PARIS –A study of the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan supports updated guidelines that encourage ARNI substitution for traditional therapies in lower-risk heart failure patients, although the study found sacubitril-valsartan does not significantly reduce central aortic stiffness, compared with enalapril therapy, according results reported here at the annual congress of the European Society of Cardiology. The study was published simultaneously in JAMA.

“The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in heart failure and reduced ejection fraction,” lead author Akshay S. Desai, MD, of Brigham and Women’s Hospital, Boston, and co-authors wrote.

The study set out to determine the pathophysiologic mechanisms behind the clinical effects of sacubitril-valsartan, compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF). The EVALUATE-HF trial evaluated 464 patients age 50 years and older with multiple cardiovascular symptoms, including chronic heart failure with ejection fraction of less than 40%. Aortic characteristic impedance, a measure of central aortic stiffness, was evaluated with two-dimensional echocardiography at screening, then at four, 12 and 24 weeks. The primary endpoint was change in aortic characteristic impedance between the two treatment groups at 12 weeks.

Aortic characteristic impedance at baseline to 12 weeks decreased from 223.8 to 218.9 dyne x s/cm ⁵ in the sacubitril-valsartan treatment group and increased from 213.2 to 214.4 dyne x s/cm ⁵ in the enalapril group. “There was no statistically significant difference between groups in the change from baseline,” the investigators wrote. The between-group difference factored out to -2.2 dyne x s/cm ⁵ , ranging from -17.6 to 13.2 dyne x s/cm ⁵ . This was despite a reduction in brachial systolic blood pressure (6.5 and 1.6 mm Hg) and central systolic blood pressure (4.9 and 2.3 mm Hg), respectively.

The sacubitril-valsartan group showed greater reductions in left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left atrial volume index and mitral E/e ′ ratio. “Although ejection fraction increased modestly by 1.9% in the sacubitril-valsartan group and by 1.3% in the enalapril group, we observed no significant between-group differences in change from baseline to 12 weeks in left ventricular ejection fraction or in other measured parameters,” the investigators wrote. Those other parameters include global longitudinal strain, mitral e ′ velocity or arterial elastance:ventricular elastance ratio. Rates of hypertension, hyperkalemia, and worsening renal function were similar in both groups.

Another secondary outcome was change from baseline in the overall 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). A post-hoc analysis evaluated patients who achieved a statistically significant 5-points-or-greater change in KCCQ score, finding the score improved by 8.9 points in the sacubitril-valsartan group and 4.3 points in the enalapril group, a difference wider than 8-month results from the PARADIGM-HF trial ( Circ Heart Fail. 2017;10:e003430). “These data suggest that clinical benefits of sacubitril-valsartan compared with enalapril in patients with HFrEF are likely unrelated to changes in central aortic stiffness or pulsatile load, despite favorable effects of neprilysin inhibition on myocardial remodeling and wall stress,” the investigators wrote.

The data support the current guidelines for substituting ARNI for angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers therapy, “even in the face of apparent clinical stability,” Dr. Desai and co-authors said. In an invited commentary, Mark H. Drazner, MD , of Texas Southwestern Medical Center in Dallas, said the EVALUATE-HF trial, along with the observational PROVE-HF trial data also reported at the ESC meeting (JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12821), “strongly suggest” ARNI therapy can promote cardiac reverse remodeling in patients with HFrEF. “As with beta-blockers and ACE inhibitors, it thus appears that the benefits of ARNI therapy on clinical outcomes in patients with HFrEF are mediated, at least in part, by their favorable effects on the adverse cardiac remodeling that characterizes the condition,” Dr. Desai and co-authors wrote.

The EVALUATE-HF trial was sponsored by Novartis. Dr. Desai disclosed financial relationships with Alnylam, AstraZeneca, Novartis, Abbott, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma and Regeneron. Dr. Drazner has no financial relationships to disclose.

SOURCE: Desai AS et al. JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12843.

PARIS –A study of the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan supports updated guidelines that encourage ARNI substitution for traditional therapies in lower-risk heart failure patients, although the study found sacubitril-valsartan does not significantly reduce central aortic stiffness, compared with enalapril therapy, according results reported here at the annual congress of the European Society of Cardiology. The study was published simultaneously in JAMA.

“The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in heart failure and reduced ejection fraction,” lead author Akshay S. Desai, MD, of Brigham and Women’s Hospital, Boston, and co-authors wrote.

