User login
Missed diagnosis common source of malpractice claims against PCPs
, according to the Medscape Primary Care Physician Malpractice Report 2021. This figure is less than the overall proportion of physicians in all specialties named in a malpractice suit (51%).
More PCPs were part of lawsuits that named multiple parties (34%) than suits that named a individual practitioners (11%). Failure to make a proper diagnosis (41%) was the most common claim in malpractice suits against PCPs, followed by poor outcome/disease progression (26%), complications from treatment/surgery (17%), wrongful death (16%), and failure to treat/delayed treatment (16%).
The report was compiled from an online survey that included more than 4,300 physicians from 29 specialties. The survey was available from May 21, 2021, to August 28, 2021, and included 732 family and internal medicine physicians. Most respondents had practiced medicine for more than 25 years (47%) or from 21-25 years (16%). Almost half of respondents (47%) were aged 60 years or older.
Most PCPs (63%) reported malpractice insurance premiums of less than $20,000 per year, which is more than the overall proportion for all specialists (52%). The typical premium for PCPs was $5,000-$9,999 (26%). Premium payments varied widely by geographic area, with a PCP in New York paying five times as much as a colleague in California, Tennessee, or Ohio would pay to obtain comparable coverage, the survey found.
More than 9 in 10 PCPs (91%) reported being “very surprised” or “somewhat surprised” to having been part of a malpractice suit and reported being upset and anxious: “Feeling betrayed by people to whom I had provided good care, and embarrassed that my colleagues might find out,” as one internist put it. The majority (84%) of PCPs said their lawsuits were unwarranted, in line with perceptions among all specialists (83%).
The largest proportions of cases were settled before trial (35%) or were dismissed within a few months of lawsuit filing (16%). A judge or jury ruled in the plaintiff’s favor only 2% of the time. Seven percent of cases are ongoing, and 3% were settled at trial, according to the survey.
The largest number of cases (40%) took between 1 and 2 years, although 30% were less than a year. Roughly one in four cases (24%) lasted 3-5 years. Almost half (47%) of any monetary payments to plaintiffs were $100,000 or less; one-third of such payments were capped at $500,000.
Two-thirds (68%) of PCPs said that the lawsuit did not negatively affect their careers, and more than one in four (28%) said they now no longer trust patients or that they treat them differently. This change in trust is slightly higher than for specialists overall (24%).
More than 4 in 10 PCPs (41%) said they would have done nothing differently despite being sued. The largest proportion of changes other PCPs would have made included improved documentation (18%) and ordering additional tests as a hedge against a lawsuit (11%); 10% said they should never have taken on the patient in the first place.
A version of this article first appeared on Medscape.com.
, according to the Medscape Primary Care Physician Malpractice Report 2021. This figure is less than the overall proportion of physicians in all specialties named in a malpractice suit (51%).
More PCPs were part of lawsuits that named multiple parties (34%) than suits that named a individual practitioners (11%). Failure to make a proper diagnosis (41%) was the most common claim in malpractice suits against PCPs, followed by poor outcome/disease progression (26%), complications from treatment/surgery (17%), wrongful death (16%), and failure to treat/delayed treatment (16%).
The report was compiled from an online survey that included more than 4,300 physicians from 29 specialties. The survey was available from May 21, 2021, to August 28, 2021, and included 732 family and internal medicine physicians. Most respondents had practiced medicine for more than 25 years (47%) or from 21-25 years (16%). Almost half of respondents (47%) were aged 60 years or older.
Most PCPs (63%) reported malpractice insurance premiums of less than $20,000 per year, which is more than the overall proportion for all specialists (52%). The typical premium for PCPs was $5,000-$9,999 (26%). Premium payments varied widely by geographic area, with a PCP in New York paying five times as much as a colleague in California, Tennessee, or Ohio would pay to obtain comparable coverage, the survey found.
More than 9 in 10 PCPs (91%) reported being “very surprised” or “somewhat surprised” to having been part of a malpractice suit and reported being upset and anxious: “Feeling betrayed by people to whom I had provided good care, and embarrassed that my colleagues might find out,” as one internist put it. The majority (84%) of PCPs said their lawsuits were unwarranted, in line with perceptions among all specialists (83%).
The largest proportions of cases were settled before trial (35%) or were dismissed within a few months of lawsuit filing (16%). A judge or jury ruled in the plaintiff’s favor only 2% of the time. Seven percent of cases are ongoing, and 3% were settled at trial, according to the survey.
The largest number of cases (40%) took between 1 and 2 years, although 30% were less than a year. Roughly one in four cases (24%) lasted 3-5 years. Almost half (47%) of any monetary payments to plaintiffs were $100,000 or less; one-third of such payments were capped at $500,000.
Two-thirds (68%) of PCPs said that the lawsuit did not negatively affect their careers, and more than one in four (28%) said they now no longer trust patients or that they treat them differently. This change in trust is slightly higher than for specialists overall (24%).
More than 4 in 10 PCPs (41%) said they would have done nothing differently despite being sued. The largest proportion of changes other PCPs would have made included improved documentation (18%) and ordering additional tests as a hedge against a lawsuit (11%); 10% said they should never have taken on the patient in the first place.
A version of this article first appeared on Medscape.com.
, according to the Medscape Primary Care Physician Malpractice Report 2021. This figure is less than the overall proportion of physicians in all specialties named in a malpractice suit (51%).
More PCPs were part of lawsuits that named multiple parties (34%) than suits that named a individual practitioners (11%). Failure to make a proper diagnosis (41%) was the most common claim in malpractice suits against PCPs, followed by poor outcome/disease progression (26%), complications from treatment/surgery (17%), wrongful death (16%), and failure to treat/delayed treatment (16%).
The report was compiled from an online survey that included more than 4,300 physicians from 29 specialties. The survey was available from May 21, 2021, to August 28, 2021, and included 732 family and internal medicine physicians. Most respondents had practiced medicine for more than 25 years (47%) or from 21-25 years (16%). Almost half of respondents (47%) were aged 60 years or older.
Most PCPs (63%) reported malpractice insurance premiums of less than $20,000 per year, which is more than the overall proportion for all specialists (52%). The typical premium for PCPs was $5,000-$9,999 (26%). Premium payments varied widely by geographic area, with a PCP in New York paying five times as much as a colleague in California, Tennessee, or Ohio would pay to obtain comparable coverage, the survey found.
More than 9 in 10 PCPs (91%) reported being “very surprised” or “somewhat surprised” to having been part of a malpractice suit and reported being upset and anxious: “Feeling betrayed by people to whom I had provided good care, and embarrassed that my colleagues might find out,” as one internist put it. The majority (84%) of PCPs said their lawsuits were unwarranted, in line with perceptions among all specialists (83%).
The largest proportions of cases were settled before trial (35%) or were dismissed within a few months of lawsuit filing (16%). A judge or jury ruled in the plaintiff’s favor only 2% of the time. Seven percent of cases are ongoing, and 3% were settled at trial, according to the survey.
The largest number of cases (40%) took between 1 and 2 years, although 30% were less than a year. Roughly one in four cases (24%) lasted 3-5 years. Almost half (47%) of any monetary payments to plaintiffs were $100,000 or less; one-third of such payments were capped at $500,000.
Two-thirds (68%) of PCPs said that the lawsuit did not negatively affect their careers, and more than one in four (28%) said they now no longer trust patients or that they treat them differently. This change in trust is slightly higher than for specialists overall (24%).
More than 4 in 10 PCPs (41%) said they would have done nothing differently despite being sued. The largest proportion of changes other PCPs would have made included improved documentation (18%) and ordering additional tests as a hedge against a lawsuit (11%); 10% said they should never have taken on the patient in the first place.
A version of this article first appeared on Medscape.com.
‘Deaths of despair’ rising, but only in the U.S.
In the United States,
This is not the case in 16 other industrialized nations, however, including Canada, Australia, and Japan, where mortality rates are actually decreasing.
One likely reason is that other countries take better care of their citizens from cradle to grave, authors Peter Sterling, PhD, and Michael Platt, PhD, of the University of Pennsylvania, Philadelphia, wrote in a special communication in JAMA Psychiatry published online Feb. 2.
In the United States, individuals and families often struggle in isolation to navigate the life cycle, whereas other countries offer communal assistance to every life stage, and this support protects individuals and families in the long term, they noted.
The United States could solve this “health crisis” by adopting the best practices of these other nations, they wrote.
U.S. is an outlier
From an anthropological perspective, Dr. Sterling and Dr. Platt point out that “hunter-gatherers” prioritized food, comfort, and companionship. When one of these needs is unexpectedly met, the surprise triggers a pulse of the feel-good hormone dopamine.
However, much of modern life offers few opportunities for surprise and dopamine pulses.
“It is the difference between a day’s hard walk to finally encounter and kill a wild pig to feed the family and community versus a quick trip to aisle 7 to select a pork roast in plastic wrap,” Dr. Sterling and Dr. Platt noted.
The hunter-gatherers were far more physically active, and cardiovascular disease, diabetes, obesity, and hypertension were virtually unknown.
The small-scale societies of hunters and gatherers depended on strong family bonds and cooperation with community members.
Modern life is more isolating, often with hours spent alone in front of a computer screen.
Yet the lack of natural dopamine producers in modern society and the increased social isolation is not unique to the United States but holds across the board for industrialized nations.
So why has the United States suffered more deaths of despair?
Dr. Sterling and Dr. Platt assert that it comes down to public support other countries provide their citizens across the life span, from prenatal care and quality preschool and elementary school to affordable (or free) education beyond high school.
This support did not require “bloody revolutions, just simple agreements to prepay basic human needs from public funds collected as taxes,” Dr. Sterling and Dr. Platt noted.
By adopting some of the best practices pioneered by other wealthy nations, the United States could reduce despair and restore to many the will to live, they added.
However, they caution against the “medicalization” of every identified cause of rising death rates.
“Every symptom of despair has been defined as a disorder or dysregulation within the individual. This incorrectly frames the problem, forcing individuals to grapple on their own,” they wrote.
“It also emphasizes treatment by pharmacology, providing innumerable drugs for anxiety, depression, anger, psychosis, and obesity, plus new drugs to treat addictions to the old drugs. We cannot defeat despair solely with pills – to the contrary, pills will only deepen it,” they added.
Dr. Platt reported receiving grant support from the National Institutes of Health, the National Science Foundation, and the Charles E. Kaufman Foundation. He is cofounder of Cogwear and a scientific adviser to Neuroflow, Amplio, Blue Horizon International, and Progenity. Dr. Sterling has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In the United States,
This is not the case in 16 other industrialized nations, however, including Canada, Australia, and Japan, where mortality rates are actually decreasing.
One likely reason is that other countries take better care of their citizens from cradle to grave, authors Peter Sterling, PhD, and Michael Platt, PhD, of the University of Pennsylvania, Philadelphia, wrote in a special communication in JAMA Psychiatry published online Feb. 2.
In the United States, individuals and families often struggle in isolation to navigate the life cycle, whereas other countries offer communal assistance to every life stage, and this support protects individuals and families in the long term, they noted.
The United States could solve this “health crisis” by adopting the best practices of these other nations, they wrote.
U.S. is an outlier
From an anthropological perspective, Dr. Sterling and Dr. Platt point out that “hunter-gatherers” prioritized food, comfort, and companionship. When one of these needs is unexpectedly met, the surprise triggers a pulse of the feel-good hormone dopamine.
However, much of modern life offers few opportunities for surprise and dopamine pulses.
“It is the difference between a day’s hard walk to finally encounter and kill a wild pig to feed the family and community versus a quick trip to aisle 7 to select a pork roast in plastic wrap,” Dr. Sterling and Dr. Platt noted.
The hunter-gatherers were far more physically active, and cardiovascular disease, diabetes, obesity, and hypertension were virtually unknown.
The small-scale societies of hunters and gatherers depended on strong family bonds and cooperation with community members.
Modern life is more isolating, often with hours spent alone in front of a computer screen.
Yet the lack of natural dopamine producers in modern society and the increased social isolation is not unique to the United States but holds across the board for industrialized nations.
So why has the United States suffered more deaths of despair?
Dr. Sterling and Dr. Platt assert that it comes down to public support other countries provide their citizens across the life span, from prenatal care and quality preschool and elementary school to affordable (or free) education beyond high school.
This support did not require “bloody revolutions, just simple agreements to prepay basic human needs from public funds collected as taxes,” Dr. Sterling and Dr. Platt noted.
By adopting some of the best practices pioneered by other wealthy nations, the United States could reduce despair and restore to many the will to live, they added.
However, they caution against the “medicalization” of every identified cause of rising death rates.
“Every symptom of despair has been defined as a disorder or dysregulation within the individual. This incorrectly frames the problem, forcing individuals to grapple on their own,” they wrote.
“It also emphasizes treatment by pharmacology, providing innumerable drugs for anxiety, depression, anger, psychosis, and obesity, plus new drugs to treat addictions to the old drugs. We cannot defeat despair solely with pills – to the contrary, pills will only deepen it,” they added.
Dr. Platt reported receiving grant support from the National Institutes of Health, the National Science Foundation, and the Charles E. Kaufman Foundation. He is cofounder of Cogwear and a scientific adviser to Neuroflow, Amplio, Blue Horizon International, and Progenity. Dr. Sterling has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In the United States,
This is not the case in 16 other industrialized nations, however, including Canada, Australia, and Japan, where mortality rates are actually decreasing.
One likely reason is that other countries take better care of their citizens from cradle to grave, authors Peter Sterling, PhD, and Michael Platt, PhD, of the University of Pennsylvania, Philadelphia, wrote in a special communication in JAMA Psychiatry published online Feb. 2.
In the United States, individuals and families often struggle in isolation to navigate the life cycle, whereas other countries offer communal assistance to every life stage, and this support protects individuals and families in the long term, they noted.
The United States could solve this “health crisis” by adopting the best practices of these other nations, they wrote.
U.S. is an outlier
From an anthropological perspective, Dr. Sterling and Dr. Platt point out that “hunter-gatherers” prioritized food, comfort, and companionship. When one of these needs is unexpectedly met, the surprise triggers a pulse of the feel-good hormone dopamine.
However, much of modern life offers few opportunities for surprise and dopamine pulses.
“It is the difference between a day’s hard walk to finally encounter and kill a wild pig to feed the family and community versus a quick trip to aisle 7 to select a pork roast in plastic wrap,” Dr. Sterling and Dr. Platt noted.
The hunter-gatherers were far more physically active, and cardiovascular disease, diabetes, obesity, and hypertension were virtually unknown.
The small-scale societies of hunters and gatherers depended on strong family bonds and cooperation with community members.
Modern life is more isolating, often with hours spent alone in front of a computer screen.
Yet the lack of natural dopamine producers in modern society and the increased social isolation is not unique to the United States but holds across the board for industrialized nations.
So why has the United States suffered more deaths of despair?
Dr. Sterling and Dr. Platt assert that it comes down to public support other countries provide their citizens across the life span, from prenatal care and quality preschool and elementary school to affordable (or free) education beyond high school.
This support did not require “bloody revolutions, just simple agreements to prepay basic human needs from public funds collected as taxes,” Dr. Sterling and Dr. Platt noted.
By adopting some of the best practices pioneered by other wealthy nations, the United States could reduce despair and restore to many the will to live, they added.
However, they caution against the “medicalization” of every identified cause of rising death rates.
“Every symptom of despair has been defined as a disorder or dysregulation within the individual. This incorrectly frames the problem, forcing individuals to grapple on their own,” they wrote.
“It also emphasizes treatment by pharmacology, providing innumerable drugs for anxiety, depression, anger, psychosis, and obesity, plus new drugs to treat addictions to the old drugs. We cannot defeat despair solely with pills – to the contrary, pills will only deepen it,” they added.
Dr. Platt reported receiving grant support from the National Institutes of Health, the National Science Foundation, and the Charles E. Kaufman Foundation. He is cofounder of Cogwear and a scientific adviser to Neuroflow, Amplio, Blue Horizon International, and Progenity. Dr. Sterling has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Antibody mix may prevent COVID symptoms in some asymptomatic people
over 28 days, new research shows.
Results of the study by Meagan P. O’Brien, MD, from Regeneron Pharmaceuticals and one of the study’s funders, and coauthors were published online Jan. 14, 2022, in an original investigation in JAMA.
The results suggest new potential for monoclonal antibodies currently used for postexposure prophylaxis and treatment of symptomatic SARS-CoV-2. It has not been clear whether monoclonal antibodies can benefit people with asymptomatic SARS-CoV-2 infection.
The trial included 314 participants (mean age, 41 years; 51.6% women). Of the participants, 310 (99.7%) completed the efficacy assessment period, and 204 were asymptomatic and tested negative at baseline and were included in the primary efficacy analysis.
The subcutaneous combination of casirivimab and imdevimab, 1,200 mg (600 mg each), significantly prevented progression to symptomatic disease (29/100 [29.0%] vs. 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% confidence interval, 0.30-0.97]; P = .04; absolute risk difference, −13.3% [95% CI, −26.3% to −0.3%]).
These results were part of a randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2–infected person at 112 sites in the United States, Romania, and Moldova. They were enrolled between July 13, 2020, and Jan. 28, 2021; follow-up ended March 11, 2021.
Asymptomatic people at least 12 years old were eligible if identified within 96 hours of index case positive test collection and were randomly assigned 1:1 to receive one dose of subcutaneous casirivimab and imdevimab (n = 158), or placebo (n = 156).
COVID-19 vaccination was prohibited before enrollment but was allowed after completing the 28-day efficacy assessment period.
