ILLUSTRATIVE CASE

A 67-year-old man with a history of type 2 diabetes, hypertension, and chronic congestive heart failure (ejection fraction = 30%) was admitted to the intensive care unit with a diagnosis of acute hypoxic respiratory failure. He was discharged after 10 days of inpatient treatment that included daily VTE prophylaxis with low-molecular-weight heparin (LMWH). Should he go home on VTE prophylaxis?

Patients hospitalized with nonsurgical conditions such as congestive heart failure, chronic obstructive pulmonary disease, sepsis, inflammatory bowel disease, or active cancers are at increased risk for VTE due to inflammation and immobility. In a US study of 158,325 hospitalized nonsurgical patients, including those with cancer, infections, congestive heart failure, or respiratory failure, 4% of patients developed deep vein thrombosis (DVT), 1.5% developed pulmonary embolism (PE), and 0.2% developed both DVT and PE, at a median time of 74 days after discharge.² Prophylaxis in medical inpatients reduces VTE incidence in the hospital by 50% to 75%, but the period of increased VTE risk after discharge is not well understood in medical patients.³ American College of Chest Physicians guidelines provide recommendations for the duration of prophylactic anticoagulation after major orthopedic surgeries but make no recommendation for medical patients.³ American Society of Hematology 2018 guidelines recommend against extending VTE prophylaxis after hospital discharge, including for patients with risk factors or chronic immobility.⁴

However, use of DOACs for short-term VTE prophylaxis as an alternative to LMWH in hospitalized patients is supported by a meta-analysis showing equivalent efficacy, safety, and cost-effectiveness.¹ The current study examined DOACs for extended postdischarge use.¹

STUDY SUMMARY

Significant benefit of DOACs demonstrated across 4 large trials

This meta-analysis of 4 large randomized controlled trials examined the safety and efficacy of 6 weeks of postdischarge DOAC thromboprophylaxis compared with placebo in 26,408 high-risk nonsurgical hospitalized patients.¹ Patients at least 40 years old were admitted with diagnoses that included New York Heart Association (NYHA) class III or IV congestive heart failure, active cancer, acute ischemic stroke, acute respiratory failure, or infectious or inflammatory disease. Study patients also had risk factors for VTE, including age 75 and older, obesity, chronic venous insufficiency, history of VTE, history of NYHA class III or IV congestive heart failure, history of cancer, thrombophilia, hormone replacement therapy, or major surgery within the 6 to 12 weeks before current medical hospitalization.

A recent meta-analysis sheds light on the benefits of extended postdischarge thromboprophylaxis in nonsurgical patients at high risk for VTE.

Patients were excluded if DOACs were contraindicated or if they had active or recent bleeding, renal failure, abnormal liver values, an upcoming need for surgery, or an indication for ongoing anticoagulation. Patients in 3 studies received 6 to 10 days of enoxaparin as prophylaxis during their inpatient stay. (The fourth study did not specify length of inpatient prophylaxis or drug used.) After discharge, patients were assigned to placebo or a regimen of rivaroxaban 10 mg daily, apixaban 2.5 mg twice daily, or betrixaban 80 mg daily for a range of 30 to 45 days. The primary outcome was the composite of total VTE and VTE-related death. A secondary outcome was the occurrence of nonfatal symptomatic VTE, and the primary safety outcome was the incidence of major bleeding.

The primary outcome occurred in 2.9% of the patients in the DOAC group compared with 3.6% of patients in the placebo group (odds ratio [OR] = 0.79; 95% CI, 0.69-0.91; number needed to treat [NNT] = 143). The secondary outcome occurred in 0.48% of patients in the DOAC group compared with 0.77% of patients in the placebo group (OR = 0.62; 95% CI, 0.47-0.83; NNT = 345). Major bleeding resulting in a decrease in hemoglobin concentration of more than 2 g/L, requiring transfusion of at least 2 units of packed red blood cells, reintervention at a previous surgical site, or bleeding in a critical organ or that was fatal, occurred in 0.58% of patients in the DOAC group compared with 0.3% of patients in the placebo group (OR = 1.9; 95% CI, 1.4-2.7; number needed to harm [NNH] = 357). Nonmajor bleeding was increased in the DOAC group compared with placebo (2.2% vs 1.2%; OR = 1.8; 95% CI, 1.5-2.1; NNH = 110).

The NNT to prevent a fatal VTE was 899 patients. After extrapolating original data on fatal PE and major bleeding to a national level, cost-benefit analysis preferred extended DOAC use, with a direct medical cost balance of $1.2 million per life saved.

Continue to: WHAT'S NEW

WHAT’S NEW

Mortality and morbidity benefit with small bleeding risk

Based on this study, for every 300 high-risk patients hospitalized with nonsurgical diagnoses who are given 6 weeks of DOAC prophylaxis, there will be 2 fewer cases of VTE and VTE-related death. In this same group of patients, there will be approximately 1 major bleeding event and 3 less serious bleeds.

Patients with preexisting medical conditions such as congestive heart failure, cancer, and sepsis and those admitted to an intensive care unit are at increased risk for DVT after discharge.⁵ Extending DOAC prophylaxis in nonsurgical patients with serious medical conditions for 6 weeks after discharge reduces the risk of VTE or VTE-related death by 0.7% compared with placebo. Treatment in this population does incur a small increased risk of major bleeding by 0.3% in the DOAC group compared with placebo.

CAVEATS

Results cannot be generalized to all patient populations

Many high-risk patients have chronic kidney disease, and because DOACs (including apixaban, rivaroxaban, and dabigatran) are renally cleared, there are limited data to establish their safety in patients with creatinine clearance ≤ 30 mL/min. Benefits seen with DOACs cannot be extrapolated to other anticoagulation agents, including warfarin or LMWH.

In accordance with new guidelines, some of the patients in this study would now receive antiplatelet therapy, eg, poststroke patients, cancer patients, and—with the ease of DOAC use—patients with atrial fibrillation. If these patients were excluded, it is not known whether the benefit would remain. Patients included in these trials were at particularly high risk for VTE, and the benefits seen in this study cannot be generalized to a patient population with fewer VTE risk factors.

CHALLENGES TO IMPLEMENTATION

High cost and lack of updated guidelines may limit DOAC thromboprophylaxis

Cost is a concern. All the new DOACs are expensive; for example, rivaroxaban costs a little less than $500 per month.⁶ Obtaining insurance coverage for a novel indication may be challenging. The American Society of Hematology and others have not yet endorsed extended posthospital thromboprophylaxis in nonsurgical patients, although the use of DOACs has expanded since the last guideline revisions.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 67-year-old man with a history of type 2 diabetes, hypertension, and chronic congestive heart failure (ejection fraction = 30%) was admitted to the intensive care unit with a diagnosis of acute hypoxic respiratory failure. He was discharged after 10 days of inpatient treatment that included daily VTE prophylaxis with low-molecular-weight heparin (LMWH). Should he go home on VTE prophylaxis?

Patients hospitalized with nonsurgical conditions such as congestive heart failure, chronic obstructive pulmonary disease, sepsis, inflammatory bowel disease, or active cancers are at increased risk for VTE due to inflammation and immobility. In a US study of 158,325 hospitalized nonsurgical patients, including those with cancer, infections, congestive heart failure, or respiratory failure, 4% of patients developed deep vein thrombosis (DVT), 1.5% developed pulmonary embolism (PE), and 0.2% developed both DVT and PE, at a median time of 74 days after discharge.² Prophylaxis in medical inpatients reduces VTE incidence in the hospital by 50% to 75%, but the period of increased VTE risk after discharge is not well understood in medical patients.³ American College of Chest Physicians guidelines provide recommendations for the duration of prophylactic anticoagulation after major orthopedic surgeries but make no recommendation for medical patients.³ American Society of Hematology 2018 guidelines recommend against extending VTE prophylaxis after hospital discharge, including for patients with risk factors or chronic immobility.⁴

However, use of DOACs for short-term VTE prophylaxis as an alternative to LMWH in hospitalized patients is supported by a meta-analysis showing equivalent efficacy, safety, and cost-effectiveness.¹ The current study examined DOACs for extended postdischarge use.¹

STUDY SUMMARY

Significant benefit of DOACs demonstrated across 4 large trials

This meta-analysis of 4 large randomized controlled trials examined the safety and efficacy of 6 weeks of postdischarge DOAC thromboprophylaxis compared with placebo in 26,408 high-risk nonsurgical hospitalized patients.¹ Patients at least 40 years old were admitted with diagnoses that included New York Heart Association (NYHA) class III or IV congestive heart failure, active cancer, acute ischemic stroke, acute respiratory failure, or infectious or inflammatory disease. Study patients also had risk factors for VTE, including age 75 and older, obesity, chronic venous insufficiency, history of VTE, history of NYHA class III or IV congestive heart failure, history of cancer, thrombophilia, hormone replacement therapy, or major surgery within the 6 to 12 weeks before current medical hospitalization.

A recent meta-analysis sheds light on the benefits of extended postdischarge thromboprophylaxis in nonsurgical patients at high risk for VTE.

Patients were excluded if DOACs were contraindicated or if they had active or recent bleeding, renal failure, abnormal liver values, an upcoming need for surgery, or an indication for ongoing anticoagulation. Patients in 3 studies received 6 to 10 days of enoxaparin as prophylaxis during their inpatient stay. (The fourth study did not specify length of inpatient prophylaxis or drug used.) After discharge, patients were assigned to placebo or a regimen of rivaroxaban 10 mg daily, apixaban 2.5 mg twice daily, or betrixaban 80 mg daily for a range of 30 to 45 days. The primary outcome was the composite of total VTE and VTE-related death. A secondary outcome was the occurrence of nonfatal symptomatic VTE, and the primary safety outcome was the incidence of major bleeding.

The primary outcome occurred in 2.9% of the patients in the DOAC group compared with 3.6% of patients in the placebo group (odds ratio [OR] = 0.79; 95% CI, 0.69-0.91; number needed to treat [NNT] = 143). The secondary outcome occurred in 0.48% of patients in the DOAC group compared with 0.77% of patients in the placebo group (OR = 0.62; 95% CI, 0.47-0.83; NNT = 345). Major bleeding resulting in a decrease in hemoglobin concentration of more than 2 g/L, requiring transfusion of at least 2 units of packed red blood cells, reintervention at a previous surgical site, or bleeding in a critical organ or that was fatal, occurred in 0.58% of patients in the DOAC group compared with 0.3% of patients in the placebo group (OR = 1.9; 95% CI, 1.4-2.7; number needed to harm [NNH] = 357). Nonmajor bleeding was increased in the DOAC group compared with placebo (2.2% vs 1.2%; OR = 1.8; 95% CI, 1.5-2.1; NNH = 110).

The NNT to prevent a fatal VTE was 899 patients. After extrapolating original data on fatal PE and major bleeding to a national level, cost-benefit analysis preferred extended DOAC use, with a direct medical cost balance of $1.2 million per life saved.

Continue to: WHAT'S NEW

WHAT’S NEW

Mortality and morbidity benefit with small bleeding risk

Based on this study, for every 300 high-risk patients hospitalized with nonsurgical diagnoses who are given 6 weeks of DOAC prophylaxis, there will be 2 fewer cases of VTE and VTE-related death. In this same group of patients, there will be approximately 1 major bleeding event and 3 less serious bleeds.

Patients with preexisting medical conditions such as congestive heart failure, cancer, and sepsis and those admitted to an intensive care unit are at increased risk for DVT after discharge.⁵ Extending DOAC prophylaxis in nonsurgical patients with serious medical conditions for 6 weeks after discharge reduces the risk of VTE or VTE-related death by 0.7% compared with placebo. Treatment in this population does incur a small increased risk of major bleeding by 0.3% in the DOAC group compared with placebo.

CAVEATS

Results cannot be generalized to all patient populations

Many high-risk patients have chronic kidney disease, and because DOACs (including apixaban, rivaroxaban, and dabigatran) are renally cleared, there are limited data to establish their safety in patients with creatinine clearance ≤ 30 mL/min. Benefits seen with DOACs cannot be extrapolated to other anticoagulation agents, including warfarin or LMWH.

In accordance with new guidelines, some of the patients in this study would now receive antiplatelet therapy, eg, poststroke patients, cancer patients, and—with the ease of DOAC use—patients with atrial fibrillation. If these patients were excluded, it is not known whether the benefit would remain. Patients included in these trials were at particularly high risk for VTE, and the benefits seen in this study cannot be generalized to a patient population with fewer VTE risk factors.

CHALLENGES TO IMPLEMENTATION

High cost and lack of updated guidelines may limit DOAC thromboprophylaxis

Cost is a concern. All the new DOACs are expensive; for example, rivaroxaban costs a little less than $500 per month.⁶ Obtaining insurance coverage for a novel indication may be challenging. The American Society of Hematology and others have not yet endorsed extended posthospital thromboprophylaxis in nonsurgical patients, although the use of DOACs has expanded since the last guideline revisions.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 67-year-old man with a history of type 2 diabetes, hypertension, and chronic congestive heart failure (ejection fraction = 30%) was admitted to the intensive care unit with a diagnosis of acute hypoxic respiratory failure. He was discharged after 10 days of inpatient treatment that included daily VTE prophylaxis with low-molecular-weight heparin (LMWH). Should he go home on VTE prophylaxis?

Patients hospitalized with nonsurgical conditions such as congestive heart failure, chronic obstructive pulmonary disease, sepsis, inflammatory bowel disease, or active cancers are at increased risk for VTE due to inflammation and immobility. In a US study of 158,325 hospitalized nonsurgical patients, including those with cancer, infections, congestive heart failure, or respiratory failure, 4% of patients developed deep vein thrombosis (DVT), 1.5% developed pulmonary embolism (PE), and 0.2% developed both DVT and PE, at a median time of 74 days after discharge.² Prophylaxis in medical inpatients reduces VTE incidence in the hospital by 50% to 75%, but the period of increased VTE risk after discharge is not well understood in medical patients.³ American College of Chest Physicians guidelines provide recommendations for the duration of prophylactic anticoagulation after major orthopedic surgeries but make no recommendation for medical patients.³ American Society of Hematology 2018 guidelines recommend against extending VTE prophylaxis after hospital discharge, including for patients with risk factors or chronic immobility.⁴

However, use of DOACs for short-term VTE prophylaxis as an alternative to LMWH in hospitalized patients is supported by a meta-analysis showing equivalent efficacy, safety, and cost-effectiveness.¹ The current study examined DOACs for extended postdischarge use.¹

STUDY SUMMARY

Significant benefit of DOACs demonstrated across 4 large trials

This meta-analysis of 4 large randomized controlled trials examined the safety and efficacy of 6 weeks of postdischarge DOAC thromboprophylaxis compared with placebo in 26,408 high-risk nonsurgical hospitalized patients.¹ Patients at least 40 years old were admitted with diagnoses that included New York Heart Association (NYHA) class III or IV congestive heart failure, active cancer, acute ischemic stroke, acute respiratory failure, or infectious or inflammatory disease. Study patients also had risk factors for VTE, including age 75 and older, obesity, chronic venous insufficiency, history of VTE, history of NYHA class III or IV congestive heart failure, history of cancer, thrombophilia, hormone replacement therapy, or major surgery within the 6 to 12 weeks before current medical hospitalization.

A recent meta-analysis sheds light on the benefits of extended postdischarge thromboprophylaxis in nonsurgical patients at high risk for VTE.

Patients were excluded if DOACs were contraindicated or if they had active or recent bleeding, renal failure, abnormal liver values, an upcoming need for surgery, or an indication for ongoing anticoagulation. Patients in 3 studies received 6 to 10 days of enoxaparin as prophylaxis during their inpatient stay. (The fourth study did not specify length of inpatient prophylaxis or drug used.) After discharge, patients were assigned to placebo or a regimen of rivaroxaban 10 mg daily, apixaban 2.5 mg twice daily, or betrixaban 80 mg daily for a range of 30 to 45 days. The primary outcome was the composite of total VTE and VTE-related death. A secondary outcome was the occurrence of nonfatal symptomatic VTE, and the primary safety outcome was the incidence of major bleeding.

The primary outcome occurred in 2.9% of the patients in the DOAC group compared with 3.6% of patients in the placebo group (odds ratio [OR] = 0.79; 95% CI, 0.69-0.91; number needed to treat [NNT] = 143). The secondary outcome occurred in 0.48% of patients in the DOAC group compared with 0.77% of patients in the placebo group (OR = 0.62; 95% CI, 0.47-0.83; NNT = 345). Major bleeding resulting in a decrease in hemoglobin concentration of more than 2 g/L, requiring transfusion of at least 2 units of packed red blood cells, reintervention at a previous surgical site, or bleeding in a critical organ or that was fatal, occurred in 0.58% of patients in the DOAC group compared with 0.3% of patients in the placebo group (OR = 1.9; 95% CI, 1.4-2.7; number needed to harm [NNH] = 357). Nonmajor bleeding was increased in the DOAC group compared with placebo (2.2% vs 1.2%; OR = 1.8; 95% CI, 1.5-2.1; NNH = 110).

The NNT to prevent a fatal VTE was 899 patients. After extrapolating original data on fatal PE and major bleeding to a national level, cost-benefit analysis preferred extended DOAC use, with a direct medical cost balance of $1.2 million per life saved.

Continue to: WHAT'S NEW

WHAT’S NEW

Mortality and morbidity benefit with small bleeding risk

Based on this study, for every 300 high-risk patients hospitalized with nonsurgical diagnoses who are given 6 weeks of DOAC prophylaxis, there will be 2 fewer cases of VTE and VTE-related death. In this same group of patients, there will be approximately 1 major bleeding event and 3 less serious bleeds.

Patients with preexisting medical conditions such as congestive heart failure, cancer, and sepsis and those admitted to an intensive care unit are at increased risk for DVT after discharge.⁵ Extending DOAC prophylaxis in nonsurgical patients with serious medical conditions for 6 weeks after discharge reduces the risk of VTE or VTE-related death by 0.7% compared with placebo. Treatment in this population does incur a small increased risk of major bleeding by 0.3% in the DOAC group compared with placebo.

CAVEATS

Results cannot be generalized to all patient populations

Many high-risk patients have chronic kidney disease, and because DOACs (including apixaban, rivaroxaban, and dabigatran) are renally cleared, there are limited data to establish their safety in patients with creatinine clearance ≤ 30 mL/min. Benefits seen with DOACs cannot be extrapolated to other anticoagulation agents, including warfarin or LMWH.

In accordance with new guidelines, some of the patients in this study would now receive antiplatelet therapy, eg, poststroke patients, cancer patients, and—with the ease of DOAC use—patients with atrial fibrillation. If these patients were excluded, it is not known whether the benefit would remain. Patients included in these trials were at particularly high risk for VTE, and the benefits seen in this study cannot be generalized to a patient population with fewer VTE risk factors.

CHALLENGES TO IMPLEMENTATION

High cost and lack of updated guidelines may limit DOAC thromboprophylaxis

Cost is a concern. All the new DOACs are expensive; for example, rivaroxaban costs a little less than $500 per month.⁶ Obtaining insurance coverage for a novel indication may be challenging. The American Society of Hematology and others have not yet endorsed extended posthospital thromboprophylaxis in nonsurgical patients, although the use of DOACs has expanded since the last guideline revisions.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

More than HIV, more than malaria. The death toll worldwide from bacterial antimicrobial resistance (AMR) in 2019 exceeded 1.2 million people, according to a new study.

In terms of preventable deaths, 1.27 million people could have been saved if drug-resistant infections were replaced with infections susceptible to current antibiotics. Furthermore, 4.95 million fewer people would have died if drug-resistant infections were replaced by no infections, researchers estimated.

Although the COVID-19 pandemic took some focus off the AMR burden worldwide over the past 2 years, the urgency to address risk to public health did not ebb. In fact, based on the findings, the researchers noted that AMR is now a leading cause of death worldwide.

“If left unchecked, the spread of AMR could make many bacterial pathogens much more lethal in the future than they are today,” the researchers noted in the study, published online Jan. 20, 2022, in The Lancet.

“These findings are a warning signal that antibiotic resistance is placing pressure on health care systems and leading to significant health loss,” study author Kevin Ikuta, MD, MPH, told this news organization.