The study set out to determine the pathophysiologic mechanisms behind the clinical effects of sacubitril-valsartan, compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF). The EVALUATE-HF trial evaluated 464 patients age 50 years and older with multiple cardiovascular symptoms, including chronic heart failure with ejection fraction of less than 40%. Aortic characteristic impedance, a measure of central aortic stiffness, was evaluated with two-dimensional echocardiography at screening, then at four, 12 and 24 weeks. The primary endpoint was change in aortic characteristic impedance between the two treatment groups at 12 weeks.

Aortic characteristic impedance at baseline to 12 weeks decreased from 223.8 to 218.9 dyne x s/cm ⁵ in the sacubitril-valsartan treatment group and increased from 213.2 to 214.4 dyne x s/cm ⁵ in the enalapril group. “There was no statistically significant difference between groups in the change from baseline,” the investigators wrote. The between-group difference factored out to -2.2 dyne x s/cm ⁵ , ranging from -17.6 to 13.2 dyne x s/cm ⁵ . This was despite a reduction in brachial systolic blood pressure (6.5 and 1.6 mm Hg) and central systolic blood pressure (4.9 and 2.3 mm Hg), respectively.

The sacubitril-valsartan group showed greater reductions in left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left atrial volume index and mitral E/e ′ ratio. “Although ejection fraction increased modestly by 1.9% in the sacubitril-valsartan group and by 1.3% in the enalapril group, we observed no significant between-group differences in change from baseline to 12 weeks in left ventricular ejection fraction or in other measured parameters,” the investigators wrote. Those other parameters include global longitudinal strain, mitral e ′ velocity or arterial elastance:ventricular elastance ratio. Rates of hypertension, hyperkalemia, and worsening renal function were similar in both groups.

Another secondary outcome was change from baseline in the overall 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). A post-hoc analysis evaluated patients who achieved a statistically significant 5-points-or-greater change in KCCQ score, finding the score improved by 8.9 points in the sacubitril-valsartan group and 4.3 points in the enalapril group, a difference wider than 8-month results from the PARADIGM-HF trial ( Circ Heart Fail. 2017;10:e003430). “These data suggest that clinical benefits of sacubitril-valsartan compared with enalapril in patients with HFrEF are likely unrelated to changes in central aortic stiffness or pulsatile load, despite favorable effects of neprilysin inhibition on myocardial remodeling and wall stress,” the investigators wrote.

The data support the current guidelines for substituting ARNI for angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers therapy, “even in the face of apparent clinical stability,” Dr. Desai and co-authors said. In an invited commentary, Mark H. Drazner, MD , of Texas Southwestern Medical Center in Dallas, said the EVALUATE-HF trial, along with the observational PROVE-HF trial data also reported at the ESC meeting (JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12821), “strongly suggest” ARNI therapy can promote cardiac reverse remodeling in patients with HFrEF. “As with beta-blockers and ACE inhibitors, it thus appears that the benefits of ARNI therapy on clinical outcomes in patients with HFrEF are mediated, at least in part, by their favorable effects on the adverse cardiac remodeling that characterizes the condition,” Dr. Desai and co-authors wrote.

The EVALUATE-HF trial was sponsored by Novartis. Dr. Desai disclosed financial relationships with Alnylam, AstraZeneca, Novartis, Abbott, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma and Regeneron. Dr. Drazner has no financial relationships to disclose.

SOURCE: Desai AS et al. JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12843.

PARIS –A study of the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan supports updated guidelines that encourage ARNI substitution for traditional therapies in lower-risk heart failure patients, although the study found sacubitril-valsartan does not significantly reduce central aortic stiffness, compared with enalapril therapy, according results reported here at the annual congress of the European Society of Cardiology. The study was published simultaneously in JAMA.

“The study findings may provide insight into mechanisms underlying the effects of sacubitril-valsartan in heart failure and reduced ejection fraction,” lead author Akshay S. Desai, MD, of Brigham and Women’s Hospital, Boston, and co-authors wrote.

