The SARS-CoV-2 variant first detected in the United Kingdom is rapidly becoming the dominant strain in several countries and is doubling every 10 days in the United States, according to new data.

The findings by Nicole L. Washington, PhD, associate director of research at the genomics company Helix, and colleagues were posted Feb. 7, 2021, on the preprint server medRxiv. The paper has not been peer-reviewed in a scientific journal.

The researchers also found that the transmission rate in the United States of the variant, labeled B.1.1.7, is 30%-40% higher than that of more common lineages.

While clinical outcomes initially were thought to be similar to those of other SARS-CoV-2 variants, early reports suggest that infection with the B.1.1.7 variant may increase death risk by about 30%. 

A coauthor of the current study, Kristian Andersen, PhD, told the New York Times , “Nothing in this paper is surprising, but people need to see it.”

Dr. Andersen, a virologist at the Scripps Research Institute in La Jolla, Calif., added that “we should probably prepare for this being the predominant lineage in most places in the United States by March.”

The study of the B.1.1.7 variant adds support for the Centers for Disease Control and Prevention prediction in January that it would dominate by March.

“Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality,” the researchers wrote.

The authors pointed out that the B.1.1.7 variant became the dominant SARS-CoV-2 strain in the United Kingdom within a couple of months of its detection.

“Since then, the variant has been increasingly observed across many European countries, including Portugal and Ireland, which, like the U.K., observed devastating waves of COVID-19 after B.1.1.7 became dominant,” the authors wrote.
 

“Category 5” storm

The B.1.1.7 variant has likely been spreading between U.S. states since at least December, they wrote.

This news organization reported on Jan. 15 that, as of Jan. 13, the B.1.1.7 variant was seen in 76 cases across 12 U.S. states, according to an early release of the CDC’s Morbidity and Mortality Weekly Report. 

As of Feb. 7, there were 690 cases of the B.1.1.7 variant in the US in 33 states, according to the CDC.

Dr. Washington and colleagues examined more than 500,000 coronavirus test samples from cases across the United States that were tested at San Mateo, Calif.–based Helix facilities since July.

In the study, they found inconsistent prevalence of the variant across states. By the last week in January, the researchers estimated the proportion of B.1.1.7 in the U.S. population to be about 2.1% of all COVID-19 cases, though they found it made up about 2% of all COVID-19 cases in California and about 4.5% of cases in Florida. The authors acknowledged that their data is less robust outside of those two states.

Though that seems a relatively low frequency, “our estimates show that its growth rate is at least 35%-45% increased and doubling every week and a half,” the authors wrote.

“Because laboratories in the U.S. are only sequencing a small subset of SARS-CoV-2 samples, the true sequence diversity of SARS-CoV-2 in this country is still unknown,” they noted.

Michael Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, said last week that the United States is facing a “Category 5” storm with the spread of the B.1.1.7 variant as well as the variants first identified in South Africa and Brazil.

“We are going to see something like we have not seen yet in this country,” Dr. Osterholm said recently on NBC’s Meet the Press.

Lead author Nicole L. Washington and many of the coauthors are employees of Helix. Other coauthors are employees of Illumina. Three coauthors own stock in ILMN. The work was funded by Illumina, Helix, the Innovative Genomics Institute, and the New Frontiers in Research Fund provided by the Canadian Institutes of Health Research.

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

The SARS-CoV-2 variant first detected in the United Kingdom is rapidly becoming the dominant strain in several countries and is doubling every 10 days in the United States, according to new data.

The findings by Nicole L. Washington, PhD, associate director of research at the genomics company Helix, and colleagues were posted Feb. 7, 2021, on the preprint server medRxiv. The paper has not been peer-reviewed in a scientific journal.

The researchers also found that the transmission rate in the United States of the variant, labeled B.1.1.7, is 30%-40% higher than that of more common lineages.

While clinical outcomes initially were thought to be similar to those of other SARS-CoV-2 variants, early reports suggest that infection with the B.1.1.7 variant may increase death risk by about 30%. 

A coauthor of the current study, Kristian Andersen, PhD, told the New York Times , “Nothing in this paper is surprising, but people need to see it.”

Dr. Andersen, a virologist at the Scripps Research Institute in La Jolla, Calif., added that “we should probably prepare for this being the predominant lineage in most places in the United States by March.”

The study of the B.1.1.7 variant adds support for the Centers for Disease Control and Prevention prediction in January that it would dominate by March.

“Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality,” the researchers wrote.

The authors pointed out that the B.1.1.7 variant became the dominant SARS-CoV-2 strain in the United Kingdom within a couple of months of its detection.

“Since then, the variant has been increasingly observed across many European countries, including Portugal and Ireland, which, like the U.K., observed devastating waves of COVID-19 after B.1.1.7 became dominant,” the authors wrote.
 

“Category 5” storm

The B.1.1.7 variant has likely been spreading between U.S. states since at least December, they wrote.

This news organization reported on Jan. 15 that, as of Jan. 13, the B.1.1.7 variant was seen in 76 cases across 12 U.S. states, according to an early release of the CDC’s Morbidity and Mortality Weekly Report. 

As of Feb. 7, there were 690 cases of the B.1.1.7 variant in the US in 33 states, according to the CDC.

Dr. Washington and colleagues examined more than 500,000 coronavirus test samples from cases across the United States that were tested at San Mateo, Calif.–based Helix facilities since July.

In the study, they found inconsistent prevalence of the variant across states. By the last week in January, the researchers estimated the proportion of B.1.1.7 in the U.S. population to be about 2.1% of all COVID-19 cases, though they found it made up about 2% of all COVID-19 cases in California and about 4.5% of cases in Florida. The authors acknowledged that their data is less robust outside of those two states.

Though that seems a relatively low frequency, “our estimates show that its growth rate is at least 35%-45% increased and doubling every week and a half,” the authors wrote.

“Because laboratories in the U.S. are only sequencing a small subset of SARS-CoV-2 samples, the true sequence diversity of SARS-CoV-2 in this country is still unknown,” they noted.

Michael Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, said last week that the United States is facing a “Category 5” storm with the spread of the B.1.1.7 variant as well as the variants first identified in South Africa and Brazil.

“We are going to see something like we have not seen yet in this country,” Dr. Osterholm said recently on NBC’s Meet the Press.

Lead author Nicole L. Washington and many of the coauthors are employees of Helix. Other coauthors are employees of Illumina. Three coauthors own stock in ILMN. The work was funded by Illumina, Helix, the Innovative Genomics Institute, and the New Frontiers in Research Fund provided by the Canadian Institutes of Health Research.

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

The SARS-CoV-2 variant first detected in the United Kingdom is rapidly becoming the dominant strain in several countries and is doubling every 10 days in the United States, according to new data.

The findings by Nicole L. Washington, PhD, associate director of research at the genomics company Helix, and colleagues were posted Feb. 7, 2021, on the preprint server medRxiv. The paper has not been peer-reviewed in a scientific journal.

The researchers also found that the transmission rate in the United States of the variant, labeled B.1.1.7, is 30%-40% higher than that of more common lineages.

While clinical outcomes initially were thought to be similar to those of other SARS-CoV-2 variants, early reports suggest that infection with the B.1.1.7 variant may increase death risk by about 30%. 

A coauthor of the current study, Kristian Andersen, PhD, told the New York Times , “Nothing in this paper is surprising, but people need to see it.”

Dr. Andersen, a virologist at the Scripps Research Institute in La Jolla, Calif., added that “we should probably prepare for this being the predominant lineage in most places in the United States by March.”

The study of the B.1.1.7 variant adds support for the Centers for Disease Control and Prevention prediction in January that it would dominate by March.

“Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality,” the researchers wrote.

The authors pointed out that the B.1.1.7 variant became the dominant SARS-CoV-2 strain in the United Kingdom within a couple of months of its detection.

“Since then, the variant has been increasingly observed across many European countries, including Portugal and Ireland, which, like the U.K., observed devastating waves of COVID-19 after B.1.1.7 became dominant,” the authors wrote.
 

“Category 5” storm

The B.1.1.7 variant has likely been spreading between U.S. states since at least December, they wrote.

This news organization reported on Jan. 15 that, as of Jan. 13, the B.1.1.7 variant was seen in 76 cases across 12 U.S. states, according to an early release of the CDC’s Morbidity and Mortality Weekly Report. 

As of Feb. 7, there were 690 cases of the B.1.1.7 variant in the US in 33 states, according to the CDC.

Dr. Washington and colleagues examined more than 500,000 coronavirus test samples from cases across the United States that were tested at San Mateo, Calif.–based Helix facilities since July.

In the study, they found inconsistent prevalence of the variant across states. By the last week in January, the researchers estimated the proportion of B.1.1.7 in the U.S. population to be about 2.1% of all COVID-19 cases, though they found it made up about 2% of all COVID-19 cases in California and about 4.5% of cases in Florida. The authors acknowledged that their data is less robust outside of those two states.

Though that seems a relatively low frequency, “our estimates show that its growth rate is at least 35%-45% increased and doubling every week and a half,” the authors wrote.

“Because laboratories in the U.S. are only sequencing a small subset of SARS-CoV-2 samples, the true sequence diversity of SARS-CoV-2 in this country is still unknown,” they noted.

Michael Osterholm, PhD, MPH, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis, said last week that the United States is facing a “Category 5” storm with the spread of the B.1.1.7 variant as well as the variants first identified in South Africa and Brazil.

“We are going to see something like we have not seen yet in this country,” Dr. Osterholm said recently on NBC’s Meet the Press.

Lead author Nicole L. Washington and many of the coauthors are employees of Helix. Other coauthors are employees of Illumina. Three coauthors own stock in ILMN. The work was funded by Illumina, Helix, the Innovative Genomics Institute, and the New Frontiers in Research Fund provided by the Canadian Institutes of Health Research.

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

The emergence of multiple inflammatory syndrome in children (MIS-C) in association with COVID-19 may be complicating the investigation and diagnosis of more common viral and bacterial infections, potentially delaying treatment and prolonging hospital stays.

Two recent articles published online in Hospital Pediatrics provide evidence of this phenomenon. The articles outlined case studies of children who underwent extensive investigation for MIS-C when in fact they had less severe and more common infections. MIS-C is a severe but rare syndrome that involves systemic hyperinflammation with fever and multisystem organ dysfunction similar to that of Kawasaki disease (KD).

In one of the articles, Matthew Molloy, MD, MPH, of the division of pediatric hospital medicine at Cincinnati Children’s Hospital Medical Center, and colleagues aptly asked: “What are we missing in our search for MIS-C?”
 

E. coli, not SARS-CoV-2

That question arose from a case involving a 3-year-old boy who had a 6-day history of fever and fatigue. Three days earlier, he had tested negative for strep antigen and COVID-19. He had a persistent, high fever, reduced appetite, and reduced urine output and was taken to the ED. On physical examination, there was no rash, skin peeling, redness of the eye or oral mucosa, congestion, rhinorrhea, cough, shortness of breath, chest pain, abdominal pain, nausea, vomiting, or diarrhea.

Urinalysis results and exam findings were suspicious for pyelonephritis. Other findings from an extensive laboratory workup raised the alarm that the boy was suffering from MIS-C as opposed to incomplete KD. After admission to hospital medicine, the cardiology, rheumatology, and infectious disease teams were called in to consult.

Repeat labs were planned for the following day before initiating therapy. On day 2, the child’s urine culture was positive for gram-negative rods, later identified as Escherichia coli. The boy was started on ceftriaxone. Left renal scarring was apparent on ultrasound. The patient’s condition resolved after 36 hours, and he was discharged home with antibiotics.
 

‘Diagnosis derailed’

Calling this a case of “diagnosis derailed,” the authors noted that, in the pre-COVID era, this child’s signs and symptoms would likely have triggered a more targeted and less costly evaluation for more common infectious and noninfectious causes, including pyelonephritis, absent any physical exam findings consistent with KD.

“However, the patient presented in the midst of the COVID-19 pandemic with growing awareness of a new clinical entity,” Dr. Molloy and colleagues wrote. “Anchored to the patient’s persistent fever, the medical team initiated an extensive, costly, and ultimately unnecessary workup to avoid missing the diagnosis of MIS-C; a not yet well-described diagnosis with potentially severe morbidity.”

Confirmation bias and diagnostic momentum likely contributed to the early focus on MIS-C rather than more common alternatives, the authors acknowledged. The addition of mildly abnormal laboratory data not typically obtained in the evaluation of fever led the team astray. “The diagnosis and definitive treatment may have been made earlier had the focus on concern for MIS-C not been present,” Dr. Molloy said in an interview.
 

Keeping value in care

The authors recognized that their initial approach to evaluating for MIS-C provided low-value care. “In our desire to not ‘miss’ MIS-C, we were performing costly evaluations that at times produced mildly abnormal, nonspecific results,” they wrote. That triggered a cascade of specialty consultations, follow-up testing, and an unwarranted diagnostic preoccupation with MIS-C.

Determining the extra price tag for the child’s workup would be complex and difficult because there is a difference in the cost to the hospital and the cost to the family, Dr. Molloy said. “However, there are potential cost savings that would be related to making a correct diagnosis in a timely manner in terms of preventing downstream effects from delayed diagnoses.”

Even as clinicians struggle with the challenging SARS-CoV-2 learning curve, Dr. Molloy and associates urged them to continue to strive for high-value care, with an unwavering focus on using only necessary resources, a stewardship the pandemic has shown to be critical.

“The COVID-19 pandemic has been an incredibly stressful time for physicians and for families,” Dr. Molloy said. “COVID-19 and related conditions like MIS-C are new, and we are learning more and more about them every week. These diagnoses are understandably on the minds of physicians and families when children present with fever.” Notwithstanding, the boy’s case underscores the need for clinicians to consider alternate diagnoses and the value of the care provided.
 

Impact of bias

Dr. Molloy’s group brings home the cognitive biases practitioners often suffer from, including anchoring and confirmation bias and diagnostic momentum, according to J. Howard Smart, MD, chief of pediatrics at Sharp Mary Birch Hospital for Women and Newborns, San Diego, and an assistant clinical professor of pediatrics at University of California, San Diego.

“But it is one thing to recognize these in retrospect and quite another to consider whether they may be happening to you yourself in real time,” he said in an interview. “It is almost as if we need to have a ‘time out,’ where we stop and ask ourselves whether there is something else that could be explaining our patient’s presentation, something that would be more common and more likely to be occurring.”

According to Dr. Smart, who was not involved in Dr. Molloy’s study, the team’s premature diagnostic focus on MIS-C was almost the inverse of what typically happens with KD. “It is usually the case that Kawasaki disease does not enter the differential diagnosis until late in the course of the fever, typically on day 5 or later, when it may have been better to think of it earlier,” he said.

In the second article, Andrea Dean, MD, of the department of pediatrics at Baylor College of Medicine and Texas Children’s Hospital, both in Houston, and colleagues outlined the cases of five patients aged 8-17 years who were hospitalized in May 2020 for suspected MIS-C. They exhibited inflammatory and other concerning indicators but were eventually discharged with a diagnosis of murine typhus.

This flea-borne infection, most commonly reported in the United States in the southeastern Gulf Coast region, Hawaii, and California, is often associated with a triad of fever, rash, and headache.

Cases have been rising in southern Texas, and Dr. Dean and colleagues postulated that school closures and social distancing may have increased exposure as a result of children spending more time outdoors or with pets. “Alternatively, parental concern for SARS-CoV-2 infection could mean children with symptoms are presenting to care and being referred or admitted to the hospital more frequently due to provider concern for MIS-C,” they wrote.
 

Cardiac involvement

The most concerning of the five cases in terms of possible MIS-C, Dr. Dean said in an interview, was that of a 12-year-old boy who had fever for 6 days in association with headache, eczematous rash, dry lips, and conjunctivitis. Laboratory tests showed a mildly elevated C-reactive protein level, hyponatremia, and thrombocytopenia, as well as sterile pyuria and mildly elevated prothrombin time. He was treated empirically with doxycycline, and his fever resolved over the next 24 hours.

An echocardiogram at initial evaluation, however, revealed mild dilation of the left anterior descending and right coronary arteries, which led to the administration of intravenous immunoglobulin and aspirin for atypical KD, in contrast to MIS-C. The authors postulated that mild cardiac involvement in disorders other than MIS-C and KD may be underrecognized.

The lesson from these cases, Dr. Dean and associates concluded, is that hospitalists must maintain a wide differential diagnosis when assessing a child with prolonged fever and evidence of systemic inflammation. The CDC stipulates that a diagnosis of MIS-C requires the absence of a plausible alternative diagnosis.

In addition to common viral, bacterial, and noninfectious disorders, a range of regional endemic rickettsial and parasitic infections must be considered as alternative diagnoses to MIS-C. “Many of these diseases cannot be reliably differentiated from MIS-C on presentation, and as community exposure to SARS-CoV-2 grows, hospitalists should be prepared to admit febrile children with evidence of systemic inflammation for brief observation periods to evaluate for MIS-C,” Dr. Dean’s group wrote. In this context, however, empiric treatment for common or even uncommon infectious diseases may avoid overdiagnosis and overtreatment of MIS-C as well as improve patient outcomes.

