medical School, both in Boston.
He pointed out that one limitation of the study is it didn’t attempt to answer the question of what parameters predict benefit from biofeedback therapy.
“I think the practice right now is that we tend to put the most weight on the balloon expulsion test. I think what this paper convincingly argues is that maybe someone who has an abnormal rectoanal gradient and a normal balloon expulsion test should also be referred for biofeedback with the caveat that we still don’t know if they’re going to do well on biofeedback or not,” said Dr. Staller.
The study included 658 patients, 474 with constipation and 184 healthy controls. In addition to HR-ARM and BET, 158 underwent defecography. Females made up 89% of constipated patients and 73% of healthy individuals. Healthy individuals were younger than constipated individuals (median age 35 versus 49 years).
Overall, 11% of healthy patients and 32% of constipated patients had prolonged BET time (P < .001) and 11% and 21% had a reduced rectoanal gradient on HR-ARM (P = .003). Among those with a normal BET time, 13% had a reduced rectoanal gradient, compared with 34% of those with a prolonged BET time (P < .001).
The authors report that HR-ARM variables had good specificity but worse sensitivity for predicting prolonged BET. The rectoanal gradient was the best-performing variable, with a specificity of 85% and a sensitivity of 36%.
HR-ARM and BET findings were associated with reduced rectal evacuation found on defecography. The median rectal evacuation was 79% if both BET and rectoanal gradient were normal, 35% if either one was abnormal, and 3% if both were abnormal (P < .001). Having either prolonged BET time or reduced anorectal gradient alone had a 73% sensitivity and specificity of 72% for incomplete evacuation on defecography. If both abnormalities were present, the sensitivity was 31% but the specificity was 95%.
A reduced rectoanal gradient was associated with incomplete rectal evacuation (odds ratio, 4.35; P = .002); prolonged BET time showed a similar association (OR, 4.57; P < .001).
The authors proposed terminology to help differentiate the findings: “probable defecatory disorder,” or “probable DD,” to describe patients with one abnormal result from the three tests and “definite DD” for those with two abnormal test results. “Although a single abnormal finding may be a false-positive result, pursuing a trial of biofeedback therapy for patients with a probable DD may be reasonable, especially when defecography is not feasible. However, this approach should be confirmed by prospective studies that assess the response to anorectal biofeedback therapy in patients with probable and definite DD, as defined above.”
The authors disclosed no conflicts of interest. Dr. Staller has consulted for GI Supply.
Among patients with constipation, reduced rectoanal gradient found during high-resolution anorectal manometry (HR-ARM) is the strongest parameter for predicting how a patient is likely to perform on a rectal balloon expulsion test (BET). Findings of both reduced rectoanal gradient and abnormal BET should be considered diagnostic for a defecatory disorder.
Those are the findings of a study out of the Mayo Clinic in Rochester, Minn., which was published in Gastroenterology. The research could help streamline diagnosis of defecatory disorders: Currently there is a lack of consensus on what tests should be performed and in what order to achieve a reliable diagnosis, according to the authors.
The authors recommend that, in patients with a suggestive history, a prolonged time on BET or reduced rectoanal gradient individually indicate a probable defecatory disorder, while the presence of both could be considered diagnostic even in the absence of defecography.
The research should provide clarity about the findings from HR-ARM, which can be complex, according to Kyle Staller, MD, who was asked to comment on the study. “You get lots of different numbers, you get lots of different parameters [with HR-ARM], and figuring out which ones are really relevant is somewhat difficult. [This study] is really a tour de force that distills down many of these parameters into some that we might want to pay attention to more than others,” said Dr. Staller, who is director of the GI Motility Laboratory at Massachusetts General Hospital and a professor of medicine at Harvard Medical School, both in Boston.
He pointed out that one limitation of the study is it didn’t attempt to answer the question of what parameters predict benefit from biofeedback therapy.
“I think the practice right now is that we tend to put the most weight on the balloon expulsion test. I think what this paper convincingly argues is that maybe someone who has an abnormal rectoanal gradient and a normal balloon expulsion test should also be referred for biofeedback with the caveat that we still don’t know if they’re going to do well on biofeedback or not,” said Dr. Staller.
The study included 658 patients, 474 with constipation and 184 healthy controls. In addition to HR-ARM and BET, 158 underwent defecography. Females made up 89% of constipated patients and 73% of healthy individuals. Healthy individuals were younger than constipated individuals (median age 35 versus 49 years).
Overall, 11% of healthy patients and 32% of constipated patients had prolonged BET time (P < .001) and 11% and 21% had a reduced rectoanal gradient on HR-ARM (P = .003). Among those with a normal BET time, 13% had a reduced rectoanal gradient, compared with 34% of those with a prolonged BET time (P < .001).
The authors report that HR-ARM variables had good specificity but worse sensitivity for predicting prolonged BET. The rectoanal gradient was the best-performing variable, with a specificity of 85% and a sensitivity of 36%.
HR-ARM and BET findings were associated with reduced rectal evacuation found on defecography. The median rectal evacuation was 79% if both BET and rectoanal gradient were normal, 35% if either one was abnormal, and 3% if both were abnormal (P < .001). Having either prolonged BET time or reduced anorectal gradient alone had a 73% sensitivity and specificity of 72% for incomplete evacuation on defecography. If both abnormalities were present, the sensitivity was 31% but the specificity was 95%.
A reduced rectoanal gradient was associated with incomplete rectal evacuation (odds ratio, 4.35; P = .002); prolonged BET time showed a similar association (OR, 4.57; P < .001).
The authors proposed terminology to help differentiate the findings: “probable defecatory disorder,” or “probable DD,” to describe patients with one abnormal result from the three tests and “definite DD” for those with two abnormal test results. “Although a single abnormal finding may be a false-positive result, pursuing a trial of biofeedback therapy for patients with a probable DD may be reasonable, especially when defecography is not feasible. However, this approach should be confirmed by prospective studies that assess the response to anorectal biofeedback therapy in patients with probable and definite DD, as defined above.”