The study set out to determine the pathophysiologic mechanisms behind the clinical effects of sacubitril-valsartan, compared with enalapril in patients with heart failure and reduced ejection fraction (HFrEF). The EVALUATE-HF trial evaluated 464 patients age 50 years and older with multiple cardiovascular symptoms, including chronic heart failure with ejection fraction of less than 40%. Aortic characteristic impedance, a measure of central aortic stiffness, was evaluated with two-dimensional echocardiography at screening, then at four, 12 and 24 weeks. The primary endpoint was change in aortic characteristic impedance between the two treatment groups at 12 weeks.

Aortic characteristic impedance at baseline to 12 weeks decreased from 223.8 to 218.9 dyne x s/cm ⁵ in the sacubitril-valsartan treatment group and increased from 213.2 to 214.4 dyne x s/cm ⁵ in the enalapril group. “There was no statistically significant difference between groups in the change from baseline,” the investigators wrote. The between-group difference factored out to -2.2 dyne x s/cm ⁵ , ranging from -17.6 to 13.2 dyne x s/cm ⁵ . This was despite a reduction in brachial systolic blood pressure (6.5 and 1.6 mm Hg) and central systolic blood pressure (4.9 and 2.3 mm Hg), respectively.

The sacubitril-valsartan group showed greater reductions in left ventricular end-diastolic volume index, left ventricular end-systolic volume index, left atrial volume index and mitral E/e ′ ratio. “Although ejection fraction increased modestly by 1.9% in the sacubitril-valsartan group and by 1.3% in the enalapril group, we observed no significant between-group differences in change from baseline to 12 weeks in left ventricular ejection fraction or in other measured parameters,” the investigators wrote. Those other parameters include global longitudinal strain, mitral e ′ velocity or arterial elastance:ventricular elastance ratio. Rates of hypertension, hyperkalemia, and worsening renal function were similar in both groups.

Another secondary outcome was change from baseline in the overall 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ). A post-hoc analysis evaluated patients who achieved a statistically significant 5-points-or-greater change in KCCQ score, finding the score improved by 8.9 points in the sacubitril-valsartan group and 4.3 points in the enalapril group, a difference wider than 8-month results from the PARADIGM-HF trial ( Circ Heart Fail. 2017;10:e003430). “These data suggest that clinical benefits of sacubitril-valsartan compared with enalapril in patients with HFrEF are likely unrelated to changes in central aortic stiffness or pulsatile load, despite favorable effects of neprilysin inhibition on myocardial remodeling and wall stress,” the investigators wrote.

The data support the current guidelines for substituting ARNI for angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers therapy, “even in the face of apparent clinical stability,” Dr. Desai and co-authors said. In an invited commentary, Mark H. Drazner, MD , of Texas Southwestern Medical Center in Dallas, said the EVALUATE-HF trial, along with the observational PROVE-HF trial data also reported at the ESC meeting (JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12821), “strongly suggest” ARNI therapy can promote cardiac reverse remodeling in patients with HFrEF. “As with beta-blockers and ACE inhibitors, it thus appears that the benefits of ARNI therapy on clinical outcomes in patients with HFrEF are mediated, at least in part, by their favorable effects on the adverse cardiac remodeling that characterizes the condition,” Dr. Desai and co-authors wrote.

The EVALUATE-HF trial was sponsored by Novartis. Dr. Desai disclosed financial relationships with Alnylam, AstraZeneca, Novartis, Abbott, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma and Regeneron. Dr. Drazner has no financial relationships to disclose.

SOURCE: Desai AS et al. JAMA. 2019 Sept 2. doi:10.1001/jama.2019.12843.

Weight-loss surgery in people with type 2 diabetes and obesity is associated with significant reductions in major adverse cardiovascular events, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.

The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.

At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).

The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA_1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.

Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).

In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.

In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m² or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.

The surgery was also associated with significantly greater reductions in HbA_1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.

The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.

In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.

“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.

“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.

The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.

“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.

The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.

SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.

Weight-loss surgery in people with type 2 diabetes and obesity is associated with significant reductions in major adverse cardiovascular events, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.

The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.

At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).

The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA_1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.

Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).

In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.

In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m² or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.

The surgery was also associated with significantly greater reductions in HbA_1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.

The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.

In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.

“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.

“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.

The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.

“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.

The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.

SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.

Weight-loss surgery in people with type 2 diabetes and obesity is associated with significant reductions in major adverse cardiovascular events, compared with nonsurgical management, according to data presented at the annual congress of the European Society of Cardiology.