“We do have specific MIS-C guidelines at our institution,” Dr. Dean said, “but like all institutions, we are dealing with the broad definition of MIS-C according to the World Health Organization and the CDC, which is really the takeaway from this paper.”
 

More difficult differentiation

Both groups of authors pointed out that, as SARS-CoV-2 spreads throughout a community, a higher percentage of the population will have positive results on antibody testing, and such results will become less useful for differentiating between MIS-C and other conditions.

Despite these series’ cautionary lessons, other experts point to the critical importance of including MIS-C early on in the interest of efficient diagnosis and therapy. “In the cases cited, other pathologies were evaluated for and treated accordingly,” said Kara Gross Margolis, MD, AGAF, an associate professor of pediatrics in the division of pediatric gastroenterology, hepatology, and nutrition at Morgan Stanley Children’s Hospital,New York. “These papers stress the need for a balance that is important, and all potential diagnoses need to be considered, but MIS-C, due to its potential severe consequences, also needs to be on our differential now.”

In her view, as this new high-morbidity entity becomes more widespread during the pandemic, it will be increasingly important to keep this condition on the diagnostic radar.

Interestingly, in a converse example of diagnostic clouding, Dr. Gross Margolis’s group reported (Gastroenterology. 2020 Oct;159[4]:1571-4.e2) last year on a pediatric case series in which the presence of gastrointestinal symptoms in children with COVID-19–related MIS-C muddied the diagnosis by confusing this potentially severe syndrome with more common and less toxic gastrointestinal infections.

According to Dr. Smart, although the two reports don’t offer evidence for a particular diagnostic practice, they can inform the decision-making process. “It may be that we will have enough evidence shortly to say what the best practice is regarding diagnostic evaluation of possible MIS-C cases,” he said. “Until then, we must remember that common things occur commonly, even during a global pandemic.”

Neither of the two reports received any specific funding. The authors disclosed no relevant financial relationships.

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

The emergence of multiple inflammatory syndrome in children (MIS-C) in association with COVID-19 may be complicating the investigation and diagnosis of more common viral and bacterial infections, potentially delaying treatment and prolonging hospital stays.

Two recent articles published online in Hospital Pediatrics provide evidence of this phenomenon. The articles outlined case studies of children who underwent extensive investigation for MIS-C when in fact they had less severe and more common infections. MIS-C is a severe but rare syndrome that involves systemic hyperinflammation with fever and multisystem organ dysfunction similar to that of Kawasaki disease (KD).

In one of the articles, Matthew Molloy, MD, MPH, of the division of pediatric hospital medicine at Cincinnati Children’s Hospital Medical Center, and colleagues aptly asked: “What are we missing in our search for MIS-C?”
 

E. coli, not SARS-CoV-2

That question arose from a case involving a 3-year-old boy who had a 6-day history of fever and fatigue. Three days earlier, he had tested negative for strep antigen and COVID-19. He had a persistent, high fever, reduced appetite, and reduced urine output and was taken to the ED. On physical examination, there was no rash, skin peeling, redness of the eye or oral mucosa, congestion, rhinorrhea, cough, shortness of breath, chest pain, abdominal pain, nausea, vomiting, or diarrhea.

Urinalysis results and exam findings were suspicious for pyelonephritis. Other findings from an extensive laboratory workup raised the alarm that the boy was suffering from MIS-C as opposed to incomplete KD. After admission to hospital medicine, the cardiology, rheumatology, and infectious disease teams were called in to consult.

Repeat labs were planned for the following day before initiating therapy. On day 2, the child’s urine culture was positive for gram-negative rods, later identified as Escherichia coli. The boy was started on ceftriaxone. Left renal scarring was apparent on ultrasound. The patient’s condition resolved after 36 hours, and he was discharged home with antibiotics.
 

‘Diagnosis derailed’

Calling this a case of “diagnosis derailed,” the authors noted that, in the pre-COVID era, this child’s signs and symptoms would likely have triggered a more targeted and less costly evaluation for more common infectious and noninfectious causes, including pyelonephritis, absent any physical exam findings consistent with KD.

“However, the patient presented in the midst of the COVID-19 pandemic with growing awareness of a new clinical entity,” Dr. Molloy and colleagues wrote. “Anchored to the patient’s persistent fever, the medical team initiated an extensive, costly, and ultimately unnecessary workup to avoid missing the diagnosis of MIS-C; a not yet well-described diagnosis with potentially severe morbidity.”

Confirmation bias and diagnostic momentum likely contributed to the early focus on MIS-C rather than more common alternatives, the authors acknowledged. The addition of mildly abnormal laboratory data not typically obtained in the evaluation of fever led the team astray. “The diagnosis and definitive treatment may have been made earlier had the focus on concern for MIS-C not been present,” Dr. Molloy said in an interview.
 

Keeping value in care

The authors recognized that their initial approach to evaluating for MIS-C provided low-value care. “In our desire to not ‘miss’ MIS-C, we were performing costly evaluations that at times produced mildly abnormal, nonspecific results,” they wrote. That triggered a cascade of specialty consultations, follow-up testing, and an unwarranted diagnostic preoccupation with MIS-C.

Determining the extra price tag for the child’s workup would be complex and difficult because there is a difference in the cost to the hospital and the cost to the family, Dr. Molloy said. “However, there are potential cost savings that would be related to making a correct diagnosis in a timely manner in terms of preventing downstream effects from delayed diagnoses.”

Even as clinicians struggle with the challenging SARS-CoV-2 learning curve, Dr. Molloy and associates urged them to continue to strive for high-value care, with an unwavering focus on using only necessary resources, a stewardship the pandemic has shown to be critical.

“The COVID-19 pandemic has been an incredibly stressful time for physicians and for families,” Dr. Molloy said. “COVID-19 and related conditions like MIS-C are new, and we are learning more and more about them every week. These diagnoses are understandably on the minds of physicians and families when children present with fever.” Notwithstanding, the boy’s case underscores the need for clinicians to consider alternate diagnoses and the value of the care provided.
 

Impact of bias

Dr. Molloy’s group brings home the cognitive biases practitioners often suffer from, including anchoring and confirmation bias and diagnostic momentum, according to J. Howard Smart, MD, chief of pediatrics at Sharp Mary Birch Hospital for Women and Newborns, San Diego, and an assistant clinical professor of pediatrics at University of California, San Diego.

“But it is one thing to recognize these in retrospect and quite another to consider whether they may be happening to you yourself in real time,” he said in an interview. “It is almost as if we need to have a ‘time out,’ where we stop and ask ourselves whether there is something else that could be explaining our patient’s presentation, something that would be more common and more likely to be occurring.”

According to Dr. Smart, who was not involved in Dr. Molloy’s study, the team’s premature diagnostic focus on MIS-C was almost the inverse of what typically happens with KD. “It is usually the case that Kawasaki disease does not enter the differential diagnosis until late in the course of the fever, typically on day 5 or later, when it may have been better to think of it earlier,” he said.

In the second article, Andrea Dean, MD, of the department of pediatrics at Baylor College of Medicine and Texas Children’s Hospital, both in Houston, and colleagues outlined the cases of five patients aged 8-17 years who were hospitalized in May 2020 for suspected MIS-C. They exhibited inflammatory and other concerning indicators but were eventually discharged with a diagnosis of murine typhus.

This flea-borne infection, most commonly reported in the United States in the southeastern Gulf Coast region, Hawaii, and California, is often associated with a triad of fever, rash, and headache.

Cases have been rising in southern Texas, and Dr. Dean and colleagues postulated that school closures and social distancing may have increased exposure as a result of children spending more time outdoors or with pets. “Alternatively, parental concern for SARS-CoV-2 infection could mean children with symptoms are presenting to care and being referred or admitted to the hospital more frequently due to provider concern for MIS-C,” they wrote.
 

Cardiac involvement

The most concerning of the five cases in terms of possible MIS-C, Dr. Dean said in an interview, was that of a 12-year-old boy who had fever for 6 days in association with headache, eczematous rash, dry lips, and conjunctivitis. Laboratory tests showed a mildly elevated C-reactive protein level, hyponatremia, and thrombocytopenia, as well as sterile pyuria and mildly elevated prothrombin time. He was treated empirically with doxycycline, and his fever resolved over the next 24 hours.

An echocardiogram at initial evaluation, however, revealed mild dilation of the left anterior descending and right coronary arteries, which led to the administration of intravenous immunoglobulin and aspirin for atypical KD, in contrast to MIS-C. The authors postulated that mild cardiac involvement in disorders other than MIS-C and KD may be underrecognized.

The lesson from these cases, Dr. Dean and associates concluded, is that hospitalists must maintain a wide differential diagnosis when assessing a child with prolonged fever and evidence of systemic inflammation. The CDC stipulates that a diagnosis of MIS-C requires the absence of a plausible alternative diagnosis.

In addition to common viral, bacterial, and noninfectious disorders, a range of regional endemic rickettsial and parasitic infections must be considered as alternative diagnoses to MIS-C. “Many of these diseases cannot be reliably differentiated from MIS-C on presentation, and as community exposure to SARS-CoV-2 grows, hospitalists should be prepared to admit febrile children with evidence of systemic inflammation for brief observation periods to evaluate for MIS-C,” Dr. Dean’s group wrote. In this context, however, empiric treatment for common or even uncommon infectious diseases may avoid overdiagnosis and overtreatment of MIS-C as well as improve patient outcomes.

“We do have specific MIS-C guidelines at our institution,” Dr. Dean said, “but like all institutions, we are dealing with the broad definition of MIS-C according to the World Health Organization and the CDC, which is really the takeaway from this paper.”
 

More difficult differentiation

Both groups of authors pointed out that, as SARS-CoV-2 spreads throughout a community, a higher percentage of the population will have positive results on antibody testing, and such results will become less useful for differentiating between MIS-C and other conditions.

Despite these series’ cautionary lessons, other experts point to the critical importance of including MIS-C early on in the interest of efficient diagnosis and therapy. “In the cases cited, other pathologies were evaluated for and treated accordingly,” said Kara Gross Margolis, MD, AGAF, an associate professor of pediatrics in the division of pediatric gastroenterology, hepatology, and nutrition at Morgan Stanley Children’s Hospital,New York. “These papers stress the need for a balance that is important, and all potential diagnoses need to be considered, but MIS-C, due to its potential severe consequences, also needs to be on our differential now.”

In her view, as this new high-morbidity entity becomes more widespread during the pandemic, it will be increasingly important to keep this condition on the diagnostic radar.

Interestingly, in a converse example of diagnostic clouding, Dr. Gross Margolis’s group reported (Gastroenterology. 2020 Oct;159[4]:1571-4.e2) last year on a pediatric case series in which the presence of gastrointestinal symptoms in children with COVID-19–related MIS-C muddied the diagnosis by confusing this potentially severe syndrome with more common and less toxic gastrointestinal infections.

According to Dr. Smart, although the two reports don’t offer evidence for a particular diagnostic practice, they can inform the decision-making process. “It may be that we will have enough evidence shortly to say what the best practice is regarding diagnostic evaluation of possible MIS-C cases,” he said. “Until then, we must remember that common things occur commonly, even during a global pandemic.”

Neither of the two reports received any specific funding. The authors disclosed no relevant financial relationships.

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

The emergence of multiple inflammatory syndrome in children (MIS-C) in association with COVID-19 may be complicating the investigation and diagnosis of more common viral and bacterial infections, potentially delaying treatment and prolonging hospital stays.

Two recent articles published online in Hospital Pediatrics provide evidence of this phenomenon. The articles outlined case studies of children who underwent extensive investigation for MIS-C when in fact they had less severe and more common infections. MIS-C is a severe but rare syndrome that involves systemic hyperinflammation with fever and multisystem organ dysfunction similar to that of Kawasaki disease (KD).

In one of the articles, Matthew Molloy, MD, MPH, of the division of pediatric hospital medicine at Cincinnati Children’s Hospital Medical Center, and colleagues aptly asked: “What are we missing in our search for MIS-C?”
 

E. coli, not SARS-CoV-2

That question arose from a case involving a 3-year-old boy who had a 6-day history of fever and fatigue. Three days earlier, he had tested negative for strep antigen and COVID-19. He had a persistent, high fever, reduced appetite, and reduced urine output and was taken to the ED. On physical examination, there was no rash, skin peeling, redness of the eye or oral mucosa, congestion, rhinorrhea, cough, shortness of breath, chest pain, abdominal pain, nausea, vomiting, or diarrhea.

Urinalysis results and exam findings were suspicious for pyelonephritis. Other findings from an extensive laboratory workup raised the alarm that the boy was suffering from MIS-C as opposed to incomplete KD. After admission to hospital medicine, the cardiology, rheumatology, and infectious disease teams were called in to consult.

Repeat labs were planned for the following day before initiating therapy. On day 2, the child’s urine culture was positive for gram-negative rods, later identified as Escherichia coli. The boy was started on ceftriaxone. Left renal scarring was apparent on ultrasound. The patient’s condition resolved after 36 hours, and he was discharged home with antibiotics.
 

‘Diagnosis derailed’

Calling this a case of “diagnosis derailed,” the authors noted that, in the pre-COVID era, this child’s signs and symptoms would likely have triggered a more targeted and less costly evaluation for more common infectious and noninfectious causes, including pyelonephritis, absent any physical exam findings consistent with KD.

“However, the patient presented in the midst of the COVID-19 pandemic with growing awareness of a new clinical entity,” Dr. Molloy and colleagues wrote. “Anchored to the patient’s persistent fever, the medical team initiated an extensive, costly, and ultimately unnecessary workup to avoid missing the diagnosis of MIS-C; a not yet well-described diagnosis with potentially severe morbidity.”

Confirmation bias and diagnostic momentum likely contributed to the early focus on MIS-C rather than more common alternatives, the authors acknowledged. The addition of mildly abnormal laboratory data not typically obtained in the evaluation of fever led the team astray. “The diagnosis and definitive treatment may have been made earlier had the focus on concern for MIS-C not been present,” Dr. Molloy said in an interview.
 

Keeping value in care

The authors recognized that their initial approach to evaluating for MIS-C provided low-value care. “In our desire to not ‘miss’ MIS-C, we were performing costly evaluations that at times produced mildly abnormal, nonspecific results,” they wrote. That triggered a cascade of specialty consultations, follow-up testing, and an unwarranted diagnostic preoccupation with MIS-C.

Determining the extra price tag for the child’s workup would be complex and difficult because there is a difference in the cost to the hospital and the cost to the family, Dr. Molloy said. “However, there are potential cost savings that would be related to making a correct diagnosis in a timely manner in terms of preventing downstream effects from delayed diagnoses.”

Even as clinicians struggle with the challenging SARS-CoV-2 learning curve, Dr. Molloy and associates urged them to continue to strive for high-value care, with an unwavering focus on using only necessary resources, a stewardship the pandemic has shown to be critical.

“The COVID-19 pandemic has been an incredibly stressful time for physicians and for families,” Dr. Molloy said. “COVID-19 and related conditions like MIS-C are new, and we are learning more and more about them every week. These diagnoses are understandably on the minds of physicians and families when children present with fever.” Notwithstanding, the boy’s case underscores the need for clinicians to consider alternate diagnoses and the value of the care provided.
 

Impact of bias

Dr. Molloy’s group brings home the cognitive biases practitioners often suffer from, including anchoring and confirmation bias and diagnostic momentum, according to J. Howard Smart, MD, chief of pediatrics at Sharp Mary Birch Hospital for Women and Newborns, San Diego, and an assistant clinical professor of pediatrics at University of California, San Diego.

“But it is one thing to recognize these in retrospect and quite another to consider whether they may be happening to you yourself in real time,” he said in an interview. “It is almost as if we need to have a ‘time out,’ where we stop and ask ourselves whether there is something else that could be explaining our patient’s presentation, something that would be more common and more likely to be occurring.”

According to Dr. Smart, who was not involved in Dr. Molloy’s study, the team’s premature diagnostic focus on MIS-C was almost the inverse of what typically happens with KD. “It is usually the case that Kawasaki disease does not enter the differential diagnosis until late in the course of the fever, typically on day 5 or later, when it may have been better to think of it earlier,” he said.

In the second article, Andrea Dean, MD, of the department of pediatrics at Baylor College of Medicine and Texas Children’s Hospital, both in Houston, and colleagues outlined the cases of five patients aged 8-17 years who were hospitalized in May 2020 for suspected MIS-C. They exhibited inflammatory and other concerning indicators but were eventually discharged with a diagnosis of murine typhus.

This flea-borne infection, most commonly reported in the United States in the southeastern Gulf Coast region, Hawaii, and California, is often associated with a triad of fever, rash, and headache.

Cases have been rising in southern Texas, and Dr. Dean and colleagues postulated that school closures and social distancing may have increased exposure as a result of children spending more time outdoors or with pets. “Alternatively, parental concern for SARS-CoV-2 infection could mean children with symptoms are presenting to care and being referred or admitted to the hospital more frequently due to provider concern for MIS-C,” they wrote.
 