Caution warranted
In an accompanying editorial, however, Jonathan Z. Li, MD, Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and Rajesh T. Gandhi, MD, Massachusetts General Hospital, Boston, and Harvard Medical School, urged caution in interpreting the results.
They wrote that, although monoclonal antibodies are generally used in individuals at high risk for severe COVID-19, this study population was less vulnerable, with an average age of 41, and 30% had no risk for the disease.
“Of the remainder, the most common risk factor was being overweight (which confers less risk than other factors),” the editorialists wrote.
They pointed out, as did the study authors, that enrollment came before the emergence of the Delta and Omicron variants, and that both casirivimab and imdevimab maintain their activity against Delta but not against Omicron.
“While prevention of symptomatic infection has benefits,” they wrote, “the primary goal of monoclonal antibody therapy is to prevent progression to severe disease; however, this trial was unable to assess this outcome because there were only three hospitalizations (all in the placebo group). Also, this study was conducted prior to widespread COVID-19 vaccination; whether monoclonal antibodies have the same benefit in people who have breakthrough infection after vaccination is not known.”
The editorialists highlighted the subcutaneous delivery in this study.
They wrote that Dr. O’Brien and coauthors provide evidence that subcutaneous administration is effective in infected individuals. “However, high serum monoclonal antibody levels are achieved more quickly after intravenous administration than following subcutaneous injection; it is unknown whether intravenous administration might have led to even greater efficacy for individuals with asymptomatic SARS-CoV-2 infection.”
The authors of the study also add that, despite efforts to recruit non-White participants, relatively few non-White people were enrolled. Additionally, few adolescents were enrolled.
The sample size was also relatively small, they acknowledge, because of a study design in which the infection status of asymptomatic participants was not confirmed at inclusion.
Several of the authors are employees/stockholders of Regeneron, and have a patent pending, which has been licensed and is receiving royalties. The study was supported by Regeneron and F. Hoffmann–La Roche. This trial was conducted jointly with the National Institute of Allergy and Infectious Diseases and the National Institutes of Health. The CoVPN (COVID-19 Prevention Network) is supported by cooperative agreement awards from the NIAID and NIH.
A version of this article first appeared on Medscape.com.
over 28 days, new research shows.
Results of the study by Meagan P. O’Brien, MD, from Regeneron Pharmaceuticals and one of the study’s funders, and coauthors were published online Jan. 14, 2022, in an original investigation in JAMA.
The results suggest new potential for monoclonal antibodies currently used for postexposure prophylaxis and treatment of symptomatic SARS-CoV-2. It has not been clear whether monoclonal antibodies can benefit people with asymptomatic SARS-CoV-2 infection.
The trial included 314 participants (mean age, 41 years; 51.6% women). Of the participants, 310 (99.7%) completed the efficacy assessment period, and 204 were asymptomatic and tested negative at baseline and were included in the primary efficacy analysis.
The subcutaneous combination of casirivimab and imdevimab, 1,200 mg (600 mg each), significantly prevented progression to symptomatic disease (29/100 [29.0%] vs. 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% confidence interval, 0.30-0.97]; P = .04; absolute risk difference, −13.3% [95% CI, −26.3% to −0.3%]).
These results were part of a randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2–infected person at 112 sites in the United States, Romania, and Moldova. They were enrolled between July 13, 2020, and Jan. 28, 2021; follow-up ended March 11, 2021.
Asymptomatic people at least 12 years old were eligible if identified within 96 hours of index case positive test collection and were randomly assigned 1:1 to receive one dose of subcutaneous casirivimab and imdevimab (n = 158), or placebo (n = 156).
COVID-19 vaccination was prohibited before enrollment but was allowed after completing the 28-day efficacy assessment period.
Caution warranted
In an accompanying editorial, however, Jonathan Z. Li, MD, Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and Rajesh T. Gandhi, MD, Massachusetts General Hospital, Boston, and Harvard Medical School, urged caution in interpreting the results.
They wrote that, although monoclonal antibodies are generally used in individuals at high risk for severe COVID-19, this study population was less vulnerable, with an average age of 41, and 30% had no risk for the disease.
“Of the remainder, the most common risk factor was being overweight (which confers less risk than other factors),” the editorialists wrote.
They pointed out, as did the study authors, that enrollment came before the emergence of the Delta and Omicron variants, and that both casirivimab and imdevimab maintain their activity against Delta but not against Omicron.
“While prevention of symptomatic infection has benefits,” they wrote, “the primary goal of monoclonal antibody therapy is to prevent progression to severe disease; however, this trial was unable to assess this outcome because there were only three hospitalizations (all in the placebo group). Also, this study was conducted prior to widespread COVID-19 vaccination; whether monoclonal antibodies have the same benefit in people who have breakthrough infection after vaccination is not known.”
The editorialists highlighted the subcutaneous delivery in this study.
They wrote that Dr. O’Brien and coauthors provide evidence that subcutaneous administration is effective in infected individuals. “However, high serum monoclonal antibody levels are achieved more quickly after intravenous administration than following subcutaneous injection; it is unknown whether intravenous administration might have led to even greater efficacy for individuals with asymptomatic SARS-CoV-2 infection.”
The authors of the study also add that, despite efforts to recruit non-White participants, relatively few non-White people were enrolled. Additionally, few adolescents were enrolled.
The sample size was also relatively small, they acknowledge, because of a study design in which the infection status of asymptomatic participants was not confirmed at inclusion.
Several of the authors are employees/stockholders of Regeneron, and have a patent pending, which has been licensed and is receiving royalties. The study was supported by Regeneron and F. Hoffmann–La Roche. This trial was conducted jointly with the National Institute of Allergy and Infectious Diseases and the National Institutes of Health. The CoVPN (COVID-19 Prevention Network) is supported by cooperative agreement awards from the NIAID and NIH.
A version of this article first appeared on Medscape.com.
over 28 days, new research shows.
Results of the study by Meagan P. O’Brien, MD, from Regeneron Pharmaceuticals and one of the study’s funders, and coauthors were published online Jan. 14, 2022, in an original investigation in JAMA.
The results suggest new potential for monoclonal antibodies currently used for postexposure prophylaxis and treatment of symptomatic SARS-CoV-2. It has not been clear whether monoclonal antibodies can benefit people with asymptomatic SARS-CoV-2 infection.
The trial included 314 participants (mean age, 41 years; 51.6% women). Of the participants, 310 (99.7%) completed the efficacy assessment period, and 204 were asymptomatic and tested negative at baseline and were included in the primary efficacy analysis.
The subcutaneous combination of casirivimab and imdevimab, 1,200 mg (600 mg each), significantly prevented progression to symptomatic disease (29/100 [29.0%] vs. 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% confidence interval, 0.30-0.97]; P = .04; absolute risk difference, −13.3% [95% CI, −26.3% to −0.3%]).
These results were part of a randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2–infected person at 112 sites in the United States, Romania, and Moldova. They were enrolled between July 13, 2020, and Jan. 28, 2021; follow-up ended March 11, 2021.
Asymptomatic people at least 12 years old were eligible if identified within 96 hours of index case positive test collection and were randomly assigned 1:1 to receive one dose of subcutaneous casirivimab and imdevimab (n = 158), or placebo (n = 156).
COVID-19 vaccination was prohibited before enrollment but was allowed after completing the 28-day efficacy assessment period.
Caution warranted
In an accompanying editorial, however, Jonathan Z. Li, MD, Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and Rajesh T. Gandhi, MD, Massachusetts General Hospital, Boston, and Harvard Medical School, urged caution in interpreting the results.
They wrote that, although monoclonal antibodies are generally used in individuals at high risk for severe COVID-19, this study population was less vulnerable, with an average age of 41, and 30% had no risk for the disease.
“Of the remainder, the most common risk factor was being overweight (which confers less risk than other factors),” the editorialists wrote.
They pointed out, as did the study authors, that enrollment came before the emergence of the Delta and Omicron variants, and that both casirivimab and imdevimab maintain their activity against Delta but not against Omicron.
“While prevention of symptomatic infection has benefits,” they wrote, “the primary goal of monoclonal antibody therapy is to prevent progression to severe disease; however, this trial was unable to assess this outcome because there were only three hospitalizations (all in the placebo group). Also, this study was conducted prior to widespread COVID-19 vaccination; whether monoclonal antibodies have the same benefit in people who have breakthrough infection after vaccination is not known.”
The editorialists highlighted the subcutaneous delivery in this study.
They wrote that Dr. O’Brien and coauthors provide evidence that subcutaneous administration is effective in infected individuals. “However, high serum monoclonal antibody levels are achieved more quickly after intravenous administration than following subcutaneous injection; it is unknown whether intravenous administration might have led to even greater efficacy for individuals with asymptomatic SARS-CoV-2 infection.”
The authors of the study also add that, despite efforts to recruit non-White participants, relatively few non-White people were enrolled. Additionally, few adolescents were enrolled.
The sample size was also relatively small, they acknowledge, because of a study design in which the infection status of asymptomatic participants was not confirmed at inclusion.
Several of the authors are employees/stockholders of Regeneron, and have a patent pending, which has been licensed and is receiving royalties. The study was supported by Regeneron and F. Hoffmann–La Roche. This trial was conducted jointly with the National Institute of Allergy and Infectious Diseases and the National Institutes of Health. The CoVPN (COVID-19 Prevention Network) is supported by cooperative agreement awards from the NIAID and NIH.
A version of this article first appeared on Medscape.com.
FROM JAMA
VARC-3 TAVR technical failure definition ‘highly clinically relevant’
A new study offers early validation of the recently released Valve Academic Research Consortium 3 (VARC-3) definition of technical success after transcatheter aortic valve replacement (TAVR) and highlights its role in patient prognosis.
Results show that one in 10 patients (11.6%) undergoing TAVR with contemporary devices and techniques experiences technical failure, according to VARC-3.
At 30 days, patients with technical failure had significantly higher rates of the composite of cardiovascular (CV) death or stroke (11.5% vs. 3.5%), CV death (6.0% vs. 1.0%), and stroke (7.2% vs. 2.9%), compared with those with technical success.
Technical failure after TAVR was also independently associated with a twofold higher risk for CV death or stroke at 1 year (20.0% vs. 10.3%; hazard ratio, 2.01; 95% CI, 1.37-2.95).
Other independent predictors were history of peripheral artery disease (HR, 1.97), New York Heart Association III or IV disease (HR, 1.86), baseline moderate or greater mitral regurgitation (HR, 1.48), atrial fibrillation (HR, 1.40), and Society of Thoracic Surgeons predicted mortality risk (HR, 1.04).
“We were expecting that we were getting better over time with device iterations, with more experience, so we weren’t surprised by the result. But I think what is somewhat surprising is how much of an impact it has on the outcome,” senior study author Thomas Pilgrim, MD, Inselspital, University of Bern, Switzerland, told this news organization.
The VARC-3 document, introduced last year to some controversy, features a heavier focus on patient outcomes, as well as composite safety and efficacy endpoints. The definition of technical success after TAVR includes freedom from death; successful access, delivery of the device, and retrieval of the delivery system; correct positioning of a prosthetic heart valve into the proper anatomical location; and freedom from surgery or intervention related to the device or to an access-related or cardiac structural complication.
The composite endpoint is meant to replace the VARC-2 definition of “device success,” which also included freedom from death and correct valve positioning but required echocardiographic evaluation. With VARC-3, there is an “immediate measure” of success without having to wait for echocardiography, observed Dr. Pilgrim.
As reported in the Journal of the American College of Cardiology Cardiovascular Interventions, TAVR was a technical success in 1,435 of 1,624 (88.4%) patients. Technical failure occurred in 189 patients related to either vascular complications (8.6%) or procedural death or cardiac complications (3.0%).
The VARC-2 endpoint of device success was observed in 66.1% of patients. The high rate of device failure was largely attributed to a 28% incidence of prosthesis-patient mismatch.
“If you use the VARC-2 device success [definition], you include this patient–prosthesis mismatch, the [valve] gradients, [and] regurgitation and then device success is always lower,” Dr. Pilgrim said.
Asked whether the VARC-3 definition may be missing case failures, he replied: “At this stage, we don’t know how important these echocardiographic parameters are for hard clinical endpoints. Maybe the VARC-2 endpoint was too sensitive or the VARC-3 endpoint is not sensitive enough. This is something we just don’t know at this stage.”
Marco Barbanti, MD, an interventional cardiologist at Rodolico Polyclinic University Hospital-San Marco, Catania, Italy, and author of an accompanying editorial, said VARC-3 represents a more accurate indicator of immediate success of the procedure.
“It’s a more pertinent definition according to what really has an impact on prognosis, and, according to the results of this paper, actually, the calibration of this new definition is quite good,” Dr. Barbanti said in an interview.
Patients with VARC-3 technical failure were older, had a higher body mass index, and had more advanced heart failure symptoms than those with technical success. There were no significant differences between the two groups in echocardiographic or CT data, anesthetic strategy, valve type or size, or use of pre- or post-dilation.
All patients underwent TAVR with current balloon-expandable (Sapien 3/Sapien Ultra, Edwards Lifesciences) or self-expanding (Evolut R/PRO [Medtronic], Portico [Abbott], Symetis ACURATE/ACURATE neo [Boston Scientific]) devices between March 2012 and December 2019. A transfemoral approach was used in 92.5% of patients.
In a landmark analysis with the landmark set at 30 days, the effect of technical failure on adverse outcome was limited to the first 30 days (composite endpoint 0-30 days: HR, 3.42; P < .001; 30-360 days: HR, 1.36; P = .266; P for interaction = .002).
At 1 year, the composite of CV death and stroke endpoint occurred in 24.1% of patients with cardiac technical failure, in 18.8% of patients with vascular technical failure, and in 10.3% of patients with technical success.
In multivariate analyses, cardiac and vascular technical failures were independently associated with a 2.6-fold and 1.9-fold increased risk, respectively, for the composite of cardiovascular death and stroke at 1 year.
Female sex, larger device landing zone calcium volume, and earlier procedures (March 2012 to July 2016) were associated with a higher risk for cardiac technical failure, whereas, consistent with previous studies, higher body mass index and use of the Prostar/Manta versus the ProGlide closure device predicted vascular technical failure.
The findings “underscore that technical success is highly clinically relevant and may serve as one of the pivotal endpoints to evaluate the improvement of TAVR or for head-to-head comparisons of new devices in future clinical trials,” the authors conclude.
The findings reflect the experience of a single high-volume center with highly experienced operators in the prospective BERN TAVR registry, however, and may not be generalizable to other heart centers, they note. Although the registry has standardized follow-up, independent analysis of echocardiographic and CT, and independent event adjudication, vascular anatomy was not systematically assessed, and the potential exists for confounding from unmeasured variables.
Dr. Pilgrim reports research grants to the institution from Edwards Lifesciences, Boston Scientific, and Biotronik, personal fees from Biotronik and Boston Scientific, and other from HighLife SAS. Dr. Barbanti is a consultant for Edwards Lifesciences and Boston Scientific.
A version of this article first appeared on Medscape.com.
A new study offers early validation of the recently released Valve Academic Research Consortium 3 (VARC-3) definition of technical success after transcatheter aortic valve replacement (TAVR) and highlights its role in patient prognosis.
Results show that one in 10 patients (11.6%) undergoing TAVR with contemporary devices and techniques experiences technical failure, according to VARC-3.
At 30 days, patients with technical failure had significantly higher rates of the composite of cardiovascular (CV) death or stroke (11.5% vs. 3.5%), CV death (6.0% vs. 1.0%), and stroke (7.2% vs. 2.9%), compared with those with technical success.
Technical failure after TAVR was also independently associated with a twofold higher risk for CV death or stroke at 1 year (20.0% vs. 10.3%; hazard ratio, 2.01; 95% CI, 1.37-2.95).
Other independent predictors were history of peripheral artery disease (HR, 1.97), New York Heart Association III or IV disease (HR, 1.86), baseline moderate or greater mitral regurgitation (HR, 1.48), atrial fibrillation (HR, 1.40), and Society of Thoracic Surgeons predicted mortality risk (HR, 1.04).
“We were expecting that we were getting better over time with device iterations, with more experience, so we weren’t surprised by the result. But I think what is somewhat surprising is how much of an impact it has on the outcome,” senior study author Thomas Pilgrim, MD, Inselspital, University of Bern, Switzerland, told this news organization.
The VARC-3 document, introduced last year to some controversy, features a heavier focus on patient outcomes, as well as composite safety and efficacy endpoints. The definition of technical success after TAVR includes freedom from death; successful access, delivery of the device, and retrieval of the delivery system; correct positioning of a prosthetic heart valve into the proper anatomical location; and freedom from surgery or intervention related to the device or to an access-related or cardiac structural complication.
The composite endpoint is meant to replace the VARC-2 definition of “device success,” which also included freedom from death and correct valve positioning but required echocardiographic evaluation. With VARC-3, there is an “immediate measure” of success without having to wait for echocardiography, observed Dr. Pilgrim.
As reported in the Journal of the American College of Cardiology Cardiovascular Interventions, TAVR was a technical success in 1,435 of 1,624 (88.4%) patients. Technical failure occurred in 189 patients related to either vascular complications (8.6%) or procedural death or cardiac complications (3.0%).
The VARC-2 endpoint of device success was observed in 66.1% of patients. The high rate of device failure was largely attributed to a 28% incidence of prosthesis-patient mismatch.
“If you use the VARC-2 device success [definition], you include this patient–prosthesis mismatch, the [valve] gradients, [and] regurgitation and then device success is always lower,” Dr. Pilgrim said.