“We need to continue to adhere to and support infection prevention and control programs, be thoughtful about our antibiotic use, and advocate for increased funding to vaccine discovery and the antibiotic development pipeline,” added Dr. Ikuta, health sciences assistant clinical professor of medicine at the University of California, Los Angeles.

Although many investigators have studied AMR, this study is the largest in scope, covering 204 countries and territories and incorporating data on a comprehensive range of pathogens and pathogen-drug combinations.

Dr. Ikuta, lead author Christopher J.L. Murray, DPhil, and colleagues estimated the global burden of AMR using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. They specifically looked at rates of death directly attributed to and separately those associated with resistance.
 

Regional differences

Broken down by 21 regions, Australasia had 6.5 deaths per 100,000 people attributable to AMR, the lowest rate reported. This region also had 28 deaths per 100,000 associated with AMR.

Researchers found the highest rates in western sub-Saharan Africa. Deaths attributable to AMR were 27.3 per 100,000 and associated death rate was 114.8 per 100,000.

Lower- and middle-income regions had the highest AMR death rates, although resistance remains a high-priority issue for high-income countries as well.

“It’s important to take a global perspective on resistant infections because we can learn about regions and countries that are experiencing the greatest burden, information that was previously unknown,” Dr. Ikuta said. “With these estimates policy makers can prioritize regions that are hotspots and would most benefit from additional interventions.”

Furthermore, the study emphasized the global nature of AMR. “We’ve seen over the last 2 years with COVID-19 that this sort of problem doesn’t respect country borders, and high rates of resistance in one location can spread across a region or spread globally pretty quickly,” Dr. Ikuta said.
 

Leading resistant infections

Lower respiratory and thorax infections, bloodstream infections, and intra-abdominal infections together accounted for almost 79% of such deaths linked to AMR.

The six leading pathogens are likely household names among infectious disease specialists. The researchers found Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, each responsible for more than 250,000 AMR-associated deaths.

The study also revealed that resistance to several first-line antibiotic agents often used empirically to treat infections accounted for more than 70% of the AMR-attributable deaths. These included fluoroquinolones and beta-lactam antibiotics such as carbapenems, cephalosporins, and penicillins.

Courtesy The Lancet

Potential solutions offered

Dr. Murray and colleagues outlined five strategies to address the challenge of bacterial AMR:

• Infection prevention and control remain paramount in minimizing infections in general and AMR infections in particular.
• More vaccines are needed to reduce the need for antibiotics. “Vaccines are available for only one of the six leading pathogens (S. pneumoniae), although new vaccine programs are underway for S. aureus, E. coli, and others,” the researchers wrote.
• Reduce antibiotic use unrelated to treatment of human disease.
• Avoid using antibiotics for viral infections and other unnecessary indications.
• Invest in new antibiotic development and ensure access to second-line agents in areas without widespread access.

“Identifying strategies that can work to reduce the burden of bacterial AMR – either across a wide range of settings or those that are specifically tailored to the resources available and leading pathogen-drug combinations in a particular setting – is an urgent priority,” the researchers noted.
 

Admirable AMR research

The results of the study are “startling, but not surprising,” said Dr. Fowler, professor of medicine at Duke University, Durham, N.C.

The authors did a “nice job” of addressing both deaths attributable and associated with AMR, Dr. Fowler added. “Those two categories unlock applications, not just in terms of how you interpret it but also what you do about it.”

The deaths attributable to AMR show that there is more work to be done regarding infection control and prevention, Dr. Fowler said, including in areas of the world like lower- and middle-income countries where infection resistance is most pronounced.

The deaths associated with AMR can be more challenging to calculate – people with infections can die for multiple reasons. However, Dr. Fowler applauded the researchers for doing “as good a job as you can” in estimating the extent of associated mortality.
 

‘The overlooked pandemic of antimicrobial resistance’

In an accompanying editorial in The Lancet, Ramanan Laxminarayan, PhD, MPH, wrote: “As COVID-19 rages on, the pandemic of antimicrobial resistance continues in the shadows. The toll taken by AMR on patients and their families is largely invisible but is reflected in prolonged bacterial infections that extend hospital stays and cause needless deaths.”

Dr. Laxminarayan pointed out an irony with AMR in different regions. Some of the AMR burden in sub-Saharan Africa is “probably due to inadequate access to antibiotics and high infection levels, albeit at low levels of resistance, whereas in south Asia and Latin America, it is because of high resistance even with good access to antibiotics.”

More funding to address AMR is needed, Dr. Laxminarayan noted. “Even the lower end of 911,000 deaths estimated by Murray and colleagues is higher than the number of deaths from HIV, which attracts close to U.S. $50 billion each year. However, global spending on addressing AMR is probably much lower than that.” Dr. Laxminarayan is an economist and epidemiologist affiliated with the Center for Disease Dynamics, Economics & Policy in Washington, D.C., and the Global Antibiotic Research and Development Partnership in Geneva.
 

An overlap with COVID-19

The Lancet report is likely “to bring more attention to AMR, especially since so many people have been distracted by COVID, and rightly so,” Dr. Fowler predicted. “The world has had its hands full with COVID.”

The two infections interact in direct ways, Dr. Fowler added. For example, some people hospitalized for COVID-19 for an extended time could develop progressively drug-resistant bacteria – leading to a superinfection.

The overlap could be illustrated by a Venn diagram, he said. A yellow circle could illustrate people with COVID-19 who are asymptomatic or who remain outpatients. Next to that would be a blue circle showing people who develop AMR infections. Where the two circles overlap would be green for those hospitalized who – because of receiving steroids, being on a ventilator, or getting a central line – develop a superinfection.
 

Official guidance continues

The study comes in the context of recent guidance and federal action on AMR. For example, the Infectious Diseases Society of America released new guidelines for AMR in November 2021 as part of ongoing advice on prevention and treatment of this “ongoing crisis.”

This most recent IDSA guidance addresses three pathogens in particular: AmpC beta-lactamase–producing Enterobacterales, carbapenem-resistant A. baumannii, and Stenotrophomonas maltophilia.

Also in November, the World Health Organization released an updated fact sheet on antimicrobial resistance. The WHO declared AMR one of the world’s top 10 global public health threats. The agency emphasized that misuse and overuse of antimicrobials are the main drivers in the development of drug-resistant pathogens. The WHO also pointed out that lack of clean water and sanitation in many areas of the world contribute to spread of microbes, including those resistant to current treatment options.

In September 2021, the Biden administration acknowledged the threat of AMR with allocation of more than $2 billion of the American Rescue Plan money for prevention and treatment of these infections.

Asked if there are any reasons for hope or optimism at this point, Dr. Ikuta said: “Definitely. We know what needs to be done to combat the spread of resistance. COVID-19 has demonstrated the importance of global commitment to infection control measures, such as hand washing and surveillance, and rapid investments in treatments, which can all be applied to antimicrobial resistance.”

The Bill & Melinda Gates Foundation, the Wellcome Trust, and the U.K. Department of Health and Social Care using U.K. aid funding managed by the Fleming Fund and other organizations provided funding for the study. Dr. Ikuta and Dr. Laxminarayan have disclosed no relevant financial relationships. Dr. Fowler reported receiving grants or honoraria, as well as serving as a consultant, for numerous sources. He also reported a patent pending in sepsis diagnostics and serving as chair of the V710 Scientific Advisory Committee (Merck).

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

More than HIV, more than malaria. The death toll worldwide from bacterial antimicrobial resistance (AMR) in 2019 exceeded 1.2 million people, according to a new study.

In terms of preventable deaths, 1.27 million people could have been saved if drug-resistant infections were replaced with infections susceptible to current antibiotics. Furthermore, 4.95 million fewer people would have died if drug-resistant infections were replaced by no infections, researchers estimated.

Although the COVID-19 pandemic took some focus off the AMR burden worldwide over the past 2 years, the urgency to address risk to public health did not ebb. In fact, based on the findings, the researchers noted that AMR is now a leading cause of death worldwide.

“If left unchecked, the spread of AMR could make many bacterial pathogens much more lethal in the future than they are today,” the researchers noted in the study, published online Jan. 20, 2022, in The Lancet.

“These findings are a warning signal that antibiotic resistance is placing pressure on health care systems and leading to significant health loss,” study author Kevin Ikuta, MD, MPH, told this news organization.

“We need to continue to adhere to and support infection prevention and control programs, be thoughtful about our antibiotic use, and advocate for increased funding to vaccine discovery and the antibiotic development pipeline,” added Dr. Ikuta, health sciences assistant clinical professor of medicine at the University of California, Los Angeles.

Although many investigators have studied AMR, this study is the largest in scope, covering 204 countries and territories and incorporating data on a comprehensive range of pathogens and pathogen-drug combinations.

Dr. Ikuta, lead author Christopher J.L. Murray, DPhil, and colleagues estimated the global burden of AMR using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. They specifically looked at rates of death directly attributed to and separately those associated with resistance.
 

Regional differences

Broken down by 21 regions, Australasia had 6.5 deaths per 100,000 people attributable to AMR, the lowest rate reported. This region also had 28 deaths per 100,000 associated with AMR.

Researchers found the highest rates in western sub-Saharan Africa. Deaths attributable to AMR were 27.3 per 100,000 and associated death rate was 114.8 per 100,000.

Lower- and middle-income regions had the highest AMR death rates, although resistance remains a high-priority issue for high-income countries as well.

“It’s important to take a global perspective on resistant infections because we can learn about regions and countries that are experiencing the greatest burden, information that was previously unknown,” Dr. Ikuta said. “With these estimates policy makers can prioritize regions that are hotspots and would most benefit from additional interventions.”

Furthermore, the study emphasized the global nature of AMR. “We’ve seen over the last 2 years with COVID-19 that this sort of problem doesn’t respect country borders, and high rates of resistance in one location can spread across a region or spread globally pretty quickly,” Dr. Ikuta said.
 

Leading resistant infections

Lower respiratory and thorax infections, bloodstream infections, and intra-abdominal infections together accounted for almost 79% of such deaths linked to AMR.

The six leading pathogens are likely household names among infectious disease specialists. The researchers found Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, each responsible for more than 250,000 AMR-associated deaths.

The study also revealed that resistance to several first-line antibiotic agents often used empirically to treat infections accounted for more than 70% of the AMR-attributable deaths. These included fluoroquinolones and beta-lactam antibiotics such as carbapenems, cephalosporins, and penicillins.

Courtesy The Lancet

Potential solutions offered

Dr. Murray and colleagues outlined five strategies to address the challenge of bacterial AMR:

• Infection prevention and control remain paramount in minimizing infections in general and AMR infections in particular.
• More vaccines are needed to reduce the need for antibiotics. “Vaccines are available for only one of the six leading pathogens (S. pneumoniae), although new vaccine programs are underway for S. aureus, E. coli, and others,” the researchers wrote.
• Reduce antibiotic use unrelated to treatment of human disease.
• Avoid using antibiotics for viral infections and other unnecessary indications.
• Invest in new antibiotic development and ensure access to second-line agents in areas without widespread access.

“Identifying strategies that can work to reduce the burden of bacterial AMR – either across a wide range of settings or those that are specifically tailored to the resources available and leading pathogen-drug combinations in a particular setting – is an urgent priority,” the researchers noted.
 

Admirable AMR research

The results of the study are “startling, but not surprising,” said Dr. Fowler, professor of medicine at Duke University, Durham, N.C.

The authors did a “nice job” of addressing both deaths attributable and associated with AMR, Dr. Fowler added. “Those two categories unlock applications, not just in terms of how you interpret it but also what you do about it.”

The deaths attributable to AMR show that there is more work to be done regarding infection control and prevention, Dr. Fowler said, including in areas of the world like lower- and middle-income countries where infection resistance is most pronounced.

The deaths associated with AMR can be more challenging to calculate – people with infections can die for multiple reasons. However, Dr. Fowler applauded the researchers for doing “as good a job as you can” in estimating the extent of associated mortality.
 

‘The overlooked pandemic of antimicrobial resistance’

In an accompanying editorial in The Lancet, Ramanan Laxminarayan, PhD, MPH, wrote: “As COVID-19 rages on, the pandemic of antimicrobial resistance continues in the shadows. The toll taken by AMR on patients and their families is largely invisible but is reflected in prolonged bacterial infections that extend hospital stays and cause needless deaths.”

Dr. Laxminarayan pointed out an irony with AMR in different regions. Some of the AMR burden in sub-Saharan Africa is “probably due to inadequate access to antibiotics and high infection levels, albeit at low levels of resistance, whereas in south Asia and Latin America, it is because of high resistance even with good access to antibiotics.”

More funding to address AMR is needed, Dr. Laxminarayan noted. “Even the lower end of 911,000 deaths estimated by Murray and colleagues is higher than the number of deaths from HIV, which attracts close to U.S. $50 billion each year. However, global spending on addressing AMR is probably much lower than that.” Dr. Laxminarayan is an economist and epidemiologist affiliated with the Center for Disease Dynamics, Economics & Policy in Washington, D.C., and the Global Antibiotic Research and Development Partnership in Geneva.
 

An overlap with COVID-19

The Lancet report is likely “to bring more attention to AMR, especially since so many people have been distracted by COVID, and rightly so,” Dr. Fowler predicted. “The world has had its hands full with COVID.”

The two infections interact in direct ways, Dr. Fowler added. For example, some people hospitalized for COVID-19 for an extended time could develop progressively drug-resistant bacteria – leading to a superinfection.

The overlap could be illustrated by a Venn diagram, he said. A yellow circle could illustrate people with COVID-19 who are asymptomatic or who remain outpatients. Next to that would be a blue circle showing people who develop AMR infections. Where the two circles overlap would be green for those hospitalized who – because of receiving steroids, being on a ventilator, or getting a central line – develop a superinfection.
 

Official guidance continues

The study comes in the context of recent guidance and federal action on AMR. For example, the Infectious Diseases Society of America released new guidelines for AMR in November 2021 as part of ongoing advice on prevention and treatment of this “ongoing crisis.”

This most recent IDSA guidance addresses three pathogens in particular: AmpC beta-lactamase–producing Enterobacterales, carbapenem-resistant A. baumannii, and Stenotrophomonas maltophilia.

Also in November, the World Health Organization released an updated fact sheet on antimicrobial resistance. The WHO declared AMR one of the world’s top 10 global public health threats. The agency emphasized that misuse and overuse of antimicrobials are the main drivers in the development of drug-resistant pathogens. The WHO also pointed out that lack of clean water and sanitation in many areas of the world contribute to spread of microbes, including those resistant to current treatment options.

In September 2021, the Biden administration acknowledged the threat of AMR with allocation of more than $2 billion of the American Rescue Plan money for prevention and treatment of these infections.

Asked if there are any reasons for hope or optimism at this point, Dr. Ikuta said: “Definitely. We know what needs to be done to combat the spread of resistance. COVID-19 has demonstrated the importance of global commitment to infection control measures, such as hand washing and surveillance, and rapid investments in treatments, which can all be applied to antimicrobial resistance.”

The Bill & Melinda Gates Foundation, the Wellcome Trust, and the U.K. Department of Health and Social Care using U.K. aid funding managed by the Fleming Fund and other organizations provided funding for the study. Dr. Ikuta and Dr. Laxminarayan have disclosed no relevant financial relationships. Dr. Fowler reported receiving grants or honoraria, as well as serving as a consultant, for numerous sources. He also reported a patent pending in sepsis diagnostics and serving as chair of the V710 Scientific Advisory Committee (Merck).

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

More than HIV, more than malaria. The death toll worldwide from bacterial antimicrobial resistance (AMR) in 2019 exceeded 1.2 million people, according to a new study.

In terms of preventable deaths, 1.27 million people could have been saved if drug-resistant infections were replaced with infections susceptible to current antibiotics. Furthermore, 4.95 million fewer people would have died if drug-resistant infections were replaced by no infections, researchers estimated.

Although the COVID-19 pandemic took some focus off the AMR burden worldwide over the past 2 years, the urgency to address risk to public health did not ebb. In fact, based on the findings, the researchers noted that AMR is now a leading cause of death worldwide.

“If left unchecked, the spread of AMR could make many bacterial pathogens much more lethal in the future than they are today,” the researchers noted in the study, published online Jan. 20, 2022, in The Lancet.

“These findings are a warning signal that antibiotic resistance is placing pressure on health care systems and leading to significant health loss,” study author Kevin Ikuta, MD, MPH, told this news organization.

“We need to continue to adhere to and support infection prevention and control programs, be thoughtful about our antibiotic use, and advocate for increased funding to vaccine discovery and the antibiotic development pipeline,” added Dr. Ikuta, health sciences assistant clinical professor of medicine at the University of California, Los Angeles.

Although many investigators have studied AMR, this study is the largest in scope, covering 204 countries and territories and incorporating data on a comprehensive range of pathogens and pathogen-drug combinations.

Dr. Ikuta, lead author Christopher J.L. Murray, DPhil, and colleagues estimated the global burden of AMR using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. They specifically looked at rates of death directly attributed to and separately those associated with resistance.
 

Regional differences

Broken down by 21 regions, Australasia had 6.5 deaths per 100,000 people attributable to AMR, the lowest rate reported. This region also had 28 deaths per 100,000 associated with AMR.

Researchers found the highest rates in western sub-Saharan Africa. Deaths attributable to AMR were 27.3 per 100,000 and associated death rate was 114.8 per 100,000.

Lower- and middle-income regions had the highest AMR death rates, although resistance remains a high-priority issue for high-income countries as well.

“It’s important to take a global perspective on resistant infections because we can learn about regions and countries that are experiencing the greatest burden, information that was previously unknown,” Dr. Ikuta said. “With these estimates policy makers can prioritize regions that are hotspots and would most benefit from additional interventions.”

Furthermore, the study emphasized the global nature of AMR. “We’ve seen over the last 2 years with COVID-19 that this sort of problem doesn’t respect country borders, and high rates of resistance in one location can spread across a region or spread globally pretty quickly,” Dr. Ikuta said.
 

Leading resistant infections

Lower respiratory and thorax infections, bloodstream infections, and intra-abdominal infections together accounted for almost 79% of such deaths linked to AMR.

The six leading pathogens are likely household names among infectious disease specialists. The researchers found Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, each responsible for more than 250,000 AMR-associated deaths.

The study also revealed that resistance to several first-line antibiotic agents often used empirically to treat infections accounted for more than 70% of the AMR-attributable deaths. These included fluoroquinolones and beta-lactam antibiotics such as carbapenems, cephalosporins, and penicillins.

Courtesy The Lancet

Potential solutions offered

Dr. Murray and colleagues outlined five strategies to address the challenge of bacterial AMR:

• Infection prevention and control remain paramount in minimizing infections in general and AMR infections in particular.
• More vaccines are needed to reduce the need for antibiotics. “Vaccines are available for only one of the six leading pathogens (S. pneumoniae), although new vaccine programs are underway for S. aureus, E. coli, and others,” the researchers wrote.
• Reduce antibiotic use unrelated to treatment of human disease.
• Avoid using antibiotics for viral infections and other unnecessary indications.
• Invest in new antibiotic development and ensure access to second-line agents in areas without widespread access.

“Identifying strategies that can work to reduce the burden of bacterial AMR – either across a wide range of settings or those that are specifically tailored to the resources available and leading pathogen-drug combinations in a particular setting – is an urgent priority,” the researchers noted.
 

Admirable AMR research

The results of the study are “startling, but not surprising,” said Dr. Fowler, professor of medicine at Duke University, Durham, N.C.

The authors did a “nice job” of addressing both deaths attributable and associated with AMR, Dr. Fowler added. “Those two categories unlock applications, not just in terms of how you interpret it but also what you do about it.”

The deaths attributable to AMR show that there is more work to be done regarding infection control and prevention, Dr. Fowler said, including in areas of the world like lower- and middle-income countries where infection resistance is most pronounced.

The deaths associated with AMR can be more challenging to calculate – people with infections can die for multiple reasons. However, Dr. Fowler applauded the researchers for doing “as good a job as you can” in estimating the extent of associated mortality.
 