Cardiac involvement

The most concerning of the five cases in terms of possible MIS-C, Dr. Dean said in an interview, was that of a 12-year-old boy who had fever for 6 days in association with headache, eczematous rash, dry lips, and conjunctivitis. Laboratory tests showed a mildly elevated C-reactive protein level, hyponatremia, and thrombocytopenia, as well as sterile pyuria and mildly elevated prothrombin time. He was treated empirically with doxycycline, and his fever resolved over the next 24 hours.

An echocardiogram at initial evaluation, however, revealed mild dilation of the left anterior descending and right coronary arteries, which led to the administration of intravenous immunoglobulin and aspirin for atypical KD, in contrast to MIS-C. The authors postulated that mild cardiac involvement in disorders other than MIS-C and KD may be underrecognized.

The lesson from these cases, Dr. Dean and associates concluded, is that hospitalists must maintain a wide differential diagnosis when assessing a child with prolonged fever and evidence of systemic inflammation. The CDC stipulates that a diagnosis of MIS-C requires the absence of a plausible alternative diagnosis.

In addition to common viral, bacterial, and noninfectious disorders, a range of regional endemic rickettsial and parasitic infections must be considered as alternative diagnoses to MIS-C. “Many of these diseases cannot be reliably differentiated from MIS-C on presentation, and as community exposure to SARS-CoV-2 grows, hospitalists should be prepared to admit febrile children with evidence of systemic inflammation for brief observation periods to evaluate for MIS-C,” Dr. Dean’s group wrote. In this context, however, empiric treatment for common or even uncommon infectious diseases may avoid overdiagnosis and overtreatment of MIS-C as well as improve patient outcomes.

“We do have specific MIS-C guidelines at our institution,” Dr. Dean said, “but like all institutions, we are dealing with the broad definition of MIS-C according to the World Health Organization and the CDC, which is really the takeaway from this paper.”
 

More difficult differentiation

Both groups of authors pointed out that, as SARS-CoV-2 spreads throughout a community, a higher percentage of the population will have positive results on antibody testing, and such results will become less useful for differentiating between MIS-C and other conditions.

Despite these series’ cautionary lessons, other experts point to the critical importance of including MIS-C early on in the interest of efficient diagnosis and therapy. “In the cases cited, other pathologies were evaluated for and treated accordingly,” said Kara Gross Margolis, MD, AGAF, an associate professor of pediatrics in the division of pediatric gastroenterology, hepatology, and nutrition at Morgan Stanley Children’s Hospital,New York. “These papers stress the need for a balance that is important, and all potential diagnoses need to be considered, but MIS-C, due to its potential severe consequences, also needs to be on our differential now.”

In her view, as this new high-morbidity entity becomes more widespread during the pandemic, it will be increasingly important to keep this condition on the diagnostic radar.

Interestingly, in a converse example of diagnostic clouding, Dr. Gross Margolis’s group reported (Gastroenterology. 2020 Oct;159[4]:1571-4.e2) last year on a pediatric case series in which the presence of gastrointestinal symptoms in children with COVID-19–related MIS-C muddied the diagnosis by confusing this potentially severe syndrome with more common and less toxic gastrointestinal infections.

According to Dr. Smart, although the two reports don’t offer evidence for a particular diagnostic practice, they can inform the decision-making process. “It may be that we will have enough evidence shortly to say what the best practice is regarding diagnostic evaluation of possible MIS-C cases,” he said. “Until then, we must remember that common things occur commonly, even during a global pandemic.”

Neither of the two reports received any specific funding. The authors disclosed no relevant financial relationships.

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

Clinical questions: What are the demographics and clinical features of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) syndromes, and which admitting demographics and clinical features are predictive of disease severity?

Background: In children, SARS-CoV-2 causes respiratory disease and multisystem inflammatory syndrome in children (MIS-C) as well as other clinical manifestations. The authors of this study chose to address the gap of identifying characteristics for severe disease caused by SARS-CoV-2, including respiratory disease, MIS-C and other manifestations.

Study design: Retrospective and prospective cohort analysis of hospitalized children

Setting: Participating hospitals in Tri-State Pediatric COVID-19 Consortium, including hospitals in New York, New Jersey, and Connecticut.

Synopsis: The authors identified hospitalized patients 22 years old or younger who had a positive SARS-CoV-2 test or met the U.S. Centers for Disease Control and Preventions’ MIS-C case definition. For comparative analysis, patients were divided into a respiratory disease group (based on the World Health Organization’s criteria for COVID-19), MIS-C group or other group (based on the primary reason for hospitalization).

The authors included 281 patients in the study. 51% of the patients presented with respiratory disease, 25% with MIS-C and 25% with other symptoms, including gastrointestinal, or fever. 51% of all patients were Hispanic and 23% were non-Black Hispanic. The most common pre-existing comorbidities amongst all groups were obesity (34%) and asthma (14%).

Patients with respiratory disease had a median age of 14 years while those with MIS-C had a median age of 7 years. Patients more commonly identified as non-Hispanic Black in the MIS-C group vs the respiratory group (35% vs. 18%). Obesity and medical complexity were more prevalent in the respiratory group relative to the MIS-C group. 75% of patients with MIS-C had gastrointestinal symptoms. 44% of respiratory patients had a chest radiograph with bilateral infiltrates on admission, and 18% or respiratory patients required invasive mechanical ventilation. The most common complications in the respiratory group were acute respiratory distress syndrome (17%) and acute kidney injury (11%), whereas shock (35%) and cardiac dysfunction (25%) were the most common complications in the MIS-C group. The median length of stay for all patients was 4 days (IQR 2-8 days).

Patients with MIS-C were more likely to be admitted to the intensive care unit (ICU) but all deaths (7 patients) occurred in the respiratory group. 40% of patients with respiratory disease, 56% of patients with MIS-C, and 6% of other patients met the authors’ definition of severe disease (ICU admission > 48 hours). For the respiratory group, younger age, obesity, increasing white blood cell count, hypoxia, and bilateral infiltrates on chest radiograph were independent predictors of severe disease based on multivariate analyses. For the MIS-C group, lower absolute lymphocyte count and increasing CRP at admission were independent predictors of severity.

Bottom line: Mortality in pediatric patients is low. Ethnicity and race were not predictive of disease severity in this model, even though 51% of the patients studied were Hispanic and 23% were non-Hispanic Black. Severity of illness for patients with respiratory disease was found to be associated with younger age, obesity, increasing white blood cell count, hypoxia, and bilateral infiltrates on chest radiograph. Severity of illness in patients with MIS-C was associated with lower absolute lymphocyte count and increasing CRP.

Citation: Fernandes DM, et al. Severe acute respiratory syndrome coronavirus 2 clinical syndromes and predictors of disease severity in hospitalized children and youth. J Pediatr. 2020 Nov 14;S0022-3476(20):31393-7. DOI: 10.1016/j.jpeds.2020.11.016.

Dr. Kumar is an assistant professor of pediatrics at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and a pediatric hospitalist at Cleveland Clinic Children’s. She is the pediatric editor of The Hospitalist.

Clinical questions: What are the demographics and clinical features of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) syndromes, and which admitting demographics and clinical features are predictive of disease severity?

Background: In children, SARS-CoV-2 causes respiratory disease and multisystem inflammatory syndrome in children (MIS-C) as well as other clinical manifestations. The authors of this study chose to address the gap of identifying characteristics for severe disease caused by SARS-CoV-2, including respiratory disease, MIS-C and other manifestations.

Study design: Retrospective and prospective cohort analysis of hospitalized children

Setting: Participating hospitals in Tri-State Pediatric COVID-19 Consortium, including hospitals in New York, New Jersey, and Connecticut.

Synopsis: The authors identified hospitalized patients 22 years old or younger who had a positive SARS-CoV-2 test or met the U.S. Centers for Disease Control and Preventions’ MIS-C case definition. For comparative analysis, patients were divided into a respiratory disease group (based on the World Health Organization’s criteria for COVID-19), MIS-C group or other group (based on the primary reason for hospitalization).

The authors included 281 patients in the study. 51% of the patients presented with respiratory disease, 25% with MIS-C and 25% with other symptoms, including gastrointestinal, or fever. 51% of all patients were Hispanic and 23% were non-Black Hispanic. The most common pre-existing comorbidities amongst all groups were obesity (34%) and asthma (14%).

Patients with respiratory disease had a median age of 14 years while those with MIS-C had a median age of 7 years. Patients more commonly identified as non-Hispanic Black in the MIS-C group vs the respiratory group (35% vs. 18%). Obesity and medical complexity were more prevalent in the respiratory group relative to the MIS-C group. 75% of patients with MIS-C had gastrointestinal symptoms. 44% of respiratory patients had a chest radiograph with bilateral infiltrates on admission, and 18% or respiratory patients required invasive mechanical ventilation. The most common complications in the respiratory group were acute respiratory distress syndrome (17%) and acute kidney injury (11%), whereas shock (35%) and cardiac dysfunction (25%) were the most common complications in the MIS-C group. The median length of stay for all patients was 4 days (IQR 2-8 days).

Patients with MIS-C were more likely to be admitted to the intensive care unit (ICU) but all deaths (7 patients) occurred in the respiratory group. 40% of patients with respiratory disease, 56% of patients with MIS-C, and 6% of other patients met the authors’ definition of severe disease (ICU admission > 48 hours). For the respiratory group, younger age, obesity, increasing white blood cell count, hypoxia, and bilateral infiltrates on chest radiograph were independent predictors of severe disease based on multivariate analyses. For the MIS-C group, lower absolute lymphocyte count and increasing CRP at admission were independent predictors of severity.

Bottom line: Mortality in pediatric patients is low. Ethnicity and race were not predictive of disease severity in this model, even though 51% of the patients studied were Hispanic and 23% were non-Hispanic Black. Severity of illness for patients with respiratory disease was found to be associated with younger age, obesity, increasing white blood cell count, hypoxia, and bilateral infiltrates on chest radiograph. Severity of illness in patients with MIS-C was associated with lower absolute lymphocyte count and increasing CRP.

Citation: Fernandes DM, et al. Severe acute respiratory syndrome coronavirus 2 clinical syndromes and predictors of disease severity in hospitalized children and youth. J Pediatr. 2020 Nov 14;S0022-3476(20):31393-7. DOI: 10.1016/j.jpeds.2020.11.016.

Dr. Kumar is an assistant professor of pediatrics at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and a pediatric hospitalist at Cleveland Clinic Children’s. She is the pediatric editor of The Hospitalist.

Clinical questions: What are the demographics and clinical features of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) syndromes, and which admitting demographics and clinical features are predictive of disease severity?

Background: In children, SARS-CoV-2 causes respiratory disease and multisystem inflammatory syndrome in children (MIS-C) as well as other clinical manifestations. The authors of this study chose to address the gap of identifying characteristics for severe disease caused by SARS-CoV-2, including respiratory disease, MIS-C and other manifestations.

Study design: Retrospective and prospective cohort analysis of hospitalized children

Setting: Participating hospitals in Tri-State Pediatric COVID-19 Consortium, including hospitals in New York, New Jersey, and Connecticut.

Synopsis: The authors identified hospitalized patients 22 years old or younger who had a positive SARS-CoV-2 test or met the U.S. Centers for Disease Control and Preventions’ MIS-C case definition. For comparative analysis, patients were divided into a respiratory disease group (based on the World Health Organization’s criteria for COVID-19), MIS-C group or other group (based on the primary reason for hospitalization).

The authors included 281 patients in the study. 51% of the patients presented with respiratory disease, 25% with MIS-C and 25% with other symptoms, including gastrointestinal, or fever. 51% of all patients were Hispanic and 23% were non-Black Hispanic. The most common pre-existing comorbidities amongst all groups were obesity (34%) and asthma (14%).

Patients with respiratory disease had a median age of 14 years while those with MIS-C had a median age of 7 years. Patients more commonly identified as non-Hispanic Black in the MIS-C group vs the respiratory group (35% vs. 18%). Obesity and medical complexity were more prevalent in the respiratory group relative to the MIS-C group. 75% of patients with MIS-C had gastrointestinal symptoms. 44% of respiratory patients had a chest radiograph with bilateral infiltrates on admission, and 18% or respiratory patients required invasive mechanical ventilation. The most common complications in the respiratory group were acute respiratory distress syndrome (17%) and acute kidney injury (11%), whereas shock (35%) and cardiac dysfunction (25%) were the most common complications in the MIS-C group. The median length of stay for all patients was 4 days (IQR 2-8 days).

Patients with MIS-C were more likely to be admitted to the intensive care unit (ICU) but all deaths (7 patients) occurred in the respiratory group. 40% of patients with respiratory disease, 56% of patients with MIS-C, and 6% of other patients met the authors’ definition of severe disease (ICU admission > 48 hours). For the respiratory group, younger age, obesity, increasing white blood cell count, hypoxia, and bilateral infiltrates on chest radiograph were independent predictors of severe disease based on multivariate analyses. For the MIS-C group, lower absolute lymphocyte count and increasing CRP at admission were independent predictors of severity.

Bottom line: Mortality in pediatric patients is low. Ethnicity and race were not predictive of disease severity in this model, even though 51% of the patients studied were Hispanic and 23% were non-Hispanic Black. Severity of illness for patients with respiratory disease was found to be associated with younger age, obesity, increasing white blood cell count, hypoxia, and bilateral infiltrates on chest radiograph. Severity of illness in patients with MIS-C was associated with lower absolute lymphocyte count and increasing CRP.

Citation: Fernandes DM, et al. Severe acute respiratory syndrome coronavirus 2 clinical syndromes and predictors of disease severity in hospitalized children and youth. J Pediatr. 2020 Nov 14;S0022-3476(20):31393-7. DOI: 10.1016/j.jpeds.2020.11.016.

Dr. Kumar is an assistant professor of pediatrics at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and a pediatric hospitalist at Cleveland Clinic Children’s. She is the pediatric editor of The Hospitalist.

Neoadjuvant atezolizumab prior to lung cancer surgery was well tolerated by patients with stage IB-IIIB lung cancer and produced a 21% major pathologic response rate, according to the primary analysis of the Lung Cancer Mutation Consortium (LCMC) 3 study.

Small pilot studies previously suggested that preoperative immune checkpoint inhibitor (ICI) therapy may benefit patients with resectable non–small cell lung cancer (NSCLC).

The LCMC3 study is “unique” because it is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC, and it’s “a landmark study” because it validated results from smaller trials and can serve as a benchmark for future ones, said Jay M. Lee, MD, of the University of California, Los Angeles.

Dr. Lee presented results from LCMC3 at the 2020 World Congress on Lung Cancer (Abstract PS01.05), which was rescheduled for January 2021.

The study included 181 patients, median age 65 years, with stage IB-IIIB NSCLC. The vast majority (90%) of patients were current/former smokers, and two-thirds had a nonsquamous histology. Patients were categorized in the following stages: 17 patients were staged at IB, 20 were IIA, 55 were IIB, 72 were IIIA, and 17 were IIIB.

Patients received 1,200 mg of neoadjuvant atezolizumab intravenously every 3 weeks for two cycles followed by resection between 30 and 50 days from the first cycle. Patients who benefited from the therapy continued adjuvant atezolizumab for 12 months.

The primary endpoint was major pathological response, defined as no more than 10% viable tumor cells at surgery, in patients without epidermal growth factor receptor or anaplastic lymphoma kinase mutations.
 

Results

Following atezolizumab treatment, 43% of patients were down-staged, and 19% were up-staged. Some degree of pathological regression was observed in all but 3 of the 159 patients who underwent resection.

Among the 144 patients included in the efficacy analysis, the major pathological response rate was 21%, with 7% of patients achieving a complete pathological response.

“We demonstrated that more than half of patients resected with a minimally invasive operation. Remarkably, only 15% required thoracotomy. The 92% complete resection rate is comparable, if not superior to, preoperative chemotherapy trials,” Dr. Lee said.

The majority (88%) of patients underwent surgical resection within a 20-day protocol window. The median time from end of neoadjuvant therapy to surgery was 22 days.

“Historically, the neoadjuvant chemotherapy window is much later for surgery, 3 weeks from neoadjuvant therapy, and that can be stretched to up to 56 days,” Dr. Lee said.

In an exploratory analysis, the 1.5-year overall survival rate was 91% for stage I and II disease and 87% for stage III disease. The survival in both cohorts was superior to that expected historically, Dr. Lee noted.

Intraoperative complications were rare (3%). Postoperative adverse reactions correlated with fewer viable tumor cells in the resected specimen.

One patient died following surgery after the first 30 days, which was deemed unrelated to treatment. Another patient died between 30 and 90 days from treatment-related pneumonitis.

“The LCMC3 study successfully met its primary endpoint of achieving major pathological response,” Dr. Lee concluded. “Neoadjuvant atezolizumab monotherapy was well tolerated, and resection was performed with low perioperative morbidity and mortality, usually within a narrow protocol window and with a short time frame from completion of atezolizumab and with a correspondingly high complete resection rate.”