Asked whether the VARC-3 definition may be missing case failures, he replied: “At this stage, we don’t know how important these echocardiographic parameters are for hard clinical endpoints. Maybe the VARC-2 endpoint was too sensitive or the VARC-3 endpoint is not sensitive enough. This is something we just don’t know at this stage.”
Marco Barbanti, MD, an interventional cardiologist at Rodolico Polyclinic University Hospital-San Marco, Catania, Italy, and author of an accompanying editorial, said VARC-3 represents a more accurate indicator of immediate success of the procedure.
“It’s a more pertinent definition according to what really has an impact on prognosis, and, according to the results of this paper, actually, the calibration of this new definition is quite good,” Dr. Barbanti said in an interview.
Patients with VARC-3 technical failure were older, had a higher body mass index, and had more advanced heart failure symptoms than those with technical success. There were no significant differences between the two groups in echocardiographic or CT data, anesthetic strategy, valve type or size, or use of pre- or post-dilation.
All patients underwent TAVR with current balloon-expandable (Sapien 3/Sapien Ultra, Edwards Lifesciences) or self-expanding (Evolut R/PRO [Medtronic], Portico [Abbott], Symetis ACURATE/ACURATE neo [Boston Scientific]) devices between March 2012 and December 2019. A transfemoral approach was used in 92.5% of patients.
In a landmark analysis with the landmark set at 30 days, the effect of technical failure on adverse outcome was limited to the first 30 days (composite endpoint 0-30 days: HR, 3.42; P < .001; 30-360 days: HR, 1.36; P = .266; P for interaction = .002).
At 1 year, the composite of CV death and stroke endpoint occurred in 24.1% of patients with cardiac technical failure, in 18.8% of patients with vascular technical failure, and in 10.3% of patients with technical success.
In multivariate analyses, cardiac and vascular technical failures were independently associated with a 2.6-fold and 1.9-fold increased risk, respectively, for the composite of cardiovascular death and stroke at 1 year.
Female sex, larger device landing zone calcium volume, and earlier procedures (March 2012 to July 2016) were associated with a higher risk for cardiac technical failure, whereas, consistent with previous studies, higher body mass index and use of the Prostar/Manta versus the ProGlide closure device predicted vascular technical failure.
The findings “underscore that technical success is highly clinically relevant and may serve as one of the pivotal endpoints to evaluate the improvement of TAVR or for head-to-head comparisons of new devices in future clinical trials,” the authors conclude.
The findings reflect the experience of a single high-volume center with highly experienced operators in the prospective BERN TAVR registry, however, and may not be generalizable to other heart centers, they note. Although the registry has standardized follow-up, independent analysis of echocardiographic and CT, and independent event adjudication, vascular anatomy was not systematically assessed, and the potential exists for confounding from unmeasured variables.
Dr. Pilgrim reports research grants to the institution from Edwards Lifesciences, Boston Scientific, and Biotronik, personal fees from Biotronik and Boston Scientific, and other from HighLife SAS. Dr. Barbanti is a consultant for Edwards Lifesciences and Boston Scientific.
A version of this article first appeared on Medscape.com.
A new study offers early validation of the recently released Valve Academic Research Consortium 3 (VARC-3) definition of technical success after transcatheter aortic valve replacement (TAVR) and highlights its role in patient prognosis.
Results show that one in 10 patients (11.6%) undergoing TAVR with contemporary devices and techniques experiences technical failure, according to VARC-3.
At 30 days, patients with technical failure had significantly higher rates of the composite of cardiovascular (CV) death or stroke (11.5% vs. 3.5%), CV death (6.0% vs. 1.0%), and stroke (7.2% vs. 2.9%), compared with those with technical success.
Technical failure after TAVR was also independently associated with a twofold higher risk for CV death or stroke at 1 year (20.0% vs. 10.3%; hazard ratio, 2.01; 95% CI, 1.37-2.95).
Other independent predictors were history of peripheral artery disease (HR, 1.97), New York Heart Association III or IV disease (HR, 1.86), baseline moderate or greater mitral regurgitation (HR, 1.48), atrial fibrillation (HR, 1.40), and Society of Thoracic Surgeons predicted mortality risk (HR, 1.04).
“We were expecting that we were getting better over time with device iterations, with more experience, so we weren’t surprised by the result. But I think what is somewhat surprising is how much of an impact it has on the outcome,” senior study author Thomas Pilgrim, MD, Inselspital, University of Bern, Switzerland, told this news organization.
The VARC-3 document, introduced last year to some controversy, features a heavier focus on patient outcomes, as well as composite safety and efficacy endpoints. The definition of technical success after TAVR includes freedom from death; successful access, delivery of the device, and retrieval of the delivery system; correct positioning of a prosthetic heart valve into the proper anatomical location; and freedom from surgery or intervention related to the device or to an access-related or cardiac structural complication.
The composite endpoint is meant to replace the VARC-2 definition of “device success,” which also included freedom from death and correct valve positioning but required echocardiographic evaluation. With VARC-3, there is an “immediate measure” of success without having to wait for echocardiography, observed Dr. Pilgrim.
As reported in the Journal of the American College of Cardiology Cardiovascular Interventions, TAVR was a technical success in 1,435 of 1,624 (88.4%) patients. Technical failure occurred in 189 patients related to either vascular complications (8.6%) or procedural death or cardiac complications (3.0%).
The VARC-2 endpoint of device success was observed in 66.1% of patients. The high rate of device failure was largely attributed to a 28% incidence of prosthesis-patient mismatch.
“If you use the VARC-2 device success [definition], you include this patient–prosthesis mismatch, the [valve] gradients, [and] regurgitation and then device success is always lower,” Dr. Pilgrim said.
Asked whether the VARC-3 definition may be missing case failures, he replied: “At this stage, we don’t know how important these echocardiographic parameters are for hard clinical endpoints. Maybe the VARC-2 endpoint was too sensitive or the VARC-3 endpoint is not sensitive enough. This is something we just don’t know at this stage.”
Marco Barbanti, MD, an interventional cardiologist at Rodolico Polyclinic University Hospital-San Marco, Catania, Italy, and author of an accompanying editorial, said VARC-3 represents a more accurate indicator of immediate success of the procedure.
“It’s a more pertinent definition according to what really has an impact on prognosis, and, according to the results of this paper, actually, the calibration of this new definition is quite good,” Dr. Barbanti said in an interview.
Patients with VARC-3 technical failure were older, had a higher body mass index, and had more advanced heart failure symptoms than those with technical success. There were no significant differences between the two groups in echocardiographic or CT data, anesthetic strategy, valve type or size, or use of pre- or post-dilation.
All patients underwent TAVR with current balloon-expandable (Sapien 3/Sapien Ultra, Edwards Lifesciences) or self-expanding (Evolut R/PRO [Medtronic], Portico [Abbott], Symetis ACURATE/ACURATE neo [Boston Scientific]) devices between March 2012 and December 2019. A transfemoral approach was used in 92.5% of patients.
In a landmark analysis with the landmark set at 30 days, the effect of technical failure on adverse outcome was limited to the first 30 days (composite endpoint 0-30 days: HR, 3.42; P < .001; 30-360 days: HR, 1.36; P = .266; P for interaction = .002).
At 1 year, the composite of CV death and stroke endpoint occurred in 24.1% of patients with cardiac technical failure, in 18.8% of patients with vascular technical failure, and in 10.3% of patients with technical success.
In multivariate analyses, cardiac and vascular technical failures were independently associated with a 2.6-fold and 1.9-fold increased risk, respectively, for the composite of cardiovascular death and stroke at 1 year.
Female sex, larger device landing zone calcium volume, and earlier procedures (March 2012 to July 2016) were associated with a higher risk for cardiac technical failure, whereas, consistent with previous studies, higher body mass index and use of the Prostar/Manta versus the ProGlide closure device predicted vascular technical failure.
The findings “underscore that technical success is highly clinically relevant and may serve as one of the pivotal endpoints to evaluate the improvement of TAVR or for head-to-head comparisons of new devices in future clinical trials,” the authors conclude.
The findings reflect the experience of a single high-volume center with highly experienced operators in the prospective BERN TAVR registry, however, and may not be generalizable to other heart centers, they note. Although the registry has standardized follow-up, independent analysis of echocardiographic and CT, and independent event adjudication, vascular anatomy was not systematically assessed, and the potential exists for confounding from unmeasured variables.
Dr. Pilgrim reports research grants to the institution from Edwards Lifesciences, Boston Scientific, and Biotronik, personal fees from Biotronik and Boston Scientific, and other from HighLife SAS. Dr. Barbanti is a consultant for Edwards Lifesciences and Boston Scientific.
A version of this article first appeared on Medscape.com.
FROM JACC: CARDIOVASCULAR INTERVENTIONS
Future respiratory infection risk raised by early life virus exposure
Many factors influence a child’s subsequent susceptibility to respiratory tract infection (RTI), including breastfeeding, crowded conditions, and exposure to environmental tobacco. Now researchers have found that asymptomatic viral infection in the first days of a baby’s life are linked to a greater risk of respiratory infections in later life.
The new research, published in Nature Microbiology, was conducted as part of the Microbiome Utrecht Infant Study (MUIS), a healthy infant birth cohort study that’s been running for 6 years.
In their study, the authors explained how the respiratory tract is “populated by a specialized microbial ecosystem, which is seeded during and directly following birth,” adding that, “despite recognition of many host and environmental factors known to modulate RTI susceptibility, the mechanism by which a child develops recurrent or severe RTIs, while others remain healthy, remains largely unknown”.
Researchers from the University of Edinburgh and University Medical Centre Utrecht (the Netherlands) examined nasal mucosa samples of 114 babies at various times from birth until 12 months of age. They then analyzed the gene activity of the babies’ nasal mucosa, the microbes present in the lining of the nose, and any viruses that infected the children.
Interferon-related mucosal gene activity
The researchers described how the microbiome – the community of microbes in the body – of a newborn baby can be influenced by many things, including delivery method, breastfeeding, antibiotics and the hospital environment. They highlighted how viruses were found to interact with a newborn’s immune system and microbiome in a way that affected both a child’s risk, and number, of subsequent infections.
They explained how when a viral infection was detected in the first days after birth, which they said largely occurred asymptomatically, specific mucosal genes were activated – genes involved with interferons – coinciding with a change in the composition of the microbiome, promoting the growth of potentially harmful microbes.
“The interferon-related gene activity caused by an early first viral infection is thought to create a proinflammatory environment that makes babies susceptible to future infections,” they said, adding that in their study they have demonstrated that “first asymptomatic viral encounters were associated with increased interferon signaling, and preceded the development of disadvantageous respiratory microbiota profiles and clinical RTIs”.
Proinflammatory and microbiologically perturbed environment
Debby Bogaert, PhD, chair of paediatric medicine at the University of Edinburgh, said: “We were surprised to see viral infections occur so early in life, and go mostly unnoticed, probably because the infant’s immune system is in what is known as a state of tolerance after birth. Despite this, these infections seem to affect a normal immune development, which is important to know.”
The authors wrote that their data supports the hypothesis that first viral encounters trigger an interferon-associated proinflammatory environment, which then further drives airway inflammation and symptomatology in a “self-enforcing positive feedback loop”. They said that this “proinflammatory and microbiologically perturbed environment in turn renders an individual more vulnerable to recurrent viral-induced RTIs”.
Wouter de Steenhuijsen, PhD, postdoctoral investigator at University Medical Centre Utrecht, said: “Although further work will be needed to confirm the causality of our findings, the data from this study indicate that early-life encounters with respiratory viruses – especially during the first days of life – may set the tone for subsequent non-beneficial host-microbe interactions, which are related to an infection risk and possibly long term respiratory health.”
Dr. Bogaert added: “Only from birth onwards will an infant start to develop its microbiome. Limiting the number of viral encounters in those first days to weeks of life might be essential for a healthy immune and microbiome development, and consequently long term respiratory health.”
A version of this article first appeared on Medscape UK.
Many factors influence a child’s subsequent susceptibility to respiratory tract infection (RTI), including breastfeeding, crowded conditions, and exposure to environmental tobacco. Now researchers have found that asymptomatic viral infection in the first days of a baby’s life are linked to a greater risk of respiratory infections in later life.
The new research, published in Nature Microbiology, was conducted as part of the Microbiome Utrecht Infant Study (MUIS), a healthy infant birth cohort study that’s been running for 6 years.
In their study, the authors explained how the respiratory tract is “populated by a specialized microbial ecosystem, which is seeded during and directly following birth,” adding that, “despite recognition of many host and environmental factors known to modulate RTI susceptibility, the mechanism by which a child develops recurrent or severe RTIs, while others remain healthy, remains largely unknown”.
Researchers from the University of Edinburgh and University Medical Centre Utrecht (the Netherlands) examined nasal mucosa samples of 114 babies at various times from birth until 12 months of age. They then analyzed the gene activity of the babies’ nasal mucosa, the microbes present in the lining of the nose, and any viruses that infected the children.
Interferon-related mucosal gene activity
The researchers described how the microbiome – the community of microbes in the body – of a newborn baby can be influenced by many things, including delivery method, breastfeeding, antibiotics and the hospital environment. They highlighted how viruses were found to interact with a newborn’s immune system and microbiome in a way that affected both a child’s risk, and number, of subsequent infections.
They explained how when a viral infection was detected in the first days after birth, which they said largely occurred asymptomatically, specific mucosal genes were activated – genes involved with interferons – coinciding with a change in the composition of the microbiome, promoting the growth of potentially harmful microbes.
“The interferon-related gene activity caused by an early first viral infection is thought to create a proinflammatory environment that makes babies susceptible to future infections,” they said, adding that in their study they have demonstrated that “first asymptomatic viral encounters were associated with increased interferon signaling, and preceded the development of disadvantageous respiratory microbiota profiles and clinical RTIs”.
Proinflammatory and microbiologically perturbed environment
Debby Bogaert, PhD, chair of paediatric medicine at the University of Edinburgh, said: “We were surprised to see viral infections occur so early in life, and go mostly unnoticed, probably because the infant’s immune system is in what is known as a state of tolerance after birth. Despite this, these infections seem to affect a normal immune development, which is important to know.”
The authors wrote that their data supports the hypothesis that first viral encounters trigger an interferon-associated proinflammatory environment, which then further drives airway inflammation and symptomatology in a “self-enforcing positive feedback loop”. They said that this “proinflammatory and microbiologically perturbed environment in turn renders an individual more vulnerable to recurrent viral-induced RTIs”.
Wouter de Steenhuijsen, PhD, postdoctoral investigator at University Medical Centre Utrecht, said: “Although further work will be needed to confirm the causality of our findings, the data from this study indicate that early-life encounters with respiratory viruses – especially during the first days of life – may set the tone for subsequent non-beneficial host-microbe interactions, which are related to an infection risk and possibly long term respiratory health.”
Dr. Bogaert added: “Only from birth onwards will an infant start to develop its microbiome. Limiting the number of viral encounters in those first days to weeks of life might be essential for a healthy immune and microbiome development, and consequently long term respiratory health.”
A version of this article first appeared on Medscape UK.
Many factors influence a child’s subsequent susceptibility to respiratory tract infection (RTI), including breastfeeding, crowded conditions, and exposure to environmental tobacco. Now researchers have found that asymptomatic viral infection in the first days of a baby’s life are linked to a greater risk of respiratory infections in later life.
The new research, published in Nature Microbiology, was conducted as part of the Microbiome Utrecht Infant Study (MUIS), a healthy infant birth cohort study that’s been running for 6 years.
In their study, the authors explained how the respiratory tract is “populated by a specialized microbial ecosystem, which is seeded during and directly following birth,” adding that, “despite recognition of many host and environmental factors known to modulate RTI susceptibility, the mechanism by which a child develops recurrent or severe RTIs, while others remain healthy, remains largely unknown”.
Researchers from the University of Edinburgh and University Medical Centre Utrecht (the Netherlands) examined nasal mucosa samples of 114 babies at various times from birth until 12 months of age. They then analyzed the gene activity of the babies’ nasal mucosa, the microbes present in the lining of the nose, and any viruses that infected the children.
Interferon-related mucosal gene activity
The researchers described how the microbiome – the community of microbes in the body – of a newborn baby can be influenced by many things, including delivery method, breastfeeding, antibiotics and the hospital environment. They highlighted how viruses were found to interact with a newborn’s immune system and microbiome in a way that affected both a child’s risk, and number, of subsequent infections.
They explained how when a viral infection was detected in the first days after birth, which they said largely occurred asymptomatically, specific mucosal genes were activated – genes involved with interferons – coinciding with a change in the composition of the microbiome, promoting the growth of potentially harmful microbes.
“The interferon-related gene activity caused by an early first viral infection is thought to create a proinflammatory environment that makes babies susceptible to future infections,” they said, adding that in their study they have demonstrated that “first asymptomatic viral encounters were associated with increased interferon signaling, and preceded the development of disadvantageous respiratory microbiota profiles and clinical RTIs”.
Proinflammatory and microbiologically perturbed environment
Debby Bogaert, PhD, chair of paediatric medicine at the University of Edinburgh, said: “We were surprised to see viral infections occur so early in life, and go mostly unnoticed, probably because the infant’s immune system is in what is known as a state of tolerance after birth. Despite this, these infections seem to affect a normal immune development, which is important to know.”
The authors wrote that their data supports the hypothesis that first viral encounters trigger an interferon-associated proinflammatory environment, which then further drives airway inflammation and symptomatology in a “self-enforcing positive feedback loop”. They said that this “proinflammatory and microbiologically perturbed environment in turn renders an individual more vulnerable to recurrent viral-induced RTIs”.