The authors disclosed no conflicts of interest. Dr. Staller has consulted for GI Supply.
Among patients with constipation, reduced rectoanal gradient found during high-resolution anorectal manometry (HR-ARM) is the strongest parameter for predicting how a patient is likely to perform on a rectal balloon expulsion test (BET). Findings of both reduced rectoanal gradient and abnormal BET should be considered diagnostic for a defecatory disorder.
Those are the findings of a study out of the Mayo Clinic in Rochester, Minn., which was published in Gastroenterology. The research could help streamline diagnosis of defecatory disorders: Currently there is a lack of consensus on what tests should be performed and in what order to achieve a reliable diagnosis, according to the authors.
The authors recommend that, in patients with a suggestive history, a prolonged time on BET or reduced rectoanal gradient individually indicate a probable defecatory disorder, while the presence of both could be considered diagnostic even in the absence of defecography.
The research should provide clarity about the findings from HR-ARM, which can be complex, according to Kyle Staller, MD, who was asked to comment on the study. “You get lots of different numbers, you get lots of different parameters [with HR-ARM], and figuring out which ones are really relevant is somewhat difficult. [This study] is really a tour de force that distills down many of these parameters into some that we might want to pay attention to more than others,” said Dr. Staller, who is director of the GI Motility Laboratory at Massachusetts General Hospital and a professor of medicine at Harvard Medical School, both in Boston.
He pointed out that one limitation of the study is it didn’t attempt to answer the question of what parameters predict benefit from biofeedback therapy.
“I think the practice right now is that we tend to put the most weight on the balloon expulsion test. I think what this paper convincingly argues is that maybe someone who has an abnormal rectoanal gradient and a normal balloon expulsion test should also be referred for biofeedback with the caveat that we still don’t know if they’re going to do well on biofeedback or not,” said Dr. Staller.
The study included 658 patients, 474 with constipation and 184 healthy controls. In addition to HR-ARM and BET, 158 underwent defecography. Females made up 89% of constipated patients and 73% of healthy individuals. Healthy individuals were younger than constipated individuals (median age 35 versus 49 years).
Overall, 11% of healthy patients and 32% of constipated patients had prolonged BET time (P < .001) and 11% and 21% had a reduced rectoanal gradient on HR-ARM (P = .003). Among those with a normal BET time, 13% had a reduced rectoanal gradient, compared with 34% of those with a prolonged BET time (P < .001).
The authors report that HR-ARM variables had good specificity but worse sensitivity for predicting prolonged BET. The rectoanal gradient was the best-performing variable, with a specificity of 85% and a sensitivity of 36%.
HR-ARM and BET findings were associated with reduced rectal evacuation found on defecography. The median rectal evacuation was 79% if both BET and rectoanal gradient were normal, 35% if either one was abnormal, and 3% if both were abnormal (P < .001). Having either prolonged BET time or reduced anorectal gradient alone had a 73% sensitivity and specificity of 72% for incomplete evacuation on defecography. If both abnormalities were present, the sensitivity was 31% but the specificity was 95%.
A reduced rectoanal gradient was associated with incomplete rectal evacuation (odds ratio, 4.35; P = .002); prolonged BET time showed a similar association (OR, 4.57; P < .001).
The authors proposed terminology to help differentiate the findings: “probable defecatory disorder,” or “probable DD,” to describe patients with one abnormal result from the three tests and “definite DD” for those with two abnormal test results. “Although a single abnormal finding may be a false-positive result, pursuing a trial of biofeedback therapy for patients with a probable DD may be reasonable, especially when defecography is not feasible. However, this approach should be confirmed by prospective studies that assess the response to anorectal biofeedback therapy in patients with probable and definite DD, as defined above.”
The authors disclosed no conflicts of interest. Dr. Staller has consulted for GI Supply.
FROM GASTROENTEROLOGY
Commentary: Evaluating HCC Treatments, October 2022
Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.
Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.
Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.
Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.
Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.
Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.
Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.
Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.
Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.
Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.
Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.
Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.
Commentary: Evaluating HCC Treatments, October 2022
Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.
Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.
Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.
Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.
Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.
Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.
Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.
Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.
Komatsu and colleagues performed a case-matched analysis to evaluate the best first-line treatment for HCC in patients with macroscopic portal vein tumor thrombus (PVTT). Patients had advanced HCC and macroscopic PVTT that invaded an ipsilateral first-order portal branch, main trunk, or contralateral portal vein. The propensity score–matched groups underwent either hepatectomy (n = 36) or received sorafenib (n = 36). To be considered for resection, patients had to have Child-Pugh (CP) grade A or B liver function, an Eastern Cooperative Oncology Group Performance Status score of ≤ 1, life expectancy of > 3 months, and the macroscopic resection of the targeted tumor could be planned with an estimated remnant liver volume ≥ 35%.
Out of 36 patients who underwent surgery, 23 underwent reductive hepatectomy, and 13 underwent complete resection of tumor. Out of 36 patients who received sorafenib, 21 underwent subsequent treatments. The median overall survival (OS) of patients who underwent hepatectomy was 15.1 months, significantly longer than the 4.5 months for patients who were treated with sorafenib. The authors concluded that selected patients who underwent tumor resection lived longer than patients who received systemic therapy with sorafenib first, despite the presence of macroscopic PVTT.