‘The overlooked pandemic of antimicrobial resistance’

In an accompanying editorial in The Lancet, Ramanan Laxminarayan, PhD, MPH, wrote: “As COVID-19 rages on, the pandemic of antimicrobial resistance continues in the shadows. The toll taken by AMR on patients and their families is largely invisible but is reflected in prolonged bacterial infections that extend hospital stays and cause needless deaths.”

Dr. Laxminarayan pointed out an irony with AMR in different regions. Some of the AMR burden in sub-Saharan Africa is “probably due to inadequate access to antibiotics and high infection levels, albeit at low levels of resistance, whereas in south Asia and Latin America, it is because of high resistance even with good access to antibiotics.”

More funding to address AMR is needed, Dr. Laxminarayan noted. “Even the lower end of 911,000 deaths estimated by Murray and colleagues is higher than the number of deaths from HIV, which attracts close to U.S. $50 billion each year. However, global spending on addressing AMR is probably much lower than that.” Dr. Laxminarayan is an economist and epidemiologist affiliated with the Center for Disease Dynamics, Economics & Policy in Washington, D.C., and the Global Antibiotic Research and Development Partnership in Geneva.
 

An overlap with COVID-19

The Lancet report is likely “to bring more attention to AMR, especially since so many people have been distracted by COVID, and rightly so,” Dr. Fowler predicted. “The world has had its hands full with COVID.”

The two infections interact in direct ways, Dr. Fowler added. For example, some people hospitalized for COVID-19 for an extended time could develop progressively drug-resistant bacteria – leading to a superinfection.

The overlap could be illustrated by a Venn diagram, he said. A yellow circle could illustrate people with COVID-19 who are asymptomatic or who remain outpatients. Next to that would be a blue circle showing people who develop AMR infections. Where the two circles overlap would be green for those hospitalized who – because of receiving steroids, being on a ventilator, or getting a central line – develop a superinfection.
 

Official guidance continues

The study comes in the context of recent guidance and federal action on AMR. For example, the Infectious Diseases Society of America released new guidelines for AMR in November 2021 as part of ongoing advice on prevention and treatment of this “ongoing crisis.”

This most recent IDSA guidance addresses three pathogens in particular: AmpC beta-lactamase–producing Enterobacterales, carbapenem-resistant A. baumannii, and Stenotrophomonas maltophilia.

Also in November, the World Health Organization released an updated fact sheet on antimicrobial resistance. The WHO declared AMR one of the world’s top 10 global public health threats. The agency emphasized that misuse and overuse of antimicrobials are the main drivers in the development of drug-resistant pathogens. The WHO also pointed out that lack of clean water and sanitation in many areas of the world contribute to spread of microbes, including those resistant to current treatment options.

In September 2021, the Biden administration acknowledged the threat of AMR with allocation of more than $2 billion of the American Rescue Plan money for prevention and treatment of these infections.

Asked if there are any reasons for hope or optimism at this point, Dr. Ikuta said: “Definitely. We know what needs to be done to combat the spread of resistance. COVID-19 has demonstrated the importance of global commitment to infection control measures, such as hand washing and surveillance, and rapid investments in treatments, which can all be applied to antimicrobial resistance.”

The Bill & Melinda Gates Foundation, the Wellcome Trust, and the U.K. Department of Health and Social Care using U.K. aid funding managed by the Fleming Fund and other organizations provided funding for the study. Dr. Ikuta and Dr. Laxminarayan have disclosed no relevant financial relationships. Dr. Fowler reported receiving grants or honoraria, as well as serving as a consultant, for numerous sources. He also reported a patent pending in sepsis diagnostics and serving as chair of the V710 Scientific Advisory Committee (Merck).

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

BUENOS AIRES – The Latin American Association of Cardiac and Endovascular Surgery (LACES) has demanded “urgent reconsideration” of the decision to downgrade the strength of the recommendation for revascularization or coronary artery bypass graft (CABG) surgery for multivessel disease in the new guideline on coronary artery revascularization, putting it in the same class as the recommendation for percutaneous coronary intervention, which has no apparent advantage over optimal medical therapy.

With the prevalence of stable ischemic heart disease in patients with multivessel disease, the contradiction between the evidence and the new recommendation “may affect the lives and survival of millions of patients worldwide and have a major socio-economic impact,” the association warned in a public letter.

In the 2011 guideline, CABG for patients with multivessel coronary artery disease was given a class I recommendation, which means that it is considered useful and effective and should be performed in the majority of patients in most circumstances. But the new, much weaker class IIb recommendation suggests that the benefit only marginally exceeds the risk and that it should be used selectively and only after careful consideration.

“It is an incomprehensible rollercoaster drop in the recommendation level. We totally disagree. In the absence of evidence, a IIb level provides equal freedom to send a patient to surgery or not. And in patients who are not being sent to surgery, it could take years of survival before we can be sure that we are doing the right thing,” said LACES president Víctor Dayan, MD, PhD, from the cardiovascular center at the Hospital de Clínicas “Dr. Manuel Quintela”, which is part of the School of Medicine at the University of the Republic, Montevideo, Uruguay.

The change in the recommendation for this indication “reflects new evidence showing no advantage of coronary artery bypass grafting over medical therapy alone to improve survival in patients with three-vessel coronary disease with preserved left ventricular function and no left main disease,” according to the authors of the guideline, issued jointly by the American College of Cardiology (ACC), the American Heart Association, and the Society for Cardiovascular Angiography and Interventions (SCAI). In particular, they cite the 2019 ISCHEMIA clinical study that failed to show that an early invasive strategy reduces major adverse cardiovascular events, compared with optimal medical therapy and a handful of meta-analyses.

However, ISCHEMIA did not discriminate between the two types of invasive strategy – CABG and percutaneous coronary intervention (PCI) – so cannot be considered as a basis to downgrade the CABG recommendation, Dr. Dayan explained.

“Furthermore, the authors neglected previous RCTs that have shown the survival benefit of CABG in these patients and decided to put PCI in the same [class of recommendation], although no RCT has been able to show any survival advantage of PCI compared to optimal medical treatment,” the LACES letter states.

Basis should be evidence, ‘not inferences’

Three large randomized clinical trials and a 1994 meta-analysis with individual patient data from seven studies firmly established that survival is better with CABG than with medical treatment, the letter continues. However, the guideline authors did not provide any additional randomized clinical trials that refute this evidence.

“Furthermore, the committee disregarded data from the Ten-Year Follow-up Survival of the Medicine, Angioplasty, or Surgery Study (MASS II) randomized control[led] trial, which showed a lower incidence of cardiac mortality (as part of its secondary outcomes) following CABG compared to optimal medical therapy and PCI,” the letter explains.

The guideline authors might have judged current optimal medical therapy to be better than what existed 10, 15, or 30 years ago, diluting the relative benefits of surgery, but the “recommendation in a guideline must act on evidence, not inferences. And there is no evidence to support this drop in recommendation class,” Dr. Dayan said.

Other experts have drawn attention to the fact that two surgical societies – the American Association for Thoracic Surgery (AAST) and the Society of Thoracic Surgeons (STS) – did not endorse the final document, despite having participated in its review, reported this news organization.

“This is a very disappointing update that will negatively affect the lives of many people,” tweeted Marc Pelletier, MD, head of cardiac surgery at University Hospitals, Case Western Reserve University, Cleveland.

Contradictions in the text that examines the evidence and the final recommendations, are “unclear” and “open to various interpretations, when they should be a pillar for decisionmaking,” said Javier Ferrari Ayarragaray, MD, president of the Argentine College of Cardiovascular Surgeons (CACCV) and vice president of LACES.

The new guidelines “show no additional randomized controlled trial to support this downgrade in the level of evidence,” according to a recent CACCV statement. “The inclusion, approval and endorsement of this type of [recommendation,] including [other] international surgical scientific societies, such as STS, AATS, EACTS, LACES[,] is necessary to obtain a better understanding and agreement on the current evidence.”

In a Dec. 17, 2021 response to LACES, Patrick O’Gara, MD, who was chair of the ACC/AHA Joint Committee on Clinical Practice Guidelines at the time, and his successor, Joshua Beckman, MD, explained that both organizations approved the guideline for publication and support its authors “in their interpretation of the published evidence and findings.”

The pair pointed out that the drafting committee members, who have extensive clinical judgment and experience, deliberated extensively on the issue and that the change from a class I to a class IIb recommendation was “carefully considered after a review of the entire available and relevant evidence.”

“When we bring together multiple organizations to review and summarize the evidence, we work collaboratively to interpret the extensive catalog of published and peer-reviewed literature and create clinical practice recommendations,” said Thomas Getchius, director of guideline strategy and operations at the AHA.

“The final guideline reflects the latest evidence-based recommendations for coronary artery revascularization, as agreed upon by the ACC, AHA, SCAI, and the full drafting committee,” Mr. Getchius said.

Dr. Dayan and Dr. Ferrari Ayarragaray have disclosed no relevant financial relationships. Mr. Getchius is an employee of the American Heart Association.

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

BUENOS AIRES – The Latin American Association of Cardiac and Endovascular Surgery (LACES) has demanded “urgent reconsideration” of the decision to downgrade the strength of the recommendation for revascularization or coronary artery bypass graft (CABG) surgery for multivessel disease in the new guideline on coronary artery revascularization, putting it in the same class as the recommendation for percutaneous coronary intervention, which has no apparent advantage over optimal medical therapy.

With the prevalence of stable ischemic heart disease in patients with multivessel disease, the contradiction between the evidence and the new recommendation “may affect the lives and survival of millions of patients worldwide and have a major socio-economic impact,” the association warned in a public letter.

In the 2011 guideline, CABG for patients with multivessel coronary artery disease was given a class I recommendation, which means that it is considered useful and effective and should be performed in the majority of patients in most circumstances. But the new, much weaker class IIb recommendation suggests that the benefit only marginally exceeds the risk and that it should be used selectively and only after careful consideration.

“It is an incomprehensible rollercoaster drop in the recommendation level. We totally disagree. In the absence of evidence, a IIb level provides equal freedom to send a patient to surgery or not. And in patients who are not being sent to surgery, it could take years of survival before we can be sure that we are doing the right thing,” said LACES president Víctor Dayan, MD, PhD, from the cardiovascular center at the Hospital de Clínicas “Dr. Manuel Quintela”, which is part of the School of Medicine at the University of the Republic, Montevideo, Uruguay.

The change in the recommendation for this indication “reflects new evidence showing no advantage of coronary artery bypass grafting over medical therapy alone to improve survival in patients with three-vessel coronary disease with preserved left ventricular function and no left main disease,” according to the authors of the guideline, issued jointly by the American College of Cardiology (ACC), the American Heart Association, and the Society for Cardiovascular Angiography and Interventions (SCAI). In particular, they cite the 2019 ISCHEMIA clinical study that failed to show that an early invasive strategy reduces major adverse cardiovascular events, compared with optimal medical therapy and a handful of meta-analyses.

However, ISCHEMIA did not discriminate between the two types of invasive strategy – CABG and percutaneous coronary intervention (PCI) – so cannot be considered as a basis to downgrade the CABG recommendation, Dr. Dayan explained.

“Furthermore, the authors neglected previous RCTs that have shown the survival benefit of CABG in these patients and decided to put PCI in the same [class of recommendation], although no RCT has been able to show any survival advantage of PCI compared to optimal medical treatment,” the LACES letter states.

Basis should be evidence, ‘not inferences’

Three large randomized clinical trials and a 1994 meta-analysis with individual patient data from seven studies firmly established that survival is better with CABG than with medical treatment, the letter continues. However, the guideline authors did not provide any additional randomized clinical trials that refute this evidence.

“Furthermore, the committee disregarded data from the Ten-Year Follow-up Survival of the Medicine, Angioplasty, or Surgery Study (MASS II) randomized control[led] trial, which showed a lower incidence of cardiac mortality (as part of its secondary outcomes) following CABG compared to optimal medical therapy and PCI,” the letter explains.

The guideline authors might have judged current optimal medical therapy to be better than what existed 10, 15, or 30 years ago, diluting the relative benefits of surgery, but the “recommendation in a guideline must act on evidence, not inferences. And there is no evidence to support this drop in recommendation class,” Dr. Dayan said.

Other experts have drawn attention to the fact that two surgical societies – the American Association for Thoracic Surgery (AAST) and the Society of Thoracic Surgeons (STS) – did not endorse the final document, despite having participated in its review, reported this news organization.

“This is a very disappointing update that will negatively affect the lives of many people,” tweeted Marc Pelletier, MD, head of cardiac surgery at University Hospitals, Case Western Reserve University, Cleveland.

Contradictions in the text that examines the evidence and the final recommendations, are “unclear” and “open to various interpretations, when they should be a pillar for decisionmaking,” said Javier Ferrari Ayarragaray, MD, president of the Argentine College of Cardiovascular Surgeons (CACCV) and vice president of LACES.

The new guidelines “show no additional randomized controlled trial to support this downgrade in the level of evidence,” according to a recent CACCV statement. “The inclusion, approval and endorsement of this type of [recommendation,] including [other] international surgical scientific societies, such as STS, AATS, EACTS, LACES[,] is necessary to obtain a better understanding and agreement on the current evidence.”

In a Dec. 17, 2021 response to LACES, Patrick O’Gara, MD, who was chair of the ACC/AHA Joint Committee on Clinical Practice Guidelines at the time, and his successor, Joshua Beckman, MD, explained that both organizations approved the guideline for publication and support its authors “in their interpretation of the published evidence and findings.”

The pair pointed out that the drafting committee members, who have extensive clinical judgment and experience, deliberated extensively on the issue and that the change from a class I to a class IIb recommendation was “carefully considered after a review of the entire available and relevant evidence.”

“When we bring together multiple organizations to review and summarize the evidence, we work collaboratively to interpret the extensive catalog of published and peer-reviewed literature and create clinical practice recommendations,” said Thomas Getchius, director of guideline strategy and operations at the AHA.

“The final guideline reflects the latest evidence-based recommendations for coronary artery revascularization, as agreed upon by the ACC, AHA, SCAI, and the full drafting committee,” Mr. Getchius said.

Dr. Dayan and Dr. Ferrari Ayarragaray have disclosed no relevant financial relationships. Mr. Getchius is an employee of the American Heart Association.

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

BUENOS AIRES – The Latin American Association of Cardiac and Endovascular Surgery (LACES) has demanded “urgent reconsideration” of the decision to downgrade the strength of the recommendation for revascularization or coronary artery bypass graft (CABG) surgery for multivessel disease in the new guideline on coronary artery revascularization, putting it in the same class as the recommendation for percutaneous coronary intervention, which has no apparent advantage over optimal medical therapy.

With the prevalence of stable ischemic heart disease in patients with multivessel disease, the contradiction between the evidence and the new recommendation “may affect the lives and survival of millions of patients worldwide and have a major socio-economic impact,” the association warned in a public letter.

In the 2011 guideline, CABG for patients with multivessel coronary artery disease was given a class I recommendation, which means that it is considered useful and effective and should be performed in the majority of patients in most circumstances. But the new, much weaker class IIb recommendation suggests that the benefit only marginally exceeds the risk and that it should be used selectively and only after careful consideration.

“It is an incomprehensible rollercoaster drop in the recommendation level. We totally disagree. In the absence of evidence, a IIb level provides equal freedom to send a patient to surgery or not. And in patients who are not being sent to surgery, it could take years of survival before we can be sure that we are doing the right thing,” said LACES president Víctor Dayan, MD, PhD, from the cardiovascular center at the Hospital de Clínicas “Dr. Manuel Quintela”, which is part of the School of Medicine at the University of the Republic, Montevideo, Uruguay.

The change in the recommendation for this indication “reflects new evidence showing no advantage of coronary artery bypass grafting over medical therapy alone to improve survival in patients with three-vessel coronary disease with preserved left ventricular function and no left main disease,” according to the authors of the guideline, issued jointly by the American College of Cardiology (ACC), the American Heart Association, and the Society for Cardiovascular Angiography and Interventions (SCAI). In particular, they cite the 2019 ISCHEMIA clinical study that failed to show that an early invasive strategy reduces major adverse cardiovascular events, compared with optimal medical therapy and a handful of meta-analyses.

However, ISCHEMIA did not discriminate between the two types of invasive strategy – CABG and percutaneous coronary intervention (PCI) – so cannot be considered as a basis to downgrade the CABG recommendation, Dr. Dayan explained.

“Furthermore, the authors neglected previous RCTs that have shown the survival benefit of CABG in these patients and decided to put PCI in the same [class of recommendation], although no RCT has been able to show any survival advantage of PCI compared to optimal medical treatment,” the LACES letter states.

Basis should be evidence, ‘not inferences’

Three large randomized clinical trials and a 1994 meta-analysis with individual patient data from seven studies firmly established that survival is better with CABG than with medical treatment, the letter continues. However, the guideline authors did not provide any additional randomized clinical trials that refute this evidence.

“Furthermore, the committee disregarded data from the Ten-Year Follow-up Survival of the Medicine, Angioplasty, or Surgery Study (MASS II) randomized control[led] trial, which showed a lower incidence of cardiac mortality (as part of its secondary outcomes) following CABG compared to optimal medical therapy and PCI,” the letter explains.

The guideline authors might have judged current optimal medical therapy to be better than what existed 10, 15, or 30 years ago, diluting the relative benefits of surgery, but the “recommendation in a guideline must act on evidence, not inferences. And there is no evidence to support this drop in recommendation class,” Dr. Dayan said.

Other experts have drawn attention to the fact that two surgical societies – the American Association for Thoracic Surgery (AAST) and the Society of Thoracic Surgeons (STS) – did not endorse the final document, despite having participated in its review, reported this news organization.

“This is a very disappointing update that will negatively affect the lives of many people,” tweeted Marc Pelletier, MD, head of cardiac surgery at University Hospitals, Case Western Reserve University, Cleveland.

Contradictions in the text that examines the evidence and the final recommendations, are “unclear” and “open to various interpretations, when they should be a pillar for decisionmaking,” said Javier Ferrari Ayarragaray, MD, president of the Argentine College of Cardiovascular Surgeons (CACCV) and vice president of LACES.

The new guidelines “show no additional randomized controlled trial to support this downgrade in the level of evidence,” according to a recent CACCV statement. “The inclusion, approval and endorsement of this type of [recommendation,] including [other] international surgical scientific societies, such as STS, AATS, EACTS, LACES[,] is necessary to obtain a better understanding and agreement on the current evidence.”

In a Dec. 17, 2021 response to LACES, Patrick O’Gara, MD, who was chair of the ACC/AHA Joint Committee on Clinical Practice Guidelines at the time, and his successor, Joshua Beckman, MD, explained that both organizations approved the guideline for publication and support its authors “in their interpretation of the published evidence and findings.”

The pair pointed out that the drafting committee members, who have extensive clinical judgment and experience, deliberated extensively on the issue and that the change from a class I to a class IIb recommendation was “carefully considered after a review of the entire available and relevant evidence.”

“When we bring together multiple organizations to review and summarize the evidence, we work collaboratively to interpret the extensive catalog of published and peer-reviewed literature and create clinical practice recommendations,” said Thomas Getchius, director of guideline strategy and operations at the AHA.

“The final guideline reflects the latest evidence-based recommendations for coronary artery revascularization, as agreed upon by the ACC, AHA, SCAI, and the full drafting committee,” Mr. Getchius said.

Dr. Dayan and Dr. Ferrari Ayarragaray have disclosed no relevant financial relationships. Mr. Getchius is an employee of the American Heart Association.

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

THE CASE

A 52-year-old man with a history of hypertension and gastroesophageal reflux disease (GERD) presented to the emergency department (ED) after an episode of syncope. He reported that the syncope occurred soon after he stood up to go to the kitchen to make dinner but was without prodrome or associated symptoms. He recalled little of the event, and the episode was unwitnessed. He had a few bruises on his arms but no significant injuries.

On questioning, he reported occasional palpitations but no changes in his normal exercise tolerance. His only medication was lisinopril 10 mg/d.

In the ED, his vital signs, physical exam (including orthostatic vital signs), basic labs (including troponin I), and a 12-lead EKG were normal. After a cardiology consultation, he was discharged home with a 30-day ambulatory rhythm monitor.