Wouter de Steenhuijsen, PhD, postdoctoral investigator at University Medical Centre Utrecht, said: “Although further work will be needed to confirm the causality of our findings, the data from this study indicate that early-life encounters with respiratory viruses – especially during the first days of life – may set the tone for subsequent non-beneficial host-microbe interactions, which are related to an infection risk and possibly long term respiratory health.”
Dr. Bogaert added: “Only from birth onwards will an infant start to develop its microbiome. Limiting the number of viral encounters in those first days to weeks of life might be essential for a healthy immune and microbiome development, and consequently long term respiratory health.”
A version of this article first appeared on Medscape UK.
FROM NATURE MICROBIOLOGY
Infectious disease pop quiz: Clinical challenge #13 for the ObGyn
For a moderately ill pregnant woman, what is the most appropriate antibiotic combination for inpatient treatment of community-acquired pneumonia?
Continue to the answer...
This patient should be treated with intravenous ceftriaxone (2 g every 24 hours) plus oral or intravenous azithromycin. The appropriate oral dose of azithromycin is 500 mg on day 1, then 250 mg daily for 4 doses. The appropriate intravenous dose of azithromycin is 500 mg every 24 hours. The goal is to provide appropriate coverage for the most likely pathogens: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and mycoplasmas. (Antibacterial drugs for community-acquired pneumonia. Med Lett Drugs Ther. 2021:63:10-14. Postma DF, van Werkoven CH, van Eldin LJ, et al; CAP-START Study Group. Antibiotic treatment strategies for community acquired pneumonia in adults. N Engl J Med. 2015;372:1312-1323.)
- Duff P. Maternal and perinatal infections: bacterial. In: Landon MB, Galan HL, Jauniaux ERM, et al. Gabbe’s Obstetrics: Normal and Problem Pregnancies. 8th ed. Elsevier; 2021:1124-1146.
- Duff P. Maternal and fetal infections. In: Resnik R, Lockwood CJ, Moore TJ, et al. Creasy & Resnik’s Maternal-Fetal Medicine: Principles and Practice. 8th ed. Elsevier; 2019:862-919.
Dr. Edwards is a Resident in the Department of Medicine, University of Florida College of Medicine, Gainesville.
Dr. Duff is Professor of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville.
The authors report no financial relationships relevant to this article.
Dr. Edwards is a Resident in the Department of Medicine, University of Florida College of Medicine, Gainesville.
Dr. Duff is Professor of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville.
The authors report no financial relationships relevant to this article.
Dr. Edwards is a Resident in the Department of Medicine, University of Florida College of Medicine, Gainesville.
Dr. Duff is Professor of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville.
The authors report no financial relationships relevant to this article.
For a moderately ill pregnant woman, what is the most appropriate antibiotic combination for inpatient treatment of community-acquired pneumonia?
Continue to the answer...
This patient should be treated with intravenous ceftriaxone (2 g every 24 hours) plus oral or intravenous azithromycin. The appropriate oral dose of azithromycin is 500 mg on day 1, then 250 mg daily for 4 doses. The appropriate intravenous dose of azithromycin is 500 mg every 24 hours. The goal is to provide appropriate coverage for the most likely pathogens: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and mycoplasmas. (Antibacterial drugs for community-acquired pneumonia. Med Lett Drugs Ther. 2021:63:10-14. Postma DF, van Werkoven CH, van Eldin LJ, et al; CAP-START Study Group. Antibiotic treatment strategies for community acquired pneumonia in adults. N Engl J Med. 2015;372:1312-1323.)
For a moderately ill pregnant woman, what is the most appropriate antibiotic combination for inpatient treatment of community-acquired pneumonia?
Continue to the answer...
This patient should be treated with intravenous ceftriaxone (2 g every 24 hours) plus oral or intravenous azithromycin. The appropriate oral dose of azithromycin is 500 mg on day 1, then 250 mg daily for 4 doses. The appropriate intravenous dose of azithromycin is 500 mg every 24 hours. The goal is to provide appropriate coverage for the most likely pathogens: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and mycoplasmas. (Antibacterial drugs for community-acquired pneumonia. Med Lett Drugs Ther. 2021:63:10-14. Postma DF, van Werkoven CH, van Eldin LJ, et al; CAP-START Study Group. Antibiotic treatment strategies for community acquired pneumonia in adults. N Engl J Med. 2015;372:1312-1323.)
- Duff P. Maternal and perinatal infections: bacterial. In: Landon MB, Galan HL, Jauniaux ERM, et al. Gabbe’s Obstetrics: Normal and Problem Pregnancies. 8th ed. Elsevier; 2021:1124-1146.
- Duff P. Maternal and fetal infections. In: Resnik R, Lockwood CJ, Moore TJ, et al. Creasy & Resnik’s Maternal-Fetal Medicine: Principles and Practice. 8th ed. Elsevier; 2019:862-919.
- Duff P. Maternal and perinatal infections: bacterial. In: Landon MB, Galan HL, Jauniaux ERM, et al. Gabbe’s Obstetrics: Normal and Problem Pregnancies. 8th ed. Elsevier; 2021:1124-1146.
- Duff P. Maternal and fetal infections. In: Resnik R, Lockwood CJ, Moore TJ, et al. Creasy & Resnik’s Maternal-Fetal Medicine: Principles and Practice. 8th ed. Elsevier; 2019:862-919.
Case report: Male with acute new-onset suicidal ideation tied to SARS-CoV-2
An otherwise healthy 55-year-old male, with no previous psychiatric or medical history, sought care with a family medicine physician for the first time in decades.
Medical symptoms began Oct. 9, 2021, with “some leg weakness and mild sniffles.” Since he was going to be at a public event, he decided to take a PCR test for the SARS-CoV-2 virus on Oct. 13. The patient tested positive.
His symptoms continued to worsen, and he experienced severe body fatigue, sleep disturbance, and lethargy. “A few days after my positive test, the cognitive and physical symptoms dramatically ramped up,” the patient recalled.
Because of those worsening symptoms, on Oct. 20, the patient obtained a new patient appointment with a family medicine physician. After a telemedicine evaluation, the family medicine physician began a multifaceted early outpatient COVID-19 treatment protocol,1 as I (C.M.W.) and colleagues wrote about late last year. However, this treatment began late in the course because of the patient’s initial resistance to seek care.
This early outpatient treatment protocol for COVID-19 included vitamin D3 125 mcg (5,000 ICU), N-acetylcysteine (NAC) 600 mg every day x 30 days; acetylsalicylic acid 325 mg every day x 30 days; azithromycin 250 mg b.i.d. before every meal x 10 days; hydroxychloroquine sulfate 200 mg b.i.d. x 10 days; ivermectin 3 mg, 5 pills daily x 10 days; zinc sulfate 220 mg (50 mg elemental) every day x 30 days; and a prednisone taper (30 mg daily x 3 days, tapering down 5 mg every 3 days). Hydroxyzine 50 mg at bedtime as needed was added for sleep. The patient did not comment to the family physician on any of the psychological or psychiatric symptoms and responded appropriately to questions during the Oct. 20 initial evaluation.
However, he later described that around the time the PCR was positive, For example, he was watching a simple YouTube video for work and “everything was confusing me ... it rattled me, and I couldn’t understand it.” He described his COVID-19 mind as: “The words in my head would come out in a jumbled order, like the message from the words in my brain to my mouth would get crossed. I had trouble spelling and texting. Total cognitive breakdown. I couldn’t do simple mathematics.”
Despite his physical exhaustion, he endured a 3-day period of sleep deprivation. During this time, he recalled looking up at the roof and thinking, “I need to jump off the roof” or thinking, “I might want to throw myself under a bus.” He did not initially reveal his suicidal thoughts to his family medicine physician. After beginning COVID-19 treatment, the patient had two nights of sleep and felt notably improved, and his physical symptoms began to remit. However, the sleeplessness quickly returned “with a vengeance” along with “silly suicidal thoughts.” The thoughts took on a more obsessional quality. For example, he repeatedly thought of jumping out of his second-story bedroom to the living room below and was preoccupied by continually looking at people’s roofs and thinking about jumping. Those thoughts intensified and culminated in his “going missing,” leading his wife to call the police. It was discovered that he had driven to a local bridge and was contemplating jumping off.
After that “going missing” incident, the patient and his wife reached out to their family medicine physician. He reevaluated the patient and, given the new information about the psychiatric symptoms, strongly recommended stat crisis and psychiatric consultation. After discussing the case on the same day, both the family medicine physician and the psychiatrist recommended stat hospital emergency department (ED) assessment on Oct. 29. In the ED, a head CT without contrast at the recommendation of both psychiatrist and family physician, routine electrolytes, CBC with differential, and EKG all were within normal limits. The ED initially discharged him home after crisis evaluation, deciding he was not an imminent risk to himself or others.
The next day, the psychiatrist spoke on the phone with the patient, family medicine physician, and the patient’s wife to arrange an initial assessment. At that time, it remained unclear to all whether the obsessional thoughts had resolved to such a degree that the patient could resist acting upon them. Further, the patient’s sleep architecture had not returned to normal. All agreed another emergency ED assessment was indicated. Ultimately, after voluntary re-evaluation and a difficult hold in the crisis unit, the patient was admitted for psychiatric hospitalization on Oct. 29 and discharged on Nov. 4.
In the psychiatric hospital, venlafaxine XR was started and titrated to 75 mg. The patient was discovered to be hypertensive, and hydrochlorothiazide was started. The discharge diagnosis was major depressive disorder, single episode, severe, without psychotic features.
Posthospitalization course
He was seen for his initial psychiatric outpatient assessment postpsychiatric hospitalization on Nov. 9, as he had not yet been formally evaluated by the psychiatrist because of the emergency situation.
Gabapentin 300 mg by mouth at bedtime was started, and his sleep architecture was restored. The initial plan to titrate venlafaxine XR into dual selective norepinephrine reuptake inhibitor dose range was terminated, and his psychiatrist considered tapering and discontinuing the venlafaxine XR. A clinical examination, additional history, and collateral data no longer necessarily pointed to an active major depressive disorder or even unspecified depressive disorder, though to be sure, the patient was taking 75 mg of venlafaxine XR. While there were seasonal stressors, historically, nothing had risen to the level of MDD.
The obsessions driving his thoughts to jump off buildings and bridges had completely remitted. His cognitive ability returned to baseline with an ability to focus and perform the complicated tasks of his high-intensity work by the Dec. 8 psychiatric examination, where he was accompanied by his wife. He described feeling like, “I snapped back to like I was before this crazy stuff happened.” His mood was reported as, “Very good; like my old self” and this was confirmed by his wife. His affect was calmer and less tense. He was now using gabapentin sparingly for sleep. We continued to entertain discontinuing the venlafaxine XR, considering this recent severe episode likely driven by the COVID-19 virus. The decision was made to continue venlafaxine XR through the winter rather than discontinuing, remaining on the conservative side of treatment. The patient’s diagnosis was changed from “MDD, single episode,” to “mood disorder due to known physiologic condition (COVID-19) (F06.31) with depressive features; resolving.” At the patient’s follow-up examination on Jan. 5, 2022, he was continuing to do well, stating, “The whole series of crazy events happened to someone else.” The hydrochlorothiazide had been discontinued, and the patient’s blood pressure and pulse were normal at 119/81 and 69, respectively. He had made strategic changes at work to lessen stressors during the typically difficult months.
Discussion
Literature has discussed neuropsychiatric sequelae of COVID-19.2 The cited example questions whether psychiatric symptoms are tied directly to the viral infection or to the “host’s immune response.” We believe our case represents a direct neurocognitive/neuropsychiatric insult due to the COVID-19 infection.
This case presents a 55-year-old male with no previous psychiatric or medical history with new onset significant and debilitating cognitive impairment and obsessive thoughts of throwing himself from his bedroom balcony ending up at a bridge struggling with an irrational thought of jumping; ultimately requiring psychiatric hospitalization for acute suicidal thoughts. The patient’s psychiatric symptoms arose prior to any and all medication treatment. The obsessive thoughts correlated both with the onset of SARS-CoV-2 infection and a period of sleep deprivation subsequent to the infection. A course of steroid treatment and taper were started after the onset of neurocognitive-psychiatric symptoms, though there is close timing. We submit that the patient experienced, as part of the initial neurocognitive psychiatric initiating cascade, a COVID-19–induced sleep deprivation that was not etiologic but part of the process; since, even when sleep returned to normal, it was still several weeks before full cognitive function returned to baseline.
An argument could be made for possible MDD or unspecified depressive disorder, as historically there had been work-related stressors for the patient at this time of year because of the chronological nature of his work; though previously nothing presented with obsessional suicidal thinking and nothing with any cognitive impairment – let alone to this incapacitating degree.
The patient describes his seasonal work much like an accountant’s work at the beginning of each year. In the patient’s case, the months of September and October are historically “nonstop, working days,” which then slow down in the winter months for a period of recuperation. In gathering his past history of symptoms, he denied neurovegetative symptoms to meet full diagnostic criteria for MDD or unspecified depressive disorder, absent this episode in the presence of SARS-CoV-2 infection.
We could also consider a contributory negative “organic push” by the viral load and prednisone helping to express an underlying unspecified depression or MDD, but for the profound and unusual presentation. There was little prodrome of depressive symptoms (again, he reported his “typical” extraordinary work burden for this time of year, which is common in his industry).
In this patient, the symptoms have remitted completely. However, the patient is currently taking venlafaxine XR 75 mg. We have considered tapering and discontinuing the venlafaxine – since it is not entirely clear that he needs to be on this medication – so this question remains an open one. We did decide, however, to continue the venlafaxine until after the winter months and to reassess at that time.
Conclusion
The patient presented with new onset psychological and psychiatric symptoms in addition to physiologic symptoms; the former symptoms were not revealed prior to initial family medicine evaluation. As the symptoms worsened, he and his wife sought additional consultation with family physician, psychiatrists, and ED. Steroid treatment may have played a part in exacerbation of symptoms, but the neuropsychiatric cognitive symptoms were present prior to initiation of all pharmacologic and medical treatment. The successful outcome of this case was based upon quick action and collaboration between the family medicine physician, the psychiatrist, and the ED physician. The value of communication, assessment, and action via phone call and text cannot be overstated. Future considerations include further large-scale evaluation of multifaceted early treatment of patients with COVID-19 within the first 72 hours of symptoms to prevent not only hospitalization, morbidity, and mortality, but newly recognized psychological and psychiatric syndromes.3,4
Lastly, fluvoxamine might have been a better choice for adjunctive early treatment of COVID-19.5 As a matter of distinction, if a lingering mood disorder or obsessive-compulsive disorder remain a result of SARS-CoV-2 or if one were to start an antidepressant during the course of illness, it would be reasonable to consider fluvoxamine as a potential first-line agent.
Dr. Kohanski is a fellowship trained forensic psychiatrist and a diplomate of the American Board of Psychiatry & Neurology. She maintains a private practice in Somerset, N.J., and is a frequent media commentator and medical podcaster. Dr. Kohanski has no conflicts of interest. Dr. Wax is a residency-trained osteopathic family medicine physician in independent private practice in Mullica Hill, N.J. He has authored multiple papers over 2 decades on topics such as SARS-CoV-2 and COVID-19 early treatment. He has been a speaker and media host over 2 decades and served on the National Physicians Council on Healthcare Policy’s congressional subcommittee. Dr. Wax has no conflicts of interest.
References
1. Rev Cardiovasc Med. 2020 Dec 30;21(4):517-30.
2. Brain Behav Immun. 2020 Jul;87:34-9.
3. Trav Med Infect Dis. 2020 May-Jun 35;10738.
4. Kirsch S. “Early treatment for COVID is key to better outcomes.” Times of India. 2021 May 21.
5. Lancet. 2022 Jan 1;10(1):E42-E51.
An otherwise healthy 55-year-old male, with no previous psychiatric or medical history, sought care with a family medicine physician for the first time in decades.
Medical symptoms began Oct. 9, 2021, with “some leg weakness and mild sniffles.” Since he was going to be at a public event, he decided to take a PCR test for the SARS-CoV-2 virus on Oct. 13. The patient tested positive.
His symptoms continued to worsen, and he experienced severe body fatigue, sleep disturbance, and lethargy. “A few days after my positive test, the cognitive and physical symptoms dramatically ramped up,” the patient recalled.
Because of those worsening symptoms, on Oct. 20, the patient obtained a new patient appointment with a family medicine physician. After a telemedicine evaluation, the family medicine physician began a multifaceted early outpatient COVID-19 treatment protocol,1 as I (C.M.W.) and colleagues wrote about late last year. However, this treatment began late in the course because of the patient’s initial resistance to seek care.
This early outpatient treatment protocol for COVID-19 included vitamin D3 125 mcg (5,000 ICU), N-acetylcysteine (NAC) 600 mg every day x 30 days; acetylsalicylic acid 325 mg every day x 30 days; azithromycin 250 mg b.i.d. before every meal x 10 days; hydroxychloroquine sulfate 200 mg b.i.d. x 10 days; ivermectin 3 mg, 5 pills daily x 10 days; zinc sulfate 220 mg (50 mg elemental) every day x 30 days; and a prednisone taper (30 mg daily x 3 days, tapering down 5 mg every 3 days). Hydroxyzine 50 mg at bedtime as needed was added for sleep. The patient did not comment to the family physician on any of the psychological or psychiatric symptoms and responded appropriately to questions during the Oct. 20 initial evaluation.