Lenvatinib is an approved treatment for patients with HCC. Because most patients with HCC have underlying cirrhosis, monitoring the underlying liver function is an important facet of patient management. Huynh and colleagues reported on patients in the REFLECT trial whose liver function deteriorated from CP-A to CP-B while receiving systemic therapy. This post hoc analysis included patients whose liver function deteriorated to CP-B or remained CP-A within 8 weeks of randomization to lenvatinib (CP-B: n = 60; CP-A: n = 413) or sorafenib (CP-B: n = 47; CP-A: n = 427). Patients receiving lenvatinib who developed CP-B cirrhosis compared with patients who maintained CP-A cirrhosis had a median progression-free survival (PFS) of 3.7 months (95% CI 1.8-7.4) vs 6.5 months (95% CI 5.6-7.4) and OS of 6.8 months (95% CI 2.6-10.3) vs 13.3 months (95% CI 11.6-16.1). CP-B patients receiving sorafenib had a median PFS and OS of only 0.5 months (95% CI 0.1-3.6) and 4.5 months (95% CI 2.9-6.1), respectively. No new safety signals were reported in CP-B patients. The investigators concluded that deterioration of liver function to CP-B does not require the discontinuation of lenvatinib therapy.
Finally, Brown and colleagues performed a meta-analysis of studies that evaluated transarterial radioembolization (TARE) and transarterial chemoembolization (TACE) in patients with HCC by reviewing 17 studies involving 2465 patients that directly compared TACE and TARE. TARE significantly prolonged the mean time to progression (17.5 vs 9.8 months; 95% CI 1.3-8.3 months) but resulted in comparable OS (absolute difference −0.55 months; 95% CI −1.95 to 3.05 months). Safety profiles appeared to favor TARE. The authors concluded that TACE and TARE should be compared in larger prospective studies to better compare survival, progression, and safety data.
Consider the mnemonic ‘CLEAR’ when counseling acne patients
to use when treating this group of patients.
During a presentation at Medscape Live’s annual Coastal Dermatology Symposium, Dr. Harper, who practices at Dermatology and Skin Care of Birmingham, Ala., elaborated on the mnemonic, as follows:
C: Communicate expectations. “I look right at the acne patient and say, ‘I know you don’t just want to be better; I know you want to be clear,’ ” she said at the meeting. “ ‘That’s my goal for you, too. That may take us more than one visit and more than one treatment, but I am on your team, and that’s what we’re shooting for.’ If you don’t communicate that, they’re going to think that their acne is not that important to you.”
L: Listen for clues to customize the patient’s treatment. “We’re quick to say, ‘my patients don’t do what I recommend,’ or ‘they didn’t do what the last doctor recommended,’ ” Dr. Harper said. “Sometimes that is true, but there may be a reason why. Maybe the medication was too expensive. Maybe it was bleaching their fabrics. Maybe the regimen was too complex. Listen for opportunities to make adjustments to get their acne closer to clear.”
E: Treat early to improve quality of life and to decrease the risk of scarring. “I have a laser in my practice that is good at treating acne scarring,” she said. “Do I ever look at my patient and say, ‘don’t worry about those scars; I can make them go away?’ No. I look at them and say, ‘we can maybe make this 40% better,’ something like that. We have to prevent acne scars, because we’re not good at treating them.”
A: Treat aggressively with more combination therapies, more hormonal therapies, more isotretinoin, and perhaps more prior authorizations. She characterized the effort to obtain a prior authorization as “our megaphone back to insurance companies that says, ‘we think it is worth taking the time to do this prior authorization because the acne patient will benefit.’ ”
R: Don’t resist isotretinoin. Dr. Harper, who began practicing dermatology more than 20 years ago, said that over time, she has gradually prescribed more isotretinoin for her patients with acne. “It’s not a first-line [treatment], but I’m not afraid of it. If I can’t get somebody clear on other oral or topical treatments, we are going to try isotretinoin.”
The goal of acne treatment, she added, is to affect four key aspects of pathogenesis: follicular epithelial hyperproliferation, inflammation, Cutibacterium acnes (C. acnes), and sebum. “That’s what we’re always shooting for,” she said.
Dr. Harper is a past president of the American Acne & Rosacea Society. She disclosed that she serves as an advisor or consultant for Almirall, BioPharmX, Cassiopeia, Cutanea, Cutera, Dermira, EPI, Galderma, LaRoche-Posay, Ortho, Vyne, Sol Gel, and Sun. She also serves as a speaker or member of a speaker’s bureau for Almirall, EPI, Galderma, Ortho, and Vyne.
Medscape Live and this news organization are owned by the same parent company.
to use when treating this group of patients.
During a presentation at Medscape Live’s annual Coastal Dermatology Symposium, Dr. Harper, who practices at Dermatology and Skin Care of Birmingham, Ala., elaborated on the mnemonic, as follows:
C: Communicate expectations. “I look right at the acne patient and say, ‘I know you don’t just want to be better; I know you want to be clear,’ ” she said at the meeting. “ ‘That’s my goal for you, too. That may take us more than one visit and more than one treatment, but I am on your team, and that’s what we’re shooting for.’ If you don’t communicate that, they’re going to think that their acne is not that important to you.”
L: Listen for clues to customize the patient’s treatment. “We’re quick to say, ‘my patients don’t do what I recommend,’ or ‘they didn’t do what the last doctor recommended,’ ” Dr. Harper said. “Sometimes that is true, but there may be a reason why. Maybe the medication was too expensive. Maybe it was bleaching their fabrics. Maybe the regimen was too complex. Listen for opportunities to make adjustments to get their acne closer to clear.”
E: Treat early to improve quality of life and to decrease the risk of scarring. “I have a laser in my practice that is good at treating acne scarring,” she said. “Do I ever look at my patient and say, ‘don’t worry about those scars; I can make them go away?’ No. I look at them and say, ‘we can maybe make this 40% better,’ something like that. We have to prevent acne scars, because we’re not good at treating them.”