The study’s results suggest that “neoadjuvant atezolizumab monotherapy is effective, well tolerated, and surgically acceptable,” said study discussant Shinichi Toyooka, MD, of Okayama (Japan) University Hospital.

“I would consider single-agent ICI neoadjuvant therapy for patients with early-stage disease and poor performance status, and an ICI plus chemotherapy for more advanced resectable cases, like locally advanced disease,” Dr. Toyooka said.

The LCMC3 study is sponsored by Genentech. Dr. Lee disclosed relationships with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis. Dr. Toyooka disclosed relationships with AstraZeneca, Chugai, Taiho Pharmaceutical Group, and Ono Pharmaceutical.

Neoadjuvant atezolizumab prior to lung cancer surgery was well tolerated by patients with stage IB-IIIB lung cancer and produced a 21% major pathologic response rate, according to the primary analysis of the Lung Cancer Mutation Consortium (LCMC) 3 study.

Small pilot studies previously suggested that preoperative immune checkpoint inhibitor (ICI) therapy may benefit patients with resectable non–small cell lung cancer (NSCLC).

The LCMC3 study is “unique” because it is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC, and it’s “a landmark study” because it validated results from smaller trials and can serve as a benchmark for future ones, said Jay M. Lee, MD, of the University of California, Los Angeles.

Dr. Lee presented results from LCMC3 at the 2020 World Congress on Lung Cancer (Abstract PS01.05), which was rescheduled for January 2021.

The study included 181 patients, median age 65 years, with stage IB-IIIB NSCLC. The vast majority (90%) of patients were current/former smokers, and two-thirds had a nonsquamous histology. Patients were categorized in the following stages: 17 patients were staged at IB, 20 were IIA, 55 were IIB, 72 were IIIA, and 17 were IIIB.

Patients received 1,200 mg of neoadjuvant atezolizumab intravenously every 3 weeks for two cycles followed by resection between 30 and 50 days from the first cycle. Patients who benefited from the therapy continued adjuvant atezolizumab for 12 months.

The primary endpoint was major pathological response, defined as no more than 10% viable tumor cells at surgery, in patients without epidermal growth factor receptor or anaplastic lymphoma kinase mutations.
 

Results

Following atezolizumab treatment, 43% of patients were down-staged, and 19% were up-staged. Some degree of pathological regression was observed in all but 3 of the 159 patients who underwent resection.

Among the 144 patients included in the efficacy analysis, the major pathological response rate was 21%, with 7% of patients achieving a complete pathological response.

“We demonstrated that more than half of patients resected with a minimally invasive operation. Remarkably, only 15% required thoracotomy. The 92% complete resection rate is comparable, if not superior to, preoperative chemotherapy trials,” Dr. Lee said.

The majority (88%) of patients underwent surgical resection within a 20-day protocol window. The median time from end of neoadjuvant therapy to surgery was 22 days.

“Historically, the neoadjuvant chemotherapy window is much later for surgery, 3 weeks from neoadjuvant therapy, and that can be stretched to up to 56 days,” Dr. Lee said.

In an exploratory analysis, the 1.5-year overall survival rate was 91% for stage I and II disease and 87% for stage III disease. The survival in both cohorts was superior to that expected historically, Dr. Lee noted.

Intraoperative complications were rare (3%). Postoperative adverse reactions correlated with fewer viable tumor cells in the resected specimen.

One patient died following surgery after the first 30 days, which was deemed unrelated to treatment. Another patient died between 30 and 90 days from treatment-related pneumonitis.

“The LCMC3 study successfully met its primary endpoint of achieving major pathological response,” Dr. Lee concluded. “Neoadjuvant atezolizumab monotherapy was well tolerated, and resection was performed with low perioperative morbidity and mortality, usually within a narrow protocol window and with a short time frame from completion of atezolizumab and with a correspondingly high complete resection rate.”

The study’s results suggest that “neoadjuvant atezolizumab monotherapy is effective, well tolerated, and surgically acceptable,” said study discussant Shinichi Toyooka, MD, of Okayama (Japan) University Hospital.

“I would consider single-agent ICI neoadjuvant therapy for patients with early-stage disease and poor performance status, and an ICI plus chemotherapy for more advanced resectable cases, like locally advanced disease,” Dr. Toyooka said.

The LCMC3 study is sponsored by Genentech. Dr. Lee disclosed relationships with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis. Dr. Toyooka disclosed relationships with AstraZeneca, Chugai, Taiho Pharmaceutical Group, and Ono Pharmaceutical.

Neoadjuvant atezolizumab prior to lung cancer surgery was well tolerated by patients with stage IB-IIIB lung cancer and produced a 21% major pathologic response rate, according to the primary analysis of the Lung Cancer Mutation Consortium (LCMC) 3 study.

Small pilot studies previously suggested that preoperative immune checkpoint inhibitor (ICI) therapy may benefit patients with resectable non–small cell lung cancer (NSCLC).

The LCMC3 study is “unique” because it is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC, and it’s “a landmark study” because it validated results from smaller trials and can serve as a benchmark for future ones, said Jay M. Lee, MD, of the University of California, Los Angeles.

Dr. Lee presented results from LCMC3 at the 2020 World Congress on Lung Cancer (Abstract PS01.05), which was rescheduled for January 2021.

The study included 181 patients, median age 65 years, with stage IB-IIIB NSCLC. The vast majority (90%) of patients were current/former smokers, and two-thirds had a nonsquamous histology. Patients were categorized in the following stages: 17 patients were staged at IB, 20 were IIA, 55 were IIB, 72 were IIIA, and 17 were IIIB.

Patients received 1,200 mg of neoadjuvant atezolizumab intravenously every 3 weeks for two cycles followed by resection between 30 and 50 days from the first cycle. Patients who benefited from the therapy continued adjuvant atezolizumab for 12 months.

The primary endpoint was major pathological response, defined as no more than 10% viable tumor cells at surgery, in patients without epidermal growth factor receptor or anaplastic lymphoma kinase mutations.
 

Results

Following atezolizumab treatment, 43% of patients were down-staged, and 19% were up-staged. Some degree of pathological regression was observed in all but 3 of the 159 patients who underwent resection.

Among the 144 patients included in the efficacy analysis, the major pathological response rate was 21%, with 7% of patients achieving a complete pathological response.

“We demonstrated that more than half of patients resected with a minimally invasive operation. Remarkably, only 15% required thoracotomy. The 92% complete resection rate is comparable, if not superior to, preoperative chemotherapy trials,” Dr. Lee said.

The majority (88%) of patients underwent surgical resection within a 20-day protocol window. The median time from end of neoadjuvant therapy to surgery was 22 days.

“Historically, the neoadjuvant chemotherapy window is much later for surgery, 3 weeks from neoadjuvant therapy, and that can be stretched to up to 56 days,” Dr. Lee said.

In an exploratory analysis, the 1.5-year overall survival rate was 91% for stage I and II disease and 87% for stage III disease. The survival in both cohorts was superior to that expected historically, Dr. Lee noted.

Intraoperative complications were rare (3%). Postoperative adverse reactions correlated with fewer viable tumor cells in the resected specimen.

One patient died following surgery after the first 30 days, which was deemed unrelated to treatment. Another patient died between 30 and 90 days from treatment-related pneumonitis.

“The LCMC3 study successfully met its primary endpoint of achieving major pathological response,” Dr. Lee concluded. “Neoadjuvant atezolizumab monotherapy was well tolerated, and resection was performed with low perioperative morbidity and mortality, usually within a narrow protocol window and with a short time frame from completion of atezolizumab and with a correspondingly high complete resection rate.”

The study’s results suggest that “neoadjuvant atezolizumab monotherapy is effective, well tolerated, and surgically acceptable,” said study discussant Shinichi Toyooka, MD, of Okayama (Japan) University Hospital.

“I would consider single-agent ICI neoadjuvant therapy for patients with early-stage disease and poor performance status, and an ICI plus chemotherapy for more advanced resectable cases, like locally advanced disease,” Dr. Toyooka said.

The LCMC3 study is sponsored by Genentech. Dr. Lee disclosed relationships with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis. Dr. Toyooka disclosed relationships with AstraZeneca, Chugai, Taiho Pharmaceutical Group, and Ono Pharmaceutical.

Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.

Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.

Factor VIII replacement therapies and gene therapy may soon reduce the need for factor VIII concentrate in hemophilia A, but concentrate, a staple of therapy for hemophilia A since the 1950s, will still likely have a role in certain circumstances, a hematology expert said.

“Factor VIII concentrate therapy should still be available for hemophilia A therapy in the future, for the treatment of breakthrough bleeds in non–factor substitution therapy cases, to obtain retain reliable levels of laboratory-measurable hemostatic activity, for enhanced global access to hemophilia A therapy, and finally – and somewhat speculatively – to treat nonhemostatic functions if these are better defined in future preclinical investigations,” said David Lillicrap, MD, from Queen’s University in Kingston, Ont.

He discussed factor VIII biology and the pros and cons of alternatives to factor VIII concentrate at the annual congress of the European Association for Haemophilia and Allied Disorders.
 

One factor, multiple sources

It has been known since at least the late 1960s and early ‘70s that the liver is a significant source of factor VIII, primarily through liver sinusoidal endothelial cells (LSECs), but more recent studies have revealed other, nonhepatic sites of factor VIII expression, including the kidneys, lungs, spleen, lymph nodes, heat, intestines, skin an pulmonary artery, he said.

Endothelial cells proven to express factor VIII included LSECs, lymphatic endothelium, glomerular endothelium, and high endothelial venules.

“This information suggests that maybe a site of factor VIII synthesis could be important for a function that we do not yet appreciate. This is speculation, of course, but this is an unusual and enigmatic group of cells, and perhaps we’re missing something here that’s biologically important,” he said.

In addition to hemophilia, factor VIII deficiency may contribute to nonhemostatic pathologies, such as osteopenia/osteoporosis and hypertension, the latter possibly related to multiple renal bleeds or endothelial cell vasomotor dysfunction, he noted.

Despite decades-long experience with factor VIII concentrates, there are still uncertainties regarding optimal effective dosing, and about the mechanisms and management of factor VIII immunogenicity, both primary inhibitor development and immune tolerance induction, Dr. Lillicrap said.
 

Alternative therapies

Both factor VIII mimetics such as emicizumab (Hemlibra) and hemostasis rebalancing agents such as fitusiran, anti–tissue factor pathway inhibitor (TFPI) antibody and activated protein C serine protease inhibitor (APC serpin) require only infrequent subcutaneous administration, are efficacious in patients with factor VIII inhibitors, and are supported by either robust phase 3 data (in the case of mimetics) or evidence from late-phase clinical trials (in the case of the rebalancing agents).

However, “for the factor VIII mimetics we know that only partial factor VIII mimetic function, somewhere in the region of 10%-15% is obtained, and because of this, breakthrough bleeds do occur in these patients,” he said.

Additionally, the mimetics have been associated with rare, sometimes poorly explained thromboembolic complications, especially when they are given concurrently with activated prothrombin complex concentrate. Mimetic are also associated with infrequent development of antidrug antibodies, and “the fact that the factor VIII mimetic function is always ‘on’ is potentially a problem.”

For the rebalancing hemostasis agents, there are concerns about the ability to respond to dynamic challenges to the hemostatic system, such as sepsis or following trauma. These agents are also associated, albeit infrequently, with thromboembolic events, and they are somewhat difficult to monitor, he said.
 

Gene therapy

Gene therapy for hemophilia has the advantages of a single administration for a long-term effect, avoiding the peaks and troughs associated with substitution therapy, and the potential for being less immunogenic than factor VIII protein replacement.

The downside of gene therapy is that some patients may be ineligible for it because of preexisting immunity in about 50% of the population to the adeno-associated virus vectors used to carry the corrective gene.

Additional limitations are the occurrence in about 60% of patients of early although usually transient hepatotoxicity, significant variability in the factor levels ultimately attained, uncertainties about the durability of response, and the potential for long-term genotoxicity, Dr. Lillicrap said.
 

Tolerance for factor VIII

In the question and answer session following the presentation, session moderator Hervé Chambost, MD, from University Hospital La Timone and Aix-Marseille University, both in Marseille, France, asked whether there was a role for factor VIII and immune tolerance therapy (ITI) among patients who have been treated with non–factor replacement therapy.

“Is it important to have an antigenic pressure to maintain factor VIII or not for these patients?” he asked.

“I think this is a critical issue, and it’s an issue that we don’t yet have objective evidence for,” Dr. Lillicrap replied. “But the idea that we need to introduce some antigenic exposure to factor VIII in these individuals is a reasonable one, whether that be with intermittent exposure to factor VIII – weekly, monthly – we simply have no idea, but I think factor VIII will still be required in these patients because of breakthrough bleeds in patients who have been treated with non–factor replacement. So maintaining tolerance is a critical issue, and we need to develop maybe prospective trials to look at what those protocols are going to be to maintain tolerance in these patients.”

“As important, if not more so, is whether children should be tolerized at all,” commented Dan Hart, PhD, from Barts and the London School of Medicine and Dentistry, who also presented data during the session.

“The U.K. currently takes the view that, in children, new inhibitors arising may be delayed into the latter part of the first decade of their life if they have not had factors as their first choice but have had [replacement] on demand. I think we are heading into challenging times of understanding how to deliver ITI to larger children, how acceptable that is, and how we do it, but enabling [factor] VIII to be used long term rather than tolerating a chronic inhibitor I think is a really important issue where we need to head toward some consensus,” he said.

No funding source was reported. Dr. Lillicrap disclosed research funding from and advisory roles for several pharmaceutical companies. Dr. Hart disclosed grant/research support and speakers bureau activity for various companies. Dr. Chambost has previously reported no disclosures relevant to the topic at hand.

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

[email protected]

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

[email protected]

Immunogenicity of the high-dose influenza vaccine (HD IIV3) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL, the precursor state to CLL) was found lower than reported in healthy adults according to a report in Vaccine.

In addition, immunogenicity to influenza B was found to be greater in those patients with MBL, compared with those with CLL.

“Acute and chronic leukemia patients hospitalized with influenza infection document a case fatality rate of 25%-37%,” according to Jennifer A. Whitaker, MD, of the Mayo Clinic, Rochester, Minn., and colleagues in pointing out the importance of their study.

The prospective pilot study assessed the humoral immune responses of patients to the 2013-2014 and 2014-2015 HD IIV3 (Fluzone High-Dose; Sanofi Pasteur), which was administered as part of routine clinical care in 30 patients (17 with previously untreated CLL and 13 with MBL). The median patient age was 69.5 years.

The primary outcomes were seroconversion and seroprotection, as measured by hemagglutination inhibition assay (HAI).
 

Lower response rate

At day 28 post vaccination, the seroprotection rates for the overall cohort were 19/30 (63.3%) for A/H1N1, 21/23 (91.3%) for A/H3N2, and 13/30 (43.3%) for influenza B. Patients with MBL achieved significantly higher day 28 HAI geometric mean titers (GMT), compared with CLL patients (54.1 vs. 12.1]; P = .01), In addition, MBL patients achieved higher day 28 seroprotection rates against the influenza B vaccine strain virus than did those with CLL (76.9% vs. 17.6%; P = .002). Seroconversion rates for the overall cohort were 3/30 (10%) for A/H1N1; 5/23 (21.7%) for A/H3N2; and 3/30 (10%) for influenza B. No individual with CLL demonstrated seroconversion for influenza B, according to the researchers.

“Our studies reinforce rigorous adherence to vaccination strategies in patients with hematologic malignancy, including those with CLL, given the increased risk of serious complications among those experiencing influenza infection,” the authors stated.

“Even suboptimal responses to influenza vaccination can provide partial protection, reduce hospitalization rates, and/or prevent serious disease complications. Given the recent major issue with novel and aggressive viruses such COVID-19, we absolutely must continue with larger prospective studies to confirm these findings and evaluate vaccine effectiveness in preventing influenza or other novel viruses in these populations,” the researchers concluded.

This study was funded by the National Institutes of Health. Dr. Whitaker reported having no disclosures. Several of the coauthors reported financial relationships with a variety of pharmaceutical and biotechnology companies.

[email protected]

Asymptomatic screening of cancer patients receiving anticancer therapy detected a very low rate of COVID-19 in a retrospective study.

Of more than 2,000 patients, less than 1% were found to be COVID-19 positive on asymptomatic screening, an investigator reported at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S09-04).

While several models have been proposed to screen for COVID-19 among cancer patients, the optimal strategy remains unknown, said investigator Justin A. Shaya, MD, of the University of California, San Diego.

The most commonly used approach is symptom/exposure-based screening and testing. However, other models have combined this method with polymerase chain reaction (PCR) testing for asymptomatic high-risk patients (such as those undergoing bone marrow transplant, receiving chemotherapy, or with hematologic malignancies) or with PCR testing for all asymptomatic cancer patients.

Dr. Shaya’s institution implemented a novel COVID-19 screening protocol for cancer patients receiving infusional anticancer therapy in May 2020.