However, he later described that around the time the PCR was positive, For example, he was watching a simple YouTube video for work and “everything was confusing me ... it rattled me, and I couldn’t understand it.” He described his COVID-19 mind as: “The words in my head would come out in a jumbled order, like the message from the words in my brain to my mouth would get crossed. I had trouble spelling and texting. Total cognitive breakdown. I couldn’t do simple mathematics.”
Despite his physical exhaustion, he endured a 3-day period of sleep deprivation. During this time, he recalled looking up at the roof and thinking, “I need to jump off the roof” or thinking, “I might want to throw myself under a bus.” He did not initially reveal his suicidal thoughts to his family medicine physician. After beginning COVID-19 treatment, the patient had two nights of sleep and felt notably improved, and his physical symptoms began to remit. However, the sleeplessness quickly returned “with a vengeance” along with “silly suicidal thoughts.” The thoughts took on a more obsessional quality. For example, he repeatedly thought of jumping out of his second-story bedroom to the living room below and was preoccupied by continually looking at people’s roofs and thinking about jumping. Those thoughts intensified and culminated in his “going missing,” leading his wife to call the police. It was discovered that he had driven to a local bridge and was contemplating jumping off.
After that “going missing” incident, the patient and his wife reached out to their family medicine physician. He reevaluated the patient and, given the new information about the psychiatric symptoms, strongly recommended stat crisis and psychiatric consultation. After discussing the case on the same day, both the family medicine physician and the psychiatrist recommended stat hospital emergency department (ED) assessment on Oct. 29. In the ED, a head CT without contrast at the recommendation of both psychiatrist and family physician, routine electrolytes, CBC with differential, and EKG all were within normal limits. The ED initially discharged him home after crisis evaluation, deciding he was not an imminent risk to himself or others.
The next day, the psychiatrist spoke on the phone with the patient, family medicine physician, and the patient’s wife to arrange an initial assessment. At that time, it remained unclear to all whether the obsessional thoughts had resolved to such a degree that the patient could resist acting upon them. Further, the patient’s sleep architecture had not returned to normal. All agreed another emergency ED assessment was indicated. Ultimately, after voluntary re-evaluation and a difficult hold in the crisis unit, the patient was admitted for psychiatric hospitalization on Oct. 29 and discharged on Nov. 4.
In the psychiatric hospital, venlafaxine XR was started and titrated to 75 mg. The patient was discovered to be hypertensive, and hydrochlorothiazide was started. The discharge diagnosis was major depressive disorder, single episode, severe, without psychotic features.
Posthospitalization course
He was seen for his initial psychiatric outpatient assessment postpsychiatric hospitalization on Nov. 9, as he had not yet been formally evaluated by the psychiatrist because of the emergency situation.
Gabapentin 300 mg by mouth at bedtime was started, and his sleep architecture was restored. The initial plan to titrate venlafaxine XR into dual selective norepinephrine reuptake inhibitor dose range was terminated, and his psychiatrist considered tapering and discontinuing the venlafaxine XR. A clinical examination, additional history, and collateral data no longer necessarily pointed to an active major depressive disorder or even unspecified depressive disorder, though to be sure, the patient was taking 75 mg of venlafaxine XR. While there were seasonal stressors, historically, nothing had risen to the level of MDD.
The obsessions driving his thoughts to jump off buildings and bridges had completely remitted. His cognitive ability returned to baseline with an ability to focus and perform the complicated tasks of his high-intensity work by the Dec. 8 psychiatric examination, where he was accompanied by his wife. He described feeling like, “I snapped back to like I was before this crazy stuff happened.” His mood was reported as, “Very good; like my old self” and this was confirmed by his wife. His affect was calmer and less tense. He was now using gabapentin sparingly for sleep. We continued to entertain discontinuing the venlafaxine XR, considering this recent severe episode likely driven by the COVID-19 virus. The decision was made to continue venlafaxine XR through the winter rather than discontinuing, remaining on the conservative side of treatment. The patient’s diagnosis was changed from “MDD, single episode,” to “mood disorder due to known physiologic condition (COVID-19) (F06.31) with depressive features; resolving.” At the patient’s follow-up examination on Jan. 5, 2022, he was continuing to do well, stating, “The whole series of crazy events happened to someone else.” The hydrochlorothiazide had been discontinued, and the patient’s blood pressure and pulse were normal at 119/81 and 69, respectively. He had made strategic changes at work to lessen stressors during the typically difficult months.
Discussion
Literature has discussed neuropsychiatric sequelae of COVID-19.2 The cited example questions whether psychiatric symptoms are tied directly to the viral infection or to the “host’s immune response.” We believe our case represents a direct neurocognitive/neuropsychiatric insult due to the COVID-19 infection.
This case presents a 55-year-old male with no previous psychiatric or medical history with new onset significant and debilitating cognitive impairment and obsessive thoughts of throwing himself from his bedroom balcony ending up at a bridge struggling with an irrational thought of jumping; ultimately requiring psychiatric hospitalization for acute suicidal thoughts. The patient’s psychiatric symptoms arose prior to any and all medication treatment. The obsessive thoughts correlated both with the onset of SARS-CoV-2 infection and a period of sleep deprivation subsequent to the infection. A course of steroid treatment and taper were started after the onset of neurocognitive-psychiatric symptoms, though there is close timing. We submit that the patient experienced, as part of the initial neurocognitive psychiatric initiating cascade, a COVID-19–induced sleep deprivation that was not etiologic but part of the process; since, even when sleep returned to normal, it was still several weeks before full cognitive function returned to baseline.
An argument could be made for possible MDD or unspecified depressive disorder, as historically there had been work-related stressors for the patient at this time of year because of the chronological nature of his work; though previously nothing presented with obsessional suicidal thinking and nothing with any cognitive impairment – let alone to this incapacitating degree.
The patient describes his seasonal work much like an accountant’s work at the beginning of each year. In the patient’s case, the months of September and October are historically “nonstop, working days,” which then slow down in the winter months for a period of recuperation. In gathering his past history of symptoms, he denied neurovegetative symptoms to meet full diagnostic criteria for MDD or unspecified depressive disorder, absent this episode in the presence of SARS-CoV-2 infection.
We could also consider a contributory negative “organic push” by the viral load and prednisone helping to express an underlying unspecified depression or MDD, but for the profound and unusual presentation. There was little prodrome of depressive symptoms (again, he reported his “typical” extraordinary work burden for this time of year, which is common in his industry).
In this patient, the symptoms have remitted completely. However, the patient is currently taking venlafaxine XR 75 mg. We have considered tapering and discontinuing the venlafaxine – since it is not entirely clear that he needs to be on this medication – so this question remains an open one. We did decide, however, to continue the venlafaxine until after the winter months and to reassess at that time.
Conclusion
The patient presented with new onset psychological and psychiatric symptoms in addition to physiologic symptoms; the former symptoms were not revealed prior to initial family medicine evaluation. As the symptoms worsened, he and his wife sought additional consultation with family physician, psychiatrists, and ED. Steroid treatment may have played a part in exacerbation of symptoms, but the neuropsychiatric cognitive symptoms were present prior to initiation of all pharmacologic and medical treatment. The successful outcome of this case was based upon quick action and collaboration between the family medicine physician, the psychiatrist, and the ED physician. The value of communication, assessment, and action via phone call and text cannot be overstated. Future considerations include further large-scale evaluation of multifaceted early treatment of patients with COVID-19 within the first 72 hours of symptoms to prevent not only hospitalization, morbidity, and mortality, but newly recognized psychological and psychiatric syndromes.3,4
Lastly, fluvoxamine might have been a better choice for adjunctive early treatment of COVID-19.5 As a matter of distinction, if a lingering mood disorder or obsessive-compulsive disorder remain a result of SARS-CoV-2 or if one were to start an antidepressant during the course of illness, it would be reasonable to consider fluvoxamine as a potential first-line agent.
Dr. Kohanski is a fellowship trained forensic psychiatrist and a diplomate of the American Board of Psychiatry & Neurology. She maintains a private practice in Somerset, N.J., and is a frequent media commentator and medical podcaster. Dr. Kohanski has no conflicts of interest. Dr. Wax is a residency-trained osteopathic family medicine physician in independent private practice in Mullica Hill, N.J. He has authored multiple papers over 2 decades on topics such as SARS-CoV-2 and COVID-19 early treatment. He has been a speaker and media host over 2 decades and served on the National Physicians Council on Healthcare Policy’s congressional subcommittee. Dr. Wax has no conflicts of interest.
References
1. Rev Cardiovasc Med. 2020 Dec 30;21(4):517-30.
2. Brain Behav Immun. 2020 Jul;87:34-9.
3. Trav Med Infect Dis. 2020 May-Jun 35;10738.
4. Kirsch S. “Early treatment for COVID is key to better outcomes.” Times of India. 2021 May 21.
5. Lancet. 2022 Jan 1;10(1):E42-E51.
An otherwise healthy 55-year-old male, with no previous psychiatric or medical history, sought care with a family medicine physician for the first time in decades.
Medical symptoms began Oct. 9, 2021, with “some leg weakness and mild sniffles.” Since he was going to be at a public event, he decided to take a PCR test for the SARS-CoV-2 virus on Oct. 13. The patient tested positive.
His symptoms continued to worsen, and he experienced severe body fatigue, sleep disturbance, and lethargy. “A few days after my positive test, the cognitive and physical symptoms dramatically ramped up,” the patient recalled.
Because of those worsening symptoms, on Oct. 20, the patient obtained a new patient appointment with a family medicine physician. After a telemedicine evaluation, the family medicine physician began a multifaceted early outpatient COVID-19 treatment protocol,1 as I (C.M.W.) and colleagues wrote about late last year. However, this treatment began late in the course because of the patient’s initial resistance to seek care.
This early outpatient treatment protocol for COVID-19 included vitamin D3 125 mcg (5,000 ICU), N-acetylcysteine (NAC) 600 mg every day x 30 days; acetylsalicylic acid 325 mg every day x 30 days; azithromycin 250 mg b.i.d. before every meal x 10 days; hydroxychloroquine sulfate 200 mg b.i.d. x 10 days; ivermectin 3 mg, 5 pills daily x 10 days; zinc sulfate 220 mg (50 mg elemental) every day x 30 days; and a prednisone taper (30 mg daily x 3 days, tapering down 5 mg every 3 days). Hydroxyzine 50 mg at bedtime as needed was added for sleep. The patient did not comment to the family physician on any of the psychological or psychiatric symptoms and responded appropriately to questions during the Oct. 20 initial evaluation.
However, he later described that around the time the PCR was positive, For example, he was watching a simple YouTube video for work and “everything was confusing me ... it rattled me, and I couldn’t understand it.” He described his COVID-19 mind as: “The words in my head would come out in a jumbled order, like the message from the words in my brain to my mouth would get crossed. I had trouble spelling and texting. Total cognitive breakdown. I couldn’t do simple mathematics.”
Despite his physical exhaustion, he endured a 3-day period of sleep deprivation. During this time, he recalled looking up at the roof and thinking, “I need to jump off the roof” or thinking, “I might want to throw myself under a bus.” He did not initially reveal his suicidal thoughts to his family medicine physician. After beginning COVID-19 treatment, the patient had two nights of sleep and felt notably improved, and his physical symptoms began to remit. However, the sleeplessness quickly returned “with a vengeance” along with “silly suicidal thoughts.” The thoughts took on a more obsessional quality. For example, he repeatedly thought of jumping out of his second-story bedroom to the living room below and was preoccupied by continually looking at people’s roofs and thinking about jumping. Those thoughts intensified and culminated in his “going missing,” leading his wife to call the police. It was discovered that he had driven to a local bridge and was contemplating jumping off.
After that “going missing” incident, the patient and his wife reached out to their family medicine physician. He reevaluated the patient and, given the new information about the psychiatric symptoms, strongly recommended stat crisis and psychiatric consultation. After discussing the case on the same day, both the family medicine physician and the psychiatrist recommended stat hospital emergency department (ED) assessment on Oct. 29. In the ED, a head CT without contrast at the recommendation of both psychiatrist and family physician, routine electrolytes, CBC with differential, and EKG all were within normal limits. The ED initially discharged him home after crisis evaluation, deciding he was not an imminent risk to himself or others.
The next day, the psychiatrist spoke on the phone with the patient, family medicine physician, and the patient’s wife to arrange an initial assessment. At that time, it remained unclear to all whether the obsessional thoughts had resolved to such a degree that the patient could resist acting upon them. Further, the patient’s sleep architecture had not returned to normal. All agreed another emergency ED assessment was indicated. Ultimately, after voluntary re-evaluation and a difficult hold in the crisis unit, the patient was admitted for psychiatric hospitalization on Oct. 29 and discharged on Nov. 4.
In the psychiatric hospital, venlafaxine XR was started and titrated to 75 mg. The patient was discovered to be hypertensive, and hydrochlorothiazide was started. The discharge diagnosis was major depressive disorder, single episode, severe, without psychotic features.
Posthospitalization course
He was seen for his initial psychiatric outpatient assessment postpsychiatric hospitalization on Nov. 9, as he had not yet been formally evaluated by the psychiatrist because of the emergency situation.
Gabapentin 300 mg by mouth at bedtime was started, and his sleep architecture was restored. The initial plan to titrate venlafaxine XR into dual selective norepinephrine reuptake inhibitor dose range was terminated, and his psychiatrist considered tapering and discontinuing the venlafaxine XR. A clinical examination, additional history, and collateral data no longer necessarily pointed to an active major depressive disorder or even unspecified depressive disorder, though to be sure, the patient was taking 75 mg of venlafaxine XR. While there were seasonal stressors, historically, nothing had risen to the level of MDD.
The obsessions driving his thoughts to jump off buildings and bridges had completely remitted. His cognitive ability returned to baseline with an ability to focus and perform the complicated tasks of his high-intensity work by the Dec. 8 psychiatric examination, where he was accompanied by his wife. He described feeling like, “I snapped back to like I was before this crazy stuff happened.” His mood was reported as, “Very good; like my old self” and this was confirmed by his wife. His affect was calmer and less tense. He was now using gabapentin sparingly for sleep. We continued to entertain discontinuing the venlafaxine XR, considering this recent severe episode likely driven by the COVID-19 virus. The decision was made to continue venlafaxine XR through the winter rather than discontinuing, remaining on the conservative side of treatment. The patient’s diagnosis was changed from “MDD, single episode,” to “mood disorder due to known physiologic condition (COVID-19) (F06.31) with depressive features; resolving.” At the patient’s follow-up examination on Jan. 5, 2022, he was continuing to do well, stating, “The whole series of crazy events happened to someone else.” The hydrochlorothiazide had been discontinued, and the patient’s blood pressure and pulse were normal at 119/81 and 69, respectively. He had made strategic changes at work to lessen stressors during the typically difficult months.
Discussion
Literature has discussed neuropsychiatric sequelae of COVID-19.2 The cited example questions whether psychiatric symptoms are tied directly to the viral infection or to the “host’s immune response.” We believe our case represents a direct neurocognitive/neuropsychiatric insult due to the COVID-19 infection.
This case presents a 55-year-old male with no previous psychiatric or medical history with new onset significant and debilitating cognitive impairment and obsessive thoughts of throwing himself from his bedroom balcony ending up at a bridge struggling with an irrational thought of jumping; ultimately requiring psychiatric hospitalization for acute suicidal thoughts. The patient’s psychiatric symptoms arose prior to any and all medication treatment. The obsessive thoughts correlated both with the onset of SARS-CoV-2 infection and a period of sleep deprivation subsequent to the infection. A course of steroid treatment and taper were started after the onset of neurocognitive-psychiatric symptoms, though there is close timing. We submit that the patient experienced, as part of the initial neurocognitive psychiatric initiating cascade, a COVID-19–induced sleep deprivation that was not etiologic but part of the process; since, even when sleep returned to normal, it was still several weeks before full cognitive function returned to baseline.
An argument could be made for possible MDD or unspecified depressive disorder, as historically there had been work-related stressors for the patient at this time of year because of the chronological nature of his work; though previously nothing presented with obsessional suicidal thinking and nothing with any cognitive impairment – let alone to this incapacitating degree.
The patient describes his seasonal work much like an accountant’s work at the beginning of each year. In the patient’s case, the months of September and October are historically “nonstop, working days,” which then slow down in the winter months for a period of recuperation. In gathering his past history of symptoms, he denied neurovegetative symptoms to meet full diagnostic criteria for MDD or unspecified depressive disorder, absent this episode in the presence of SARS-CoV-2 infection.
We could also consider a contributory negative “organic push” by the viral load and prednisone helping to express an underlying unspecified depression or MDD, but for the profound and unusual presentation. There was little prodrome of depressive symptoms (again, he reported his “typical” extraordinary work burden for this time of year, which is common in his industry).
In this patient, the symptoms have remitted completely. However, the patient is currently taking venlafaxine XR 75 mg. We have considered tapering and discontinuing the venlafaxine – since it is not entirely clear that he needs to be on this medication – so this question remains an open one. We did decide, however, to continue the venlafaxine until after the winter months and to reassess at that time.