A few days later, while walking up and down some hills, he experienced about 15 seconds of chest pain accompanied by mild lightheadedness. Thinking it might be related to his GERD, he took some over-the-counter antacids when he returned home, since these had been effective for him in the past.

However, the rhythm monitoring company contacted the EKG lab to transmit a concerning strip (FIGURE). They also reported that the patient had been contacted and reported no further symptoms.

IMAGES COURTESY OF HARBORVIEW MEDICAL CENTER EKG LABORATORY

THE DIAGNOSIS

Most notable on the patient’s rhythm strip was a continuously varying QRS complex, which was indicative of polymorphic ventricular tachycardia and consistent with the patient’s syncope and other symptoms. Less obvious at first glance was an ST-segment elevation in the preceding beats. Comparison to a post-episode tracing (FIGURE) highlights the abnormality. Polymorphic ventricular tachycardia resolves in 1 of 2 ways: It will either stop on its own (causing syncope if it lasts more than a few seconds) or it will devolve into ventricular fibrillation, causing cardiac arrest.¹

The combination of these findings and the clinical scenario prompted a recommendation that the patient report to the ED for admission (his wife drove him). He was admitted to the intensive care unit (ICU) for continuous telemetry monitoring, and a cardiac catheterization was ordered. The procedure revealed a 99% thrombotic mid-right coronary artery lesion, for which aspiration thrombectomy and uncomplicated stenting were performed.

Continue to: DISCUSSION

Guidelines from the American College of Cardiology/American Heart Association/Heart Rhythm Society recommend a detailed history and physical exam, as well as an EKG, for the initial evaluation of syncope.² If this does not point to a diagnosis (and depending on the presentation and other factors), an ambulatory rhythm monitor can be considered. Other possible testing modalities include stress testing, resting transthoracic echocardiography, electrophysiologic testing, and cardiac magnetic resonance imaging or computed tomography.

Is the cause cardiac? The guidelines suggest that a cardiac cause of syncope is more likely if several of the following factors are present: age > 60 years; male sex; presence of known heart disease (acquired or congenital); brief prodrome (eg, palpitations) or no prodrome; exertional or supine syncope; 1 to 2 episodes; an abnormal cardiac exam; and a family history of premature sudden death.² A noncardiac cause is suggested by other factors: younger age; no known cardiac disease; standing or a position change from supine to sitting/standing; prodrome; specific triggers (eg, dehydration, pain); and frequent and prolonged stereotypic episodes.²

Our patient experienced syncope upon standing, which suggested a noncardiac cause. However, his history of palpitations increased our suspicion for a cardiac cause.

While the guidelines do not specify the number of factors or endorse a specific scoring system, such tools have been developed. For example, the EGSYS (Evaluation of Guidelines in Syncope Study) Score assigns 1 point for each of 6 factors: palpitations; heart disease and/or abnormal EKG; effort syncope; supine syncope; precipitating or predisposing factors; and autonomic prodromes. A score ≥ 3 identified cardiac syncope with a sensitivity of 95%, but with a specificity of only 61%. In the derivation study, patients with a score ≥ 3 had higher mortality than those with a lower score (17 vs 3%; P < .001).³

Myocardial ischemia can trigger ventricular arrhythmias. In the GUSTO-1 trial of fibrinolytic therapy in patients with acute ST-segment elevation myocardial infarction (n = 40,895), the incidence of ventricular tachycardia or ventricular fibrillation was 10.2%.⁴ In a pooled analysis (4 trials; n = 26,416) of patients who were treated for non–ST-segment elevation or unstable ­angina-type acute coronary syndromes, the rate of these arrhythmias was markedly lower (2.1%).⁵ The risk of ventricular arrhythmia is one reason close monitoring (eg, continuous telemetry, ICU admission) is the standard of care for patients with acute coronary syndromes.

Our patient experienced syncope upon standing, which suggested a noncardiac cause (usually orthostatic hypotension). However, the history of palpitations increased the suspicion for a cardiac cause, and thus the rhythm monitor was ordered.

THE TAKEAWAY

This case was unusual in that ambulatory monitoring captured electrocardiographic evidence of myocardial ischemia leading directly to a ventricular arrhythmia. In the evaluation of syncope, a detailed history, physical exam, and a baseline 12-lead EKG can sometimes give clues to an arrhythmic cause of syncope (eg, Brugada syndrome, prior infarct pattern, prolonged QTc, bradycardia, heart block, arrhythmogenic right ventricular cardiomyopathy)—but prolonged rhythm monitoring is sometimes needed to identify a cause.

CORRESPONDENCE
Michael A. Chen, MD, PhD, Harborview Medical Center, University of Washington School of Medicine, 325 9th Avenue, Box 359748 (Cardiology), Seattle, WA 98104; [email protected]

THE CASE

A 52-year-old man with a history of hypertension and gastroesophageal reflux disease (GERD) presented to the emergency department (ED) after an episode of syncope. He reported that the syncope occurred soon after he stood up to go to the kitchen to make dinner but was without prodrome or associated symptoms. He recalled little of the event, and the episode was unwitnessed. He had a few bruises on his arms but no significant injuries.

On questioning, he reported occasional palpitations but no changes in his normal exercise tolerance. His only medication was lisinopril 10 mg/d.

In the ED, his vital signs, physical exam (including orthostatic vital signs), basic labs (including troponin I), and a 12-lead EKG were normal. After a cardiology consultation, he was discharged home with a 30-day ambulatory rhythm monitor.

A few days later, while walking up and down some hills, he experienced about 15 seconds of chest pain accompanied by mild lightheadedness. Thinking it might be related to his GERD, he took some over-the-counter antacids when he returned home, since these had been effective for him in the past.

However, the rhythm monitoring company contacted the EKG lab to transmit a concerning strip (FIGURE). They also reported that the patient had been contacted and reported no further symptoms.

IMAGES COURTESY OF HARBORVIEW MEDICAL CENTER EKG LABORATORY

THE DIAGNOSIS

Most notable on the patient’s rhythm strip was a continuously varying QRS complex, which was indicative of polymorphic ventricular tachycardia and consistent with the patient’s syncope and other symptoms. Less obvious at first glance was an ST-segment elevation in the preceding beats. Comparison to a post-episode tracing (FIGURE) highlights the abnormality. Polymorphic ventricular tachycardia resolves in 1 of 2 ways: It will either stop on its own (causing syncope if it lasts more than a few seconds) or it will devolve into ventricular fibrillation, causing cardiac arrest.¹

The combination of these findings and the clinical scenario prompted a recommendation that the patient report to the ED for admission (his wife drove him). He was admitted to the intensive care unit (ICU) for continuous telemetry monitoring, and a cardiac catheterization was ordered. The procedure revealed a 99% thrombotic mid-right coronary artery lesion, for which aspiration thrombectomy and uncomplicated stenting were performed.

Continue to: DISCUSSION

Guidelines from the American College of Cardiology/American Heart Association/Heart Rhythm Society recommend a detailed history and physical exam, as well as an EKG, for the initial evaluation of syncope.² If this does not point to a diagnosis (and depending on the presentation and other factors), an ambulatory rhythm monitor can be considered. Other possible testing modalities include stress testing, resting transthoracic echocardiography, electrophysiologic testing, and cardiac magnetic resonance imaging or computed tomography.

Is the cause cardiac? The guidelines suggest that a cardiac cause of syncope is more likely if several of the following factors are present: age > 60 years; male sex; presence of known heart disease (acquired or congenital); brief prodrome (eg, palpitations) or no prodrome; exertional or supine syncope; 1 to 2 episodes; an abnormal cardiac exam; and a family history of premature sudden death.² A noncardiac cause is suggested by other factors: younger age; no known cardiac disease; standing or a position change from supine to sitting/standing; prodrome; specific triggers (eg, dehydration, pain); and frequent and prolonged stereotypic episodes.²

Our patient experienced syncope upon standing, which suggested a noncardiac cause. However, his history of palpitations increased our suspicion for a cardiac cause.

While the guidelines do not specify the number of factors or endorse a specific scoring system, such tools have been developed. For example, the EGSYS (Evaluation of Guidelines in Syncope Study) Score assigns 1 point for each of 6 factors: palpitations; heart disease and/or abnormal EKG; effort syncope; supine syncope; precipitating or predisposing factors; and autonomic prodromes. A score ≥ 3 identified cardiac syncope with a sensitivity of 95%, but with a specificity of only 61%. In the derivation study, patients with a score ≥ 3 had higher mortality than those with a lower score (17 vs 3%; P < .001).³

Myocardial ischemia can trigger ventricular arrhythmias. In the GUSTO-1 trial of fibrinolytic therapy in patients with acute ST-segment elevation myocardial infarction (n = 40,895), the incidence of ventricular tachycardia or ventricular fibrillation was 10.2%.⁴ In a pooled analysis (4 trials; n = 26,416) of patients who were treated for non–ST-segment elevation or unstable ­angina-type acute coronary syndromes, the rate of these arrhythmias was markedly lower (2.1%).⁵ The risk of ventricular arrhythmia is one reason close monitoring (eg, continuous telemetry, ICU admission) is the standard of care for patients with acute coronary syndromes.

Our patient experienced syncope upon standing, which suggested a noncardiac cause (usually orthostatic hypotension). However, the history of palpitations increased the suspicion for a cardiac cause, and thus the rhythm monitor was ordered.

THE TAKEAWAY

This case was unusual in that ambulatory monitoring captured electrocardiographic evidence of myocardial ischemia leading directly to a ventricular arrhythmia. In the evaluation of syncope, a detailed history, physical exam, and a baseline 12-lead EKG can sometimes give clues to an arrhythmic cause of syncope (eg, Brugada syndrome, prior infarct pattern, prolonged QTc, bradycardia, heart block, arrhythmogenic right ventricular cardiomyopathy)—but prolonged rhythm monitoring is sometimes needed to identify a cause.

CORRESPONDENCE
Michael A. Chen, MD, PhD, Harborview Medical Center, University of Washington School of Medicine, 325 9th Avenue, Box 359748 (Cardiology), Seattle, WA 98104; [email protected]

THE CASE

A 52-year-old man with a history of hypertension and gastroesophageal reflux disease (GERD) presented to the emergency department (ED) after an episode of syncope. He reported that the syncope occurred soon after he stood up to go to the kitchen to make dinner but was without prodrome or associated symptoms. He recalled little of the event, and the episode was unwitnessed. He had a few bruises on his arms but no significant injuries.

On questioning, he reported occasional palpitations but no changes in his normal exercise tolerance. His only medication was lisinopril 10 mg/d.

In the ED, his vital signs, physical exam (including orthostatic vital signs), basic labs (including troponin I), and a 12-lead EKG were normal. After a cardiology consultation, he was discharged home with a 30-day ambulatory rhythm monitor.

A few days later, while walking up and down some hills, he experienced about 15 seconds of chest pain accompanied by mild lightheadedness. Thinking it might be related to his GERD, he took some over-the-counter antacids when he returned home, since these had been effective for him in the past.

However, the rhythm monitoring company contacted the EKG lab to transmit a concerning strip (FIGURE). They also reported that the patient had been contacted and reported no further symptoms.

IMAGES COURTESY OF HARBORVIEW MEDICAL CENTER EKG LABORATORY

THE DIAGNOSIS

Most notable on the patient’s rhythm strip was a continuously varying QRS complex, which was indicative of polymorphic ventricular tachycardia and consistent with the patient’s syncope and other symptoms. Less obvious at first glance was an ST-segment elevation in the preceding beats. Comparison to a post-episode tracing (FIGURE) highlights the abnormality. Polymorphic ventricular tachycardia resolves in 1 of 2 ways: It will either stop on its own (causing syncope if it lasts more than a few seconds) or it will devolve into ventricular fibrillation, causing cardiac arrest.¹

The combination of these findings and the clinical scenario prompted a recommendation that the patient report to the ED for admission (his wife drove him). He was admitted to the intensive care unit (ICU) for continuous telemetry monitoring, and a cardiac catheterization was ordered. The procedure revealed a 99% thrombotic mid-right coronary artery lesion, for which aspiration thrombectomy and uncomplicated stenting were performed.

Continue to: DISCUSSION

Guidelines from the American College of Cardiology/American Heart Association/Heart Rhythm Society recommend a detailed history and physical exam, as well as an EKG, for the initial evaluation of syncope.² If this does not point to a diagnosis (and depending on the presentation and other factors), an ambulatory rhythm monitor can be considered. Other possible testing modalities include stress testing, resting transthoracic echocardiography, electrophysiologic testing, and cardiac magnetic resonance imaging or computed tomography.

Is the cause cardiac? The guidelines suggest that a cardiac cause of syncope is more likely if several of the following factors are present: age > 60 years; male sex; presence of known heart disease (acquired or congenital); brief prodrome (eg, palpitations) or no prodrome; exertional or supine syncope; 1 to 2 episodes; an abnormal cardiac exam; and a family history of premature sudden death.² A noncardiac cause is suggested by other factors: younger age; no known cardiac disease; standing or a position change from supine to sitting/standing; prodrome; specific triggers (eg, dehydration, pain); and frequent and prolonged stereotypic episodes.²

Our patient experienced syncope upon standing, which suggested a noncardiac cause. However, his history of palpitations increased our suspicion for a cardiac cause.

While the guidelines do not specify the number of factors or endorse a specific scoring system, such tools have been developed. For example, the EGSYS (Evaluation of Guidelines in Syncope Study) Score assigns 1 point for each of 6 factors: palpitations; heart disease and/or abnormal EKG; effort syncope; supine syncope; precipitating or predisposing factors; and autonomic prodromes. A score ≥ 3 identified cardiac syncope with a sensitivity of 95%, but with a specificity of only 61%. In the derivation study, patients with a score ≥ 3 had higher mortality than those with a lower score (17 vs 3%; P < .001).³

Myocardial ischemia can trigger ventricular arrhythmias. In the GUSTO-1 trial of fibrinolytic therapy in patients with acute ST-segment elevation myocardial infarction (n = 40,895), the incidence of ventricular tachycardia or ventricular fibrillation was 10.2%.⁴ In a pooled analysis (4 trials; n = 26,416) of patients who were treated for non–ST-segment elevation or unstable ­angina-type acute coronary syndromes, the rate of these arrhythmias was markedly lower (2.1%).⁵ The risk of ventricular arrhythmia is one reason close monitoring (eg, continuous telemetry, ICU admission) is the standard of care for patients with acute coronary syndromes.

Our patient experienced syncope upon standing, which suggested a noncardiac cause (usually orthostatic hypotension). However, the history of palpitations increased the suspicion for a cardiac cause, and thus the rhythm monitor was ordered.

THE TAKEAWAY

This case was unusual in that ambulatory monitoring captured electrocardiographic evidence of myocardial ischemia leading directly to a ventricular arrhythmia. In the evaluation of syncope, a detailed history, physical exam, and a baseline 12-lead EKG can sometimes give clues to an arrhythmic cause of syncope (eg, Brugada syndrome, prior infarct pattern, prolonged QTc, bradycardia, heart block, arrhythmogenic right ventricular cardiomyopathy)—but prolonged rhythm monitoring is sometimes needed to identify a cause.

CORRESPONDENCE
Michael A. Chen, MD, PhD, Harborview Medical Center, University of Washington School of Medicine, 325 9th Avenue, Box 359748 (Cardiology), Seattle, WA 98104; [email protected]

THE CASE

Paul F* is a 16-year-old White boy who lives with his mother and spends some weekends with his father who has shared custody. He recently presented to the clinic for treatment due to an arrest for disorderly conduct at school. He and a friend were found drinking liquor outside the school building when they were scheduled to be in class. Paul reported that he and his friends often drink at school and at extracurricular functions. He has been using alcohol for the past 2 years, with escalating consumption (5 or more drinks per episode) in the past year. Paul has been drinking most days of the week and has even driven under the influence at times. He said, “I just feel happier when I am drinking.” An accomplished soccer player recruited by colleges, Paul recently was suspended from the team due to his poor grades. His response was, “It’s stupid anyway. What’s the point of playing?”

● How would you proceed with this patient?

* The patient’s name and some personal details have been changed to protect his identity.

Alcohol is the number 1 substance of abuse for adolescents, used more than tobacco or drugs.^1-3 In 2007 and again in 2016, the Surgeon General of the United States issued reports to highlight this important topic,^1,2 noting that early and repeated exposure to alcohol during this crucial time of brain development increases the risk for future problems, including addiction.²

Adolescent alcohol use is often underestimated by parents and physicians, including misjudging how much, how often, and how young children are when they begin to drink.¹ Boys and girls tend to start drinking at similar ages (13.9 and 14.4 years, respectively),³ but as girls age, they tend to drink more and binge more.⁴ In 2019, 1 in 4 adolescents reported drinking and more than 4 million reported at least 1 episode of binge drinking in the prior month.⁴ These numbers have further ramifications: early drinking is associated with alcohol dependence, relapse, use of other substances, risky sexual behaviors, injurious behaviors, suicide, motor vehicle accidents, and dating violence.^4-6

Diagnosing alcohol use disorder

The range of alcohol use includes consumption, bingeing, abuse, and dependence.^7,8 Consumption is defined as the drinking of alcoholic beverages. Bingeing is the consumption of more than 5 drinks for men or 4 drinks for women in 2 hours, according to the National Institute on Alcohol Abuse and Alcoholism.⁷ However, the criterion is slightly different for the Substance Abuse and Mental Health Services Administration, which broadens the timeframe to “on the same occasion.”⁹ While previously known as separate disorders, alcohol abuse (or misuse) and alcohol dependence are now diagnostically classified together as alcohol use disorders (AUDs), per the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5).⁸ AUD is further stratified as mild, moderate, or severe, depending on the number of criteria that are met by the patient (TABLE).^8,10

Alcohol screening

Currently, the US Preventive Services Task Force (USPSTF) does not recommend screening adolescents ages 12 to 17 for AUD, and has instead issued an “I” statement (insufficient evidence).¹¹ While the USPSTF recognizes the potential burdens of adolescent alcohol use, the potential harms of screening include “stigma, anxiety, labeling, discrimination, privacy concerns, and interference with the patient–clinician relationship.”¹¹ The USPSTF also notes that it “did not find any evidence that specifically examined the harms of screening for alcohol use in adolescents.”¹¹

The Screening to Brief Intervention (S2BI) tool can quickly and efficiently stratify a patient’s risk of substance use disorder.

This is at odds with recommendations from the American Academy of Pediatrics (AAP), which in 2011 released a policy statement advocating screening, brief intervention, and referral to treatment for adolescent substance use.¹² In the United States, even though 83% of adolescents see a physician at least once each year,^12,13 alcohol misuse screening still varies, occurring in the range of 50% to 86% of office visits.¹² When screening does occur, it is often based on clinical impression only.¹² Studies have shown that when a screening tool is not used, up to two-thirds of substance use disorders may be missed.^12-15

Continue to: A full and complete biopsychosocial interview

A full and complete biopsychosocial interview with adolescents is a necessity, and should include queries about alcohol, drugs, and other substances. Acknowledgment of use should trigger further investigation into the substance use areas. Interviews may start with open-ended questions about alcohol use at home or at school before moving to more personalized and detailed questioning and use of screening tools.¹⁶

While various screening instruments exist, for the sake of brevity we provide as an example the Screening to Brief Intervention (S2BI) tool. It is an efficient, single-page tool that can help clinicians in their routine care of adolescents to quickly stratify the patient risk of substance use disorder as none/low, moderate, or severe.¹² It can be found here: www.mcpap.com/pdf/S2Bi%20Toolkit.pdf (see page 10).

Studies have demonstrated a strong link between insomnia and anxiety, and again between anxiety and alcohol use disorder.