The protocol required SARS-CoV-2 PCR testing for asymptomatic patients 24-96 hours prior to infusion. However, testing was only required before the administration of anticancer therapy. Infusion visits for supportive care interventions did not require previsit testing.

The researchers retrospectively analyzed data from patients with active cancer receiving infusional anticancer therapy who had at least one asymptomatic SARS-CoV-2 PCR test between June 1 and Dec. 1, 2020. The primary outcome was the rate of COVID-19 positivity among asymptomatic patients.

Results

Among 2,202 patients identified, 21 (0.95%) were found to be COVID-19 positive on asymptomatic screening. Most of these patients (90.5%) had solid tumors, but two (9.5%) had hematologic malignancies.

With respect to treatment, 16 patients (76.2%) received cytotoxic chemotherapy, 2 (9.5%) received targeted therapy, 1 (4.7%) received immunotherapy, and 2 (9.5%) were on a clinical trial.

At a median follow-up of 174 days from a positive PCR test (range, 55-223 days), only two patients (9.5%) developed COVID-related symptoms. Both patients had acute leukemia, and one required hospitalization for COVID-related complications.

In the COVID-19–positive cohort, 20 (95.2%) patients had their anticancer therapy delayed or deferred, with a median delay of 21 days (range, 7-77 days).

In the overall cohort, an additional 26 patients (1.2%) developed symptomatic COVID-19 during the study period.

“These results are particularly interesting because they come from a high-quality center that sees a large number of patients,” said Solange Peters, MD, PhD, of the University of Lausanne (Switzerland), who was not involved in this study.

“As they suggest, it is still a debate on how efficient routine screening is, asking the question whether we’re really detecting COVID-19 infection in our patients. Of course, it depends on the time and environment,” Dr. Peters added.

Dr. Shaya acknowledged that the small sample size was a key limitation of the study. Thus, the results may not be generalizable to other regions.

“One of the most striking things is that asymptomatic patients suffer very few consequences of COVID-19 infection, except for patients with hematologic malignancies,” Dr. Shaya said during a live discussion. “The majority of our patients had solid tumors and failed to develop any signs/symptoms of COVID infection.

“Routine screening provides a lot of security, and our institution is big enough to allow for it, and it seems our teams enjoy the fact of knowing the COVID status for each patient,” he continued.

Dr. Shaya and Dr. Peters disclosed no conflicts of interest. No funding sources were reported in the presentation.

Asymptomatic screening of cancer patients receiving anticancer therapy detected a very low rate of COVID-19 in a retrospective study.

Of more than 2,000 patients, less than 1% were found to be COVID-19 positive on asymptomatic screening, an investigator reported at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S09-04).

While several models have been proposed to screen for COVID-19 among cancer patients, the optimal strategy remains unknown, said investigator Justin A. Shaya, MD, of the University of California, San Diego.

The most commonly used approach is symptom/exposure-based screening and testing. However, other models have combined this method with polymerase chain reaction (PCR) testing for asymptomatic high-risk patients (such as those undergoing bone marrow transplant, receiving chemotherapy, or with hematologic malignancies) or with PCR testing for all asymptomatic cancer patients.

Dr. Shaya’s institution implemented a novel COVID-19 screening protocol for cancer patients receiving infusional anticancer therapy in May 2020.

The protocol required SARS-CoV-2 PCR testing for asymptomatic patients 24-96 hours prior to infusion. However, testing was only required before the administration of anticancer therapy. Infusion visits for supportive care interventions did not require previsit testing.

The researchers retrospectively analyzed data from patients with active cancer receiving infusional anticancer therapy who had at least one asymptomatic SARS-CoV-2 PCR test between June 1 and Dec. 1, 2020. The primary outcome was the rate of COVID-19 positivity among asymptomatic patients.

Results

Among 2,202 patients identified, 21 (0.95%) were found to be COVID-19 positive on asymptomatic screening. Most of these patients (90.5%) had solid tumors, but two (9.5%) had hematologic malignancies.

With respect to treatment, 16 patients (76.2%) received cytotoxic chemotherapy, 2 (9.5%) received targeted therapy, 1 (4.7%) received immunotherapy, and 2 (9.5%) were on a clinical trial.

At a median follow-up of 174 days from a positive PCR test (range, 55-223 days), only two patients (9.5%) developed COVID-related symptoms. Both patients had acute leukemia, and one required hospitalization for COVID-related complications.

In the COVID-19–positive cohort, 20 (95.2%) patients had their anticancer therapy delayed or deferred, with a median delay of 21 days (range, 7-77 days).

In the overall cohort, an additional 26 patients (1.2%) developed symptomatic COVID-19 during the study period.

“These results are particularly interesting because they come from a high-quality center that sees a large number of patients,” said Solange Peters, MD, PhD, of the University of Lausanne (Switzerland), who was not involved in this study.

“As they suggest, it is still a debate on how efficient routine screening is, asking the question whether we’re really detecting COVID-19 infection in our patients. Of course, it depends on the time and environment,” Dr. Peters added.

Dr. Shaya acknowledged that the small sample size was a key limitation of the study. Thus, the results may not be generalizable to other regions.

“One of the most striking things is that asymptomatic patients suffer very few consequences of COVID-19 infection, except for patients with hematologic malignancies,” Dr. Shaya said during a live discussion. “The majority of our patients had solid tumors and failed to develop any signs/symptoms of COVID infection.

“Routine screening provides a lot of security, and our institution is big enough to allow for it, and it seems our teams enjoy the fact of knowing the COVID status for each patient,” he continued.

Dr. Shaya and Dr. Peters disclosed no conflicts of interest. No funding sources were reported in the presentation.

Asymptomatic screening of cancer patients receiving anticancer therapy detected a very low rate of COVID-19 in a retrospective study.

Of more than 2,000 patients, less than 1% were found to be COVID-19 positive on asymptomatic screening, an investigator reported at the AACR Virtual Meeting: COVID-19 and Cancer (Abstract S09-04).

While several models have been proposed to screen for COVID-19 among cancer patients, the optimal strategy remains unknown, said investigator Justin A. Shaya, MD, of the University of California, San Diego.

The most commonly used approach is symptom/exposure-based screening and testing. However, other models have combined this method with polymerase chain reaction (PCR) testing for asymptomatic high-risk patients (such as those undergoing bone marrow transplant, receiving chemotherapy, or with hematologic malignancies) or with PCR testing for all asymptomatic cancer patients.

Dr. Shaya’s institution implemented a novel COVID-19 screening protocol for cancer patients receiving infusional anticancer therapy in May 2020.

The protocol required SARS-CoV-2 PCR testing for asymptomatic patients 24-96 hours prior to infusion. However, testing was only required before the administration of anticancer therapy. Infusion visits for supportive care interventions did not require previsit testing.

The researchers retrospectively analyzed data from patients with active cancer receiving infusional anticancer therapy who had at least one asymptomatic SARS-CoV-2 PCR test between June 1 and Dec. 1, 2020. The primary outcome was the rate of COVID-19 positivity among asymptomatic patients.

Results

Among 2,202 patients identified, 21 (0.95%) were found to be COVID-19 positive on asymptomatic screening. Most of these patients (90.5%) had solid tumors, but two (9.5%) had hematologic malignancies.

With respect to treatment, 16 patients (76.2%) received cytotoxic chemotherapy, 2 (9.5%) received targeted therapy, 1 (4.7%) received immunotherapy, and 2 (9.5%) were on a clinical trial.

At a median follow-up of 174 days from a positive PCR test (range, 55-223 days), only two patients (9.5%) developed COVID-related symptoms. Both patients had acute leukemia, and one required hospitalization for COVID-related complications.

In the COVID-19–positive cohort, 20 (95.2%) patients had their anticancer therapy delayed or deferred, with a median delay of 21 days (range, 7-77 days).

In the overall cohort, an additional 26 patients (1.2%) developed symptomatic COVID-19 during the study period.

“These results are particularly interesting because they come from a high-quality center that sees a large number of patients,” said Solange Peters, MD, PhD, of the University of Lausanne (Switzerland), who was not involved in this study.

“As they suggest, it is still a debate on how efficient routine screening is, asking the question whether we’re really detecting COVID-19 infection in our patients. Of course, it depends on the time and environment,” Dr. Peters added.

Dr. Shaya acknowledged that the small sample size was a key limitation of the study. Thus, the results may not be generalizable to other regions.

“One of the most striking things is that asymptomatic patients suffer very few consequences of COVID-19 infection, except for patients with hematologic malignancies,” Dr. Shaya said during a live discussion. “The majority of our patients had solid tumors and failed to develop any signs/symptoms of COVID infection.

“Routine screening provides a lot of security, and our institution is big enough to allow for it, and it seems our teams enjoy the fact of knowing the COVID status for each patient,” he continued.

Dr. Shaya and Dr. Peters disclosed no conflicts of interest. No funding sources were reported in the presentation.

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

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

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

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

States that implemented mask mandates in 2020 saw a decline in the growth of COVID-19 hospitalizations between March and October 2020, according to a new study published Feb. 5 in the CDC’s Morbidity and Mortality Weekly Report.

Hospitalization growth rates declined by 5.5 percentage points for adults between ages 18-64 about 3 weeks after the mandates were implemented, compared with climbing growth rates in the 4 weeks before mandates.

CDC Director Rochelle Walensky said she was pleased to see the results, but that it’s “too early” to tell whether President Joe Biden’s recent mask orders have had an effect on cases and hospitalizations in 2021.

“We’re going to be watching the mask data very carefully,” she said during a news briefing with the White House COVID-19 Response Team on Feb. 5. “I think it’s probably still a bit too early to tell, but I’m encouraged with the decrease in case rates right now.”

In another study published Feb. 5 in the Morbidity and Mortality Weekly Report, trained observers tracked mask use at six universities with mask mandates between September and November 2020. Overall, observers reported that about 92% of people wore masks correctly indoors, which varied based on the type of mask.

About 97% of people used N95 masks correctly, compared with 92% who used cloth masks, and 79% who used bandanas, scarves, or neck gaiters. Cloth masks were most common, and bandanas and scarves were least common.

The Biden administration is considering whether to send masks directly to American households to encourage people to wear them, according to NBC News. The White House COVID-19 Response Team is debating the logistics of mailing out masks, including how many to send and what the mask material would be, the news outlet reported.

Wisconsin Gov. Tony Evers reissued a new statewide mask mandate on Feb. 4, just an hour after the Republican-controlled legislature voted to repeal his previous mandate, according to The Associated Press. Gov. Evers said his priority is to keep people safe and that wearing a mask is the easiest way to do so.

“If the legislature keeps playing politics and we don’t keep wearing masks, we’re going to see more preventable deaths,” he said. “It’s going to take even longer to get our state and our economy back on track.”

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

Branching of the great vessels from the aorta normally progresses with the brachiocephalic trunk as the first takeoff followed by the left common carotid and left subclavian artery in approximately 85% of cases.¹ Variants of great vessel branching patterns include the so-called bovine arch, arteria lusoria or aberrant right subclavian artery (ARSA), aberrant origin of the vertebral arteries, and truncus bicaroticus, or common origin of the carotid arteries (COCA). These aberrancies are quite rare, some with an incidence of < 1%.^1,2

These vascular anomalies become clinically relevant when they pose difficulty for operators in surgical and interventional specialties, necessitating unique approaches, catheters, and techniques to overcome. We present a case of concomitant aortic arch abnormalities during a diagnostic workup for transcatheter aortic valve replacement (TAVR) in a patient with previous coronary artery bypass grafting (CABG).

Case Presentation

A 66-year-old woman with coronary artery disease (CAD) status post-CABG and stage D1 aortic stenosis (AS) presented with exertional dyspnea. She was referred for coronary angiography as part of a workup for TAVR. Echocardiography confirmed severe AS with a peak velocity of 4.1 m/s, mean pressure gradient of 50 mm Hg, and an aortic valve area of 0.7 cm². The patient was scheduled for cardiac catheterization with anticipated left radial artery approach for intubation and opacification of the left internal mammary artery (LIMA). However, this approach was abandoned during the procedure due to discovery of aberrant left radial artery anatomy, and the procedure was completed via femoral access.

Subsequent coronary angiography revealed 3-vessel CAD, patent saphenous vein grafts (SVG) to the right coronary artery (RCA) and a diagonal branch vessel with an occluded SVG to the left circumflex. Difficulty was encountered when engaging the left subclavian artery using a JR 4.0 diagnostic catheter for LIMA angiography. Nonselective angiography of the aortic arch was performed and demonstrated an uncommon anatomical variant (Figure 1, left). The right common carotid artery (CCA) [A] and the left CCA [B] arose from a single trunk, consistent with truncus bicaroticus or COCA [C]. The right subclavian artery [D] originated distal to the left subclavian artery otherwise known as arteria lusoria or ARSA forming an incomplete vascular ring [E]. Selective engagement of the left subclavian artery remained problematic even with the use of specialty arch catheters (Headhunter and LIMA catheters). The procedure concluded without confirming patency of the LIMA graft. A total of 145 mL of Omnipaque (iohexol injection) contrast was used for the procedure, and no adverse events occurred.

Same-day access of the ipsilateral ulnar artery was not pursued because of the risk of hand ischemia. The patient underwent repeat catheterization utilizing left ulnar artery access after adequate recovery time from the initial left radial approach. Selective LIMA angiography was achieved and demonstrated a patent LIMA to LAD graft. A computed tomography (CT) aorta for purposes of TAVR planning was able to reconstruct the aortic arch vasculature (Figure 1, right) confirming the presence of both ARSA and COCA. The patient went on to undergo successful TAVR with subsequent improvement of clinical symptoms.

Discussion

Arteria lusoria is defined as an anomalous right subclavian artery arising distal to the origin of the left subclavian artery on the aortic arch. It has an estimated incidence of 0.5 to 2% and occurs as a consequence of abnormal embryologic involution of the right fourth aortic arch and right proximal dorsal aorta. This causes the origin of the right subclavian artery to shift onto the descending aorta and cross the mediastinum from left to right, passing behind the esophagus and the trachea.^1,3-5

ARSA is often associated with other anatomic abnormalities, including COCA, right-sided aortic arch, interrupted aortic arch, aortic coarctation, tetralogy of Fallot, truncus arteriosus, transposition of the great arteries, atrial septal defects, and ventricular septal defects.Underlying genetic disorders, such as Edwards, Down, DiGeorge syndromes, aneurysms, and arterioesophageal fistulae can accompany these vascular malformations.⁶

COCA, such as we encountered, is the presence of a single branch from the aorta giving off both right and left common carotid arteries. It has an incidence of < 0.1% in isolation and is discovered most often in cadaveric dissections or incidentally on imaging.¹ Its embryologic origin results from the third pair of cervical aortic arches persisting as a common bicarotid trunk.^1,4,5 The combination of ARSA and COCA is rare. Of the 0.5 to 2% of ARSA cases discovered, only 20% of those cases present with associated COCA for a combined prevalence estimated at < 0.05%.⁷

The majority of patients with either anatomic abnormality are asymptomatic. However, a few classic clinical manifestations have been described. ARSA can rarely present with dysphagia lusoria, a condition resulting from an incomplete vascular ring formed by the abnormal course of the right subclavian compressing the esophagus. Although not seen in our patient, it should be considered in the differential diagnosis for dysphagia.^1,2,7 Ortner syndrome can result from right laryngeal nerve compression and palsy resultant from the aberrant course of the right subclavian artery.⁸ Another clinically relevant feature of ARSA is the presence of a diverticulum of Kommerell or dilatation at the origin of the right subclavian artery. It is a type of retroesophageal diverticulum resulting from persistence of a segment of the right sixth aortic arch.⁹ Finally, the spatial arrangement of ARSA increases risk for injury during head and neck surgical procedures, such as thyroidectomy, tracheotomy, and lymph node dissection of the right paratracheal fossa.⁶ Although the incidence is not well described, COCA has been described in several case reports as causing tracheal compression with dyspnea and in some cases, ischemic stroke.^4,5,10

Diagnosis

The diagnosis of ARSA and COCA is often made incidentally on diagnostic imaging studies such as endovascular imaging, CT angiography, magnetic resonance (MR) angiography, postmortem cadaveric dissections, or, as in our case, during cardiac catheterization.^11,12 A classification system for aortic arch branching patterns exists published by Adachi and Williams.⁶ The classification includes ARSA and differentiates it into 4 subtypes (Figure 2). Our patient exhibited type H-1, indicating ARSA as the distal most branch of the aortic arch with coexistence of COCA.⁶ The primary clinical implication of ARSA and COCA in our case was increased difficulty and complexity when performing coronary angiography. Available literature has well characterized the challenges operators encounter when cannulating aberrant great vessel anatomy, often electing to perform nonselective aortography to define a patient’s anatomy.^7,9,13 A comparison of diagnostic imaging techniques for vascular rings such as ARSA have shown MR, CT, and endovascular angiography to be the most reliable modalities to delineate vascular anatomy.¹⁴