Conclusion
The patient presented with new onset psychological and psychiatric symptoms in addition to physiologic symptoms; the former symptoms were not revealed prior to initial family medicine evaluation. As the symptoms worsened, he and his wife sought additional consultation with family physician, psychiatrists, and ED. Steroid treatment may have played a part in exacerbation of symptoms, but the neuropsychiatric cognitive symptoms were present prior to initiation of all pharmacologic and medical treatment. The successful outcome of this case was based upon quick action and collaboration between the family medicine physician, the psychiatrist, and the ED physician. The value of communication, assessment, and action via phone call and text cannot be overstated. Future considerations include further large-scale evaluation of multifaceted early treatment of patients with COVID-19 within the first 72 hours of symptoms to prevent not only hospitalization, morbidity, and mortality, but newly recognized psychological and psychiatric syndromes.3,4
Lastly, fluvoxamine might have been a better choice for adjunctive early treatment of COVID-19.5 As a matter of distinction, if a lingering mood disorder or obsessive-compulsive disorder remain a result of SARS-CoV-2 or if one were to start an antidepressant during the course of illness, it would be reasonable to consider fluvoxamine as a potential first-line agent.
Dr. Kohanski is a fellowship trained forensic psychiatrist and a diplomate of the American Board of Psychiatry & Neurology. She maintains a private practice in Somerset, N.J., and is a frequent media commentator and medical podcaster. Dr. Kohanski has no conflicts of interest. Dr. Wax is a residency-trained osteopathic family medicine physician in independent private practice in Mullica Hill, N.J. He has authored multiple papers over 2 decades on topics such as SARS-CoV-2 and COVID-19 early treatment. He has been a speaker and media host over 2 decades and served on the National Physicians Council on Healthcare Policy’s congressional subcommittee. Dr. Wax has no conflicts of interest.
References
1. Rev Cardiovasc Med. 2020 Dec 30;21(4):517-30.
2. Brain Behav Immun. 2020 Jul;87:34-9.
3. Trav Med Infect Dis. 2020 May-Jun 35;10738.
4. Kirsch S. “Early treatment for COVID is key to better outcomes.” Times of India. 2021 May 21.
5. Lancet. 2022 Jan 1;10(1):E42-E51.
Pencil-core Granuloma Forming 62 Years After Initial Injury
To the Editor:
Trauma from a pencil tip can sometimes result in a fragment of lead being left embedded within the skin. Pencil lead is composed of 66% graphite carbon, 26% aluminum silicate, and 8% paraffin.1,2 While the toxicity of these individual elements is low, paraffin can cause nonallergic foreign-body reactions, aluminum silicate can induce epithelioid granulomatous reactions, and graphite has been reported to cause chronic granulomatous reactions in the lungs of those who work with graphite.2 Penetrating trauma with a pencil can result in the formation of a cutaneous granulomatous reaction that can sometimes occur years to decades after the initial injury.3,4 Several cases of pencil-core granulomas have been published, with lag times between the initial trauma and lesion growth as long as 58 years.1-10 The pencil-core granuloma may simulate malignant melanoma, as it presents clinically as a growing, darkly pigmented lesion, thus prompting biopsy. We present a case of a pencil-core granuloma that began to grow 62 years after the initial trauma.
A 72-year-old woman was referred to our clinic for evaluation of a dark nodule on the forehead. The lesion had been present since the age of 10 years, reportedly from an accidental stabbing with a pencil. The lesion had been flat, stable, and asymptomatic since the trauma occurred; however, the patient reported that approximately 9 months prior to presentation, it had started growing and became painful. Physical examination revealed a 1.0-cm, round, bluish-black nodule on the right superior forehead (Figure 1A). No satellite lesions or local lymphadenopathy were noted on general examination.
An elliptical excision of the lesion with 1-cm margins revealed a bluish-black mass extending through the dermis, through the frontalis muscle, and into the periosteum and frontal bone (Figure 1B). A No. 15 blade was then used to remove the remaining pigment from the outer table of the frontal bone. Histopathologic findings demonstrated a sarcoidal granulomatous dermatitis associated with abundant, nonpolarizable, black, granular pigment consistent with carbon tattoo. This foreign material was readily identifiable in large extracellular deposits and also within histiocytes, including numerous multinucleated giant cells (Figure 2). Immunostaining for MART-1 and SOX-10 antigens failed to demonstrate a melanocytic proliferation. These findings were consistent with a sarcoidal foreign-body granulomatous reaction to carbon tattoo following traumatic graphite implantation.
Granulomatous reactions to carbon tattoo may be sarcoidal (foreign-body granulomatous dermatitis), palisading, or rarely tuberculoid (caseating). Sarcoidal granulomatous tattoo reactions may occur in patients with sarcoidosis due to koebnerization, and histology alone is not discriminatory; however, in our patient, the absence of underlying sarcoidosis or clinical or histologic findings of sarcoidosis outside of the site of the pencil-core granuloma excluded that possibility.11 Pencil-core granulomas are characterized by a delayed foreign-body reaction to retained fragments of lead often years following a penetrating trauma with a pencil. Previous reports have described various lag times from injury to lesion growth of up to 58 years.1-10 Our patient claimed to have noticed the lesion growing and becoming painful only after a 62-year lag time following the initial trauma. To our knowledge, this is the longest lag time between the initial pencil injury and induction of the foreign-body reaction reported in the literature. Clinically, the lesion appeared and behaved very similar to a melanoma, prompting further treatment and evaluation.
It has been suggested that the lag period between the initial trauma and the rapid growth of the lesion may correspond to the amount of time required for the breakdown of the pencil lead to a critical size followed by the dispersal of those particles within the interstitium, where they can induce a granulomatous reaction.1,2,9 One case described a patient who reported that the growth and clinical change of the pencil-core granuloma only started when the patient accidentally hit the area where the trauma had occurred 31 years prior.1 This additional trauma may have caused further mechanical breakdown of the lead to set off the tissue reaction. In our case, the patient did not recall any additional trauma to the head prior to the onset of growth of the nodule on the forehead.
Our case indicates that carbon tattoo may be a possible sequela of a penetrating injury from a pencil with retained pencil lead fragments; however, many of these carbon tattoos may remain stable throughout the remainder of the patient’s life.
- Gormley RH, Kovach SJ III, Zhang PJ. Role for trauma in inducing pencil “lead” granuloma in the skin. J Am Acad Dermatol. 2010;62:1074-1075.
- Terasawa N, Kishimoto S, Kibe Y, et al. Graphite foreign body granuloma. Br J Dermatol. 1999;141:774-776.
- Fukunaga Y, Hashimoto I, Nakanishi H, et al. Pencil-core granuloma of the face: report of two rare cases. J Plast Reconstr Aesthet Surg. 2011;64:1235-1237.
- Aswani VH, Kim SL. Fifty-three years after a pencil puncture wound. Case Rep Dermatol. 2015;7:303-305.
- Taylor B, Frumkin A, Pitha JV. Delayed reaction to “lead” pencil simulating melanoma. Cutis. 1988;42:199-201.
- Granick MS, Erickson ER, Solomon MP. Pencil-core granuloma. Plast Reconstr Surg. 1992;89:136-138.
- Andreano J. Stump the experts. foreign body granuloma. J Dermatol Surg Oncol. 1992;18:277, 343.
- Yoshitatsu S, Takagi T. A case of giant pencil-core granuloma. J Dermatol. 2000;27:329-332.
- Hatano Y, Asada Y, Komada S, et al. A case of pencil core granuloma with an unusual temporal profile. Dermatology. 2000;201:151-153.
- Seitz IA, Silva BA, Schechter LS. Unusual sequela from a pencil stab wound reveals a retained graphite foreign body. Pediatr Emerg Care. 2014;30:568-570.
- Motaparthi K. Tattoo ink. In: Cockerell CJ, Hall BJ, eds. Nonneoplastic Dermatopathology. 2nd ed. Amirsys; 2016: 270.
To the Editor:
Trauma from a pencil tip can sometimes result in a fragment of lead being left embedded within the skin. Pencil lead is composed of 66% graphite carbon, 26% aluminum silicate, and 8% paraffin.1,2 While the toxicity of these individual elements is low, paraffin can cause nonallergic foreign-body reactions, aluminum silicate can induce epithelioid granulomatous reactions, and graphite has been reported to cause chronic granulomatous reactions in the lungs of those who work with graphite.2 Penetrating trauma with a pencil can result in the formation of a cutaneous granulomatous reaction that can sometimes occur years to decades after the initial injury.3,4 Several cases of pencil-core granulomas have been published, with lag times between the initial trauma and lesion growth as long as 58 years.1-10 The pencil-core granuloma may simulate malignant melanoma, as it presents clinically as a growing, darkly pigmented lesion, thus prompting biopsy. We present a case of a pencil-core granuloma that began to grow 62 years after the initial trauma.
A 72-year-old woman was referred to our clinic for evaluation of a dark nodule on the forehead. The lesion had been present since the age of 10 years, reportedly from an accidental stabbing with a pencil. The lesion had been flat, stable, and asymptomatic since the trauma occurred; however, the patient reported that approximately 9 months prior to presentation, it had started growing and became painful. Physical examination revealed a 1.0-cm, round, bluish-black nodule on the right superior forehead (Figure 1A). No satellite lesions or local lymphadenopathy were noted on general examination.
An elliptical excision of the lesion with 1-cm margins revealed a bluish-black mass extending through the dermis, through the frontalis muscle, and into the periosteum and frontal bone (Figure 1B). A No. 15 blade was then used to remove the remaining pigment from the outer table of the frontal bone. Histopathologic findings demonstrated a sarcoidal granulomatous dermatitis associated with abundant, nonpolarizable, black, granular pigment consistent with carbon tattoo. This foreign material was readily identifiable in large extracellular deposits and also within histiocytes, including numerous multinucleated giant cells (Figure 2). Immunostaining for MART-1 and SOX-10 antigens failed to demonstrate a melanocytic proliferation. These findings were consistent with a sarcoidal foreign-body granulomatous reaction to carbon tattoo following traumatic graphite implantation.
Granulomatous reactions to carbon tattoo may be sarcoidal (foreign-body granulomatous dermatitis), palisading, or rarely tuberculoid (caseating). Sarcoidal granulomatous tattoo reactions may occur in patients with sarcoidosis due to koebnerization, and histology alone is not discriminatory; however, in our patient, the absence of underlying sarcoidosis or clinical or histologic findings of sarcoidosis outside of the site of the pencil-core granuloma excluded that possibility.11 Pencil-core granulomas are characterized by a delayed foreign-body reaction to retained fragments of lead often years following a penetrating trauma with a pencil. Previous reports have described various lag times from injury to lesion growth of up to 58 years.1-10 Our patient claimed to have noticed the lesion growing and becoming painful only after a 62-year lag time following the initial trauma. To our knowledge, this is the longest lag time between the initial pencil injury and induction of the foreign-body reaction reported in the literature. Clinically, the lesion appeared and behaved very similar to a melanoma, prompting further treatment and evaluation.
It has been suggested that the lag period between the initial trauma and the rapid growth of the lesion may correspond to the amount of time required for the breakdown of the pencil lead to a critical size followed by the dispersal of those particles within the interstitium, where they can induce a granulomatous reaction.1,2,9 One case described a patient who reported that the growth and clinical change of the pencil-core granuloma only started when the patient accidentally hit the area where the trauma had occurred 31 years prior.1 This additional trauma may have caused further mechanical breakdown of the lead to set off the tissue reaction. In our case, the patient did not recall any additional trauma to the head prior to the onset of growth of the nodule on the forehead.
Our case indicates that carbon tattoo may be a possible sequela of a penetrating injury from a pencil with retained pencil lead fragments; however, many of these carbon tattoos may remain stable throughout the remainder of the patient’s life.
To the Editor:
Trauma from a pencil tip can sometimes result in a fragment of lead being left embedded within the skin. Pencil lead is composed of 66% graphite carbon, 26% aluminum silicate, and 8% paraffin.1,2 While the toxicity of these individual elements is low, paraffin can cause nonallergic foreign-body reactions, aluminum silicate can induce epithelioid granulomatous reactions, and graphite has been reported to cause chronic granulomatous reactions in the lungs of those who work with graphite.2 Penetrating trauma with a pencil can result in the formation of a cutaneous granulomatous reaction that can sometimes occur years to decades after the initial injury.3,4 Several cases of pencil-core granulomas have been published, with lag times between the initial trauma and lesion growth as long as 58 years.1-10 The pencil-core granuloma may simulate malignant melanoma, as it presents clinically as a growing, darkly pigmented lesion, thus prompting biopsy. We present a case of a pencil-core granuloma that began to grow 62 years after the initial trauma.
A 72-year-old woman was referred to our clinic for evaluation of a dark nodule on the forehead. The lesion had been present since the age of 10 years, reportedly from an accidental stabbing with a pencil. The lesion had been flat, stable, and asymptomatic since the trauma occurred; however, the patient reported that approximately 9 months prior to presentation, it had started growing and became painful. Physical examination revealed a 1.0-cm, round, bluish-black nodule on the right superior forehead (Figure 1A). No satellite lesions or local lymphadenopathy were noted on general examination.
An elliptical excision of the lesion with 1-cm margins revealed a bluish-black mass extending through the dermis, through the frontalis muscle, and into the periosteum and frontal bone (Figure 1B). A No. 15 blade was then used to remove the remaining pigment from the outer table of the frontal bone. Histopathologic findings demonstrated a sarcoidal granulomatous dermatitis associated with abundant, nonpolarizable, black, granular pigment consistent with carbon tattoo. This foreign material was readily identifiable in large extracellular deposits and also within histiocytes, including numerous multinucleated giant cells (Figure 2). Immunostaining for MART-1 and SOX-10 antigens failed to demonstrate a melanocytic proliferation. These findings were consistent with a sarcoidal foreign-body granulomatous reaction to carbon tattoo following traumatic graphite implantation.
Granulomatous reactions to carbon tattoo may be sarcoidal (foreign-body granulomatous dermatitis), palisading, or rarely tuberculoid (caseating). Sarcoidal granulomatous tattoo reactions may occur in patients with sarcoidosis due to koebnerization, and histology alone is not discriminatory; however, in our patient, the absence of underlying sarcoidosis or clinical or histologic findings of sarcoidosis outside of the site of the pencil-core granuloma excluded that possibility.11 Pencil-core granulomas are characterized by a delayed foreign-body reaction to retained fragments of lead often years following a penetrating trauma with a pencil. Previous reports have described various lag times from injury to lesion growth of up to 58 years.1-10 Our patient claimed to have noticed the lesion growing and becoming painful only after a 62-year lag time following the initial trauma. To our knowledge, this is the longest lag time between the initial pencil injury and induction of the foreign-body reaction reported in the literature. Clinically, the lesion appeared and behaved very similar to a melanoma, prompting further treatment and evaluation.
It has been suggested that the lag period between the initial trauma and the rapid growth of the lesion may correspond to the amount of time required for the breakdown of the pencil lead to a critical size followed by the dispersal of those particles within the interstitium, where they can induce a granulomatous reaction.1,2,9 One case described a patient who reported that the growth and clinical change of the pencil-core granuloma only started when the patient accidentally hit the area where the trauma had occurred 31 years prior.1 This additional trauma may have caused further mechanical breakdown of the lead to set off the tissue reaction. In our case, the patient did not recall any additional trauma to the head prior to the onset of growth of the nodule on the forehead.
Our case indicates that carbon tattoo may be a possible sequela of a penetrating injury from a pencil with retained pencil lead fragments; however, many of these carbon tattoos may remain stable throughout the remainder of the patient’s life.
- Gormley RH, Kovach SJ III, Zhang PJ. Role for trauma in inducing pencil “lead” granuloma in the skin. J Am Acad Dermatol. 2010;62:1074-1075.
- Terasawa N, Kishimoto S, Kibe Y, et al. Graphite foreign body granuloma. Br J Dermatol. 1999;141:774-776.
- Fukunaga Y, Hashimoto I, Nakanishi H, et al. Pencil-core granuloma of the face: report of two rare cases. J Plast Reconstr Aesthet Surg. 2011;64:1235-1237.
- Aswani VH, Kim SL. Fifty-three years after a pencil puncture wound. Case Rep Dermatol. 2015;7:303-305.
- Taylor B, Frumkin A, Pitha JV. Delayed reaction to “lead” pencil simulating melanoma. Cutis. 1988;42:199-201.
- Granick MS, Erickson ER, Solomon MP. Pencil-core granuloma. Plast Reconstr Surg. 1992;89:136-138.
- Andreano J. Stump the experts. foreign body granuloma. J Dermatol Surg Oncol. 1992;18:277, 343.
- Yoshitatsu S, Takagi T. A case of giant pencil-core granuloma. J Dermatol. 2000;27:329-332.
- Hatano Y, Asada Y, Komada S, et al. A case of pencil core granuloma with an unusual temporal profile. Dermatology. 2000;201:151-153.
- Seitz IA, Silva BA, Schechter LS. Unusual sequela from a pencil stab wound reveals a retained graphite foreign body. Pediatr Emerg Care. 2014;30:568-570.
- Motaparthi K. Tattoo ink. In: Cockerell CJ, Hall BJ, eds. Nonneoplastic Dermatopathology. 2nd ed. Amirsys; 2016: 270.
- Gormley RH, Kovach SJ III, Zhang PJ. Role for trauma in inducing pencil “lead” granuloma in the skin. J Am Acad Dermatol. 2010;62:1074-1075.
- Terasawa N, Kishimoto S, Kibe Y, et al. Graphite foreign body granuloma. Br J Dermatol. 1999;141:774-776.
- Fukunaga Y, Hashimoto I, Nakanishi H, et al. Pencil-core granuloma of the face: report of two rare cases. J Plast Reconstr Aesthet Surg. 2011;64:1235-1237.
- Aswani VH, Kim SL. Fifty-three years after a pencil puncture wound. Case Rep Dermatol. 2015;7:303-305.