For all patients, but particularly for adolescents, confidentiality is important, and many specialty societies have created language to address this issue.¹² Discuss confidentiality with both the adolescent patient and the patient’s caregiver simultaneously, with dialogue that includes: (a) the need to speak with adolescents alone during the office visit, (b) the benefits of confidentiality in the ­physician–patient relationship, and (c) the need to disclose selected information to keep patients safe.¹² Describing the process for required disclosures is essential. Benefits of disclosure include further support for the adolescent patient as well as appropriate parental participation and support for possible referrals.¹²

Treating AUD  

Treatment for AUD should be multifaceted. Screen for comorbid mood disorders, such as generalized anxiety,^17,18 social anxiety,¹⁸ and depression,¹⁹ as well as for insomnia.¹⁸ Studies have demonstrated a strong link between insomnia and anxiety, and again between anxiety and AUD.^17-19 Finally, screen for adverse childhood events such as trauma, victimization, and abuse.²⁰ Addressing issues discovered in screening allows for more targeted and personalized treatment of AUD.

The National Institute on Drug Abuse categorizes evidence-based treatment into 3 areas: behavioral therapies, family therapies, and medications.²¹

Continue to: Behavioral therapies

Behavioral therapies can include group therapy, cognitive behavioral therapy (CBT), motivational enhancement therapy, 12-Step facilitation, and contingency management, in which small rewards or incentives are given for participation in treatment to reinforce positive behaviors.²¹

Family-based therapies, such as brief strategic family therapy, functional family therapy, and multisystem therapy recognize that adolescents exist in systems of families in communities, and that the patient’s success in treatment may be supported by these relationships.²¹

Some medications may achieve modest benefit for treatment of adolescents with AUD. Naltrexone, acamprosate, and disulfiram have all been used successfully to treat AUD in adults²¹; some physicians may choose to use these medications “off label” in adolescents. Bupropion has been used successfully in the treatment of nicotine use disorder,²¹ and a small study in 2005 showed some success with bupropion in treating adolescents with ­attention-deficit/hyperactivity disorder, comorbid depression, and substance use disorder.²² Naltrexone has also been studied in adolescents with opioid use disorder, although these were not large studies.²³

Adolescents with serious, sustained issues with AUD may require more in-depth treatments such as an intensive outpatient program, a partial hospitalization program, or a residential treatment program.¹⁵ The least-­restrictive environment is preferable.¹⁵ Families are generally included as part of the treatment and recovery process in those settings.²¹ Some patients may require detoxification prior to referral to residential treatment settings; the American Society of Addiction Medicine has published a comprehensive guideline on alcohol withdrawal.²⁴

THE CASE

Paul’s family physician diagnosed his condition as AUD and referred him for CBT with a psychologist, who treated him for both the AUD and an underlying depressive disorder that was later identified. CBT focused on cognitive restructuring of depressive thoughts as well as support for continued abstinence from alcohol. The patient, with family support, declined antidepressant medication.

After 6 months of treatment, Paul and his parents were pleased with his progress. His grades improved to the point that he was permitted to play soccer again, and he was seriously looking at his future college options.

CORRESPONDENCE
Scott A. Fields, PhD, 3200 MacCorkle Avenue Southeast, 5th Floor, Robert C. Byrd Clinical Teaching Center, Department of Family Medicine, Charleston, WV 25304; [email protected]

THE CASE

Paul F* is a 16-year-old White boy who lives with his mother and spends some weekends with his father who has shared custody. He recently presented to the clinic for treatment due to an arrest for disorderly conduct at school. He and a friend were found drinking liquor outside the school building when they were scheduled to be in class. Paul reported that he and his friends often drink at school and at extracurricular functions. He has been using alcohol for the past 2 years, with escalating consumption (5 or more drinks per episode) in the past year. Paul has been drinking most days of the week and has even driven under the influence at times. He said, “I just feel happier when I am drinking.” An accomplished soccer player recruited by colleges, Paul recently was suspended from the team due to his poor grades. His response was, “It’s stupid anyway. What’s the point of playing?”

● How would you proceed with this patient?

* The patient’s name and some personal details have been changed to protect his identity.

Alcohol is the number 1 substance of abuse for adolescents, used more than tobacco or drugs.^1-3 In 2007 and again in 2016, the Surgeon General of the United States issued reports to highlight this important topic,^1,2 noting that early and repeated exposure to alcohol during this crucial time of brain development increases the risk for future problems, including addiction.²

Adolescent alcohol use is often underestimated by parents and physicians, including misjudging how much, how often, and how young children are when they begin to drink.¹ Boys and girls tend to start drinking at similar ages (13.9 and 14.4 years, respectively),³ but as girls age, they tend to drink more and binge more.⁴ In 2019, 1 in 4 adolescents reported drinking and more than 4 million reported at least 1 episode of binge drinking in the prior month.⁴ These numbers have further ramifications: early drinking is associated with alcohol dependence, relapse, use of other substances, risky sexual behaviors, injurious behaviors, suicide, motor vehicle accidents, and dating violence.^4-6

Diagnosing alcohol use disorder

The range of alcohol use includes consumption, bingeing, abuse, and dependence.^7,8 Consumption is defined as the drinking of alcoholic beverages. Bingeing is the consumption of more than 5 drinks for men or 4 drinks for women in 2 hours, according to the National Institute on Alcohol Abuse and Alcoholism.⁷ However, the criterion is slightly different for the Substance Abuse and Mental Health Services Administration, which broadens the timeframe to “on the same occasion.”⁹ While previously known as separate disorders, alcohol abuse (or misuse) and alcohol dependence are now diagnostically classified together as alcohol use disorders (AUDs), per the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5).⁸ AUD is further stratified as mild, moderate, or severe, depending on the number of criteria that are met by the patient (TABLE).^8,10

Alcohol screening

Currently, the US Preventive Services Task Force (USPSTF) does not recommend screening adolescents ages 12 to 17 for AUD, and has instead issued an “I” statement (insufficient evidence).¹¹ While the USPSTF recognizes the potential burdens of adolescent alcohol use, the potential harms of screening include “stigma, anxiety, labeling, discrimination, privacy concerns, and interference with the patient–clinician relationship.”¹¹ The USPSTF also notes that it “did not find any evidence that specifically examined the harms of screening for alcohol use in adolescents.”¹¹

The Screening to Brief Intervention (S2BI) tool can quickly and efficiently stratify a patient’s risk of substance use disorder.

This is at odds with recommendations from the American Academy of Pediatrics (AAP), which in 2011 released a policy statement advocating screening, brief intervention, and referral to treatment for adolescent substance use.¹² In the United States, even though 83% of adolescents see a physician at least once each year,^12,13 alcohol misuse screening still varies, occurring in the range of 50% to 86% of office visits.¹² When screening does occur, it is often based on clinical impression only.¹² Studies have shown that when a screening tool is not used, up to two-thirds of substance use disorders may be missed.^12-15

Continue to: A full and complete biopsychosocial interview

A full and complete biopsychosocial interview with adolescents is a necessity, and should include queries about alcohol, drugs, and other substances. Acknowledgment of use should trigger further investigation into the substance use areas. Interviews may start with open-ended questions about alcohol use at home or at school before moving to more personalized and detailed questioning and use of screening tools.¹⁶

While various screening instruments exist, for the sake of brevity we provide as an example the Screening to Brief Intervention (S2BI) tool. It is an efficient, single-page tool that can help clinicians in their routine care of adolescents to quickly stratify the patient risk of substance use disorder as none/low, moderate, or severe.¹² It can be found here: www.mcpap.com/pdf/S2Bi%20Toolkit.pdf (see page 10).

Studies have demonstrated a strong link between insomnia and anxiety, and again between anxiety and alcohol use disorder.

For all patients, but particularly for adolescents, confidentiality is important, and many specialty societies have created language to address this issue.¹² Discuss confidentiality with both the adolescent patient and the patient’s caregiver simultaneously, with dialogue that includes: (a) the need to speak with adolescents alone during the office visit, (b) the benefits of confidentiality in the ­physician–patient relationship, and (c) the need to disclose selected information to keep patients safe.¹² Describing the process for required disclosures is essential. Benefits of disclosure include further support for the adolescent patient as well as appropriate parental participation and support for possible referrals.¹²

Treating AUD  

Treatment for AUD should be multifaceted. Screen for comorbid mood disorders, such as generalized anxiety,^17,18 social anxiety,¹⁸ and depression,¹⁹ as well as for insomnia.¹⁸ Studies have demonstrated a strong link between insomnia and anxiety, and again between anxiety and AUD.^17-19 Finally, screen for adverse childhood events such as trauma, victimization, and abuse.²⁰ Addressing issues discovered in screening allows for more targeted and personalized treatment of AUD.

The National Institute on Drug Abuse categorizes evidence-based treatment into 3 areas: behavioral therapies, family therapies, and medications.²¹

Continue to: Behavioral therapies

Behavioral therapies can include group therapy, cognitive behavioral therapy (CBT), motivational enhancement therapy, 12-Step facilitation, and contingency management, in which small rewards or incentives are given for participation in treatment to reinforce positive behaviors.²¹

Family-based therapies, such as brief strategic family therapy, functional family therapy, and multisystem therapy recognize that adolescents exist in systems of families in communities, and that the patient’s success in treatment may be supported by these relationships.²¹

Some medications may achieve modest benefit for treatment of adolescents with AUD. Naltrexone, acamprosate, and disulfiram have all been used successfully to treat AUD in adults²¹; some physicians may choose to use these medications “off label” in adolescents. Bupropion has been used successfully in the treatment of nicotine use disorder,²¹ and a small study in 2005 showed some success with bupropion in treating adolescents with ­attention-deficit/hyperactivity disorder, comorbid depression, and substance use disorder.²² Naltrexone has also been studied in adolescents with opioid use disorder, although these were not large studies.²³

Adolescents with serious, sustained issues with AUD may require more in-depth treatments such as an intensive outpatient program, a partial hospitalization program, or a residential treatment program.¹⁵ The least-­restrictive environment is preferable.¹⁵ Families are generally included as part of the treatment and recovery process in those settings.²¹ Some patients may require detoxification prior to referral to residential treatment settings; the American Society of Addiction Medicine has published a comprehensive guideline on alcohol withdrawal.²⁴

THE CASE

Paul’s family physician diagnosed his condition as AUD and referred him for CBT with a psychologist, who treated him for both the AUD and an underlying depressive disorder that was later identified. CBT focused on cognitive restructuring of depressive thoughts as well as support for continued abstinence from alcohol. The patient, with family support, declined antidepressant medication.

After 6 months of treatment, Paul and his parents were pleased with his progress. His grades improved to the point that he was permitted to play soccer again, and he was seriously looking at his future college options.

CORRESPONDENCE
Scott A. Fields, PhD, 3200 MacCorkle Avenue Southeast, 5th Floor, Robert C. Byrd Clinical Teaching Center, Department of Family Medicine, Charleston, WV 25304; [email protected]

THE CASE

Paul F* is a 16-year-old White boy who lives with his mother and spends some weekends with his father who has shared custody. He recently presented to the clinic for treatment due to an arrest for disorderly conduct at school. He and a friend were found drinking liquor outside the school building when they were scheduled to be in class. Paul reported that he and his friends often drink at school and at extracurricular functions. He has been using alcohol for the past 2 years, with escalating consumption (5 or more drinks per episode) in the past year. Paul has been drinking most days of the week and has even driven under the influence at times. He said, “I just feel happier when I am drinking.” An accomplished soccer player recruited by colleges, Paul recently was suspended from the team due to his poor grades. His response was, “It’s stupid anyway. What’s the point of playing?”

● How would you proceed with this patient?

* The patient’s name and some personal details have been changed to protect his identity.

Alcohol is the number 1 substance of abuse for adolescents, used more than tobacco or drugs.^1-3 In 2007 and again in 2016, the Surgeon General of the United States issued reports to highlight this important topic,^1,2 noting that early and repeated exposure to alcohol during this crucial time of brain development increases the risk for future problems, including addiction.²

Adolescent alcohol use is often underestimated by parents and physicians, including misjudging how much, how often, and how young children are when they begin to drink.¹ Boys and girls tend to start drinking at similar ages (13.9 and 14.4 years, respectively),³ but as girls age, they tend to drink more and binge more.⁴ In 2019, 1 in 4 adolescents reported drinking and more than 4 million reported at least 1 episode of binge drinking in the prior month.⁴ These numbers have further ramifications: early drinking is associated with alcohol dependence, relapse, use of other substances, risky sexual behaviors, injurious behaviors, suicide, motor vehicle accidents, and dating violence.^4-6

Diagnosing alcohol use disorder

The range of alcohol use includes consumption, bingeing, abuse, and dependence.^7,8 Consumption is defined as the drinking of alcoholic beverages. Bingeing is the consumption of more than 5 drinks for men or 4 drinks for women in 2 hours, according to the National Institute on Alcohol Abuse and Alcoholism.⁷ However, the criterion is slightly different for the Substance Abuse and Mental Health Services Administration, which broadens the timeframe to “on the same occasion.”⁹ While previously known as separate disorders, alcohol abuse (or misuse) and alcohol dependence are now diagnostically classified together as alcohol use disorders (AUDs), per the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5).⁸ AUD is further stratified as mild, moderate, or severe, depending on the number of criteria that are met by the patient (TABLE).^8,10

Alcohol screening

Currently, the US Preventive Services Task Force (USPSTF) does not recommend screening adolescents ages 12 to 17 for AUD, and has instead issued an “I” statement (insufficient evidence).¹¹ While the USPSTF recognizes the potential burdens of adolescent alcohol use, the potential harms of screening include “stigma, anxiety, labeling, discrimination, privacy concerns, and interference with the patient–clinician relationship.”¹¹ The USPSTF also notes that it “did not find any evidence that specifically examined the harms of screening for alcohol use in adolescents.”¹¹

The Screening to Brief Intervention (S2BI) tool can quickly and efficiently stratify a patient’s risk of substance use disorder.

This is at odds with recommendations from the American Academy of Pediatrics (AAP), which in 2011 released a policy statement advocating screening, brief intervention, and referral to treatment for adolescent substance use.¹² In the United States, even though 83% of adolescents see a physician at least once each year,^12,13 alcohol misuse screening still varies, occurring in the range of 50% to 86% of office visits.¹² When screening does occur, it is often based on clinical impression only.¹² Studies have shown that when a screening tool is not used, up to two-thirds of substance use disorders may be missed.^12-15

Continue to: A full and complete biopsychosocial interview

A full and complete biopsychosocial interview with adolescents is a necessity, and should include queries about alcohol, drugs, and other substances. Acknowledgment of use should trigger further investigation into the substance use areas. Interviews may start with open-ended questions about alcohol use at home or at school before moving to more personalized and detailed questioning and use of screening tools.¹⁶

While various screening instruments exist, for the sake of brevity we provide as an example the Screening to Brief Intervention (S2BI) tool. It is an efficient, single-page tool that can help clinicians in their routine care of adolescents to quickly stratify the patient risk of substance use disorder as none/low, moderate, or severe.¹² It can be found here: www.mcpap.com/pdf/S2Bi%20Toolkit.pdf (see page 10).

Studies have demonstrated a strong link between insomnia and anxiety, and again between anxiety and alcohol use disorder.

For all patients, but particularly for adolescents, confidentiality is important, and many specialty societies have created language to address this issue.¹² Discuss confidentiality with both the adolescent patient and the patient’s caregiver simultaneously, with dialogue that includes: (a) the need to speak with adolescents alone during the office visit, (b) the benefits of confidentiality in the ­physician–patient relationship, and (c) the need to disclose selected information to keep patients safe.¹² Describing the process for required disclosures is essential. Benefits of disclosure include further support for the adolescent patient as well as appropriate parental participation and support for possible referrals.¹²

Treating AUD  

Treatment for AUD should be multifaceted. Screen for comorbid mood disorders, such as generalized anxiety,^17,18 social anxiety,¹⁸ and depression,¹⁹ as well as for insomnia.¹⁸ Studies have demonstrated a strong link between insomnia and anxiety, and again between anxiety and AUD.^17-19 Finally, screen for adverse childhood events such as trauma, victimization, and abuse.²⁰ Addressing issues discovered in screening allows for more targeted and personalized treatment of AUD.

The National Institute on Drug Abuse categorizes evidence-based treatment into 3 areas: behavioral therapies, family therapies, and medications.²¹

Continue to: Behavioral therapies

Behavioral therapies can include group therapy, cognitive behavioral therapy (CBT), motivational enhancement therapy, 12-Step facilitation, and contingency management, in which small rewards or incentives are given for participation in treatment to reinforce positive behaviors.²¹

Family-based therapies, such as brief strategic family therapy, functional family therapy, and multisystem therapy recognize that adolescents exist in systems of families in communities, and that the patient’s success in treatment may be supported by these relationships.²¹

Some medications may achieve modest benefit for treatment of adolescents with AUD. Naltrexone, acamprosate, and disulfiram have all been used successfully to treat AUD in adults²¹; some physicians may choose to use these medications “off label” in adolescents. Bupropion has been used successfully in the treatment of nicotine use disorder,²¹ and a small study in 2005 showed some success with bupropion in treating adolescents with ­attention-deficit/hyperactivity disorder, comorbid depression, and substance use disorder.²² Naltrexone has also been studied in adolescents with opioid use disorder, although these were not large studies.²³

Adolescents with serious, sustained issues with AUD may require more in-depth treatments such as an intensive outpatient program, a partial hospitalization program, or a residential treatment program.¹⁵ The least-­restrictive environment is preferable.¹⁵ Families are generally included as part of the treatment and recovery process in those settings.²¹ Some patients may require detoxification prior to referral to residential treatment settings; the American Society of Addiction Medicine has published a comprehensive guideline on alcohol withdrawal.²⁴

THE CASE

Paul’s family physician diagnosed his condition as AUD and referred him for CBT with a psychologist, who treated him for both the AUD and an underlying depressive disorder that was later identified. CBT focused on cognitive restructuring of depressive thoughts as well as support for continued abstinence from alcohol. The patient, with family support, declined antidepressant medication.

After 6 months of treatment, Paul and his parents were pleased with his progress. His grades improved to the point that he was permitted to play soccer again, and he was seriously looking at his future college options.

CORRESPONDENCE
Scott A. Fields, PhD, 3200 MacCorkle Avenue Southeast, 5th Floor, Robert C. Byrd Clinical Teaching Center, Department of Family Medicine, Charleston, WV 25304; [email protected]

CASE

A 35-year-old man with a body mass index of 20 presented to the emergency department after 24 hours of abdominal pain that began in the periumbilical region and then migrated to the right lower quadrant. The pain was exacerbated during ambulation and was intense when the car transporting him to the hospital encountered bumps in the road. After his pain started, he had associated anorexia, followed by nausea and emesis. He reported fever and chills. On examination, his temperature was 100.8 °F (38.2 °C), and palpation of the right and left lower quadrants elicited right lower quadrant pain. Laboratory evaluation revealed a white blood cell (WBC) count of 14,000 cells/mcL with 85% neutrophils, C-reactive protein of 40 mg/L, and a negative urinalysis.

How would you proceed with this patient?

Acute appendicitis is the most common cause of abdominal pain resulting in the need for surgical treatment; lifetime risk of appendicitis is 6% to 7%.¹ Appendicitis is caused by intraluminal obstruction in the appendix from enlarged lymphoid tissue or a fecalith. The obstruction leads to elevated intraluminal pressure due to persistent mucus and gas production by bacteria, ultimately leading to ischemia and perforation.¹ Additionally, obstruction leads to bacterial overgrowth, most commonly colonic flora such as Escherichia coli, Bacteroides fragilis, Streptococcus viridans, Enterococcus sp., Pseudomonas aeruginosa, and Klebsiella pneumoniaei.^1,2

The following review provides a look at how 3 clinical scoring systems compare in the identification of acute appendicitis and details which imaging studies you should order—and when. But first, we’ll quickly detail the relevant physical findings and lab values that point to a diagnosis of acute appendicitis.