Methods

Due to the presence of CABG in our patient, left radial and ulnar artery approaches were used rather than a right radial artery approach. Engagement of the LIMA is performed most commonly with left radial or femoral artery access using an internal mammary catheter that has a more steeply angled tip (80º-85º) compared with the standard JR catheter. An accessory left radial artery anatomic variant was encountered in our case precluding left radial approach. In addition, abnormal takeoffs of the great vessels thwarted multiple attempts at intubation of the LSA (Figure 1, right). Some data suggest CT imaging can be of assistance in establishing patency of bypass grafts in CABG patients.¹⁵ This can be considered an option if branch-vessel anatomy remains unclear. Our patient exhibited several risk factors for stroke, including female gender, hypertension, and prior CABG. These and other risk factors may influence clinical decisions such as continued catheter manipulation, choice of catheter type, and further contrast studies.¹⁶

Nonselective angiography in these cases often can require excessive iodinated contrast, exposing the patient to increased risk of contrast-induced nephropathy (CIN).^7,17 Although the amount of contrast used in our case was average for diagnostic catheterization,the patient went on to undergo a second catheterization and CT angiography to establish LIMA graft patency.¹⁷ CT imaging reconstruction elucidated her aberrant branch-vessel anatomy. Patients are at increased risk of CIN with contrast loads < 200 mL per study, and this effect is compounded when the patient is elderly, has diabetes mellitus, and/or antecedent renal disease.¹⁸ Attention to the patient’s preoperative glomerular filtration rate, avoidance of nephrotoxic agents, and intraoperative left ventricular end-diastolic pressure during cardiac catheterization with postcontrast administration of IV isotonic fluids have been shown to prevent CIN.^19,20 In the POSEIDON trial, fluid administration on a sliding scale based on the left ventricular end-diastolic pressure resulted in lower absolute risk of CIN postcatheterization vs standard postprocedure hydration in cardiac catheterization.²¹ Further, the now widespread use of low and iso-osmolar contrast agents further reduces the risk of CIN.²²

For cardiac catheter laboratory operators, it is important to note that ARSA is more frequently encountered due to increased use of the transradial approach to coronary angiography.¹¹ It should be suspected when accessing the ascending aorta proves exceptionally challenging and the catheter has a predilection for entering the descending aorta.¹¹ While more technically demanding, 2 cases described by Allen and colleagues exhibited safe and successful entry into the ascending aorta with catheter rotation and hydrophilic support wires indicating the right radial approach is feasible despite presence of ARSA.¹² Several patient-initiated maneuvers can be utilized to aid in accessing the ascending aorta. For example, deep inspiration to reduce the angulation between the aortic arch and ARSA. The use of curved catheters, such as Amplatz left, internal mammary catheter, or Simmons catheter may be considered to cannulate the ascending aorta if ARSA is encountered. Complications associated with a transradial approach include dissection and intramural hematoma. Minor bleeds and vasospasm also can occur secondary to increased procedural duration.^6,8

Treatment

ARSA and COCA are considered normal anatomic variants and no treatment is indicated if the patient is asymptomatic. If symptoms are present, they often arise from aneurysmal or occlusive complications of the vascular anatomy. In patients with isolated ARSA and mild dysphasia or reflux symptoms, the use of prokinetics and antireflux medications may provide relief. It is important to note the coexistence of ARSA and COCA is more likely to produce esophageal compression compared to ARSA alone due to formation of a more complete vascular ring. Surgical management has been described in severe cases of ARSA involving risk of aneurysm rupture, right upper limb ischemia, or compression of the esophagus or trachea.

Several surgical approaches have been described, including simple ligation and division of ARSA and reimplantation of the RSA into the right CCA or ascending aorta.⁵ A recent review of 180 cases of ARSA diagnosed on CT angiography with concomitant common carotid trunk in half of studied individuals focused on a hybrid open and intravascular procedure. This procedure involved a double transposition or bypass (LSA to left common carotid artery and ARSA to the right CCA) followed by implantation of a thoracic stent graft. Few cases are eligible for these procedures or require them for definitive treatment.²³

Conclusions

Recognition of aortic arch anatomical variants such as our case of ARSA with concomitant COCA may influence clinician decisions in various specialties, such as interventional cardiology, interventional neurology, cardiothoracic surgery, and gastroenterology. While most patients with these conditions are asymptomatic, some may present with dysphagia, dyspnea, and/or stroke symptoms. In our practice, discovery of such anomalies periprocedurally may affect cardiac catheterization access site, catheter selection, and additional imaging. The presence of arteria lusoria can be of critical importance when encountering a patient with myocardial infarction as switching from transradial to transfemoral approach may be required to gain access to the ascending aorta. Overall, transradial coronary angiography and percutaneous coronary intervention is not contraindicated in the setting of ARSA/COCA and can be safely performed by an experienced operator.

It is important for surgical specialists to be aware of the coexistence of anomalies where the discovery of one aberrancy can signal coexistent variant anatomy. If aortic arch anatomy is unclear, it is useful to perform nonselective angiography and/or further imaging with CT angiography. Knowledge of abnormal aortic arch anatomy can decrease fluoroscopy time and contrast load administered, thereby reducing potential periprocedural adverse events.

Branching of the great vessels from the aorta normally progresses with the brachiocephalic trunk as the first takeoff followed by the left common carotid and left subclavian artery in approximately 85% of cases.¹ Variants of great vessel branching patterns include the so-called bovine arch, arteria lusoria or aberrant right subclavian artery (ARSA), aberrant origin of the vertebral arteries, and truncus bicaroticus, or common origin of the carotid arteries (COCA). These aberrancies are quite rare, some with an incidence of < 1%.^1,2

These vascular anomalies become clinically relevant when they pose difficulty for operators in surgical and interventional specialties, necessitating unique approaches, catheters, and techniques to overcome. We present a case of concomitant aortic arch abnormalities during a diagnostic workup for transcatheter aortic valve replacement (TAVR) in a patient with previous coronary artery bypass grafting (CABG).

Case Presentation

A 66-year-old woman with coronary artery disease (CAD) status post-CABG and stage D1 aortic stenosis (AS) presented with exertional dyspnea. She was referred for coronary angiography as part of a workup for TAVR. Echocardiography confirmed severe AS with a peak velocity of 4.1 m/s, mean pressure gradient of 50 mm Hg, and an aortic valve area of 0.7 cm². The patient was scheduled for cardiac catheterization with anticipated left radial artery approach for intubation and opacification of the left internal mammary artery (LIMA). However, this approach was abandoned during the procedure due to discovery of aberrant left radial artery anatomy, and the procedure was completed via femoral access.

Subsequent coronary angiography revealed 3-vessel CAD, patent saphenous vein grafts (SVG) to the right coronary artery (RCA) and a diagonal branch vessel with an occluded SVG to the left circumflex. Difficulty was encountered when engaging the left subclavian artery using a JR 4.0 diagnostic catheter for LIMA angiography. Nonselective angiography of the aortic arch was performed and demonstrated an uncommon anatomical variant (Figure 1, left). The right common carotid artery (CCA) [A] and the left CCA [B] arose from a single trunk, consistent with truncus bicaroticus or COCA [C]. The right subclavian artery [D] originated distal to the left subclavian artery otherwise known as arteria lusoria or ARSA forming an incomplete vascular ring [E]. Selective engagement of the left subclavian artery remained problematic even with the use of specialty arch catheters (Headhunter and LIMA catheters). The procedure concluded without confirming patency of the LIMA graft. A total of 145 mL of Omnipaque (iohexol injection) contrast was used for the procedure, and no adverse events occurred.

Same-day access of the ipsilateral ulnar artery was not pursued because of the risk of hand ischemia. The patient underwent repeat catheterization utilizing left ulnar artery access after adequate recovery time from the initial left radial approach. Selective LIMA angiography was achieved and demonstrated a patent LIMA to LAD graft. A computed tomography (CT) aorta for purposes of TAVR planning was able to reconstruct the aortic arch vasculature (Figure 1, right) confirming the presence of both ARSA and COCA. The patient went on to undergo successful TAVR with subsequent improvement of clinical symptoms.

Discussion

Arteria lusoria is defined as an anomalous right subclavian artery arising distal to the origin of the left subclavian artery on the aortic arch. It has an estimated incidence of 0.5 to 2% and occurs as a consequence of abnormal embryologic involution of the right fourth aortic arch and right proximal dorsal aorta. This causes the origin of the right subclavian artery to shift onto the descending aorta and cross the mediastinum from left to right, passing behind the esophagus and the trachea.^1,3-5

ARSA is often associated with other anatomic abnormalities, including COCA, right-sided aortic arch, interrupted aortic arch, aortic coarctation, tetralogy of Fallot, truncus arteriosus, transposition of the great arteries, atrial septal defects, and ventricular septal defects.Underlying genetic disorders, such as Edwards, Down, DiGeorge syndromes, aneurysms, and arterioesophageal fistulae can accompany these vascular malformations.⁶

COCA, such as we encountered, is the presence of a single branch from the aorta giving off both right and left common carotid arteries. It has an incidence of < 0.1% in isolation and is discovered most often in cadaveric dissections or incidentally on imaging.¹ Its embryologic origin results from the third pair of cervical aortic arches persisting as a common bicarotid trunk.^1,4,5 The combination of ARSA and COCA is rare. Of the 0.5 to 2% of ARSA cases discovered, only 20% of those cases present with associated COCA for a combined prevalence estimated at < 0.05%.⁷

The majority of patients with either anatomic abnormality are asymptomatic. However, a few classic clinical manifestations have been described. ARSA can rarely present with dysphagia lusoria, a condition resulting from an incomplete vascular ring formed by the abnormal course of the right subclavian compressing the esophagus. Although not seen in our patient, it should be considered in the differential diagnosis for dysphagia.^1,2,7 Ortner syndrome can result from right laryngeal nerve compression and palsy resultant from the aberrant course of the right subclavian artery.⁸ Another clinically relevant feature of ARSA is the presence of a diverticulum of Kommerell or dilatation at the origin of the right subclavian artery. It is a type of retroesophageal diverticulum resulting from persistence of a segment of the right sixth aortic arch.⁹ Finally, the spatial arrangement of ARSA increases risk for injury during head and neck surgical procedures, such as thyroidectomy, tracheotomy, and lymph node dissection of the right paratracheal fossa.⁶ Although the incidence is not well described, COCA has been described in several case reports as causing tracheal compression with dyspnea and in some cases, ischemic stroke.^4,5,10

Diagnosis

The diagnosis of ARSA and COCA is often made incidentally on diagnostic imaging studies such as endovascular imaging, CT angiography, magnetic resonance (MR) angiography, postmortem cadaveric dissections, or, as in our case, during cardiac catheterization.^11,12 A classification system for aortic arch branching patterns exists published by Adachi and Williams.⁶ The classification includes ARSA and differentiates it into 4 subtypes (Figure 2). Our patient exhibited type H-1, indicating ARSA as the distal most branch of the aortic arch with coexistence of COCA.⁶ The primary clinical implication of ARSA and COCA in our case was increased difficulty and complexity when performing coronary angiography. Available literature has well characterized the challenges operators encounter when cannulating aberrant great vessel anatomy, often electing to perform nonselective aortography to define a patient’s anatomy.^7,9,13 A comparison of diagnostic imaging techniques for vascular rings such as ARSA have shown MR, CT, and endovascular angiography to be the most reliable modalities to delineate vascular anatomy.¹⁴

Methods

Due to the presence of CABG in our patient, left radial and ulnar artery approaches were used rather than a right radial artery approach. Engagement of the LIMA is performed most commonly with left radial or femoral artery access using an internal mammary catheter that has a more steeply angled tip (80º-85º) compared with the standard JR catheter. An accessory left radial artery anatomic variant was encountered in our case precluding left radial approach. In addition, abnormal takeoffs of the great vessels thwarted multiple attempts at intubation of the LSA (Figure 1, right). Some data suggest CT imaging can be of assistance in establishing patency of bypass grafts in CABG patients.¹⁵ This can be considered an option if branch-vessel anatomy remains unclear. Our patient exhibited several risk factors for stroke, including female gender, hypertension, and prior CABG. These and other risk factors may influence clinical decisions such as continued catheter manipulation, choice of catheter type, and further contrast studies.¹⁶

Nonselective angiography in these cases often can require excessive iodinated contrast, exposing the patient to increased risk of contrast-induced nephropathy (CIN).^7,17 Although the amount of contrast used in our case was average for diagnostic catheterization,the patient went on to undergo a second catheterization and CT angiography to establish LIMA graft patency.¹⁷ CT imaging reconstruction elucidated her aberrant branch-vessel anatomy. Patients are at increased risk of CIN with contrast loads < 200 mL per study, and this effect is compounded when the patient is elderly, has diabetes mellitus, and/or antecedent renal disease.¹⁸ Attention to the patient’s preoperative glomerular filtration rate, avoidance of nephrotoxic agents, and intraoperative left ventricular end-diastolic pressure during cardiac catheterization with postcontrast administration of IV isotonic fluids have been shown to prevent CIN.^19,20 In the POSEIDON trial, fluid administration on a sliding scale based on the left ventricular end-diastolic pressure resulted in lower absolute risk of CIN postcatheterization vs standard postprocedure hydration in cardiac catheterization.²¹ Further, the now widespread use of low and iso-osmolar contrast agents further reduces the risk of CIN.²²

For cardiac catheter laboratory operators, it is important to note that ARSA is more frequently encountered due to increased use of the transradial approach to coronary angiography.¹¹ It should be suspected when accessing the ascending aorta proves exceptionally challenging and the catheter has a predilection for entering the descending aorta.¹¹ While more technically demanding, 2 cases described by Allen and colleagues exhibited safe and successful entry into the ascending aorta with catheter rotation and hydrophilic support wires indicating the right radial approach is feasible despite presence of ARSA.¹² Several patient-initiated maneuvers can be utilized to aid in accessing the ascending aorta. For example, deep inspiration to reduce the angulation between the aortic arch and ARSA. The use of curved catheters, such as Amplatz left, internal mammary catheter, or Simmons catheter may be considered to cannulate the ascending aorta if ARSA is encountered. Complications associated with a transradial approach include dissection and intramural hematoma. Minor bleeds and vasospasm also can occur secondary to increased procedural duration.^6,8

Treatment

ARSA and COCA are considered normal anatomic variants and no treatment is indicated if the patient is asymptomatic. If symptoms are present, they often arise from aneurysmal or occlusive complications of the vascular anatomy. In patients with isolated ARSA and mild dysphasia or reflux symptoms, the use of prokinetics and antireflux medications may provide relief. It is important to note the coexistence of ARSA and COCA is more likely to produce esophageal compression compared to ARSA alone due to formation of a more complete vascular ring. Surgical management has been described in severe cases of ARSA involving risk of aneurysm rupture, right upper limb ischemia, or compression of the esophagus or trachea.

Several surgical approaches have been described, including simple ligation and division of ARSA and reimplantation of the RSA into the right CCA or ascending aorta.⁵ A recent review of 180 cases of ARSA diagnosed on CT angiography with concomitant common carotid trunk in half of studied individuals focused on a hybrid open and intravascular procedure. This procedure involved a double transposition or bypass (LSA to left common carotid artery and ARSA to the right CCA) followed by implantation of a thoracic stent graft. Few cases are eligible for these procedures or require them for definitive treatment.²³

Conclusions

Recognition of aortic arch anatomical variants such as our case of ARSA with concomitant COCA may influence clinician decisions in various specialties, such as interventional cardiology, interventional neurology, cardiothoracic surgery, and gastroenterology. While most patients with these conditions are asymptomatic, some may present with dysphagia, dyspnea, and/or stroke symptoms. In our practice, discovery of such anomalies periprocedurally may affect cardiac catheterization access site, catheter selection, and additional imaging. The presence of arteria lusoria can be of critical importance when encountering a patient with myocardial infarction as switching from transradial to transfemoral approach may be required to gain access to the ascending aorta. Overall, transradial coronary angiography and percutaneous coronary intervention is not contraindicated in the setting of ARSA/COCA and can be safely performed by an experienced operator.

It is important for surgical specialists to be aware of the coexistence of anomalies where the discovery of one aberrancy can signal coexistent variant anatomy. If aortic arch anatomy is unclear, it is useful to perform nonselective angiography and/or further imaging with CT angiography. Knowledge of abnormal aortic arch anatomy can decrease fluoroscopy time and contrast load administered, thereby reducing potential periprocedural adverse events.

Branching of the great vessels from the aorta normally progresses with the brachiocephalic trunk as the first takeoff followed by the left common carotid and left subclavian artery in approximately 85% of cases.¹ Variants of great vessel branching patterns include the so-called bovine arch, arteria lusoria or aberrant right subclavian artery (ARSA), aberrant origin of the vertebral arteries, and truncus bicaroticus, or common origin of the carotid arteries (COCA). These aberrancies are quite rare, some with an incidence of < 1%.^1,2

These vascular anomalies become clinically relevant when they pose difficulty for operators in surgical and interventional specialties, necessitating unique approaches, catheters, and techniques to overcome. We present a case of concomitant aortic arch abnormalities during a diagnostic workup for transcatheter aortic valve replacement (TAVR) in a patient with previous coronary artery bypass grafting (CABG).