A: Treat aggressively with more combination therapies, more hormonal therapies, more isotretinoin, and perhaps more prior authorizations. She characterized the effort to obtain a prior authorization as “our megaphone back to insurance companies that says, ‘we think it is worth taking the time to do this prior authorization because the acne patient will benefit.’ ”
R: Don’t resist isotretinoin. Dr. Harper, who began practicing dermatology more than 20 years ago, said that over time, she has gradually prescribed more isotretinoin for her patients with acne. “It’s not a first-line [treatment], but I’m not afraid of it. If I can’t get somebody clear on other oral or topical treatments, we are going to try isotretinoin.”
The goal of acne treatment, she added, is to affect four key aspects of pathogenesis: follicular epithelial hyperproliferation, inflammation, Cutibacterium acnes (C. acnes), and sebum. “That’s what we’re always shooting for,” she said.
Dr. Harper is a past president of the American Acne & Rosacea Society. She disclosed that she serves as an advisor or consultant for Almirall, BioPharmX, Cassiopeia, Cutanea, Cutera, Dermira, EPI, Galderma, LaRoche-Posay, Ortho, Vyne, Sol Gel, and Sun. She also serves as a speaker or member of a speaker’s bureau for Almirall, EPI, Galderma, Ortho, and Vyne.
Medscape Live and this news organization are owned by the same parent company.
to use when treating this group of patients.
During a presentation at Medscape Live’s annual Coastal Dermatology Symposium, Dr. Harper, who practices at Dermatology and Skin Care of Birmingham, Ala., elaborated on the mnemonic, as follows:
C: Communicate expectations. “I look right at the acne patient and say, ‘I know you don’t just want to be better; I know you want to be clear,’ ” she said at the meeting. “ ‘That’s my goal for you, too. That may take us more than one visit and more than one treatment, but I am on your team, and that’s what we’re shooting for.’ If you don’t communicate that, they’re going to think that their acne is not that important to you.”
L: Listen for clues to customize the patient’s treatment. “We’re quick to say, ‘my patients don’t do what I recommend,’ or ‘they didn’t do what the last doctor recommended,’ ” Dr. Harper said. “Sometimes that is true, but there may be a reason why. Maybe the medication was too expensive. Maybe it was bleaching their fabrics. Maybe the regimen was too complex. Listen for opportunities to make adjustments to get their acne closer to clear.”
E: Treat early to improve quality of life and to decrease the risk of scarring. “I have a laser in my practice that is good at treating acne scarring,” she said. “Do I ever look at my patient and say, ‘don’t worry about those scars; I can make them go away?’ No. I look at them and say, ‘we can maybe make this 40% better,’ something like that. We have to prevent acne scars, because we’re not good at treating them.”
A: Treat aggressively with more combination therapies, more hormonal therapies, more isotretinoin, and perhaps more prior authorizations. She characterized the effort to obtain a prior authorization as “our megaphone back to insurance companies that says, ‘we think it is worth taking the time to do this prior authorization because the acne patient will benefit.’ ”
R: Don’t resist isotretinoin. Dr. Harper, who began practicing dermatology more than 20 years ago, said that over time, she has gradually prescribed more isotretinoin for her patients with acne. “It’s not a first-line [treatment], but I’m not afraid of it. If I can’t get somebody clear on other oral or topical treatments, we are going to try isotretinoin.”
The goal of acne treatment, she added, is to affect four key aspects of pathogenesis: follicular epithelial hyperproliferation, inflammation, Cutibacterium acnes (C. acnes), and sebum. “That’s what we’re always shooting for,” she said.
Dr. Harper is a past president of the American Acne & Rosacea Society. She disclosed that she serves as an advisor or consultant for Almirall, BioPharmX, Cassiopeia, Cutanea, Cutera, Dermira, EPI, Galderma, LaRoche-Posay, Ortho, Vyne, Sol Gel, and Sun. She also serves as a speaker or member of a speaker’s bureau for Almirall, EPI, Galderma, Ortho, and Vyne.
Medscape Live and this news organization are owned by the same parent company.
FROM MEDSCAPE LIVE COASTAL DERM
What we know about long COVID so far
Long COVID: The name says it all. It’s an illness that, for many people, has not yet stopped.
Eric Roach became ill with COVID-19 in November 2020, and he’s still sick. “I have brain fog, memory loss,” says the 67-year-old Navy veteran from Spearfish, S.D. “The fatigue has just been insane.”
Long COVID, more formally known as post-acute sequelae of COVID (PASC), is the lay term to describe when people start to recover, or seem to recover, from a bout of COVID-19 but then continue to suffer from symptoms. For some, it’s gone on for 2 years or longer. While the governments of the United Statesand several other countries formally recognize the existence of long COVID, the National Institutes of Health (NIH) has yet to formally define it. There’s no approved treatment, and the causes are not understood.
Here’s what is known: and it is affecting enough people to cause concern for employers, health insurers, and governments.
First, the many symptoms
According to the Centers for Disease Control and Prvention, long COVID symptoms may include:
- Tiredness or fatigue that interferes with daily life.
- Symptoms that get worse after physical or mental effort.
- Fever.
- Difficulty breathing or shortness of breath.
- Cough.
- Chest pain.
- Heart palpitations.
- Difficulty thinking or concentrating (sometimes referred to as “brain fog”).
- Headache.
- Sleep problems.
- Dizziness when standing.
- Pins-and-needles feelings.
- Change in smell or taste.
- Depression or anxiety.
- Diarrhea.
- Stomach pain.
- Joint or muscle pain.
- Rash.
- Changes in menstrual cycles.
“People with post-COVID conditions may develop or continue to have symptoms that are hard to explain and manage,” the CDC says on its website. “Clinical evaluations and results of routine blood tests, chest x-rays, and electrocardiograms may be normal. The symptoms are similar to those reported by people with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) and other poorly understood chronic illnesses that may occur after other infections.”