Physical findings. The patient typically first experiences vague abdominal pain that then localizes to the right lower quadrant due to peritoneal inflammation. Anorexia and nausea typically follow the abdominal pain. On examination, the patient often appears ill and exhibits abdominal guarding due to peritonitis. Tachycardia and fever are common; however, the absence of either does not exclude appendicitis. Classically, on palpation, the patient will have pain at McBurney’s point (one-third the distance from the anterior iliac spine to the umbilicus). The exact point of maximal tenderness can differ because of the varying anatomy of the appendix (retrocecal, paracolic, pelvic, pre/post ileal, promontoric, or subcecal).¹ Right lower quadrant pain, abdominal rigidity, and radiation of periumbilical pain to the right lower quadrant are the most accurate findings in adults to rule in appendicitis.³ For children, physical exam findings have the highest likelihood in predicting appendicitis and include a positive Obturator sign, positive Rovsing sign, or a positive Psoas sign, and absent or decreased bowel sounds.⁴

Laboratory studies can support a diagnosis of appendicitis but cannot exclude it. Leukocytosis with neutrophil predominance is present in 90% of cases.⁵ An elevated C-reactive protein level renders the highest diagnostic accuracy.⁵ Perform a pregnancy test for any woman of child-bearing age, to assist in the diagnosis and guide imaging choices for evaluation. Additional laboratory tests are not needed unless there are concerns about volume depletion.

Clinical scoring systems

Several clinical scoring systems (TABLE^6-10) have been validated to aid clinicians in evaluating patients with possible appendicitis, to decrease unnecessary exposure to ionizing radiation from computed tomography (CT) scans, to identify and reassure patients with low likelihoods of appendicitis, and to conduct outpatient follow-up.

Continue to: The Alvarado score

The Alvarado score is the oldest scoring rule, developed in 1986; it entails 8 clinical and laboratory variables.⁶ Ebell et al altered the proposed cutoff values of the Alvarado score to be low risk (< 4), intermediate risk (4-8), and high risk (≥ 9), effectively improving the sensitivity and specificity rates.⁷

Screening tools cannot confirm appendicitis. Their usefulness is in helping to rule out appendicitis and in deciding for or against imaging.

In a meta-analysis of the Alvarado score that included 42 studies of men, women, and children, the sensitivity for “ruling out” appendicitis with a cutoff of 5 points was 96% for men, 99% for women, and 99% for children.⁸ The accuracy of a high-risk score (> 7) for “ruling in” appendicitis was less with an overall specificity of 82%.⁸ The Alvarado score did seem to overestimate appendicitis in women in all score categories.⁸

The Pediatric Appendicitis Score (PAS) is similar to Alvarado and was prospectively validated in 1170 children in 2002 for more specific guidance in this age group.⁹ The PAS had excellent specificity in the study; those with a score of ≥ 6 had a high probability of appendicitis. In a study comparing Alvarado with PAS in 311 patients, insignificant differences were noted at a score of ≥ 7 for both tests (sensitivity 86% vs 89%, and specificity 59% vs 50%, respectively).¹¹ No scoring system has been found to be sufficiently accurate for use in children 4 years of age and younger.¹²

The Appendicitis Inflammatory Response (AIR) Score was prospectively validated in 545 patients representing all age groups.¹⁰ Subsequently, in a larger prospective multicenter study of 3878 patients older than 5 years, the original cut points were altered, thereby improving test sensitivity and negative predictive value to 99% for those with low probability (0 to 3), and test specificity to 98% for those with high-­probability (9 to 12).¹³ Compared with the Alvarado Score, the AIR Score has higher specificity for those in the high-probability range, and similar exclusion rates in the low-probability range.¹⁴

Caveats with clinical decision scores. These tools are accepted and often used. However, challenges that affect generalizability of study data include differences in patient selection for each study (undifferentiated abdominal pain vs appendicitis), prospective vs retrospective designs, and age and gender variations in the patient populations. Despite the numerous scoring systems developed, none can accurately be used to rule in appendicitis. They are best used to assist in ruling out appendicitis and to aid in deciding for or against imaging.

Continue to: A look at the imaging options

Advanced imaging technology can affirm or refute a diagnosis of appendicitis and reduce the negative appendectomy rate, previously reported to be 15%.¹⁵ Ultrasonography (US), abdominal CT, and magnetic resonance imaging (MRI) are the most commonly used modalities. Point-of-care ultrasound ­(POCUS) is an option to start the diagnostic evaluation, given its relative ease of access, rapidity, and lack of radiation. However, a stand-alone POCUS at this time should not be the only imaging tool to rule out appendicitis.^16-18 Its accuracy depends on operator skill and is limited by patient-specific factors such as obesity.^16-19 If results are equivocal or the diagnosis otherwise remains unclear, arrange for different imaging.^16-18

Abdominal CT has sensitivity and specificity rates between 76% and 100% and 83% and 100%, respectively.^15,20,21 Ultrasonography has sensitivity and specificity rates of 71% to 94% and 81% to 98%, respectively.^15,20,21 Formal US is reliable to confirm appendicitis, but less so to rule out appendicitis. Special considerations for imagining in pregnant patients and children are discussed in a bit.

Timing of surgical consultation

Surgical consultation is paramount once the diagnosis of appendicitis is probable. Imaging is best obtained prior to surgical consultation to streamline evaluation and enhance decision- making. Typically, patients will be categorized as complicated or uncomplicated based on the presence or absence of perforation, a gangrenous appendix, an intra-abdominal abscess (IAA), or purulent peritonitis. Active continuous surgical involvement (­co-management or assumption of care) is recommended in all cases of appendicitis, especially if nonoperative management is selected, given that some cases must convert to immediate operative treatment or may be selected for delayed future (interval) appendectomy.²²

Management

Uncomplicated appendicitis

Prompt appendectomy has been the gold standard of care for uncomplicated acute appendicitis for 60 years. However, several studies have investigated an antibiotic-based strategy rather than surgical treatment for uncomplicated appendicitis.

Antibiotics vs appendectomy. In 2020, the CODA Collaborative published a randomized trial comparing a 10-day course of antibiotics with appendectomy in patients with uncomplicated appendicitis. In this multicenter study based in the United States, 1552 patients 18 years of age or older were randomized to receive antibiotics or undergo appendectomy (95% performed laparoscopically). The antibiotic treatment consisted of at least 24 hours of IV antibiotics, with or without admission to the hospital. Antibiotic choice was individualized according to guidelines for intra-abdominal infection published by the Infectious Diseases Society of America, with the most common IV medications being ertapenem, cefoxitin, or metronidazole plus one of the following: ceftriaxone, cefazolin, or levofloxacin. For the remaining 10 days, oral metronidazole plus ciprofloxacin or cefdinir were used.²²

Continue to: The primary endpoint...

The primary endpoint was the European Quality of Life-5 Dimensions (EQ-5D) questionnaire, with secondary outcomes including appendectomy in the antibiotics group and complications through 90 days. Exclusion criteria included pregnancy, sepsis, peritonitis, recurrent appendicitis, severe phlegmon on imaging, or evidence of neoplasm.²²

Antibiotics were noninferior to appendectomy for the 30-day study. However, antibiotics failed in 29%, who then proceeded to appendectomy by 90 days; these patients also accounted for 41% of those with an appendicolith. Overall complications were more common in the antibiotics group than in the appendectomy group (8.1 vs 3.5 per 100 participants; 95% CI, 1.3-3.98). Also more common in the antibiotic group were serious adverse events (4 vs 3 per 100 participants; hazard ratio [HR] = 1.29; 95% CI, 0.67-2.50). The presence of an appendicolith in the antibiotics group increased the conversion risk to appendectomy, as well as adverse events risk.²²

The takeaway. Antibiotic treatment is a noninferior method to treat acute uncomplicated appendicitis. However, the informed consent process is important, given the ~30% failure rate. Patient factors such as continued access to care should help inform the decision.

Two main surgical approaches exist for appendectomy: open and minimally invasive. At this time, the minimally invasive options include laparoscopic, single incision laparoscopic surgery (SILS), and robotic appendectomy. A study comparing cost, availability, or complications of these options has not been conducted at this time.

Antibiotic treatment is a noninferior method to treat acute uncomplicated appendicitis. However, the informed consent process is important, given the ~30% failure rate.

A large Cochrane review of 67 studies examining open vs laparoscopic appendectomy in adults and children completed in 2018 revealed that the laparoscopic approach reduced early postoperative pain intensity and led to a shorter hospital stay, earlier return to work or usual activities, and a decrease in wound infections.²³ The odds of IAA occurring with laparoscopic appendectomy increased by 65% compared with an open procedure; however, postoperative bowel obstruction and incisional hernias were less likely to occur.²³ Additionally, following laparoscopic surgery, postoperative bowel obstruction and incisional hernias are less likely to occur. The laparoscopic approach is preferred due to overall increased patient satisfaction and a reduction in most, if not all, complications.

Continue to: Complicated appendicitis

Complicated appendicitis

Excluding patients with severe sepsis or purulent peritonitis requiring resuscitation and immediate surgical intervention of intra-abdominal infection, the approach to patients with complicated appendicitis varies between aggressive surgical intervention and nonoperative management.

In a 2007 meta-analysis reviewing nonsurgical treatment of appendiceal abscess/phlegmon, immediate surgery was associated with higher morbidity.²⁴ Within the nonoperative management group 7.2% (CI, 4.0-10.5) required surgical intervention and 19.7% (CI, 11.0-28.3) required abscess drainage. Malignant disease was detected in 1.2% (CI, 0.6-1.7).²⁴ Small subsequent studies concluded different results.²⁵

Ultimately, the 2015 European Association of Endoscopic Surgery guidelines recommend a new systematic review; but with current data, initial nonoperative management is preferred.¹⁵ After initial nonoperative treatment, the only benefits from interval appendectomy are identification of an underlying malignancy (6% to 20%) and mitigating the risk of recurrent appendicitis (5% to 44%).^15,25-30

Multiple single institutional series found increased neoplasm incidence (9% to 20%) in complicated appendicitis in patients 40 years and older.^26-30 Prior to interval appendectomy in patients 45 years and older, ensuring they have an up-to-date screening colonoscopy is important. This is in line with 2021 US Preventive Services Task Force (Grade “B” recommendation), 2018 American Cancer Society (qualified recommendation), and 2021 American College of Gastroenterology (conditional recommendation) guidelines for colorectal cancer screening to start at age 45 in average-risk patients.³¹ Patients younger than 45 can consider screening through shared decision-making.

Special populations

Pregnant patients

In pregnancy, challenges exist with the presence of traditional signs and symptoms of appendicitis, with the most predictive sign being a WBC count higher than 18,000.³² The American College of Radiology’s (ACR) Appropriateness Criteria recommend US as the imaging modality of choice in pregnancy, with MRI as the best option when US is inconclusive.³³ Two meta-analyses demonstrated high sensitivity (91.8%-96.6%) and specificity (95.9%-97.9%) of MRI in diagnosing appendicitis.^34,35 CT scan is not the preferred initial imagining modality in pregnancy unless urgent information is needed and other modalities are insufficient or unavailable.³⁶

Continue to: The most common...

The most common nonobstetric surgical intervention during pregnancy is appendectomy, at a rate of 6.3/10,000 person-years, which increases to 9.9/10,000 in the postpartum period.³⁷ Two large population studies demonstrate the rate of appendicitis varies over the course of pregnancy, with the lowest rates in the third trimester,^38,39 and a significant rebound lasting for 2 years postpartum.³⁹ Peritonitis, septic shock, pneumonia, postoperative infection, and longer hospital stays occur more frequently in pregnant women than in nonpregnant women with appendicitis.⁴⁰ Fetal loss is higher in the first trimester.³²

In pregnancy, the most predictive sign of appendicitis is a white blood cell count > 18,000.

In a 14-year review of 63,145 appendicitis cases, an increased risk of fetal loss and maternal death was noted across ages and ethnicities, with the largest risk of maternal death occurring in Hispanics and fetal death in non-Hispanic Blacks.⁴¹ In a large study of 1018 adverse events after appendectomy or cholecystectomy, the 3 most common events were preterm delivery (35.4%), preterm labor without preterm delivery (26.4%), and miscarriage (25.7%).⁴² The surgery itself was not a major risk factor for adverse events. Major risk factors included cervical incompetence (odds ratio [OR] = 24.3), preterm labor in current pregnancy (OR = 18.3), and presence of vulvovaginitis (OR = 5.2).⁴²

Nonoperative management in pregnancy is not recommended; only 1 prospective trial has been done, with 20 patients, showing a 25% failure rate.⁴³ Two meta-analyses published in 2019 highlight the potential increase of fetal loss with laparoscopic approaches to appendectomy.^44,45 However, recently published literature demonstrates no significant maternal-fetal morbidity. Current guidelines of the Society of American Gastrointestinal and Endoscopic Surgeons agree that laparoscopy is the operative choice in pregnancy.³⁶

Children

Acute appendicitis is the most common surgical emergency in children.⁴ Physical exam findings and laboratory results are not classic in this population, obtaining an accurate history can be challenging, and results of clinical scoring systems can be inconclusive.⁴ Additional serum biomarkers, procalcitonin and calprotectin, are gaining evidence for use in improving scoring systems to refine low-risk groups. Unavailability of timely, reliable biomarker testing in rural practice locations limits definitive recommendations at this time.⁴⁶ ACR recommends no imaging in a pediatric patient whose risk of having appendicitis is low based on any of several scoring systems.⁴⁷ For those assessed as having higher risk, US is the recommended initial modality,with CT with IV contrast or MRI without contrast equally recommended if the US is equivocal.⁴⁷

Despite promising data from trials of nonoperative treatment for adults with appendicitis, no definitive evidence and recommendations are available for children.

Despite promising data from trials of nonoperative treatment for adults with appendicitis, no definitive evidence and recommendations are available for children. Two systematic reviews show nonoperative treatment is safe, with an efficacy rate of 76% to 82% at long-term follow-up,^48,49 although the success of antibiotic regimens varies. Within the nonoperative treatment group, 16% of patients had appendectomy during the follow-up period, which varied from 8 weeks to 4 years.⁴⁸ A randomized controlled trial is needed for final guidance.

Continue to: CASE

CASE

The patient had an Alvarado score of 9 (high probability) and an AIR score of 6 (intermediate probability). A CT with IV contrast showed a 9-mm fluid-filled appendix with periappendiceal fluid. During surgical consultation, he was offered laparoscopic appendectomy or nonoperative treatment with antibiotics. He opted for a preoperative dose of piperacillin-tazobactam 3.375 g IV and laparoscopic appendectomy. The patient was discharged home 6 hours after his procedure.

CORRESPONDENCE
Jessica Servey, MD, MHPE, 4301 Jones Bridge Road, Bethesda, MD 20814; [email protected]

CASE

A 35-year-old man with a body mass index of 20 presented to the emergency department after 24 hours of abdominal pain that began in the periumbilical region and then migrated to the right lower quadrant. The pain was exacerbated during ambulation and was intense when the car transporting him to the hospital encountered bumps in the road. After his pain started, he had associated anorexia, followed by nausea and emesis. He reported fever and chills. On examination, his temperature was 100.8 °F (38.2 °C), and palpation of the right and left lower quadrants elicited right lower quadrant pain. Laboratory evaluation revealed a white blood cell (WBC) count of 14,000 cells/mcL with 85% neutrophils, C-reactive protein of 40 mg/L, and a negative urinalysis.

How would you proceed with this patient?

Acute appendicitis is the most common cause of abdominal pain resulting in the need for surgical treatment; lifetime risk of appendicitis is 6% to 7%.¹ Appendicitis is caused by intraluminal obstruction in the appendix from enlarged lymphoid tissue or a fecalith. The obstruction leads to elevated intraluminal pressure due to persistent mucus and gas production by bacteria, ultimately leading to ischemia and perforation.¹ Additionally, obstruction leads to bacterial overgrowth, most commonly colonic flora such as Escherichia coli, Bacteroides fragilis, Streptococcus viridans, Enterococcus sp., Pseudomonas aeruginosa, and Klebsiella pneumoniaei.^1,2

The following review provides a look at how 3 clinical scoring systems compare in the identification of acute appendicitis and details which imaging studies you should order—and when. But first, we’ll quickly detail the relevant physical findings and lab values that point to a diagnosis of acute appendicitis.

Physical findings. The patient typically first experiences vague abdominal pain that then localizes to the right lower quadrant due to peritoneal inflammation. Anorexia and nausea typically follow the abdominal pain. On examination, the patient often appears ill and exhibits abdominal guarding due to peritonitis. Tachycardia and fever are common; however, the absence of either does not exclude appendicitis. Classically, on palpation, the patient will have pain at McBurney’s point (one-third the distance from the anterior iliac spine to the umbilicus). The exact point of maximal tenderness can differ because of the varying anatomy of the appendix (retrocecal, paracolic, pelvic, pre/post ileal, promontoric, or subcecal).¹ Right lower quadrant pain, abdominal rigidity, and radiation of periumbilical pain to the right lower quadrant are the most accurate findings in adults to rule in appendicitis.³ For children, physical exam findings have the highest likelihood in predicting appendicitis and include a positive Obturator sign, positive Rovsing sign, or a positive Psoas sign, and absent or decreased bowel sounds.⁴

Laboratory studies can support a diagnosis of appendicitis but cannot exclude it. Leukocytosis with neutrophil predominance is present in 90% of cases.⁵ An elevated C-reactive protein level renders the highest diagnostic accuracy.⁵ Perform a pregnancy test for any woman of child-bearing age, to assist in the diagnosis and guide imaging choices for evaluation. Additional laboratory tests are not needed unless there are concerns about volume depletion.

Clinical scoring systems

Several clinical scoring systems (TABLE^6-10) have been validated to aid clinicians in evaluating patients with possible appendicitis, to decrease unnecessary exposure to ionizing radiation from computed tomography (CT) scans, to identify and reassure patients with low likelihoods of appendicitis, and to conduct outpatient follow-up.

Continue to: The Alvarado score

The Alvarado score is the oldest scoring rule, developed in 1986; it entails 8 clinical and laboratory variables.⁶ Ebell et al altered the proposed cutoff values of the Alvarado score to be low risk (< 4), intermediate risk (4-8), and high risk (≥ 9), effectively improving the sensitivity and specificity rates.⁷

Screening tools cannot confirm appendicitis. Their usefulness is in helping to rule out appendicitis and in deciding for or against imaging.

In a meta-analysis of the Alvarado score that included 42 studies of men, women, and children, the sensitivity for “ruling out” appendicitis with a cutoff of 5 points was 96% for men, 99% for women, and 99% for children.⁸ The accuracy of a high-risk score (> 7) for “ruling in” appendicitis was less with an overall specificity of 82%.⁸ The Alvarado score did seem to overestimate appendicitis in women in all score categories.⁸

The Pediatric Appendicitis Score (PAS) is similar to Alvarado and was prospectively validated in 1170 children in 2002 for more specific guidance in this age group.⁹ The PAS had excellent specificity in the study; those with a score of ≥ 6 had a high probability of appendicitis. In a study comparing Alvarado with PAS in 311 patients, insignificant differences were noted at a score of ≥ 7 for both tests (sensitivity 86% vs 89%, and specificity 59% vs 50%, respectively).¹¹ No scoring system has been found to be sufficiently accurate for use in children 4 years of age and younger.¹²

The Appendicitis Inflammatory Response (AIR) Score was prospectively validated in 545 patients representing all age groups.¹⁰ Subsequently, in a larger prospective multicenter study of 3878 patients older than 5 years, the original cut points were altered, thereby improving test sensitivity and negative predictive value to 99% for those with low probability (0 to 3), and test specificity to 98% for those with high-­probability (9 to 12).¹³ Compared with the Alvarado Score, the AIR Score has higher specificity for those in the high-probability range, and similar exclusion rates in the low-probability range.¹⁴

Caveats with clinical decision scores. These tools are accepted and often used. However, challenges that affect generalizability of study data include differences in patient selection for each study (undifferentiated abdominal pain vs appendicitis), prospective vs retrospective designs, and age and gender variations in the patient populations. Despite the numerous scoring systems developed, none can accurately be used to rule in appendicitis. They are best used to assist in ruling out appendicitis and to aid in deciding for or against imaging.