Case Presentation

A 66-year-old woman with coronary artery disease (CAD) status post-CABG and stage D1 aortic stenosis (AS) presented with exertional dyspnea. She was referred for coronary angiography as part of a workup for TAVR. Echocardiography confirmed severe AS with a peak velocity of 4.1 m/s, mean pressure gradient of 50 mm Hg, and an aortic valve area of 0.7 cm². The patient was scheduled for cardiac catheterization with anticipated left radial artery approach for intubation and opacification of the left internal mammary artery (LIMA). However, this approach was abandoned during the procedure due to discovery of aberrant left radial artery anatomy, and the procedure was completed via femoral access.

Subsequent coronary angiography revealed 3-vessel CAD, patent saphenous vein grafts (SVG) to the right coronary artery (RCA) and a diagonal branch vessel with an occluded SVG to the left circumflex. Difficulty was encountered when engaging the left subclavian artery using a JR 4.0 diagnostic catheter for LIMA angiography. Nonselective angiography of the aortic arch was performed and demonstrated an uncommon anatomical variant (Figure 1, left). The right common carotid artery (CCA) [A] and the left CCA [B] arose from a single trunk, consistent with truncus bicaroticus or COCA [C]. The right subclavian artery [D] originated distal to the left subclavian artery otherwise known as arteria lusoria or ARSA forming an incomplete vascular ring [E]. Selective engagement of the left subclavian artery remained problematic even with the use of specialty arch catheters (Headhunter and LIMA catheters). The procedure concluded without confirming patency of the LIMA graft. A total of 145 mL of Omnipaque (iohexol injection) contrast was used for the procedure, and no adverse events occurred.

Same-day access of the ipsilateral ulnar artery was not pursued because of the risk of hand ischemia. The patient underwent repeat catheterization utilizing left ulnar artery access after adequate recovery time from the initial left radial approach. Selective LIMA angiography was achieved and demonstrated a patent LIMA to LAD graft. A computed tomography (CT) aorta for purposes of TAVR planning was able to reconstruct the aortic arch vasculature (Figure 1, right) confirming the presence of both ARSA and COCA. The patient went on to undergo successful TAVR with subsequent improvement of clinical symptoms.

Discussion

Arteria lusoria is defined as an anomalous right subclavian artery arising distal to the origin of the left subclavian artery on the aortic arch. It has an estimated incidence of 0.5 to 2% and occurs as a consequence of abnormal embryologic involution of the right fourth aortic arch and right proximal dorsal aorta. This causes the origin of the right subclavian artery to shift onto the descending aorta and cross the mediastinum from left to right, passing behind the esophagus and the trachea.^1,3-5

ARSA is often associated with other anatomic abnormalities, including COCA, right-sided aortic arch, interrupted aortic arch, aortic coarctation, tetralogy of Fallot, truncus arteriosus, transposition of the great arteries, atrial septal defects, and ventricular septal defects.Underlying genetic disorders, such as Edwards, Down, DiGeorge syndromes, aneurysms, and arterioesophageal fistulae can accompany these vascular malformations.⁶

COCA, such as we encountered, is the presence of a single branch from the aorta giving off both right and left common carotid arteries. It has an incidence of < 0.1% in isolation and is discovered most often in cadaveric dissections or incidentally on imaging.¹ Its embryologic origin results from the third pair of cervical aortic arches persisting as a common bicarotid trunk.^1,4,5 The combination of ARSA and COCA is rare. Of the 0.5 to 2% of ARSA cases discovered, only 20% of those cases present with associated COCA for a combined prevalence estimated at < 0.05%.⁷

The majority of patients with either anatomic abnormality are asymptomatic. However, a few classic clinical manifestations have been described. ARSA can rarely present with dysphagia lusoria, a condition resulting from an incomplete vascular ring formed by the abnormal course of the right subclavian compressing the esophagus. Although not seen in our patient, it should be considered in the differential diagnosis for dysphagia.^1,2,7 Ortner syndrome can result from right laryngeal nerve compression and palsy resultant from the aberrant course of the right subclavian artery.⁸ Another clinically relevant feature of ARSA is the presence of a diverticulum of Kommerell or dilatation at the origin of the right subclavian artery. It is a type of retroesophageal diverticulum resulting from persistence of a segment of the right sixth aortic arch.⁹ Finally, the spatial arrangement of ARSA increases risk for injury during head and neck surgical procedures, such as thyroidectomy, tracheotomy, and lymph node dissection of the right paratracheal fossa.⁶ Although the incidence is not well described, COCA has been described in several case reports as causing tracheal compression with dyspnea and in some cases, ischemic stroke.^4,5,10

Diagnosis

The diagnosis of ARSA and COCA is often made incidentally on diagnostic imaging studies such as endovascular imaging, CT angiography, magnetic resonance (MR) angiography, postmortem cadaveric dissections, or, as in our case, during cardiac catheterization.^11,12 A classification system for aortic arch branching patterns exists published by Adachi and Williams.⁶ The classification includes ARSA and differentiates it into 4 subtypes (Figure 2). Our patient exhibited type H-1, indicating ARSA as the distal most branch of the aortic arch with coexistence of COCA.⁶ The primary clinical implication of ARSA and COCA in our case was increased difficulty and complexity when performing coronary angiography. Available literature has well characterized the challenges operators encounter when cannulating aberrant great vessel anatomy, often electing to perform nonselective aortography to define a patient’s anatomy.^7,9,13 A comparison of diagnostic imaging techniques for vascular rings such as ARSA have shown MR, CT, and endovascular angiography to be the most reliable modalities to delineate vascular anatomy.¹⁴

Methods

Due to the presence of CABG in our patient, left radial and ulnar artery approaches were used rather than a right radial artery approach. Engagement of the LIMA is performed most commonly with left radial or femoral artery access using an internal mammary catheter that has a more steeply angled tip (80º-85º) compared with the standard JR catheter. An accessory left radial artery anatomic variant was encountered in our case precluding left radial approach. In addition, abnormal takeoffs of the great vessels thwarted multiple attempts at intubation of the LSA (Figure 1, right). Some data suggest CT imaging can be of assistance in establishing patency of bypass grafts in CABG patients.¹⁵ This can be considered an option if branch-vessel anatomy remains unclear. Our patient exhibited several risk factors for stroke, including female gender, hypertension, and prior CABG. These and other risk factors may influence clinical decisions such as continued catheter manipulation, choice of catheter type, and further contrast studies.¹⁶

Nonselective angiography in these cases often can require excessive iodinated contrast, exposing the patient to increased risk of contrast-induced nephropathy (CIN).^7,17 Although the amount of contrast used in our case was average for diagnostic catheterization,the patient went on to undergo a second catheterization and CT angiography to establish LIMA graft patency.¹⁷ CT imaging reconstruction elucidated her aberrant branch-vessel anatomy. Patients are at increased risk of CIN with contrast loads < 200 mL per study, and this effect is compounded when the patient is elderly, has diabetes mellitus, and/or antecedent renal disease.¹⁸ Attention to the patient’s preoperative glomerular filtration rate, avoidance of nephrotoxic agents, and intraoperative left ventricular end-diastolic pressure during cardiac catheterization with postcontrast administration of IV isotonic fluids have been shown to prevent CIN.^19,20 In the POSEIDON trial, fluid administration on a sliding scale based on the left ventricular end-diastolic pressure resulted in lower absolute risk of CIN postcatheterization vs standard postprocedure hydration in cardiac catheterization.²¹ Further, the now widespread use of low and iso-osmolar contrast agents further reduces the risk of CIN.²²

For cardiac catheter laboratory operators, it is important to note that ARSA is more frequently encountered due to increased use of the transradial approach to coronary angiography.¹¹ It should be suspected when accessing the ascending aorta proves exceptionally challenging and the catheter has a predilection for entering the descending aorta.¹¹ While more technically demanding, 2 cases described by Allen and colleagues exhibited safe and successful entry into the ascending aorta with catheter rotation and hydrophilic support wires indicating the right radial approach is feasible despite presence of ARSA.¹² Several patient-initiated maneuvers can be utilized to aid in accessing the ascending aorta. For example, deep inspiration to reduce the angulation between the aortic arch and ARSA. The use of curved catheters, such as Amplatz left, internal mammary catheter, or Simmons catheter may be considered to cannulate the ascending aorta if ARSA is encountered. Complications associated with a transradial approach include dissection and intramural hematoma. Minor bleeds and vasospasm also can occur secondary to increased procedural duration.^6,8

Treatment

ARSA and COCA are considered normal anatomic variants and no treatment is indicated if the patient is asymptomatic. If symptoms are present, they often arise from aneurysmal or occlusive complications of the vascular anatomy. In patients with isolated ARSA and mild dysphasia or reflux symptoms, the use of prokinetics and antireflux medications may provide relief. It is important to note the coexistence of ARSA and COCA is more likely to produce esophageal compression compared to ARSA alone due to formation of a more complete vascular ring. Surgical management has been described in severe cases of ARSA involving risk of aneurysm rupture, right upper limb ischemia, or compression of the esophagus or trachea.

Several surgical approaches have been described, including simple ligation and division of ARSA and reimplantation of the RSA into the right CCA or ascending aorta.⁵ A recent review of 180 cases of ARSA diagnosed on CT angiography with concomitant common carotid trunk in half of studied individuals focused on a hybrid open and intravascular procedure. This procedure involved a double transposition or bypass (LSA to left common carotid artery and ARSA to the right CCA) followed by implantation of a thoracic stent graft. Few cases are eligible for these procedures or require them for definitive treatment.²³

Conclusions

Recognition of aortic arch anatomical variants such as our case of ARSA with concomitant COCA may influence clinician decisions in various specialties, such as interventional cardiology, interventional neurology, cardiothoracic surgery, and gastroenterology. While most patients with these conditions are asymptomatic, some may present with dysphagia, dyspnea, and/or stroke symptoms. In our practice, discovery of such anomalies periprocedurally may affect cardiac catheterization access site, catheter selection, and additional imaging. The presence of arteria lusoria can be of critical importance when encountering a patient with myocardial infarction as switching from transradial to transfemoral approach may be required to gain access to the ascending aorta. Overall, transradial coronary angiography and percutaneous coronary intervention is not contraindicated in the setting of ARSA/COCA and can be safely performed by an experienced operator.

It is important for surgical specialists to be aware of the coexistence of anomalies where the discovery of one aberrancy can signal coexistent variant anatomy. If aortic arch anatomy is unclear, it is useful to perform nonselective angiography and/or further imaging with CT angiography. Knowledge of abnormal aortic arch anatomy can decrease fluoroscopy time and contrast load administered, thereby reducing potential periprocedural adverse events.

Suicide is a global phenomenon and a worldwide public health concern.¹ The World Health Organization estimates that > 800,000 people die by suicide every year. In the US, suicide is the 10th leading cause of death, and on average, 129 Americans die by suicide each day.² In 2018, the suicide rate for all veterans was 1.5 times higher than the rate for nonveterans, after adjusting for population differences in age and sex. Among female veterans, the rate of suicide was 2.1 times higher than the rate for female nonveterans.³

In light of this disparity, suicide prevention is one of the highest priorities for the US Department of Veterans Affairs (VA). In 2018, the VA developed and published the National Strategy for Preventing Veteran Suicide.⁴ One major goal of this strategy is to reduce access to lethal means (ie, firearms, medications, chemicals, or poisons) among veterans at high risk for suicide. Reducing access to lethal means has been found to decrease suicide rates.^4,5

Step 1: Determine Suicide Risk

Although it is impossible to predict with certainty an individual’s risk of suicide, several patient characteristics and life circumstances have been identified as risk factors. The strongest predictor of suicide is the presence of psychiatric disease.⁸ More than 90% of those who have had a death by suicide have a psychiatric diagnosis at the time of death, and suicide rates in those with mental illness are at least 10 times as high as in the general population.^9,10 Depression is the leading cause of death by suicide worldwide, followed by substance-related disorders (22.4%), personality disorders (11.6%), schizophrenia (10.6%), and anxiety/somatoform disorders (6.1%).^8,11-13

Clinicians also can use various risk assessment tools to identify patients at high risk for suicide. The Veterans Health Administration (VHA) Stratification Tool for Opioid Risk Mitigation (STORM) calculates patients’ risk based on data extracted from the electronic health record and is less time intensive, more easily refined, and may be more powerful than standard risk assessment tools because it can be deployed on a large scale.^14,15 The VHA also developed the Suicide Prevention Population Risk Identification and Tracking for Exigencies (SPPRITE) tool to assist clinicians in tracking patients with current (or recent) high levels of suicide risk. This tool unifies specific patient information gathered from the patient’s electronic health record and from other predictive model dashboards (such as STORM).

Step 2: Identify Substances Strongly Associated With Fatalities

According to the American Association of Poison Control Centers (AAPCC), the pharmaceutical classes associated with the largest number of fatalities are analgesics, followed by stimulants and street drugs, cardiovascular agents, antidepressants, antipsychotics, and sedatives/hypnotics (Table 1).¹⁶ Stimulants and street drugs accounted for 694 fatalities of 39,238 single-substance exposures (mortality rate: 1.8%).¹⁶ Drugs of abuse, including cocaine, hallucinogenic amphetamines, heroin, and kratom, have shown an increased trend in use.¹⁶

In 2018 there were 834 fatalities from 174,269 single-substance exposure to analgesics, which include opioids and acetaminophen, for a mortality rate of 0.5%.¹⁶ The opioid epidemic is one of the main drivers of the increase in drug overdose deaths in the US.^16,17 The opioid with the highest drug overdose fatality rate is illicitly manufactured fentanyl, which often is combined with other substances, such as heroin, to increase its potency at a low cost.¹⁸ These combinations also increase the risk of overdose fatality.

Acetaminophen is unique among the top substances associated with fatalities because it is obtained easily without a prescription. An acetaminophen overdose can cause hepatic injury, which may progress to fulminant hepatic failure and death.¹⁹ The recommended maximum dose of acetaminophen is 4 g/d in an adult and 50 to 75 mg/kg/d in children. A single acute ingestion of > 7.5 g in an adult or 150 mg/kg in children has been considered potentially toxic.^19,20 The use of combination analgesics that contain both an opioid and acetaminophen can pose an even greater risk due to the potential for respiratory depression and hepatotoxicity.

Cardiovascular drugs accounted for 232 fatalities from 46,499 single-substance exposures (mortality rate: 0.5%).¹⁶ According to the AAPCC, calcium channel blockers (CCB) and β-blockers accounted for 63% of overdose deaths by cardiovascular drugs because they can cause severe hypotension, bradycardia, and hemodynamic collapse.^16,21,22

In the past, the nondihydropyridine CCBs verapamil and diltiazem were associated with increased overdose fatalities. However, the most recent data show that dihydropyridine CCBs such as amlodipine also have significant risk for lethality.¹⁶ Metoprolol was associated with more overdose deaths in the past year among β-blockers. However, caution also should be used with agents such as propranolol and labetalol, which can antagonize sodium channels in overdose and may be associated with a higher risk of mortality than other β-blockers.²²

Step 3: Consider Potential Drug-Drug Interactions

Suicide attempts involving multiple substances carry increased risk. Only 12.1% of all fatal overdoses, according to AAPCC, involved single-substance exposure, whereas 56.3% were attributed to multiple substance exposures.¹⁶ It is important for clinicians to be aware of and avoid possibly fatal drug-drug interactions, such as the combination of opioids and sedative-hypnotics, like BZDs, which can lead to fatal respiratory depression. Clinicians also should be aware of a patient’s history of illicit opioid and alcohol use before prescribing opioids and BZDs. Clinicians can use various online databases to detect potential drug-drug interactions.

Step 4: Address Risks

If a patient is deemed to be at high risk for suicide, but it is not imminent and the patient will be managed as an outpatient, then it may be preferential to prescribe medications that are less lethal, such as SSRIs, instead of TCAs or MAOIs. If a potentially lethal medication is indicated, such as lithium or clozapine, both of which have been found to reduce suicidal behavior, then dispensing a limited quantity of pills and having more frequent follow-up visits are some ways to lessen risk.^24,25 A clinical pearl published in Current Psychiatry provided an equation to determine the lethality of a 30-day supply of medications.²⁶ This equation uses lethal dose 50 (LD50), which is the dose of a medication that results in the death of 50% of the animals used in a controlled experiment, and the maximum daily dose of the medication (D) to find the human equivalent dose (HED) relative lethality. The HED relative lethality calculation may help prescribers determine which medications should have a limited quantity dispensed to patients at risk of medication-related suicide. Any value for the HED relative lethality that is > 100% is considered a lethal dose for humans. Therefore, it would be appropriate to avoid or limit the quantity of medications with a HED relative lethality > 100%. Table 4 lists the psychotropic agents with the highest relative lethality for a 30-day supply. The psychotropic agents with the lowest HED relative lethality are SSRIs: desvenlafaxine, mirtazapine, topiramate, and aripiprazole.²⁶

Limiting drugs with a narrow therapeutic index should be considered when aiming to reduce the risk of medication-related suicide. These drugs present a high risk in the event of an overdose. Clinicians can monitor the levels of lithium, clozapine, or TCAs to ensure that a patient is taking the medication as prescribed rather than stockpiling it at home. If the patient is in a monitored setting, such as a partial hospital program or intensive outpatient program, then the medication can be given while under direct observation.