Doctors may not fully appreciate the subtle nature of some of the symptoms.
“People with these unexplained symptoms may be misunderstood by their health care providers, which can result in a long time for them to get a diagnosis and receive appropriate care or treatment,” the CDC says.
Health professionals should recognize that long COVID can be disabling, the U.S. Department of Health and Human Services says. “Long COVID can substantially limit a major life activity,” HHS says in civil rights guidance. One possible example: “A person with long COVID who has lung damage that causes shortness of breath, fatigue, and related effects is substantially limited in respiratory function, among other major life activities,” the HHS notes.
How many people are affected?
This has been difficult to judge because not everyone who has had COVID-19 gets tested for it and there are no formal diagnostic criteria yet for long COVID. The CDC estimates that 19% of patients in the United States who have ever had COVID-19 have long COVID symptoms.
Some estimates go higher. A University of Oxford study in September 2021 found more than a third of patients had symptoms of long COVID between 3 months and 6 months after a COVID-19 diagnosis. As many as 55% of COVID-19 patients in one Chinese study had one or more lingering symptoms 2 years later, Lixue Huang, MD, of the China-Japan Friendship Hospital in Beijing, and colleagues reported in the journal Lancet Respiratory Medicine in May.
According to the CDC, age is a factor. “Older adults are less likely to have long COVID than younger adults. Nearly three times as many adults ages 50-59 currently have long COVID than those age 80 and older,” the CDC says. Women and racial and ethnic minorities are more likely to be affected.
Many people are experiencing neurological effects, such as the so-called brain fog, according to Ziyad Al-Aly, MD, of Washington University and the VA St. Louis Health Care System, and colleagues, whose report was published in Nature Medicine in September. They estimated that 6.6 million Americans have brain impairments associated with COVID infection.
“Some of the neurologic disorders reported here are serious chronic conditions that will impact some people for a lifetime,” they wrote. “Given the colossal scale of the pandemic, and even though the absolute numbers reported in this work are small, these may translate into a large number of affected individuals around the world – and this will likely contribute to a rise in the burden of neurologic diseases.”
Causes
It’s not clear what the underlying causes are, but most research points to a combination of factors. Suspects include ongoing inflammation, tiny blood clots, and reactivation of latent viruses. In May, Brent Palmer, PhD, of the University of Colorado, Denver, and colleagues found people with long COVID had persistent activation of T-cells that were specific for SARS-CoV-2.
COVID-19 itself can damage organs, and long COVID might be caused by ongoing damage. In August, Alexandros Rovas, MD, of University Hospital Munster in Germany, and colleagues found patients with long COVID had evidence of damage to their capillaries. “Whether, to what extent, and when the observed damage might be reversible remains unclear,” they wrote in the journal Angiogenesis.
People with long COVID have immune responses to other viruses, such as Epstein-Barr – evidence that COVID-19 might reactivate latent viruses. “Our data suggest the involvement of persistent antigen, reactivation of latent herpesviruses, and chronic inflammation,” immunobiologist Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., and colleagues wrote in a study posted in August that had not yet been peer-reviewed for publication.
This might be causing an autoimmune response. “The infection may cause the immune system to start making autoantibodies that attack a person’s own organs and tissues,” the NIH says.
There could be other factors. A study by Harvard researchers found that people who felt stressed, depressed, or lonely before catching COVID-19 were more likely to develop long COVID afterward. “Distress was more strongly associated with developing long COVID than physical health risk factors such as obesity, asthma, and hypertension,” Siwen Wang, MD, a research fellow with Harvard University’s T.H. Chan School of Public Health, Boston, said in a statement. Plus, nearly 44% of those in the study developed COVID-19 infections after having been assessed for stress, Dr. Wang and colleagues reported in the journal JAMA Psychiatry.
Vaccine protection
There’s evidence that vaccination protects against long COVID, both by preventing infection in the first place, but also even for people who have breakthrough infections.
A meta-analysis covering studies involving 17 million people found evidence vaccination might reduce the severity of COVID-19 or might help the body clear any lingering virus after an infection.
“Overall, vaccination was associated with reduced risks or odds of long COVID, with preliminary evidence suggesting that two doses are more effective than one dose,” wrote Cesar Fernandez de las Penas, PhD, of King Juan Carlos University in Madrid, and colleagues. Their report is in The Lancet’s eClinicalMedicine.
A team in Milan found that unvaccinated people in their study were nearly three times as likely to have serious symptoms for longer than 4 weeks compared to vaccinated volunteers. According to their report in JAMA, Elena Azzolini, MD, PhD, assistant professor at Humanitas Research Hospital, and colleagues found two or three doses of vaccine reduced the risk of hospitalization from COVID to 16% or 17% compared to 42% for the unvaccinated.
Treatments
With no diagnostic criteria and no understanding of the causes, it’s hard for doctors to determine treatments.
Most experts dealing with long COVID, even those at the specialty centers that have been set up at hospitals and health systems in the United States, recommend that patients start with their primary care doctors before moving on to specialists.
“The mainstay of management is supportive, holistic care, symptom control, and detection of treatable complications,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford, England, and colleagues wrote in the journal The BMJ in September. “Patients with long COVID greatly value input from their primary care clinician. Generalist clinicians can help patients considerably by hearing the patient’s story and validating their experience … (and) making the diagnosis of long COVID (which does not have to be by exclusion) and excluding alternative diagnoses.”
Evidence is building that long COVID closely resembles other postviral conditions – something that can provide clues for treatment. For example, several studies indicate that exercise doesn’t help most patients.
But there are approaches that can work. Treatments may include pulmonary rehabilitation; autonomic conditioning therapy, which includes breathing therapy; and cognitive rehabilitation to relieve brain fog. Doctors are also trying the antidepressant amitriptyline to help with sleep disturbances and headaches; the antiseizure medication gabapentin to help with pain, numbness, and other neurological symptoms; and drugs to relieve low blood pressure in patients experiencing postural orthostatic tachycardia syndrome (POTS).