Continue to: A look at the imaging options

Advanced imaging technology can affirm or refute a diagnosis of appendicitis and reduce the negative appendectomy rate, previously reported to be 15%.¹⁵ Ultrasonography (US), abdominal CT, and magnetic resonance imaging (MRI) are the most commonly used modalities. Point-of-care ultrasound ­(POCUS) is an option to start the diagnostic evaluation, given its relative ease of access, rapidity, and lack of radiation. However, a stand-alone POCUS at this time should not be the only imaging tool to rule out appendicitis.^16-18 Its accuracy depends on operator skill and is limited by patient-specific factors such as obesity.^16-19 If results are equivocal or the diagnosis otherwise remains unclear, arrange for different imaging.^16-18

Abdominal CT has sensitivity and specificity rates between 76% and 100% and 83% and 100%, respectively.^15,20,21 Ultrasonography has sensitivity and specificity rates of 71% to 94% and 81% to 98%, respectively.^15,20,21 Formal US is reliable to confirm appendicitis, but less so to rule out appendicitis. Special considerations for imagining in pregnant patients and children are discussed in a bit.

Timing of surgical consultation

Surgical consultation is paramount once the diagnosis of appendicitis is probable. Imaging is best obtained prior to surgical consultation to streamline evaluation and enhance decision- making. Typically, patients will be categorized as complicated or uncomplicated based on the presence or absence of perforation, a gangrenous appendix, an intra-abdominal abscess (IAA), or purulent peritonitis. Active continuous surgical involvement (­co-management or assumption of care) is recommended in all cases of appendicitis, especially if nonoperative management is selected, given that some cases must convert to immediate operative treatment or may be selected for delayed future (interval) appendectomy.²²

Management

Uncomplicated appendicitis

Prompt appendectomy has been the gold standard of care for uncomplicated acute appendicitis for 60 years. However, several studies have investigated an antibiotic-based strategy rather than surgical treatment for uncomplicated appendicitis.

Antibiotics vs appendectomy. In 2020, the CODA Collaborative published a randomized trial comparing a 10-day course of antibiotics with appendectomy in patients with uncomplicated appendicitis. In this multicenter study based in the United States, 1552 patients 18 years of age or older were randomized to receive antibiotics or undergo appendectomy (95% performed laparoscopically). The antibiotic treatment consisted of at least 24 hours of IV antibiotics, with or without admission to the hospital. Antibiotic choice was individualized according to guidelines for intra-abdominal infection published by the Infectious Diseases Society of America, with the most common IV medications being ertapenem, cefoxitin, or metronidazole plus one of the following: ceftriaxone, cefazolin, or levofloxacin. For the remaining 10 days, oral metronidazole plus ciprofloxacin or cefdinir were used.²²

Continue to: The primary endpoint...

The primary endpoint was the European Quality of Life-5 Dimensions (EQ-5D) questionnaire, with secondary outcomes including appendectomy in the antibiotics group and complications through 90 days. Exclusion criteria included pregnancy, sepsis, peritonitis, recurrent appendicitis, severe phlegmon on imaging, or evidence of neoplasm.²²

Antibiotics were noninferior to appendectomy for the 30-day study. However, antibiotics failed in 29%, who then proceeded to appendectomy by 90 days; these patients also accounted for 41% of those with an appendicolith. Overall complications were more common in the antibiotics group than in the appendectomy group (8.1 vs 3.5 per 100 participants; 95% CI, 1.3-3.98). Also more common in the antibiotic group were serious adverse events (4 vs 3 per 100 participants; hazard ratio [HR] = 1.29; 95% CI, 0.67-2.50). The presence of an appendicolith in the antibiotics group increased the conversion risk to appendectomy, as well as adverse events risk.²²

The takeaway. Antibiotic treatment is a noninferior method to treat acute uncomplicated appendicitis. However, the informed consent process is important, given the ~30% failure rate. Patient factors such as continued access to care should help inform the decision.

Two main surgical approaches exist for appendectomy: open and minimally invasive. At this time, the minimally invasive options include laparoscopic, single incision laparoscopic surgery (SILS), and robotic appendectomy. A study comparing cost, availability, or complications of these options has not been conducted at this time.

Antibiotic treatment is a noninferior method to treat acute uncomplicated appendicitis. However, the informed consent process is important, given the ~30% failure rate.

A large Cochrane review of 67 studies examining open vs laparoscopic appendectomy in adults and children completed in 2018 revealed that the laparoscopic approach reduced early postoperative pain intensity and led to a shorter hospital stay, earlier return to work or usual activities, and a decrease in wound infections.²³ The odds of IAA occurring with laparoscopic appendectomy increased by 65% compared with an open procedure; however, postoperative bowel obstruction and incisional hernias were less likely to occur.²³ Additionally, following laparoscopic surgery, postoperative bowel obstruction and incisional hernias are less likely to occur. The laparoscopic approach is preferred due to overall increased patient satisfaction and a reduction in most, if not all, complications.

Continue to: Complicated appendicitis

Complicated appendicitis

Excluding patients with severe sepsis or purulent peritonitis requiring resuscitation and immediate surgical intervention of intra-abdominal infection, the approach to patients with complicated appendicitis varies between aggressive surgical intervention and nonoperative management.

In a 2007 meta-analysis reviewing nonsurgical treatment of appendiceal abscess/phlegmon, immediate surgery was associated with higher morbidity.²⁴ Within the nonoperative management group 7.2% (CI, 4.0-10.5) required surgical intervention and 19.7% (CI, 11.0-28.3) required abscess drainage. Malignant disease was detected in 1.2% (CI, 0.6-1.7).²⁴ Small subsequent studies concluded different results.²⁵

Ultimately, the 2015 European Association of Endoscopic Surgery guidelines recommend a new systematic review; but with current data, initial nonoperative management is preferred.¹⁵ After initial nonoperative treatment, the only benefits from interval appendectomy are identification of an underlying malignancy (6% to 20%) and mitigating the risk of recurrent appendicitis (5% to 44%).^15,25-30

Multiple single institutional series found increased neoplasm incidence (9% to 20%) in complicated appendicitis in patients 40 years and older.^26-30 Prior to interval appendectomy in patients 45 years and older, ensuring they have an up-to-date screening colonoscopy is important. This is in line with 2021 US Preventive Services Task Force (Grade “B” recommendation), 2018 American Cancer Society (qualified recommendation), and 2021 American College of Gastroenterology (conditional recommendation) guidelines for colorectal cancer screening to start at age 45 in average-risk patients.³¹ Patients younger than 45 can consider screening through shared decision-making.

Special populations

Pregnant patients

In pregnancy, challenges exist with the presence of traditional signs and symptoms of appendicitis, with the most predictive sign being a WBC count higher than 18,000.³² The American College of Radiology’s (ACR) Appropriateness Criteria recommend US as the imaging modality of choice in pregnancy, with MRI as the best option when US is inconclusive.³³ Two meta-analyses demonstrated high sensitivity (91.8%-96.6%) and specificity (95.9%-97.9%) of MRI in diagnosing appendicitis.^34,35 CT scan is not the preferred initial imagining modality in pregnancy unless urgent information is needed and other modalities are insufficient or unavailable.³⁶

Continue to: The most common...

The most common nonobstetric surgical intervention during pregnancy is appendectomy, at a rate of 6.3/10,000 person-years, which increases to 9.9/10,000 in the postpartum period.³⁷ Two large population studies demonstrate the rate of appendicitis varies over the course of pregnancy, with the lowest rates in the third trimester,^38,39 and a significant rebound lasting for 2 years postpartum.³⁹ Peritonitis, septic shock, pneumonia, postoperative infection, and longer hospital stays occur more frequently in pregnant women than in nonpregnant women with appendicitis.⁴⁰ Fetal loss is higher in the first trimester.³²

In pregnancy, the most predictive sign of appendicitis is a white blood cell count > 18,000.

In a 14-year review of 63,145 appendicitis cases, an increased risk of fetal loss and maternal death was noted across ages and ethnicities, with the largest risk of maternal death occurring in Hispanics and fetal death in non-Hispanic Blacks.⁴¹ In a large study of 1018 adverse events after appendectomy or cholecystectomy, the 3 most common events were preterm delivery (35.4%), preterm labor without preterm delivery (26.4%), and miscarriage (25.7%).⁴² The surgery itself was not a major risk factor for adverse events. Major risk factors included cervical incompetence (odds ratio [OR] = 24.3), preterm labor in current pregnancy (OR = 18.3), and presence of vulvovaginitis (OR = 5.2).⁴²

Nonoperative management in pregnancy is not recommended; only 1 prospective trial has been done, with 20 patients, showing a 25% failure rate.⁴³ Two meta-analyses published in 2019 highlight the potential increase of fetal loss with laparoscopic approaches to appendectomy.^44,45 However, recently published literature demonstrates no significant maternal-fetal morbidity. Current guidelines of the Society of American Gastrointestinal and Endoscopic Surgeons agree that laparoscopy is the operative choice in pregnancy.³⁶

Children

Acute appendicitis is the most common surgical emergency in children.⁴ Physical exam findings and laboratory results are not classic in this population, obtaining an accurate history can be challenging, and results of clinical scoring systems can be inconclusive.⁴ Additional serum biomarkers, procalcitonin and calprotectin, are gaining evidence for use in improving scoring systems to refine low-risk groups. Unavailability of timely, reliable biomarker testing in rural practice locations limits definitive recommendations at this time.⁴⁶ ACR recommends no imaging in a pediatric patient whose risk of having appendicitis is low based on any of several scoring systems.⁴⁷ For those assessed as having higher risk, US is the recommended initial modality,with CT with IV contrast or MRI without contrast equally recommended if the US is equivocal.⁴⁷

Despite promising data from trials of nonoperative treatment for adults with appendicitis, no definitive evidence and recommendations are available for children.

Despite promising data from trials of nonoperative treatment for adults with appendicitis, no definitive evidence and recommendations are available for children. Two systematic reviews show nonoperative treatment is safe, with an efficacy rate of 76% to 82% at long-term follow-up,^48,49 although the success of antibiotic regimens varies. Within the nonoperative treatment group, 16% of patients had appendectomy during the follow-up period, which varied from 8 weeks to 4 years.⁴⁸ A randomized controlled trial is needed for final guidance.

Continue to: CASE

CASE

The patient had an Alvarado score of 9 (high probability) and an AIR score of 6 (intermediate probability). A CT with IV contrast showed a 9-mm fluid-filled appendix with periappendiceal fluid. During surgical consultation, he was offered laparoscopic appendectomy or nonoperative treatment with antibiotics. He opted for a preoperative dose of piperacillin-tazobactam 3.375 g IV and laparoscopic appendectomy. The patient was discharged home 6 hours after his procedure.

CORRESPONDENCE
Jessica Servey, MD, MHPE, 4301 Jones Bridge Road, Bethesda, MD 20814; [email protected]

CASE

A 35-year-old man with a body mass index of 20 presented to the emergency department after 24 hours of abdominal pain that began in the periumbilical region and then migrated to the right lower quadrant. The pain was exacerbated during ambulation and was intense when the car transporting him to the hospital encountered bumps in the road. After his pain started, he had associated anorexia, followed by nausea and emesis. He reported fever and chills. On examination, his temperature was 100.8 °F (38.2 °C), and palpation of the right and left lower quadrants elicited right lower quadrant pain. Laboratory evaluation revealed a white blood cell (WBC) count of 14,000 cells/mcL with 85% neutrophils, C-reactive protein of 40 mg/L, and a negative urinalysis.

How would you proceed with this patient?

Acute appendicitis is the most common cause of abdominal pain resulting in the need for surgical treatment; lifetime risk of appendicitis is 6% to 7%.¹ Appendicitis is caused by intraluminal obstruction in the appendix from enlarged lymphoid tissue or a fecalith. The obstruction leads to elevated intraluminal pressure due to persistent mucus and gas production by bacteria, ultimately leading to ischemia and perforation.¹ Additionally, obstruction leads to bacterial overgrowth, most commonly colonic flora such as Escherichia coli, Bacteroides fragilis, Streptococcus viridans, Enterococcus sp., Pseudomonas aeruginosa, and Klebsiella pneumoniaei.^1,2

The following review provides a look at how 3 clinical scoring systems compare in the identification of acute appendicitis and details which imaging studies you should order—and when. But first, we’ll quickly detail the relevant physical findings and lab values that point to a diagnosis of acute appendicitis.

Physical findings. The patient typically first experiences vague abdominal pain that then localizes to the right lower quadrant due to peritoneal inflammation. Anorexia and nausea typically follow the abdominal pain. On examination, the patient often appears ill and exhibits abdominal guarding due to peritonitis. Tachycardia and fever are common; however, the absence of either does not exclude appendicitis. Classically, on palpation, the patient will have pain at McBurney’s point (one-third the distance from the anterior iliac spine to the umbilicus). The exact point of maximal tenderness can differ because of the varying anatomy of the appendix (retrocecal, paracolic, pelvic, pre/post ileal, promontoric, or subcecal).¹ Right lower quadrant pain, abdominal rigidity, and radiation of periumbilical pain to the right lower quadrant are the most accurate findings in adults to rule in appendicitis.³ For children, physical exam findings have the highest likelihood in predicting appendicitis and include a positive Obturator sign, positive Rovsing sign, or a positive Psoas sign, and absent or decreased bowel sounds.⁴

Laboratory studies can support a diagnosis of appendicitis but cannot exclude it. Leukocytosis with neutrophil predominance is present in 90% of cases.⁵ An elevated C-reactive protein level renders the highest diagnostic accuracy.⁵ Perform a pregnancy test for any woman of child-bearing age, to assist in the diagnosis and guide imaging choices for evaluation. Additional laboratory tests are not needed unless there are concerns about volume depletion.

Clinical scoring systems

Several clinical scoring systems (TABLE^6-10) have been validated to aid clinicians in evaluating patients with possible appendicitis, to decrease unnecessary exposure to ionizing radiation from computed tomography (CT) scans, to identify and reassure patients with low likelihoods of appendicitis, and to conduct outpatient follow-up.

Continue to: The Alvarado score

The Alvarado score is the oldest scoring rule, developed in 1986; it entails 8 clinical and laboratory variables.⁶ Ebell et al altered the proposed cutoff values of the Alvarado score to be low risk (< 4), intermediate risk (4-8), and high risk (≥ 9), effectively improving the sensitivity and specificity rates.⁷

Screening tools cannot confirm appendicitis. Their usefulness is in helping to rule out appendicitis and in deciding for or against imaging.

In a meta-analysis of the Alvarado score that included 42 studies of men, women, and children, the sensitivity for “ruling out” appendicitis with a cutoff of 5 points was 96% for men, 99% for women, and 99% for children.⁸ The accuracy of a high-risk score (> 7) for “ruling in” appendicitis was less with an overall specificity of 82%.⁸ The Alvarado score did seem to overestimate appendicitis in women in all score categories.⁸

The Pediatric Appendicitis Score (PAS) is similar to Alvarado and was prospectively validated in 1170 children in 2002 for more specific guidance in this age group.⁹ The PAS had excellent specificity in the study; those with a score of ≥ 6 had a high probability of appendicitis. In a study comparing Alvarado with PAS in 311 patients, insignificant differences were noted at a score of ≥ 7 for both tests (sensitivity 86% vs 89%, and specificity 59% vs 50%, respectively).¹¹ No scoring system has been found to be sufficiently accurate for use in children 4 years of age and younger.¹²

The Appendicitis Inflammatory Response (AIR) Score was prospectively validated in 545 patients representing all age groups.¹⁰ Subsequently, in a larger prospective multicenter study of 3878 patients older than 5 years, the original cut points were altered, thereby improving test sensitivity and negative predictive value to 99% for those with low probability (0 to 3), and test specificity to 98% for those with high-­probability (9 to 12).¹³ Compared with the Alvarado Score, the AIR Score has higher specificity for those in the high-probability range, and similar exclusion rates in the low-probability range.¹⁴

Caveats with clinical decision scores. These tools are accepted and often used. However, challenges that affect generalizability of study data include differences in patient selection for each study (undifferentiated abdominal pain vs appendicitis), prospective vs retrospective designs, and age and gender variations in the patient populations. Despite the numerous scoring systems developed, none can accurately be used to rule in appendicitis. They are best used to assist in ruling out appendicitis and to aid in deciding for or against imaging.

Continue to: A look at the imaging options

Advanced imaging technology can affirm or refute a diagnosis of appendicitis and reduce the negative appendectomy rate, previously reported to be 15%.¹⁵ Ultrasonography (US), abdominal CT, and magnetic resonance imaging (MRI) are the most commonly used modalities. Point-of-care ultrasound ­(POCUS) is an option to start the diagnostic evaluation, given its relative ease of access, rapidity, and lack of radiation. However, a stand-alone POCUS at this time should not be the only imaging tool to rule out appendicitis.^16-18 Its accuracy depends on operator skill and is limited by patient-specific factors such as obesity.^16-19 If results are equivocal or the diagnosis otherwise remains unclear, arrange for different imaging.^16-18

Abdominal CT has sensitivity and specificity rates between 76% and 100% and 83% and 100%, respectively.^15,20,21 Ultrasonography has sensitivity and specificity rates of 71% to 94% and 81% to 98%, respectively.^15,20,21 Formal US is reliable to confirm appendicitis, but less so to rule out appendicitis. Special considerations for imagining in pregnant patients and children are discussed in a bit.

Timing of surgical consultation

Surgical consultation is paramount once the diagnosis of appendicitis is probable. Imaging is best obtained prior to surgical consultation to streamline evaluation and enhance decision- making. Typically, patients will be categorized as complicated or uncomplicated based on the presence or absence of perforation, a gangrenous appendix, an intra-abdominal abscess (IAA), or purulent peritonitis. Active continuous surgical involvement (­co-management or assumption of care) is recommended in all cases of appendicitis, especially if nonoperative management is selected, given that some cases must convert to immediate operative treatment or may be selected for delayed future (interval) appendectomy.²²

Management

Uncomplicated appendicitis

Prompt appendectomy has been the gold standard of care for uncomplicated acute appendicitis for 60 years. However, several studies have investigated an antibiotic-based strategy rather than surgical treatment for uncomplicated appendicitis.

Antibiotics vs appendectomy. In 2020, the CODA Collaborative published a randomized trial comparing a 10-day course of antibiotics with appendectomy in patients with uncomplicated appendicitis. In this multicenter study based in the United States, 1552 patients 18 years of age or older were randomized to receive antibiotics or undergo appendectomy (95% performed laparoscopically). The antibiotic treatment consisted of at least 24 hours of IV antibiotics, with or without admission to the hospital. Antibiotic choice was individualized according to guidelines for intra-abdominal infection published by the Infectious Diseases Society of America, with the most common IV medications being ertapenem, cefoxitin, or metronidazole plus one of the following: ceftriaxone, cefazolin, or levofloxacin. For the remaining 10 days, oral metronidazole plus ciprofloxacin or cefdinir were used.²²

Continue to: The primary endpoint...

The primary endpoint was the European Quality of Life-5 Dimensions (EQ-5D) questionnaire, with secondary outcomes including appendectomy in the antibiotics group and complications through 90 days. Exclusion criteria included pregnancy, sepsis, peritonitis, recurrent appendicitis, severe phlegmon on imaging, or evidence of neoplasm.²²

Antibiotics were noninferior to appendectomy for the 30-day study. However, antibiotics failed in 29%, who then proceeded to appendectomy by 90 days; these patients also accounted for 41% of those with an appendicolith. Overall complications were more common in the antibiotics group than in the appendectomy group (8.1 vs 3.5 per 100 participants; 95% CI, 1.3-3.98). Also more common in the antibiotic group were serious adverse events (4 vs 3 per 100 participants; hazard ratio [HR] = 1.29; 95% CI, 0.67-2.50). The presence of an appendicolith in the antibiotics group increased the conversion risk to appendectomy, as well as adverse events risk.²²

The takeaway. Antibiotic treatment is a noninferior method to treat acute uncomplicated appendicitis. However, the informed consent process is important, given the ~30% failure rate. Patient factors such as continued access to care should help inform the decision.

Two main surgical approaches exist for appendectomy: open and minimally invasive. At this time, the minimally invasive options include laparoscopic, single incision laparoscopic surgery (SILS), and robotic appendectomy. A study comparing cost, availability, or complications of these options has not been conducted at this time.

Antibiotic treatment is a noninferior method to treat acute uncomplicated appendicitis. However, the informed consent process is important, given the ~30% failure rate.