- Taylor B, Frumkin A, Pitha JV. Delayed reaction to “lead” pencil simulating melanoma. Cutis. 1988;42:199-201.
- Granick MS, Erickson ER, Solomon MP. Pencil-core granuloma. Plast Reconstr Surg. 1992;89:136-138.
- Andreano J. Stump the experts. foreign body granuloma. J Dermatol Surg Oncol. 1992;18:277, 343.
- Yoshitatsu S, Takagi T. A case of giant pencil-core granuloma. J Dermatol. 2000;27:329-332.
- Hatano Y, Asada Y, Komada S, et al. A case of pencil core granuloma with an unusual temporal profile. Dermatology. 2000;201:151-153.
- Seitz IA, Silva BA, Schechter LS. Unusual sequela from a pencil stab wound reveals a retained graphite foreign body. Pediatr Emerg Care. 2014;30:568-570.
- Motaparthi K. Tattoo ink. In: Cockerell CJ, Hall BJ, eds. Nonneoplastic Dermatopathology. 2nd ed. Amirsys; 2016: 270.
Practice Points
- Pencil-core granulomas can arise even decades after the lead is embedded in the skin.
- It is important to biopsy to confirm the diagnosis, as pencil-core granulomas can very closely mimic melanomas.
ARFID or reasonable food restriction? The jury is out
Problems with eating and nutrition are common among patients with inflammatory bowel disease (IBD) and other gastrointestinal disorders, but clinicians who treat them should be careful not to automatically assume that patients have eating disorders, according to a psychologist who specializes in the psychological and social aspects of chronic digestive diseases.
On the other hand, clinicians must also be aware of the possibility that patients could have a recently identified syndrome cluster called avoidant restrictive food intake disorder (ARFID), said Tiffany Taft, PsyD, a research associate professor of medicine (gastroenterology and hepatology), medical social sciences, and psychiatry and behavioral sciences at Northwestern University, Chicago. In a recent study, she and her colleagues defined ARFID as “failure to meet one’s nutritional needs owing to sensory hypersensitivity, lack of interest in eating, or fear of aversive consequences from eating, and is associated with negative medical and psychosocial outcomes.”
ARFID “is a hot topic that we really don’t understand,” she said in an online presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Nutritional deficiencies
Nutritional deficiencies are common among patients with IBD, “and nutritional deficiencies themselves can lead to symptoms or side effects that can cause people to eat less,” she said.
“As our vitamin B12 goes down, our cognitive functioning starts to decline, and we might not be making clear decisions in how we’re deciding what to eat, when to eat, if we should be eating at all – just something to think about in your patients who have nutritional deficiencies,” she told the audience.
Other common nutritional deficiencies that can affect eating and food choice among patients with IBD include low folate (B9) levels associated with sore tongue and weight loss, low iron levels leading to nausea and loss of appetite, and zinc deficiency leading to loss of appetite and alterations in taste and/or smell, she said.
Newly recognized in GI
She noted that “ARFID actually originates in the pediatric psychiatric literature, mostly in children with sensory issues [such as] autism spectrum disorder, so this is not a construct that started in digestive disease, but has been adapted and applied to patients with digestive disease, including IBD.”
The DSM-5 lists four criteria for ARFID: significant weight loss, significant nutritional deficiency, dependence on enteral nutrition or oral supplements, and marked interference with psychosocial functions.
Helen Burton Murray, PhD, director of the gastrointestinal behavioral health program in the Center for Neurointestinal Health at Massachusetts General Hospital, Boston, who is familiar with Dr. Taft’s work, said in an interview that inclusion of ARFID in DSM-5 has put a name to a syndrome or symptom cluster that in all likelihood already existed.
However, “the jury is still out about whether, if we do diagnose patients who have digestive diseases with ARFID, that then helps them get to a treatment that improves their relationship with food and improves nutritional issues that may have occurred as a result of a restricted food intake,” she said.
“We don’t know yet if the diagnosis will actually improve things. In our clinical practice, anecdotally, it has, both for patients with IBDs and for patients with other GI conditions, particularly GI functional motility disorders. We’re a little bit more confident about making the diagnosis of ARFID in GI functional motility disorders than we are in IBD of course,” she said.
Screening measures
To get a better sense of the prevalence of ARFID, compared with reasonable responses to digestive diseases, Dr. Taft and colleagues conducted their cross-sectional study in 289 adults with achalasia, celiac, eosinophilic esophagitis, or IBD.
They found that 51.3% of the total sample met the diagnostic criteria for ARFID based on the Nine-Item ARFID Screen (NIAS), including 75.7 % of patients with achalasia. But Dr. Taft had cautions
“I can tell you, working with achalasia patients, 75% do not have ARFID,” Dr. Taft said.
She noted that the 51.3% of patients with IBD identified by NIAS or the 53% identified by the ARFID+ scale as having ARFID was also highly doubtful.
Dr. Taft and colleagues determined that nearly half of the variance in the NIAS could be accounted for by GI symptoms rather than psychosocial factors, making it less than ideal for use in the clinic or by researchers.
She also noted, however, that she received an email from one of the creators of NIAS, Hana F. Zickgraf, PhD, from the University of South Alabama, Mobile. Dr. Zickgraf agreed that the scale had drawbacks when applied to patients with GI disease, and pointed instead to the Fear of Food Questionnaire, a newly developed 18-item GI disease-specific instrument. Dr. Taft recommended the new questionnaire for research purposes, and expressed hope that a shorter version could be made available for screening patients in clinic.
Dr. Burton Murray said that while the Fear of Food Questionnaire, perhaps in combination with NIAS, has the potential to be a useful screening tool, cutoffs for it have yet to be established.
“At the end of the day, the diagnosis would be made by a clinician who is able to determine whether the life impairment or if the nutritional impairment or restricted food intake are reasonable in the realm of their digestive disease, or could a treatment for ARFID be warranted to help them to make changes to improve their quality of life and nutrition,” she said.
Check biases at the door
Before arriving at a diagnosis of ARFID, clinicians should also consider biases, Dr. Taft said.
“Eating disorders are highly stigmatized and stereotyped diagnoses,” more often attributed to young White women than to either men or to people of racial or ethnic minorities, she said.
Cultural background may contribute to food restrictions, and the risk may increase with age, with 68% of patients with later-onset IBD restricting diets to control the disease. It’s also possible that beliefs about food and “clean and healthy” eating may influence food and eating choices after a patient receives an IBD diagnosis.
Dr. Taft also pointed out that clinicians and patients may have different ideas about what constitutes significant food avoidance. Clinicians may expect patients with IBD to eat despite feeling nauseated, having abdominal pains, or diarrhea, for example, when the same food avoidance might be deemed reasonable in patients with short-term GI infections.
“Severe IBD symptoms are a significant predictor of posttraumatic stress disorder symptoms, and PTSD is hallmarked by avoidance behaviors,” she added.
She emphasized the need for clinicians to ask the right questions of patients to get at the roots of their nutritional deficiency or eating behavior, and to refer patients to mental health professionals with expertise in disordered eating or GI psychology.
Dr. Taft and Dr. Burton Murray reported having no conflicts of interest to disclose.
This article was updated on Feb. 4, 2022.
Problems with eating and nutrition are common among patients with inflammatory bowel disease (IBD) and other gastrointestinal disorders, but clinicians who treat them should be careful not to automatically assume that patients have eating disorders, according to a psychologist who specializes in the psychological and social aspects of chronic digestive diseases.
On the other hand, clinicians must also be aware of the possibility that patients could have a recently identified syndrome cluster called avoidant restrictive food intake disorder (ARFID), said Tiffany Taft, PsyD, a research associate professor of medicine (gastroenterology and hepatology), medical social sciences, and psychiatry and behavioral sciences at Northwestern University, Chicago. In a recent study, she and her colleagues defined ARFID as “failure to meet one’s nutritional needs owing to sensory hypersensitivity, lack of interest in eating, or fear of aversive consequences from eating, and is associated with negative medical and psychosocial outcomes.”
ARFID “is a hot topic that we really don’t understand,” she said in an online presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Nutritional deficiencies
Nutritional deficiencies are common among patients with IBD, “and nutritional deficiencies themselves can lead to symptoms or side effects that can cause people to eat less,” she said.
“As our vitamin B12 goes down, our cognitive functioning starts to decline, and we might not be making clear decisions in how we’re deciding what to eat, when to eat, if we should be eating at all – just something to think about in your patients who have nutritional deficiencies,” she told the audience.
Other common nutritional deficiencies that can affect eating and food choice among patients with IBD include low folate (B9) levels associated with sore tongue and weight loss, low iron levels leading to nausea and loss of appetite, and zinc deficiency leading to loss of appetite and alterations in taste and/or smell, she said.
Newly recognized in GI
She noted that “ARFID actually originates in the pediatric psychiatric literature, mostly in children with sensory issues [such as] autism spectrum disorder, so this is not a construct that started in digestive disease, but has been adapted and applied to patients with digestive disease, including IBD.”
The DSM-5 lists four criteria for ARFID: significant weight loss, significant nutritional deficiency, dependence on enteral nutrition or oral supplements, and marked interference with psychosocial functions.
Helen Burton Murray, PhD, director of the gastrointestinal behavioral health program in the Center for Neurointestinal Health at Massachusetts General Hospital, Boston, who is familiar with Dr. Taft’s work, said in an interview that inclusion of ARFID in DSM-5 has put a name to a syndrome or symptom cluster that in all likelihood already existed.
However, “the jury is still out about whether, if we do diagnose patients who have digestive diseases with ARFID, that then helps them get to a treatment that improves their relationship with food and improves nutritional issues that may have occurred as a result of a restricted food intake,” she said.
“We don’t know yet if the diagnosis will actually improve things. In our clinical practice, anecdotally, it has, both for patients with IBDs and for patients with other GI conditions, particularly GI functional motility disorders. We’re a little bit more confident about making the diagnosis of ARFID in GI functional motility disorders than we are in IBD of course,” she said.
Screening measures
To get a better sense of the prevalence of ARFID, compared with reasonable responses to digestive diseases, Dr. Taft and colleagues conducted their cross-sectional study in 289 adults with achalasia, celiac, eosinophilic esophagitis, or IBD.
They found that 51.3% of the total sample met the diagnostic criteria for ARFID based on the Nine-Item ARFID Screen (NIAS), including 75.7 % of patients with achalasia. But Dr. Taft had cautions
“I can tell you, working with achalasia patients, 75% do not have ARFID,” Dr. Taft said.
She noted that the 51.3% of patients with IBD identified by NIAS or the 53% identified by the ARFID+ scale as having ARFID was also highly doubtful.
Dr. Taft and colleagues determined that nearly half of the variance in the NIAS could be accounted for by GI symptoms rather than psychosocial factors, making it less than ideal for use in the clinic or by researchers.
She also noted, however, that she received an email from one of the creators of NIAS, Hana F. Zickgraf, PhD, from the University of South Alabama, Mobile. Dr. Zickgraf agreed that the scale had drawbacks when applied to patients with GI disease, and pointed instead to the Fear of Food Questionnaire, a newly developed 18-item GI disease-specific instrument. Dr. Taft recommended the new questionnaire for research purposes, and expressed hope that a shorter version could be made available for screening patients in clinic.
Dr. Burton Murray said that while the Fear of Food Questionnaire, perhaps in combination with NIAS, has the potential to be a useful screening tool, cutoffs for it have yet to be established.
“At the end of the day, the diagnosis would be made by a clinician who is able to determine whether the life impairment or if the nutritional impairment or restricted food intake are reasonable in the realm of their digestive disease, or could a treatment for ARFID be warranted to help them to make changes to improve their quality of life and nutrition,” she said.
Check biases at the door
Before arriving at a diagnosis of ARFID, clinicians should also consider biases, Dr. Taft said.
“Eating disorders are highly stigmatized and stereotyped diagnoses,” more often attributed to young White women than to either men or to people of racial or ethnic minorities, she said.
Cultural background may contribute to food restrictions, and the risk may increase with age, with 68% of patients with later-onset IBD restricting diets to control the disease. It’s also possible that beliefs about food and “clean and healthy” eating may influence food and eating choices after a patient receives an IBD diagnosis.
Dr. Taft also pointed out that clinicians and patients may have different ideas about what constitutes significant food avoidance. Clinicians may expect patients with IBD to eat despite feeling nauseated, having abdominal pains, or diarrhea, for example, when the same food avoidance might be deemed reasonable in patients with short-term GI infections.
“Severe IBD symptoms are a significant predictor of posttraumatic stress disorder symptoms, and PTSD is hallmarked by avoidance behaviors,” she added.
She emphasized the need for clinicians to ask the right questions of patients to get at the roots of their nutritional deficiency or eating behavior, and to refer patients to mental health professionals with expertise in disordered eating or GI psychology.
Dr. Taft and Dr. Burton Murray reported having no conflicts of interest to disclose.
This article was updated on Feb. 4, 2022.
Problems with eating and nutrition are common among patients with inflammatory bowel disease (IBD) and other gastrointestinal disorders, but clinicians who treat them should be careful not to automatically assume that patients have eating disorders, according to a psychologist who specializes in the psychological and social aspects of chronic digestive diseases.
On the other hand, clinicians must also be aware of the possibility that patients could have a recently identified syndrome cluster called avoidant restrictive food intake disorder (ARFID), said Tiffany Taft, PsyD, a research associate professor of medicine (gastroenterology and hepatology), medical social sciences, and psychiatry and behavioral sciences at Northwestern University, Chicago. In a recent study, she and her colleagues defined ARFID as “failure to meet one’s nutritional needs owing to sensory hypersensitivity, lack of interest in eating, or fear of aversive consequences from eating, and is associated with negative medical and psychosocial outcomes.”
ARFID “is a hot topic that we really don’t understand,” she said in an online presentation at the annual Crohn’s & Colitis Congress®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Nutritional deficiencies
Nutritional deficiencies are common among patients with IBD, “and nutritional deficiencies themselves can lead to symptoms or side effects that can cause people to eat less,” she said.
“As our vitamin B12 goes down, our cognitive functioning starts to decline, and we might not be making clear decisions in how we’re deciding what to eat, when to eat, if we should be eating at all – just something to think about in your patients who have nutritional deficiencies,” she told the audience.
Other common nutritional deficiencies that can affect eating and food choice among patients with IBD include low folate (B9) levels associated with sore tongue and weight loss, low iron levels leading to nausea and loss of appetite, and zinc deficiency leading to loss of appetite and alterations in taste and/or smell, she said.
Newly recognized in GI
She noted that “ARFID actually originates in the pediatric psychiatric literature, mostly in children with sensory issues [such as] autism spectrum disorder, so this is not a construct that started in digestive disease, but has been adapted and applied to patients with digestive disease, including IBD.”
The DSM-5 lists four criteria for ARFID: significant weight loss, significant nutritional deficiency, dependence on enteral nutrition or oral supplements, and marked interference with psychosocial functions.
Helen Burton Murray, PhD, director of the gastrointestinal behavioral health program in the Center for Neurointestinal Health at Massachusetts General Hospital, Boston, who is familiar with Dr. Taft’s work, said in an interview that inclusion of ARFID in DSM-5 has put a name to a syndrome or symptom cluster that in all likelihood already existed.
However, “the jury is still out about whether, if we do diagnose patients who have digestive diseases with ARFID, that then helps them get to a treatment that improves their relationship with food and improves nutritional issues that may have occurred as a result of a restricted food intake,” she said.
“We don’t know yet if the diagnosis will actually improve things. In our clinical practice, anecdotally, it has, both for patients with IBDs and for patients with other GI conditions, particularly GI functional motility disorders. We’re a little bit more confident about making the diagnosis of ARFID in GI functional motility disorders than we are in IBD of course,” she said.
Screening measures
To get a better sense of the prevalence of ARFID, compared with reasonable responses to digestive diseases, Dr. Taft and colleagues conducted their cross-sectional study in 289 adults with achalasia, celiac, eosinophilic esophagitis, or IBD.
They found that 51.3% of the total sample met the diagnostic criteria for ARFID based on the Nine-Item ARFID Screen (NIAS), including 75.7 % of patients with achalasia. But Dr. Taft had cautions
“I can tell you, working with achalasia patients, 75% do not have ARFID,” Dr. Taft said.
She noted that the 51.3% of patients with IBD identified by NIAS or the 53% identified by the ARFID+ scale as having ARFID was also highly doubtful.
Dr. Taft and colleagues determined that nearly half of the variance in the NIAS could be accounted for by GI symptoms rather than psychosocial factors, making it less than ideal for use in the clinic or by researchers.
She also noted, however, that she received an email from one of the creators of NIAS, Hana F. Zickgraf, PhD, from the University of South Alabama, Mobile. Dr. Zickgraf agreed that the scale had drawbacks when applied to patients with GI disease, and pointed instead to the Fear of Food Questionnaire, a newly developed 18-item GI disease-specific instrument. Dr. Taft recommended the new questionnaire for research purposes, and expressed hope that a shorter version could be made available for screening patients in clinic.
Dr. Burton Murray said that while the Fear of Food Questionnaire, perhaps in combination with NIAS, has the potential to be a useful screening tool, cutoffs for it have yet to be established.
“At the end of the day, the diagnosis would be made by a clinician who is able to determine whether the life impairment or if the nutritional impairment or restricted food intake are reasonable in the realm of their digestive disease, or could a treatment for ARFID be warranted to help them to make changes to improve their quality of life and nutrition,” she said.
Check biases at the door
Before arriving at a diagnosis of ARFID, clinicians should also consider biases, Dr. Taft said.