The retrospective cohort study, simultaneously published in JAMA, looked at outcomes in 13,722 individuals with type 2 diabetes and obesity, 2,287 of whom underwent metabolic surgery and the rest of the matched cohort receiving usual care.

At 8 years of follow-up, the cumulative incidence of the primary endpoint – a composite of first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation – was 30.8% in the weight loss–surgery group and 47.7% in the nonsurgical-control group, representing a 39% lower risk with weight loss surgery (P less than .001).

The analysis failed to find any interaction with sex, age, body mass index (BMI), HbA_1c level, estimated glomerular filtration rate, or use of insulin, sulfonylureas, or lipid-lowering medications.

Metabolic surgery was also associated with a significantly lower cumulative incidence of myocardial infarction, ischemic stroke and mortality than usual care (17% vs. 27.6%).

In particular, researchers saw a significant 41% reduction in the risk of death at eight years in the surgical group compared to usual care (10% vs. 17.8%), a 62% reduction in the risk of heart failure, a 31% reduction in the risk of coronary artery disease, and a 60% reduction in nephropathy risk. Metabolic surgery was also associated with a 33% reduction in cerebrovascular disease risk, and a 22% lower risk of atrial fibrillation.

In the group that underwent metabolic surgery, mean bodyweight at 8 years was reduced by 29.1 kg, compared with 8.7 kg in the control group. At baseline, 75% of the metabolic surgery group had a BMI of 40 kg/m² or above, 20% had a BMI between 35-39.9, and 5% had a BMI between 30-34.9.

The surgery was also associated with significantly greater reductions in HbA_1c, and in the use of noninsulin diabetes medications, insulin, antihypertensive medications, lipid-lowering therapies, and aspirin.

The most common surgical weight loss procedure was Roux-en-Y gastric bypass (63%), followed by sleeve gastrectomy (32%), and adjustable gastric banding (5%). Five patients underwent duodenal switch.

In the 90 days after surgery, 3% of patients experienced bleeding that required transfusion, 2.5% experienced pulmonary adverse events, 1% experienced venous thromboembolism, 0.7% experienced cardiac events, and 0.2% experienced renal failure that required dialysis. There were also 15 deaths (0.7%) in the surgical group, and 4.8% of patients required abdominal surgical intervention.

“We speculate that the lower rate of [major adverse cardiovascular events] after metabolic surgery observed in this study may be related to substantial and sustained weight loss with subsequent improvement in metabolic, structural, hemodynamic, and neurohormonal abnormalities,” wrote Ali Aminian, MD, of the Bariatric and Metabolic Institute at the Cleveland Clinic, and coauthors.

“Although large and sustained surgically induced weight loss has profound physiologic effects, a growing body of evidence indicates that some of the beneficial metabolic and neurohormonal changes that occur after metabolic surgical procedures are related to anatomical changes in the gastrointestinal tract that are partially independent of weight loss,” they wrote.

The authors, however, were also keen to point out that their study was observational, and should therefore be considered “hypothesis generating.” While the two study groups were matched on 37 baseline covariates, those in the surgical group did have a higher body weight, higher BMI, higher rates of dyslipidemia, and higher rates of hypertension.

“The findings from this observational study must be confirmed in randomized clinical trials,” they noted.

The study was partly funded by Medtronic, and one author was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. Five authors declared funding and support from private industry, including from Medtronic, and one author declared institutional grants.

SOURCE: Aminian A et al. JAMA 2019, Sept 2. DOI: 10.1001/jama.2019.14231.

A novel marker of repolarization may identify patients with cardiomyopathy who would benefit from an implanted cardioverter defibrillator, according to a European research study presented at the annual congress of the European Society of Cardiology and published simultaneously in The Lancet.

High periodic repolarization dynamics were linked to substantial reductions in mortality in a prespecified substudy of the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators).

The degree of periodic repolarization dynamics correlated with reductions in mortality in the 1,371 patients, 968 of whom had ICD implantation and 403 of whom were treated conservatively, in the prospective, nonrandomized controlled cohort study conducted at 44 centers in 15 countries within the European Union. At a median follow-up of 2-7 years, the ICD group had a mortality rate of 14%; at a follow-up of 1-2 years, the control group had a mortality rate of 16%, resulting in a 43% overall reduction in mortality for the ICD group.