A large Cochrane review of 67 studies examining open vs laparoscopic appendectomy in adults and children completed in 2018 revealed that the laparoscopic approach reduced early postoperative pain intensity and led to a shorter hospital stay, earlier return to work or usual activities, and a decrease in wound infections.²³ The odds of IAA occurring with laparoscopic appendectomy increased by 65% compared with an open procedure; however, postoperative bowel obstruction and incisional hernias were less likely to occur.²³ Additionally, following laparoscopic surgery, postoperative bowel obstruction and incisional hernias are less likely to occur. The laparoscopic approach is preferred due to overall increased patient satisfaction and a reduction in most, if not all, complications.

Continue to: Complicated appendicitis

Complicated appendicitis

Excluding patients with severe sepsis or purulent peritonitis requiring resuscitation and immediate surgical intervention of intra-abdominal infection, the approach to patients with complicated appendicitis varies between aggressive surgical intervention and nonoperative management.

In a 2007 meta-analysis reviewing nonsurgical treatment of appendiceal abscess/phlegmon, immediate surgery was associated with higher morbidity.²⁴ Within the nonoperative management group 7.2% (CI, 4.0-10.5) required surgical intervention and 19.7% (CI, 11.0-28.3) required abscess drainage. Malignant disease was detected in 1.2% (CI, 0.6-1.7).²⁴ Small subsequent studies concluded different results.²⁵

Ultimately, the 2015 European Association of Endoscopic Surgery guidelines recommend a new systematic review; but with current data, initial nonoperative management is preferred.¹⁵ After initial nonoperative treatment, the only benefits from interval appendectomy are identification of an underlying malignancy (6% to 20%) and mitigating the risk of recurrent appendicitis (5% to 44%).^15,25-30

Multiple single institutional series found increased neoplasm incidence (9% to 20%) in complicated appendicitis in patients 40 years and older.^26-30 Prior to interval appendectomy in patients 45 years and older, ensuring they have an up-to-date screening colonoscopy is important. This is in line with 2021 US Preventive Services Task Force (Grade “B” recommendation), 2018 American Cancer Society (qualified recommendation), and 2021 American College of Gastroenterology (conditional recommendation) guidelines for colorectal cancer screening to start at age 45 in average-risk patients.³¹ Patients younger than 45 can consider screening through shared decision-making.

Special populations

Pregnant patients

In pregnancy, challenges exist with the presence of traditional signs and symptoms of appendicitis, with the most predictive sign being a WBC count higher than 18,000.³² The American College of Radiology’s (ACR) Appropriateness Criteria recommend US as the imaging modality of choice in pregnancy, with MRI as the best option when US is inconclusive.³³ Two meta-analyses demonstrated high sensitivity (91.8%-96.6%) and specificity (95.9%-97.9%) of MRI in diagnosing appendicitis.^34,35 CT scan is not the preferred initial imagining modality in pregnancy unless urgent information is needed and other modalities are insufficient or unavailable.³⁶

Continue to: The most common...

The most common nonobstetric surgical intervention during pregnancy is appendectomy, at a rate of 6.3/10,000 person-years, which increases to 9.9/10,000 in the postpartum period.³⁷ Two large population studies demonstrate the rate of appendicitis varies over the course of pregnancy, with the lowest rates in the third trimester,^38,39 and a significant rebound lasting for 2 years postpartum.³⁹ Peritonitis, septic shock, pneumonia, postoperative infection, and longer hospital stays occur more frequently in pregnant women than in nonpregnant women with appendicitis.⁴⁰ Fetal loss is higher in the first trimester.³²

In pregnancy, the most predictive sign of appendicitis is a white blood cell count > 18,000.

In a 14-year review of 63,145 appendicitis cases, an increased risk of fetal loss and maternal death was noted across ages and ethnicities, with the largest risk of maternal death occurring in Hispanics and fetal death in non-Hispanic Blacks.⁴¹ In a large study of 1018 adverse events after appendectomy or cholecystectomy, the 3 most common events were preterm delivery (35.4%), preterm labor without preterm delivery (26.4%), and miscarriage (25.7%).⁴² The surgery itself was not a major risk factor for adverse events. Major risk factors included cervical incompetence (odds ratio [OR] = 24.3), preterm labor in current pregnancy (OR = 18.3), and presence of vulvovaginitis (OR = 5.2).⁴²

Nonoperative management in pregnancy is not recommended; only 1 prospective trial has been done, with 20 patients, showing a 25% failure rate.⁴³ Two meta-analyses published in 2019 highlight the potential increase of fetal loss with laparoscopic approaches to appendectomy.^44,45 However, recently published literature demonstrates no significant maternal-fetal morbidity. Current guidelines of the Society of American Gastrointestinal and Endoscopic Surgeons agree that laparoscopy is the operative choice in pregnancy.³⁶

Children

Acute appendicitis is the most common surgical emergency in children.⁴ Physical exam findings and laboratory results are not classic in this population, obtaining an accurate history can be challenging, and results of clinical scoring systems can be inconclusive.⁴ Additional serum biomarkers, procalcitonin and calprotectin, are gaining evidence for use in improving scoring systems to refine low-risk groups. Unavailability of timely, reliable biomarker testing in rural practice locations limits definitive recommendations at this time.⁴⁶ ACR recommends no imaging in a pediatric patient whose risk of having appendicitis is low based on any of several scoring systems.⁴⁷ For those assessed as having higher risk, US is the recommended initial modality,with CT with IV contrast or MRI without contrast equally recommended if the US is equivocal.⁴⁷

Despite promising data from trials of nonoperative treatment for adults with appendicitis, no definitive evidence and recommendations are available for children.

Despite promising data from trials of nonoperative treatment for adults with appendicitis, no definitive evidence and recommendations are available for children. Two systematic reviews show nonoperative treatment is safe, with an efficacy rate of 76% to 82% at long-term follow-up,^48,49 although the success of antibiotic regimens varies. Within the nonoperative treatment group, 16% of patients had appendectomy during the follow-up period, which varied from 8 weeks to 4 years.⁴⁸ A randomized controlled trial is needed for final guidance.

Continue to: CASE

CASE

The patient had an Alvarado score of 9 (high probability) and an AIR score of 6 (intermediate probability). A CT with IV contrast showed a 9-mm fluid-filled appendix with periappendiceal fluid. During surgical consultation, he was offered laparoscopic appendectomy or nonoperative treatment with antibiotics. He opted for a preoperative dose of piperacillin-tazobactam 3.375 g IV and laparoscopic appendectomy. The patient was discharged home 6 hours after his procedure.

CORRESPONDENCE
Jessica Servey, MD, MHPE, 4301 Jones Bridge Road, Bethesda, MD 20814; [email protected]

When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.

“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.

Courtesy DKMS.org

In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.

“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.

Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).

In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”

From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.

Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
 

World’s largest registry

“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.

“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,

In 2022, DKMS is the largest global bone marrow donor recruitment organization, with more than 10.6 million potential donors registered. Worldwide, more than 91,000 patients have received bone marrow or stem cell grafts donated by registered volunteers.

Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.

Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
 

Global partners

DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.

“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.

The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
 

Pandemic affects donations

But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.

Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.

“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.

However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.

“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
 

Workforce and clinical problems

Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.

“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.

“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.

Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.

“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.

In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.

“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.

To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.

The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
 

‘Every patient saved’

The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.

DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.

In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.

The last word goes to Mechtild Harf’s daughter Katharina.

“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”

“I have to believe that this dream will come true because otherwise, why dream, right?” she said.

Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.

When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.

“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.

Courtesy DKMS.org

In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.

“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.

Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).

In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”

From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.

Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
 

World’s largest registry

“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.

“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,

In 2022, DKMS is the largest global bone marrow donor recruitment organization, with more than 10.6 million potential donors registered. Worldwide, more than 91,000 patients have received bone marrow or stem cell grafts donated by registered volunteers.

Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.

Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
 

Global partners

DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.

“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.

The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
 

Pandemic affects donations

But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.

Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.

“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.

However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.

“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
 

Workforce and clinical problems

Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.

“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.

“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.

Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.

“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.

In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.

“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.

To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.

The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
 

‘Every patient saved’

The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.

DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.

In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.

The last word goes to Mechtild Harf’s daughter Katharina.

“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”

“I have to believe that this dream will come true because otherwise, why dream, right?” she said.

Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.

When Mechtild Harf was diagnosed with acute leukemia in 1990, physicians told her and her husband Peter that a bone marrow transplant was her best hope for survival. Back then, her native Germany had only 3,000 registered donors, and none was a match.

“My dad just went crazy, you know, to save his wife,” recalled Katharina Harf, who was a young teen at the time of her mother’s diagnosis.

Courtesy DKMS.org

In the course of 1 year, the Harfs recruited more than 68,000 potential bone marrow donors, but their heroic efforts couldn’t save Mechtild.

“She unfortunately didn’t make it. She died because of leukemia,” Katharina said.

Although Mechtild Harf did not survive, her legacy lives on in the bone marrow and stem cell donor recruitment organization DKMS (Deutsche Knochenmarkspenderdatei, or German Bone Marrow Donor Center).

In May of 1991, Peter Harf and Gerhard Ehninger, MD, the hematologist who treated Mechtild, founded DKMS with the mission, as its website states, “to provide as many blood cancer patients as possible with a second chance at life.”

From its German roots, the nonprofit organization has extended its mission to the United States (where it was initially known as Delete Blood Cancer DKMS), Poland, the United Kingdom, Chile, and in 2021, to South Africa.

Three decades after her mother’s death, Katharina Harf serves as Executive Chairwoman of DKMS U.S., based in New York.
 

World’s largest registry

“DKMS has the largest number of unrelated donors of any organization in the world,” noted Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston.

“In a large fraction of our donor searches, we find matches that are in the DKMS registry,” he said in an interview,

In 2022, DKMS is the largest global bone marrow donor recruitment organization, with more than 10.6 million potential donors registered. Worldwide, more than 91,000 patients have received bone marrow or stem cell grafts donated by registered volunteers.

Alexander Schmidt, MD, PhD, global chief medical officer for DKMS, said that approximately 25% of all registered donors worldwide were recruited by his organization, and 39% of all unrelated donor transplants are made with peripheral blood stem cell or bone marrow products, donated by volunteers who are recruited by DKMS.

Since its founding, DKMS has registered 7.1 million potential donors in Germany, who made a total of 80,000 stem cell donations. DKMS U.S., which began operations in 2004, has registered 1.1 million donors and enabled 4,700 donations.
 

Global partners

DKMS partners with donor centers and recruitment organizations in each country where it operates. In the United States, DKMS works with the National Marrow Donor Program (NMDP) and its “Be The Match” donor registry.

“DKMS donors, both those from DKMS in Germany and those from DKMS in the United States are also listed in the NMDP registry, to make it easier for US search coordinators to accept these donors,” Dr. Schmidt explained in an interview.

The international cooperation and coordination makes it possible for a donor in the UK, for example, to save a life of a patient in Germany, the U.S., Chile, India, or many other parts of the world – anywhere that can be reached in time for a patient in need to receive a stem cell donation.
 

Pandemic affects donations

But, as with just about every aspect of life, the COVID-19 pandemic has created enormous challenges for recruiters, donor centers, and stem cell transplant centers.

Dr. Schmidt said that decline in donations during the pandemic was less severe than initially feared, with a decrease of just 3.5% in 2020, compared with the prepandemic year of 2019. In contrast, though, the average annual growth rate for donations prior to the pandemic was about 4%.

“Nevertheless, at the beginning of the pandemic in March 2020, for a few days things looked quite terrible, because all the borders were closed and flights were canceled, and about 50% of all stem cell products go abroad, and between 20% and 25% go intercontinental,” Dr. Schmidt said.

However, close cooperation and coordination between donor centers and national health authorities soon resolved the problem and helped insure that the flow of life-saving donations could continue with minimal disruption, he noted.

“I don’t think we had any product that could not be delivered at the end of the day, due to the pandemic,” he told this news organization.
 

Workforce and clinical problems

Although the flow of donations within and between nations has continued, the COVID-19 pandemic has had profound negative effects on transplant centers, particularly during the wave of infections caused by the Omicron variant, according to a transplant expert.

“With this most recent strain and how transmissible it is, what we’re dealing with is mass workforce shortages,” said Yi-Bin Chen, MD, director of the bone marrow transplant program at Massachusetts General Hospital in Boston.

“On top of a short-staffed hospital, you then take a very transmissible variant and deplete it even more due to the need to quarantine,” he said in an interview.

Both Dr. Champlin and Dr. Chen said that on-again, off-again pandemic travel bans and donor illnesses have necessitated first obtaining products and cryopreserving them before starting the recipient on a conditioning regimen for the transplant.

“The problem is that, while you can preserve peripheral blood stem cells pretty reliably, cryopreserving bone marrow is a bit more difficult,” Dr. Chen said.

In addition, evidence from recent studies comparing stem cell sources suggest that outcomes are less good with cryopreserved products than with fresh products, and with peripheral blood stem cells compared with bone marrow.

“But you’ve got to make do. A transplant with a cryopreserved product is better than no transplant,” Dr. Chen said.

To make things even more frustrating, as the pandemic waxed and waned throughout 2020 and 2021, the recommendations from donor centers seesawed between using fresh or cryopreserved product, making it difficult to plan a transplant for an individual patient.

The Omicron wave has also resulted in a much higher rate of donor dropout than anticipated, making it that much harder to schedule a transplant, Dr. Chen noted.
 

‘Every patient saved’

The pandemic will eventually subside, however, while the need for stem cell transplantation to treat hematologic malignancies will continue.

DKMS recently launched special aid programs to improve access to stem cell transplants in developing nations by offering financial support, free HLA typing, and other services.

In addition to its core mission of recruiting donors, DKMS is dedicated to improving the quality and efficiency of stem cell transplants. For example, in 2017 scientists in DKMS’ Life Science Lab created an antibody test for donor cytomegalovirus (CMV) infection, using a simple buccal swab rather than a more invasive blood sample. CMV infections can compromise the integrity of stem cell grafts and could be fatal to immunocompromised transplant recipients.

The last word goes to Mechtild Harf’s daughter Katharina.

“My big dream is that every patient will be saved from blood cancer,” she said in a video posted on the DKMS website. “When they get sick, we have a solution for them, whether it’s because they need a donor, with research, building hospitals, providing them with the best medical care we can. I will just keep fighting and keep spreading the word, recruiting donors, raising money – all the things that it takes for us to delete blood cancer.”

“I have to believe that this dream will come true because otherwise, why dream, right?” she said.

Dr. Champlin was the recipient of a Mechtild Harf Science Award and is a member of the board of DKMS U.S. Dr. Schmidt is employed by DKMS. Dr. Chen reported having no relevant disclosures.

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Gastroenterology, an AGA journal, is proud to announce the release of a special collection of articles focused on the intersection of diversity, equity, and inclusion (DEI) within gastroenterology and hepatology. This curated collection, under the guidance of the journal’s new DEI section editor Chyke Doubeni, MBBS, MPH, includes original research, reviews, commentaries, and editorials on matters of health disparities, socioeconomic determinants of health outcomes, and population-based studies on disease incidence among races and ethnicities, among others. New articles are added to the collection as they are published.

View the special collection on Gastroenterology’s website, which is designed to help you quickly and easily look over the latest DEI articles and content of interest. Recent articles include the following:

• “How to incorporate health equity training into GI/hepatology fellowships,” by Jannel Lee-Allen, MD, and Brijen J. Shah, MD.
• “Disparities in preventable mortality from colorectal cancer: Are they the result of structural racism?” by Chyke A. Doubeni, MBBS, MPH; Kevin Selby, MD; and Theodore R. Levin, MD.
• “COVID-19 pediatric patients: GI symptoms, presentations and disparities by race/ethnicity in a large, multicenter U.S. study,” by Yusuf Ashktorab, MD; Anas Brim, MD; Antonio Pizuorno, MD; Vijay Gayam, MD; Sahar Nikdel, MD; and Hassan Brim, PhD.

View all of Gastroenterology’s curated article collections.

Gastroenterology, an AGA journal, is proud to announce the release of a special collection of articles focused on the intersection of diversity, equity, and inclusion (DEI) within gastroenterology and hepatology. This curated collection, under the guidance of the journal’s new DEI section editor Chyke Doubeni, MBBS, MPH, includes original research, reviews, commentaries, and editorials on matters of health disparities, socioeconomic determinants of health outcomes, and population-based studies on disease incidence among races and ethnicities, among others. New articles are added to the collection as they are published.

View the special collection on Gastroenterology’s website, which is designed to help you quickly and easily look over the latest DEI articles and content of interest. Recent articles include the following:

• “How to incorporate health equity training into GI/hepatology fellowships,” by Jannel Lee-Allen, MD, and Brijen J. Shah, MD.
• “Disparities in preventable mortality from colorectal cancer: Are they the result of structural racism?” by Chyke A. Doubeni, MBBS, MPH; Kevin Selby, MD; and Theodore R. Levin, MD.
• “COVID-19 pediatric patients: GI symptoms, presentations and disparities by race/ethnicity in a large, multicenter U.S. study,” by Yusuf Ashktorab, MD; Anas Brim, MD; Antonio Pizuorno, MD; Vijay Gayam, MD; Sahar Nikdel, MD; and Hassan Brim, PhD.

View all of Gastroenterology’s curated article collections.

Gastroenterology, an AGA journal, is proud to announce the release of a special collection of articles focused on the intersection of diversity, equity, and inclusion (DEI) within gastroenterology and hepatology. This curated collection, under the guidance of the journal’s new DEI section editor Chyke Doubeni, MBBS, MPH, includes original research, reviews, commentaries, and editorials on matters of health disparities, socioeconomic determinants of health outcomes, and population-based studies on disease incidence among races and ethnicities, among others. New articles are added to the collection as they are published.

View the special collection on Gastroenterology’s website, which is designed to help you quickly and easily look over the latest DEI articles and content of interest. Recent articles include the following:

• “How to incorporate health equity training into GI/hepatology fellowships,” by Jannel Lee-Allen, MD, and Brijen J. Shah, MD.
• “Disparities in preventable mortality from colorectal cancer: Are they the result of structural racism?” by Chyke A. Doubeni, MBBS, MPH; Kevin Selby, MD; and Theodore R. Levin, MD.
• “COVID-19 pediatric patients: GI symptoms, presentations and disparities by race/ethnicity in a large, multicenter U.S. study,” by Yusuf Ashktorab, MD; Anas Brim, MD; Antonio Pizuorno, MD; Vijay Gayam, MD; Sahar Nikdel, MD; and Hassan Brim, PhD.

View all of Gastroenterology’s curated article collections.

The new AGA Clinical Practice Update on Surveillance After Pathologically Curative Endoscopic Submucosal Dissection of Early Gastrointestinal Neoplasia in the United States: Commentary offers advice regarding surveillance intervals using endoscopy and other relevant modalities after endoscopic removal of dysplastic lesions and early GI cancers with endoscopic submucosal dissection (ESD) which were deemed pathologically curative.

Main takeaway: Patients with malignant lesions removed by curative ESD possess a higher risk of lymph node metastasis and should be surveilled more closely than those with resection dysplasia not associated with lymphatic spread. 

The new AGA Clinical Practice Update on Surveillance After Pathologically Curative Endoscopic Submucosal Dissection of Early Gastrointestinal Neoplasia in the United States: Commentary offers advice regarding surveillance intervals using endoscopy and other relevant modalities after endoscopic removal of dysplastic lesions and early GI cancers with endoscopic submucosal dissection (ESD) which were deemed pathologically curative.

Main takeaway: Patients with malignant lesions removed by curative ESD possess a higher risk of lymph node metastasis and should be surveilled more closely than those with resection dysplasia not associated with lymphatic spread. 

The new AGA Clinical Practice Update on Surveillance After Pathologically Curative Endoscopic Submucosal Dissection of Early Gastrointestinal Neoplasia in the United States: Commentary offers advice regarding surveillance intervals using endoscopy and other relevant modalities after endoscopic removal of dysplastic lesions and early GI cancers with endoscopic submucosal dissection (ESD) which were deemed pathologically curative.

Main takeaway: Patients with malignant lesions removed by curative ESD possess a higher risk of lymph node metastasis and should be surveilled more closely than those with resection dysplasia not associated with lymphatic spread.