The NIH is sponsoring studies that have recruited just over 8,200 adults. And more than two dozen researchers from Harvard; Stanford; the University of California, San Francisco; the J. Craig Venter Institute; Johns Hopkins University; the University of Pennsylvania; Mount Sinai Hospitals; Cardiff University; and Yale announced in September they were forming the Long COVID Research Initiative to speed up studies.
The group, with funding from private enterprise, plans to conduct tissue biopsy, imaging studies, and autopsies and will search for potential biomarkers in the blood of patients.
A version of this article first appeared on WebMD.com.
Long COVID: The name says it all. It’s an illness that, for many people, has not yet stopped.
Eric Roach became ill with COVID-19 in November 2020, and he’s still sick. “I have brain fog, memory loss,” says the 67-year-old Navy veteran from Spearfish, S.D. “The fatigue has just been insane.”
Long COVID, more formally known as post-acute sequelae of COVID (PASC), is the lay term to describe when people start to recover, or seem to recover, from a bout of COVID-19 but then continue to suffer from symptoms. For some, it’s gone on for 2 years or longer. While the governments of the United Statesand several other countries formally recognize the existence of long COVID, the National Institutes of Health (NIH) has yet to formally define it. There’s no approved treatment, and the causes are not understood.
Here’s what is known: and it is affecting enough people to cause concern for employers, health insurers, and governments.
First, the many symptoms
According to the Centers for Disease Control and Prvention, long COVID symptoms may include:
- Tiredness or fatigue that interferes with daily life.
- Symptoms that get worse after physical or mental effort.
- Fever.
- Difficulty breathing or shortness of breath.
- Cough.
- Chest pain.
- Heart palpitations.
- Difficulty thinking or concentrating (sometimes referred to as “brain fog”).
- Headache.
- Sleep problems.
- Dizziness when standing.
- Pins-and-needles feelings.
- Change in smell or taste.
- Depression or anxiety.
- Diarrhea.
- Stomach pain.
- Joint or muscle pain.
- Rash.
- Changes in menstrual cycles.
“People with post-COVID conditions may develop or continue to have symptoms that are hard to explain and manage,” the CDC says on its website. “Clinical evaluations and results of routine blood tests, chest x-rays, and electrocardiograms may be normal. The symptoms are similar to those reported by people with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) and other poorly understood chronic illnesses that may occur after other infections.”
Doctors may not fully appreciate the subtle nature of some of the symptoms.
“People with these unexplained symptoms may be misunderstood by their health care providers, which can result in a long time for them to get a diagnosis and receive appropriate care or treatment,” the CDC says.
Health professionals should recognize that long COVID can be disabling, the U.S. Department of Health and Human Services says. “Long COVID can substantially limit a major life activity,” HHS says in civil rights guidance. One possible example: “A person with long COVID who has lung damage that causes shortness of breath, fatigue, and related effects is substantially limited in respiratory function, among other major life activities,” the HHS notes.
How many people are affected?
This has been difficult to judge because not everyone who has had COVID-19 gets tested for it and there are no formal diagnostic criteria yet for long COVID. The CDC estimates that 19% of patients in the United States who have ever had COVID-19 have long COVID symptoms.
Some estimates go higher. A University of Oxford study in September 2021 found more than a third of patients had symptoms of long COVID between 3 months and 6 months after a COVID-19 diagnosis. As many as 55% of COVID-19 patients in one Chinese study had one or more lingering symptoms 2 years later, Lixue Huang, MD, of the China-Japan Friendship Hospital in Beijing, and colleagues reported in the journal Lancet Respiratory Medicine in May.
According to the CDC, age is a factor. “Older adults are less likely to have long COVID than younger adults. Nearly three times as many adults ages 50-59 currently have long COVID than those age 80 and older,” the CDC says. Women and racial and ethnic minorities are more likely to be affected.
Many people are experiencing neurological effects, such as the so-called brain fog, according to Ziyad Al-Aly, MD, of Washington University and the VA St. Louis Health Care System, and colleagues, whose report was published in Nature Medicine in September. They estimated that 6.6 million Americans have brain impairments associated with COVID infection.
“Some of the neurologic disorders reported here are serious chronic conditions that will impact some people for a lifetime,” they wrote. “Given the colossal scale of the pandemic, and even though the absolute numbers reported in this work are small, these may translate into a large number of affected individuals around the world – and this will likely contribute to a rise in the burden of neurologic diseases.”
Causes
It’s not clear what the underlying causes are, but most research points to a combination of factors. Suspects include ongoing inflammation, tiny blood clots, and reactivation of latent viruses. In May, Brent Palmer, PhD, of the University of Colorado, Denver, and colleagues found people with long COVID had persistent activation of T-cells that were specific for SARS-CoV-2.
COVID-19 itself can damage organs, and long COVID might be caused by ongoing damage. In August, Alexandros Rovas, MD, of University Hospital Munster in Germany, and colleagues found patients with long COVID had evidence of damage to their capillaries. “Whether, to what extent, and when the observed damage might be reversible remains unclear,” they wrote in the journal Angiogenesis.
People with long COVID have immune responses to other viruses, such as Epstein-Barr – evidence that COVID-19 might reactivate latent viruses. “Our data suggest the involvement of persistent antigen, reactivation of latent herpesviruses, and chronic inflammation,” immunobiologist Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., and colleagues wrote in a study posted in August that had not yet been peer-reviewed for publication.
This might be causing an autoimmune response. “The infection may cause the immune system to start making autoantibodies that attack a person’s own organs and tissues,” the NIH says.