Clinicians should obtain an accurate and detailed medication and illicit drug use history from patients. It also is important to review the prescription drug monitoring program to limit access to potentially lethal combinations of medications.²⁷ Clinicians can additionally employ risk mitigation strategies (eg, providing naloxone kits) for patients who are prescribed or abuse opioids.

Finally, all patients with a high risk of suicide should receive lethal means counseling, which involves first determining whether patients have access to lethal means, such as firearms or medications with high lethality, then limiting their access to these lethal means. This includes advising patients and family members to safely dispose medications that are no longer in use and in some cases recommending that a family member keep medications locked and dispense them on a daily basis.

Conclusions

Suicide is a major public health concern that affects tens of thousands of Americans annually. Furthermore, veterans are more likely to die by suicide than those in the general population. Firearms continue to be the most lethal means for suicide. However, intentional poisoning with medications or substances also is a common method for suicide, especially in female veterans. Having knowledge of medications with high lethality and limiting access to these agents can be a successful strategy for reducing suicide deaths.

Suicide is a global phenomenon and a worldwide public health concern.¹ The World Health Organization estimates that > 800,000 people die by suicide every year. In the US, suicide is the 10th leading cause of death, and on average, 129 Americans die by suicide each day.² In 2018, the suicide rate for all veterans was 1.5 times higher than the rate for nonveterans, after adjusting for population differences in age and sex. Among female veterans, the rate of suicide was 2.1 times higher than the rate for female nonveterans.³

In light of this disparity, suicide prevention is one of the highest priorities for the US Department of Veterans Affairs (VA). In 2018, the VA developed and published the National Strategy for Preventing Veteran Suicide.⁴ One major goal of this strategy is to reduce access to lethal means (ie, firearms, medications, chemicals, or poisons) among veterans at high risk for suicide. Reducing access to lethal means has been found to decrease suicide rates.^4,5

Step 1: Determine Suicide Risk

Although it is impossible to predict with certainty an individual’s risk of suicide, several patient characteristics and life circumstances have been identified as risk factors. The strongest predictor of suicide is the presence of psychiatric disease.⁸ More than 90% of those who have had a death by suicide have a psychiatric diagnosis at the time of death, and suicide rates in those with mental illness are at least 10 times as high as in the general population.^9,10 Depression is the leading cause of death by suicide worldwide, followed by substance-related disorders (22.4%), personality disorders (11.6%), schizophrenia (10.6%), and anxiety/somatoform disorders (6.1%).^8,11-13

Clinicians also can use various risk assessment tools to identify patients at high risk for suicide. The Veterans Health Administration (VHA) Stratification Tool for Opioid Risk Mitigation (STORM) calculates patients’ risk based on data extracted from the electronic health record and is less time intensive, more easily refined, and may be more powerful than standard risk assessment tools because it can be deployed on a large scale.^14,15 The VHA also developed the Suicide Prevention Population Risk Identification and Tracking for Exigencies (SPPRITE) tool to assist clinicians in tracking patients with current (or recent) high levels of suicide risk. This tool unifies specific patient information gathered from the patient’s electronic health record and from other predictive model dashboards (such as STORM).

Step 2: Identify Substances Strongly Associated With Fatalities

According to the American Association of Poison Control Centers (AAPCC), the pharmaceutical classes associated with the largest number of fatalities are analgesics, followed by stimulants and street drugs, cardiovascular agents, antidepressants, antipsychotics, and sedatives/hypnotics (Table 1).¹⁶ Stimulants and street drugs accounted for 694 fatalities of 39,238 single-substance exposures (mortality rate: 1.8%).¹⁶ Drugs of abuse, including cocaine, hallucinogenic amphetamines, heroin, and kratom, have shown an increased trend in use.¹⁶

In 2018 there were 834 fatalities from 174,269 single-substance exposure to analgesics, which include opioids and acetaminophen, for a mortality rate of 0.5%.¹⁶ The opioid epidemic is one of the main drivers of the increase in drug overdose deaths in the US.^16,17 The opioid with the highest drug overdose fatality rate is illicitly manufactured fentanyl, which often is combined with other substances, such as heroin, to increase its potency at a low cost.¹⁸ These combinations also increase the risk of overdose fatality.

Acetaminophen is unique among the top substances associated with fatalities because it is obtained easily without a prescription. An acetaminophen overdose can cause hepatic injury, which may progress to fulminant hepatic failure and death.¹⁹ The recommended maximum dose of acetaminophen is 4 g/d in an adult and 50 to 75 mg/kg/d in children. A single acute ingestion of > 7.5 g in an adult or 150 mg/kg in children has been considered potentially toxic.^19,20 The use of combination analgesics that contain both an opioid and acetaminophen can pose an even greater risk due to the potential for respiratory depression and hepatotoxicity.

Cardiovascular drugs accounted for 232 fatalities from 46,499 single-substance exposures (mortality rate: 0.5%).¹⁶ According to the AAPCC, calcium channel blockers (CCB) and β-blockers accounted for 63% of overdose deaths by cardiovascular drugs because they can cause severe hypotension, bradycardia, and hemodynamic collapse.^16,21,22

In the past, the nondihydropyridine CCBs verapamil and diltiazem were associated with increased overdose fatalities. However, the most recent data show that dihydropyridine CCBs such as amlodipine also have significant risk for lethality.¹⁶ Metoprolol was associated with more overdose deaths in the past year among β-blockers. However, caution also should be used with agents such as propranolol and labetalol, which can antagonize sodium channels in overdose and may be associated with a higher risk of mortality than other β-blockers.²²

Step 3: Consider Potential Drug-Drug Interactions

Suicide attempts involving multiple substances carry increased risk. Only 12.1% of all fatal overdoses, according to AAPCC, involved single-substance exposure, whereas 56.3% were attributed to multiple substance exposures.¹⁶ It is important for clinicians to be aware of and avoid possibly fatal drug-drug interactions, such as the combination of opioids and sedative-hypnotics, like BZDs, which can lead to fatal respiratory depression. Clinicians also should be aware of a patient’s history of illicit opioid and alcohol use before prescribing opioids and BZDs. Clinicians can use various online databases to detect potential drug-drug interactions.

Step 4: Address Risks

If a patient is deemed to be at high risk for suicide, but it is not imminent and the patient will be managed as an outpatient, then it may be preferential to prescribe medications that are less lethal, such as SSRIs, instead of TCAs or MAOIs. If a potentially lethal medication is indicated, such as lithium or clozapine, both of which have been found to reduce suicidal behavior, then dispensing a limited quantity of pills and having more frequent follow-up visits are some ways to lessen risk.^24,25 A clinical pearl published in Current Psychiatry provided an equation to determine the lethality of a 30-day supply of medications.²⁶ This equation uses lethal dose 50 (LD50), which is the dose of a medication that results in the death of 50% of the animals used in a controlled experiment, and the maximum daily dose of the medication (D) to find the human equivalent dose (HED) relative lethality. The HED relative lethality calculation may help prescribers determine which medications should have a limited quantity dispensed to patients at risk of medication-related suicide. Any value for the HED relative lethality that is > 100% is considered a lethal dose for humans. Therefore, it would be appropriate to avoid or limit the quantity of medications with a HED relative lethality > 100%. Table 4 lists the psychotropic agents with the highest relative lethality for a 30-day supply. The psychotropic agents with the lowest HED relative lethality are SSRIs: desvenlafaxine, mirtazapine, topiramate, and aripiprazole.²⁶

Limiting drugs with a narrow therapeutic index should be considered when aiming to reduce the risk of medication-related suicide. These drugs present a high risk in the event of an overdose. Clinicians can monitor the levels of lithium, clozapine, or TCAs to ensure that a patient is taking the medication as prescribed rather than stockpiling it at home. If the patient is in a monitored setting, such as a partial hospital program or intensive outpatient program, then the medication can be given while under direct observation.

Clinicians should obtain an accurate and detailed medication and illicit drug use history from patients. It also is important to review the prescription drug monitoring program to limit access to potentially lethal combinations of medications.²⁷ Clinicians can additionally employ risk mitigation strategies (eg, providing naloxone kits) for patients who are prescribed or abuse opioids.

Finally, all patients with a high risk of suicide should receive lethal means counseling, which involves first determining whether patients have access to lethal means, such as firearms or medications with high lethality, then limiting their access to these lethal means. This includes advising patients and family members to safely dispose medications that are no longer in use and in some cases recommending that a family member keep medications locked and dispense them on a daily basis.

Conclusions

Suicide is a major public health concern that affects tens of thousands of Americans annually. Furthermore, veterans are more likely to die by suicide than those in the general population. Firearms continue to be the most lethal means for suicide. However, intentional poisoning with medications or substances also is a common method for suicide, especially in female veterans. Having knowledge of medications with high lethality and limiting access to these agents can be a successful strategy for reducing suicide deaths.

Suicide is a global phenomenon and a worldwide public health concern.¹ The World Health Organization estimates that > 800,000 people die by suicide every year. In the US, suicide is the 10th leading cause of death, and on average, 129 Americans die by suicide each day.² In 2018, the suicide rate for all veterans was 1.5 times higher than the rate for nonveterans, after adjusting for population differences in age and sex. Among female veterans, the rate of suicide was 2.1 times higher than the rate for female nonveterans.³

In light of this disparity, suicide prevention is one of the highest priorities for the US Department of Veterans Affairs (VA). In 2018, the VA developed and published the National Strategy for Preventing Veteran Suicide.⁴ One major goal of this strategy is to reduce access to lethal means (ie, firearms, medications, chemicals, or poisons) among veterans at high risk for suicide. Reducing access to lethal means has been found to decrease suicide rates.^4,5

Step 1: Determine Suicide Risk

Although it is impossible to predict with certainty an individual’s risk of suicide, several patient characteristics and life circumstances have been identified as risk factors. The strongest predictor of suicide is the presence of psychiatric disease.⁸ More than 90% of those who have had a death by suicide have a psychiatric diagnosis at the time of death, and suicide rates in those with mental illness are at least 10 times as high as in the general population.^9,10 Depression is the leading cause of death by suicide worldwide, followed by substance-related disorders (22.4%), personality disorders (11.6%), schizophrenia (10.6%), and anxiety/somatoform disorders (6.1%).^8,11-13

Clinicians also can use various risk assessment tools to identify patients at high risk for suicide. The Veterans Health Administration (VHA) Stratification Tool for Opioid Risk Mitigation (STORM) calculates patients’ risk based on data extracted from the electronic health record and is less time intensive, more easily refined, and may be more powerful than standard risk assessment tools because it can be deployed on a large scale.^14,15 The VHA also developed the Suicide Prevention Population Risk Identification and Tracking for Exigencies (SPPRITE) tool to assist clinicians in tracking patients with current (or recent) high levels of suicide risk. This tool unifies specific patient information gathered from the patient’s electronic health record and from other predictive model dashboards (such as STORM).

Step 2: Identify Substances Strongly Associated With Fatalities

According to the American Association of Poison Control Centers (AAPCC), the pharmaceutical classes associated with the largest number of fatalities are analgesics, followed by stimulants and street drugs, cardiovascular agents, antidepressants, antipsychotics, and sedatives/hypnotics (Table 1).¹⁶ Stimulants and street drugs accounted for 694 fatalities of 39,238 single-substance exposures (mortality rate: 1.8%).¹⁶ Drugs of abuse, including cocaine, hallucinogenic amphetamines, heroin, and kratom, have shown an increased trend in use.¹⁶

In 2018 there were 834 fatalities from 174,269 single-substance exposure to analgesics, which include opioids and acetaminophen, for a mortality rate of 0.5%.¹⁶ The opioid epidemic is one of the main drivers of the increase in drug overdose deaths in the US.^16,17 The opioid with the highest drug overdose fatality rate is illicitly manufactured fentanyl, which often is combined with other substances, such as heroin, to increase its potency at a low cost.¹⁸ These combinations also increase the risk of overdose fatality.

Acetaminophen is unique among the top substances associated with fatalities because it is obtained easily without a prescription. An acetaminophen overdose can cause hepatic injury, which may progress to fulminant hepatic failure and death.¹⁹ The recommended maximum dose of acetaminophen is 4 g/d in an adult and 50 to 75 mg/kg/d in children. A single acute ingestion of > 7.5 g in an adult or 150 mg/kg in children has been considered potentially toxic.^19,20 The use of combination analgesics that contain both an opioid and acetaminophen can pose an even greater risk due to the potential for respiratory depression and hepatotoxicity.

Cardiovascular drugs accounted for 232 fatalities from 46,499 single-substance exposures (mortality rate: 0.5%).¹⁶ According to the AAPCC, calcium channel blockers (CCB) and β-blockers accounted for 63% of overdose deaths by cardiovascular drugs because they can cause severe hypotension, bradycardia, and hemodynamic collapse.^16,21,22

In the past, the nondihydropyridine CCBs verapamil and diltiazem were associated with increased overdose fatalities. However, the most recent data show that dihydropyridine CCBs such as amlodipine also have significant risk for lethality.¹⁶ Metoprolol was associated with more overdose deaths in the past year among β-blockers. However, caution also should be used with agents such as propranolol and labetalol, which can antagonize sodium channels in overdose and may be associated with a higher risk of mortality than other β-blockers.²²

Step 3: Consider Potential Drug-Drug Interactions

Suicide attempts involving multiple substances carry increased risk. Only 12.1% of all fatal overdoses, according to AAPCC, involved single-substance exposure, whereas 56.3% were attributed to multiple substance exposures.¹⁶ It is important for clinicians to be aware of and avoid possibly fatal drug-drug interactions, such as the combination of opioids and sedative-hypnotics, like BZDs, which can lead to fatal respiratory depression. Clinicians also should be aware of a patient’s history of illicit opioid and alcohol use before prescribing opioids and BZDs. Clinicians can use various online databases to detect potential drug-drug interactions.

Step 4: Address Risks

If a patient is deemed to be at high risk for suicide, but it is not imminent and the patient will be managed as an outpatient, then it may be preferential to prescribe medications that are less lethal, such as SSRIs, instead of TCAs or MAOIs. If a potentially lethal medication is indicated, such as lithium or clozapine, both of which have been found to reduce suicidal behavior, then dispensing a limited quantity of pills and having more frequent follow-up visits are some ways to lessen risk.^24,25 A clinical pearl published in Current Psychiatry provided an equation to determine the lethality of a 30-day supply of medications.²⁶ This equation uses lethal dose 50 (LD50), which is the dose of a medication that results in the death of 50% of the animals used in a controlled experiment, and the maximum daily dose of the medication (D) to find the human equivalent dose (HED) relative lethality. The HED relative lethality calculation may help prescribers determine which medications should have a limited quantity dispensed to patients at risk of medication-related suicide. Any value for the HED relative lethality that is > 100% is considered a lethal dose for humans. Therefore, it would be appropriate to avoid or limit the quantity of medications with a HED relative lethality > 100%. Table 4 lists the psychotropic agents with the highest relative lethality for a 30-day supply. The psychotropic agents with the lowest HED relative lethality are SSRIs: desvenlafaxine, mirtazapine, topiramate, and aripiprazole.²⁶

Limiting drugs with a narrow therapeutic index should be considered when aiming to reduce the risk of medication-related suicide. These drugs present a high risk in the event of an overdose. Clinicians can monitor the levels of lithium, clozapine, or TCAs to ensure that a patient is taking the medication as prescribed rather than stockpiling it at home. If the patient is in a monitored setting, such as a partial hospital program or intensive outpatient program, then the medication can be given while under direct observation.

Clinicians should obtain an accurate and detailed medication and illicit drug use history from patients. It also is important to review the prescription drug monitoring program to limit access to potentially lethal combinations of medications.²⁷ Clinicians can additionally employ risk mitigation strategies (eg, providing naloxone kits) for patients who are prescribed or abuse opioids.

Finally, all patients with a high risk of suicide should receive lethal means counseling, which involves first determining whether patients have access to lethal means, such as firearms or medications with high lethality, then limiting their access to these lethal means. This includes advising patients and family members to safely dispose medications that are no longer in use and in some cases recommending that a family member keep medications locked and dispense them on a daily basis.

Conclusions

Suicide is a major public health concern that affects tens of thousands of Americans annually. Furthermore, veterans are more likely to die by suicide than those in the general population. Firearms continue to be the most lethal means for suicide. However, intentional poisoning with medications or substances also is a common method for suicide, especially in female veterans. Having knowledge of medications with high lethality and limiting access to these agents can be a successful strategy for reducing suicide deaths.