“Eating disorders are highly stigmatized and stereotyped diagnoses,” more often attributed to young White women than to either men or to people of racial or ethnic minorities, she said.
Cultural background may contribute to food restrictions, and the risk may increase with age, with 68% of patients with later-onset IBD restricting diets to control the disease. It’s also possible that beliefs about food and “clean and healthy” eating may influence food and eating choices after a patient receives an IBD diagnosis.
Dr. Taft also pointed out that clinicians and patients may have different ideas about what constitutes significant food avoidance. Clinicians may expect patients with IBD to eat despite feeling nauseated, having abdominal pains, or diarrhea, for example, when the same food avoidance might be deemed reasonable in patients with short-term GI infections.
“Severe IBD symptoms are a significant predictor of posttraumatic stress disorder symptoms, and PTSD is hallmarked by avoidance behaviors,” she added.
She emphasized the need for clinicians to ask the right questions of patients to get at the roots of their nutritional deficiency or eating behavior, and to refer patients to mental health professionals with expertise in disordered eating or GI psychology.
Dr. Taft and Dr. Burton Murray reported having no conflicts of interest to disclose.
This article was updated on Feb. 4, 2022.
FROM CROHN’S & COLITIS CONGRESS
Lower Leg Hyperpigmentation in MYH9-Related Disorder
To the Editor:
MYH9-related disorder is an autosomal-dominant disorder characterized by macrothrombocytopenia and neutrophil inclusions secondary to defective myosin-9.1 We describe a case of lower leg hyperpigmentation secondary to hemosiderin deposition from MYH9-related disorder.
A 31-year-old woman with a history of MYH9-related disorder and mixed connective tissue disease presented to the outpatient dermatology clinic with asymptomatic brown patches on the lower legs (Figure) of 10 years’ duration. She also had epistaxis, hearing loss, renal disease, and menorrhagia secondary to MYH9-related disorder. The patient had been started on hydroxychloroquine 2 years earlier by rheumatology for mixed connective tissue disorder. A biopsy was not performed, given the risk of bleeding from thrombocytopenia. Ammonium lactate lotion was recommended for the leg patches. No further interventions were undertaken. At 6-month follow-up, hyperpigmentation on the lower legs was stable. The patient expressed no desire for cosmetic intervention.
Prior to discovery of a common gene, MYH9-related disorder was classified as 4 overlapping syndromes: May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian syndrome.2 More than 30 MYH9 mutations have been identified, all of which encode for myosin-9, a subunit of myosin IIA,1,3 that is a nonmuscle myosin needed for cell movement, shape, and cytokinesis. Although most cells use myosin IIA to IIC, certain cells, such as platelets and neutrophils, use myosin IIA exclusively.
In neutrophils of patients with MYH9-related disorder, nonfunctional myosin-9 clumps to form hallmark inclusion bodies, which are seen on the peripheral blood smear. Macrothrombocytopenia, another hallmark of MYH9-related disorder, also can be seen on the peripheral smear of all affected patients. Approximately 30%of patients develop clinical manifestations of the disorder (eg, bleeding, renal failure, hearing loss, presenile cataracts). Bleeding tendency usually is mild; epistaxis and menorrhagia are the most common hematologic manifestations.4
We attribute the lower leg hyperpigmentation in our patient to a severe phenotype of MYH9-related disorder. In addition to hyperpigmentation, our patient had menorrhagia requiring treatment with tranexamic acid, renal failure, and hearing loss, further pointing to a more severe phenotype. Furthermore, it is likely that our patient’s hyperpigmentation was made worse by hydroxychloroquine and a coexisting diagnosis of mixed connective tissue disease, which led to a propensity for increased vessel fragility in the setting of thrombocytopenia.
The workup of suspected MYH9-related disorder includes exclusion of iron-deficiency anemia, which can increase bleeding in patients with the disorder. The presence of small red blood cells (RBCs) in microcytic anemia and large platelets of MYH9-related disorder can lead to a situation in which platelets travel near the center of the lumen of blood vessels, while RBCs travel to the periphery. This decrease in the platelet-endothelium interaction increases the risk for bleeding. Our patient’s hemoglobin level was within reference range, without evidence of iron-deficiency anemia. Correction of iron-deficiency anemia, if applicable, can prevent bleeding brought on by the mechanism of decreased platelet-endothelium interaction and avoid unnecessary antiplatelet medication because of misdiagnosis based on an erroneous platelet count.
The workup of MYH9-related disorder also should include audiography, ophthalmologic examination, and renal function testing for hearing loss, cataracts, and renal disease, respectively. Referral to genetics also may be warranted.
It also is of clinical interest that automated cell counters may underestimate the count of abnormally large platelets in MYH9-related disorder, counting them as RBCs or white blood cells. The platelet count in MYH9-related disorder may be underestimated by 4-fold or greater.4-7
Treatment of leg hyperpigmentation can prove challenging, given the location of dermal hemosiderin. Topical therapy likely is ineffective. Lasers and intense pulsed light therapy are treatment modalities to consider for the hyperpigmentation of MYH9-related disorder. There have been reports of improved cosmesis in dermal hemosiderin depositional disorders, such as venous stasis.4 Our patient was given ammonium lactate lotion to thicken collagen, possibly preventing future bleeding episodes.
- Pecci A, Canobbio I, Balduini A, et al. Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations. Hum Mol Genet. 2005;14:3169-3178. doi:10.1093/hmg/ddi344
- Seri M, Pecci A, Di Bari F, et al. MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore). 2003;82:203-215. doi:10.1097/01.md.0000076006.64510.5c
- Medline Plus. MYH9-related disorder. National Library of Medicine website. Updated August 18, 2020. Accessed January 21, 2022. https://ghr.nlm.nih.gov/condition/myh9-related-disorder#diagnosis
- Althaus K, Greinachar A. MYH9-related platelet disorders. Semin Thromb Hemost. 2009;35:189-203. doi:10.1055/s-0029-1220327
- Kunishima S, Hamaguchi M, Saito H. Differential expression of wild-type and mutant NMMHC-IIA polypeptides in blood cells suggests cell-specific regulation mechanisms in MYH9 disorders. Blood. 2008;111:3015-3023. doi:10.1182/blood-2007-10-116194
- Arrondel C, Vodovar N, Knebelmann B, et al. Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndromes. J Am Soc Nephrol. 2002;13:65-74. doi:10.1681/ASN.V13165
- Selleng K, Lubenow LE, Greinacher A, et al. Perioperative management of MYH9 hereditary macrothrombocytopenia (Fechtner syndrome). Eur J Haematol. 2007;79:263-268. doi:10.1111/j.1600-0609.2007.00913.x
To the Editor:
MYH9-related disorder is an autosomal-dominant disorder characterized by macrothrombocytopenia and neutrophil inclusions secondary to defective myosin-9.1 We describe a case of lower leg hyperpigmentation secondary to hemosiderin deposition from MYH9-related disorder.
A 31-year-old woman with a history of MYH9-related disorder and mixed connective tissue disease presented to the outpatient dermatology clinic with asymptomatic brown patches on the lower legs (Figure) of 10 years’ duration. She also had epistaxis, hearing loss, renal disease, and menorrhagia secondary to MYH9-related disorder. The patient had been started on hydroxychloroquine 2 years earlier by rheumatology for mixed connective tissue disorder. A biopsy was not performed, given the risk of bleeding from thrombocytopenia. Ammonium lactate lotion was recommended for the leg patches. No further interventions were undertaken. At 6-month follow-up, hyperpigmentation on the lower legs was stable. The patient expressed no desire for cosmetic intervention.
Prior to discovery of a common gene, MYH9-related disorder was classified as 4 overlapping syndromes: May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian syndrome.2 More than 30 MYH9 mutations have been identified, all of which encode for myosin-9, a subunit of myosin IIA,1,3 that is a nonmuscle myosin needed for cell movement, shape, and cytokinesis. Although most cells use myosin IIA to IIC, certain cells, such as platelets and neutrophils, use myosin IIA exclusively.
In neutrophils of patients with MYH9-related disorder, nonfunctional myosin-9 clumps to form hallmark inclusion bodies, which are seen on the peripheral blood smear. Macrothrombocytopenia, another hallmark of MYH9-related disorder, also can be seen on the peripheral smear of all affected patients. Approximately 30%of patients develop clinical manifestations of the disorder (eg, bleeding, renal failure, hearing loss, presenile cataracts). Bleeding tendency usually is mild; epistaxis and menorrhagia are the most common hematologic manifestations.4
We attribute the lower leg hyperpigmentation in our patient to a severe phenotype of MYH9-related disorder. In addition to hyperpigmentation, our patient had menorrhagia requiring treatment with tranexamic acid, renal failure, and hearing loss, further pointing to a more severe phenotype. Furthermore, it is likely that our patient’s hyperpigmentation was made worse by hydroxychloroquine and a coexisting diagnosis of mixed connective tissue disease, which led to a propensity for increased vessel fragility in the setting of thrombocytopenia.
The workup of suspected MYH9-related disorder includes exclusion of iron-deficiency anemia, which can increase bleeding in patients with the disorder. The presence of small red blood cells (RBCs) in microcytic anemia and large platelets of MYH9-related disorder can lead to a situation in which platelets travel near the center of the lumen of blood vessels, while RBCs travel to the periphery. This decrease in the platelet-endothelium interaction increases the risk for bleeding. Our patient’s hemoglobin level was within reference range, without evidence of iron-deficiency anemia. Correction of iron-deficiency anemia, if applicable, can prevent bleeding brought on by the mechanism of decreased platelet-endothelium interaction and avoid unnecessary antiplatelet medication because of misdiagnosis based on an erroneous platelet count.
The workup of MYH9-related disorder also should include audiography, ophthalmologic examination, and renal function testing for hearing loss, cataracts, and renal disease, respectively. Referral to genetics also may be warranted.
It also is of clinical interest that automated cell counters may underestimate the count of abnormally large platelets in MYH9-related disorder, counting them as RBCs or white blood cells. The platelet count in MYH9-related disorder may be underestimated by 4-fold or greater.4-7
Treatment of leg hyperpigmentation can prove challenging, given the location of dermal hemosiderin. Topical therapy likely is ineffective. Lasers and intense pulsed light therapy are treatment modalities to consider for the hyperpigmentation of MYH9-related disorder. There have been reports of improved cosmesis in dermal hemosiderin depositional disorders, such as venous stasis.4 Our patient was given ammonium lactate lotion to thicken collagen, possibly preventing future bleeding episodes.
To the Editor:
MYH9-related disorder is an autosomal-dominant disorder characterized by macrothrombocytopenia and neutrophil inclusions secondary to defective myosin-9.1 We describe a case of lower leg hyperpigmentation secondary to hemosiderin deposition from MYH9-related disorder.
A 31-year-old woman with a history of MYH9-related disorder and mixed connective tissue disease presented to the outpatient dermatology clinic with asymptomatic brown patches on the lower legs (Figure) of 10 years’ duration. She also had epistaxis, hearing loss, renal disease, and menorrhagia secondary to MYH9-related disorder. The patient had been started on hydroxychloroquine 2 years earlier by rheumatology for mixed connective tissue disorder. A biopsy was not performed, given the risk of bleeding from thrombocytopenia. Ammonium lactate lotion was recommended for the leg patches. No further interventions were undertaken. At 6-month follow-up, hyperpigmentation on the lower legs was stable. The patient expressed no desire for cosmetic intervention.
Prior to discovery of a common gene, MYH9-related disorder was classified as 4 overlapping syndromes: May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian syndrome.2 More than 30 MYH9 mutations have been identified, all of which encode for myosin-9, a subunit of myosin IIA,1,3 that is a nonmuscle myosin needed for cell movement, shape, and cytokinesis. Although most cells use myosin IIA to IIC, certain cells, such as platelets and neutrophils, use myosin IIA exclusively.
In neutrophils of patients with MYH9-related disorder, nonfunctional myosin-9 clumps to form hallmark inclusion bodies, which are seen on the peripheral blood smear. Macrothrombocytopenia, another hallmark of MYH9-related disorder, also can be seen on the peripheral smear of all affected patients. Approximately 30%of patients develop clinical manifestations of the disorder (eg, bleeding, renal failure, hearing loss, presenile cataracts). Bleeding tendency usually is mild; epistaxis and menorrhagia are the most common hematologic manifestations.4
We attribute the lower leg hyperpigmentation in our patient to a severe phenotype of MYH9-related disorder. In addition to hyperpigmentation, our patient had menorrhagia requiring treatment with tranexamic acid, renal failure, and hearing loss, further pointing to a more severe phenotype. Furthermore, it is likely that our patient’s hyperpigmentation was made worse by hydroxychloroquine and a coexisting diagnosis of mixed connective tissue disease, which led to a propensity for increased vessel fragility in the setting of thrombocytopenia.
The workup of suspected MYH9-related disorder includes exclusion of iron-deficiency anemia, which can increase bleeding in patients with the disorder. The presence of small red blood cells (RBCs) in microcytic anemia and large platelets of MYH9-related disorder can lead to a situation in which platelets travel near the center of the lumen of blood vessels, while RBCs travel to the periphery. This decrease in the platelet-endothelium interaction increases the risk for bleeding. Our patient’s hemoglobin level was within reference range, without evidence of iron-deficiency anemia. Correction of iron-deficiency anemia, if applicable, can prevent bleeding brought on by the mechanism of decreased platelet-endothelium interaction and avoid unnecessary antiplatelet medication because of misdiagnosis based on an erroneous platelet count.
The workup of MYH9-related disorder also should include audiography, ophthalmologic examination, and renal function testing for hearing loss, cataracts, and renal disease, respectively. Referral to genetics also may be warranted.
It also is of clinical interest that automated cell counters may underestimate the count of abnormally large platelets in MYH9-related disorder, counting them as RBCs or white blood cells. The platelet count in MYH9-related disorder may be underestimated by 4-fold or greater.4-7
Treatment of leg hyperpigmentation can prove challenging, given the location of dermal hemosiderin. Topical therapy likely is ineffective. Lasers and intense pulsed light therapy are treatment modalities to consider for the hyperpigmentation of MYH9-related disorder. There have been reports of improved cosmesis in dermal hemosiderin depositional disorders, such as venous stasis.4 Our patient was given ammonium lactate lotion to thicken collagen, possibly preventing future bleeding episodes.
- Pecci A, Canobbio I, Balduini A, et al. Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations. Hum Mol Genet. 2005;14:3169-3178. doi:10.1093/hmg/ddi344
- Seri M, Pecci A, Di Bari F, et al. MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore). 2003;82:203-215. doi:10.1097/01.md.0000076006.64510.5c
- Medline Plus. MYH9-related disorder. National Library of Medicine website. Updated August 18, 2020. Accessed January 21, 2022. https://ghr.nlm.nih.gov/condition/myh9-related-disorder#diagnosis
- Althaus K, Greinachar A. MYH9-related platelet disorders. Semin Thromb Hemost. 2009;35:189-203. doi:10.1055/s-0029-1220327
- Kunishima S, Hamaguchi M, Saito H. Differential expression of wild-type and mutant NMMHC-IIA polypeptides in blood cells suggests cell-specific regulation mechanisms in MYH9 disorders. Blood. 2008;111:3015-3023. doi:10.1182/blood-2007-10-116194
- Arrondel C, Vodovar N, Knebelmann B, et al. Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndromes. J Am Soc Nephrol. 2002;13:65-74. doi:10.1681/ASN.V13165
- Selleng K, Lubenow LE, Greinacher A, et al. Perioperative management of MYH9 hereditary macrothrombocytopenia (Fechtner syndrome). Eur J Haematol. 2007;79:263-268. doi:10.1111/j.1600-0609.2007.00913.x
- Pecci A, Canobbio I, Balduini A, et al. Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations. Hum Mol Genet. 2005;14:3169-3178. doi:10.1093/hmg/ddi344
- Seri M, Pecci A, Di Bari F, et al. MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore). 2003;82:203-215. doi:10.1097/01.md.0000076006.64510.5c
- Medline Plus. MYH9-related disorder. National Library of Medicine website. Updated August 18, 2020. Accessed January 21, 2022. https://ghr.nlm.nih.gov/condition/myh9-related-disorder#diagnosis
- Althaus K, Greinachar A. MYH9-related platelet disorders. Semin Thromb Hemost. 2009;35:189-203. doi:10.1055/s-0029-1220327
- Kunishima S, Hamaguchi M, Saito H. Differential expression of wild-type and mutant NMMHC-IIA polypeptides in blood cells suggests cell-specific regulation mechanisms in MYH9 disorders. Blood. 2008;111:3015-3023. doi:10.1182/blood-2007-10-116194
- Arrondel C, Vodovar N, Knebelmann B, et al. Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndromes. J Am Soc Nephrol. 2002;13:65-74. doi:10.1681/ASN.V13165
- Selleng K, Lubenow LE, Greinacher A, et al. Perioperative management of MYH9 hereditary macrothrombocytopenia (Fechtner syndrome). Eur J Haematol. 2007;79:263-268. doi:10.1111/j.1600-0609.2007.00913.x
Practice Points
- MYH9-related disorder is an autosomal-dominant disorder characterized by macrothrombocytopenia and neutrophil inclusions secondary to defective myosin-9.
- Leg hyperpigmentation can occur secondary to hemosiderin deposition from MYH9-related disorder.
- The workup of suspected MYH9-related disorder includes exclusion of iron-deficiency anemia, which can increase bleeding in patients with the disorder.
- Lasers and intense pulsed light therapy are modalities to consider for the hyperpigmentation of MYH9- related disorder.