There could be other factors. A study by Harvard researchers found that people who felt stressed, depressed, or lonely before catching COVID-19 were more likely to develop long COVID afterward. “Distress was more strongly associated with developing long COVID than physical health risk factors such as obesity, asthma, and hypertension,” Siwen Wang, MD, a research fellow with Harvard University’s T.H. Chan School of Public Health, Boston, said in a statement. Plus, nearly 44% of those in the study developed COVID-19 infections after having been assessed for stress, Dr. Wang and colleagues reported in the journal JAMA Psychiatry.
Vaccine protection
There’s evidence that vaccination protects against long COVID, both by preventing infection in the first place, but also even for people who have breakthrough infections.
A meta-analysis covering studies involving 17 million people found evidence vaccination might reduce the severity of COVID-19 or might help the body clear any lingering virus after an infection.
“Overall, vaccination was associated with reduced risks or odds of long COVID, with preliminary evidence suggesting that two doses are more effective than one dose,” wrote Cesar Fernandez de las Penas, PhD, of King Juan Carlos University in Madrid, and colleagues. Their report is in The Lancet’s eClinicalMedicine.
A team in Milan found that unvaccinated people in their study were nearly three times as likely to have serious symptoms for longer than 4 weeks compared to vaccinated volunteers. According to their report in JAMA, Elena Azzolini, MD, PhD, assistant professor at Humanitas Research Hospital, and colleagues found two or three doses of vaccine reduced the risk of hospitalization from COVID to 16% or 17% compared to 42% for the unvaccinated.
Treatments
With no diagnostic criteria and no understanding of the causes, it’s hard for doctors to determine treatments.
Most experts dealing with long COVID, even those at the specialty centers that have been set up at hospitals and health systems in the United States, recommend that patients start with their primary care doctors before moving on to specialists.
“The mainstay of management is supportive, holistic care, symptom control, and detection of treatable complications,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford, England, and colleagues wrote in the journal The BMJ in September. “Patients with long COVID greatly value input from their primary care clinician. Generalist clinicians can help patients considerably by hearing the patient’s story and validating their experience … (and) making the diagnosis of long COVID (which does not have to be by exclusion) and excluding alternative diagnoses.”
Evidence is building that long COVID closely resembles other postviral conditions – something that can provide clues for treatment. For example, several studies indicate that exercise doesn’t help most patients.
But there are approaches that can work. Treatments may include pulmonary rehabilitation; autonomic conditioning therapy, which includes breathing therapy; and cognitive rehabilitation to relieve brain fog. Doctors are also trying the antidepressant amitriptyline to help with sleep disturbances and headaches; the antiseizure medication gabapentin to help with pain, numbness, and other neurological symptoms; and drugs to relieve low blood pressure in patients experiencing postural orthostatic tachycardia syndrome (POTS).
The NIH is sponsoring studies that have recruited just over 8,200 adults. And more than two dozen researchers from Harvard; Stanford; the University of California, San Francisco; the J. Craig Venter Institute; Johns Hopkins University; the University of Pennsylvania; Mount Sinai Hospitals; Cardiff University; and Yale announced in September they were forming the Long COVID Research Initiative to speed up studies.
The group, with funding from private enterprise, plans to conduct tissue biopsy, imaging studies, and autopsies and will search for potential biomarkers in the blood of patients.
A version of this article first appeared on WebMD.com.
Long COVID: The name says it all. It’s an illness that, for many people, has not yet stopped.
Eric Roach became ill with COVID-19 in November 2020, and he’s still sick. “I have brain fog, memory loss,” says the 67-year-old Navy veteran from Spearfish, S.D. “The fatigue has just been insane.”
Long COVID, more formally known as post-acute sequelae of COVID (PASC), is the lay term to describe when people start to recover, or seem to recover, from a bout of COVID-19 but then continue to suffer from symptoms. For some, it’s gone on for 2 years or longer. While the governments of the United Statesand several other countries formally recognize the existence of long COVID, the National Institutes of Health (NIH) has yet to formally define it. There’s no approved treatment, and the causes are not understood.
Here’s what is known: and it is affecting enough people to cause concern for employers, health insurers, and governments.
First, the many symptoms
According to the Centers for Disease Control and Prvention, long COVID symptoms may include:
- Tiredness or fatigue that interferes with daily life.
- Symptoms that get worse after physical or mental effort.
- Fever.
- Difficulty breathing or shortness of breath.
- Cough.
- Chest pain.
- Heart palpitations.
- Difficulty thinking or concentrating (sometimes referred to as “brain fog”).
- Headache.
- Sleep problems.
- Dizziness when standing.
- Pins-and-needles feelings.
- Change in smell or taste.
- Depression or anxiety.
- Diarrhea.
- Stomach pain.
- Joint or muscle pain.
- Rash.
- Changes in menstrual cycles.
“People with post-COVID conditions may develop or continue to have symptoms that are hard to explain and manage,” the CDC says on its website. “Clinical evaluations and results of routine blood tests, chest x-rays, and electrocardiograms may be normal. The symptoms are similar to those reported by people with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) and other poorly understood chronic illnesses that may occur after other infections.”
Doctors may not fully appreciate the subtle nature of some of the symptoms.
“People with these unexplained symptoms may be misunderstood by their health care providers, which can result in a long time for them to get a diagnosis and receive appropriate care or treatment,” the CDC says.
Health professionals should recognize that long COVID can be disabling, the U.S. Department of Health and Human Services says. “Long COVID can substantially limit a major life activity,” HHS says in civil rights guidance. One possible example: “A person with long COVID who has lung damage that causes shortness of breath, fatigue, and related effects is substantially limited in respiratory function, among other major life activities,” the HHS notes.
How many people are affected?
This has been difficult to judge because not everyone who has had COVID-19 gets tested for it and there are no formal diagnostic criteria yet for long COVID. The CDC estimates that 19% of patients in the United States who have ever had COVID-19 have long COVID symptoms.
Some estimates go higher. A University of Oxford study in September 2021 found more than a third of patients had symptoms of long COVID between 3 months and 6 months after a COVID-19 diagnosis. As many as 55% of COVID-19 patients in one Chinese study had one or more lingering symptoms 2 years later, Lixue Huang, MD, of the China-Japan Friendship Hospital in Beijing, and colleagues reported in the journal Lancet Respiratory Medicine in May.
According to the CDC, age is a factor. “Older adults are less likely to have long COVID than younger adults. Nearly three times as many adults ages 50-59 currently have long COVID than those age 80 and older,” the CDC says. Women and racial and ethnic minorities are more likely to be affected.
Many people are experiencing neurological effects, such as the so-called brain fog, according to Ziyad Al-Aly, MD, of Washington University and the VA St. Louis Health Care System, and colleagues, whose report was published in Nature Medicine in September. They estimated that 6.6 million Americans have brain impairments associated with COVID infection.
“Some of the neurologic disorders reported here are serious chronic conditions that will impact some people for a lifetime,” they wrote. “Given the colossal scale of the pandemic, and even though the absolute numbers reported in this work are small, these may translate into a large number of affected individuals around the world – and this will likely contribute to a rise in the burden of neurologic diseases.”
Causes
It’s not clear what the underlying causes are, but most research points to a combination of factors. Suspects include ongoing inflammation, tiny blood clots, and reactivation of latent viruses. In May, Brent Palmer, PhD, of the University of Colorado, Denver, and colleagues found people with long COVID had persistent activation of T-cells that were specific for SARS-CoV-2.
COVID-19 itself can damage organs, and long COVID might be caused by ongoing damage. In August, Alexandros Rovas, MD, of University Hospital Munster in Germany, and colleagues found patients with long COVID had evidence of damage to their capillaries. “Whether, to what extent, and when the observed damage might be reversible remains unclear,” they wrote in the journal Angiogenesis.
People with long COVID have immune responses to other viruses, such as Epstein-Barr – evidence that COVID-19 might reactivate latent viruses. “Our data suggest the involvement of persistent antigen, reactivation of latent herpesviruses, and chronic inflammation,” immunobiologist Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., and colleagues wrote in a study posted in August that had not yet been peer-reviewed for publication.
This might be causing an autoimmune response. “The infection may cause the immune system to start making autoantibodies that attack a person’s own organs and tissues,” the NIH says.
There could be other factors. A study by Harvard researchers found that people who felt stressed, depressed, or lonely before catching COVID-19 were more likely to develop long COVID afterward. “Distress was more strongly associated with developing long COVID than physical health risk factors such as obesity, asthma, and hypertension,” Siwen Wang, MD, a research fellow with Harvard University’s T.H. Chan School of Public Health, Boston, said in a statement. Plus, nearly 44% of those in the study developed COVID-19 infections after having been assessed for stress, Dr. Wang and colleagues reported in the journal JAMA Psychiatry.
Vaccine protection
There’s evidence that vaccination protects against long COVID, both by preventing infection in the first place, but also even for people who have breakthrough infections.
A meta-analysis covering studies involving 17 million people found evidence vaccination might reduce the severity of COVID-19 or might help the body clear any lingering virus after an infection.
“Overall, vaccination was associated with reduced risks or odds of long COVID, with preliminary evidence suggesting that two doses are more effective than one dose,” wrote Cesar Fernandez de las Penas, PhD, of King Juan Carlos University in Madrid, and colleagues. Their report is in The Lancet’s eClinicalMedicine.
A team in Milan found that unvaccinated people in their study were nearly three times as likely to have serious symptoms for longer than 4 weeks compared to vaccinated volunteers. According to their report in JAMA, Elena Azzolini, MD, PhD, assistant professor at Humanitas Research Hospital, and colleagues found two or three doses of vaccine reduced the risk of hospitalization from COVID to 16% or 17% compared to 42% for the unvaccinated.
Treatments
With no diagnostic criteria and no understanding of the causes, it’s hard for doctors to determine treatments.
Most experts dealing with long COVID, even those at the specialty centers that have been set up at hospitals and health systems in the United States, recommend that patients start with their primary care doctors before moving on to specialists.
“The mainstay of management is supportive, holistic care, symptom control, and detection of treatable complications,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford, England, and colleagues wrote in the journal The BMJ in September. “Patients with long COVID greatly value input from their primary care clinician. Generalist clinicians can help patients considerably by hearing the patient’s story and validating their experience … (and) making the diagnosis of long COVID (which does not have to be by exclusion) and excluding alternative diagnoses.”
Evidence is building that long COVID closely resembles other postviral conditions – something that can provide clues for treatment. For example, several studies indicate that exercise doesn’t help most patients.
But there are approaches that can work. Treatments may include pulmonary rehabilitation; autonomic conditioning therapy, which includes breathing therapy; and cognitive rehabilitation to relieve brain fog. Doctors are also trying the antidepressant amitriptyline to help with sleep disturbances and headaches; the antiseizure medication gabapentin to help with pain, numbness, and other neurological symptoms; and drugs to relieve low blood pressure in patients experiencing postural orthostatic tachycardia syndrome (POTS).
The NIH is sponsoring studies that have recruited just over 8,200 adults. And more than two dozen researchers from Harvard; Stanford; the University of California, San Francisco; the J. Craig Venter Institute; Johns Hopkins University; the University of Pennsylvania; Mount Sinai Hospitals; Cardiff University; and Yale announced in September they were forming the Long COVID Research Initiative to speed up studies.
The group, with funding from private enterprise, plans to conduct tissue biopsy, imaging studies, and autopsies and will search for potential biomarkers in the blood of patients.
A version of this article first appeared on WebMD.com.