Low periodic repolarization dynamics were associated with a low reduction in ICD-related death, whereas high periodic repolarization dynamics were linked to substantial reductions in mortality. In 199 patients with periodic repolarization dynamics of 7.5% or higher, ICD implantation resulted in a 75% reduction in death, compared with controls. Periodic repolarization dynamics also served as reliable predictors of appropriate shocks in patients with ICDs as well as death in controls.

Because of the link between high periodic repolarization dynamics and greater benefits, cardiologists may be able to use the measure as a marker to individualize treatment decisions about the use of ICDs, said Axel Bauer, MD, director of University Hospital for Internal Medicine III, Cardiology and Angiology at Medical University Innsbruck, Austria, and coauthors. “Better patient selection could lead to a reduced number of devices needing to be implanted to save a life.

“Our results should help patients to make decisions about their treatment that take into account individual circumstances and preferences,” the researchers noted.

SOURCE: Bauer A et al. Lancet. 2019 Sep 2. doi: 10.1016/S0140-6736(19)31996-8.

A novel marker of repolarization may identify patients with cardiomyopathy who would benefit from an implanted cardioverter defibrillator, according to a European research study presented at the annual congress of the European Society of Cardiology and published simultaneously in The Lancet.

High periodic repolarization dynamics were linked to substantial reductions in mortality in a prespecified substudy of the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators).

The degree of periodic repolarization dynamics correlated with reductions in mortality in the 1,371 patients, 968 of whom had ICD implantation and 403 of whom were treated conservatively, in the prospective, nonrandomized controlled cohort study conducted at 44 centers in 15 countries within the European Union. At a median follow-up of 2-7 years, the ICD group had a mortality rate of 14%; at a follow-up of 1-2 years, the control group had a mortality rate of 16%, resulting in a 43% overall reduction in mortality for the ICD group.

Low periodic repolarization dynamics were associated with a low reduction in ICD-related death, whereas high periodic repolarization dynamics were linked to substantial reductions in mortality. In 199 patients with periodic repolarization dynamics of 7.5% or higher, ICD implantation resulted in a 75% reduction in death, compared with controls. Periodic repolarization dynamics also served as reliable predictors of appropriate shocks in patients with ICDs as well as death in controls.

Because of the link between high periodic repolarization dynamics and greater benefits, cardiologists may be able to use the measure as a marker to individualize treatment decisions about the use of ICDs, said Axel Bauer, MD, director of University Hospital for Internal Medicine III, Cardiology and Angiology at Medical University Innsbruck, Austria, and coauthors. “Better patient selection could lead to a reduced number of devices needing to be implanted to save a life.

“Our results should help patients to make decisions about their treatment that take into account individual circumstances and preferences,” the researchers noted.

SOURCE: Bauer A et al. Lancet. 2019 Sep 2. doi: 10.1016/S0140-6736(19)31996-8.

A novel marker of repolarization may identify patients with cardiomyopathy who would benefit from an implanted cardioverter defibrillator, according to a European research study presented at the annual congress of the European Society of Cardiology and published simultaneously in The Lancet.

High periodic repolarization dynamics were linked to substantial reductions in mortality in a prespecified substudy of the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators).

The degree of periodic repolarization dynamics correlated with reductions in mortality in the 1,371 patients, 968 of whom had ICD implantation and 403 of whom were treated conservatively, in the prospective, nonrandomized controlled cohort study conducted at 44 centers in 15 countries within the European Union. At a median follow-up of 2-7 years, the ICD group had a mortality rate of 14%; at a follow-up of 1-2 years, the control group had a mortality rate of 16%, resulting in a 43% overall reduction in mortality for the ICD group.

Low periodic repolarization dynamics were associated with a low reduction in ICD-related death, whereas high periodic repolarization dynamics were linked to substantial reductions in mortality. In 199 patients with periodic repolarization dynamics of 7.5% or higher, ICD implantation resulted in a 75% reduction in death, compared with controls. Periodic repolarization dynamics also served as reliable predictors of appropriate shocks in patients with ICDs as well as death in controls.

Because of the link between high periodic repolarization dynamics and greater benefits, cardiologists may be able to use the measure as a marker to individualize treatment decisions about the use of ICDs, said Axel Bauer, MD, director of University Hospital for Internal Medicine III, Cardiology and Angiology at Medical University Innsbruck, Austria, and coauthors. “Better patient selection could lead to a reduced number of devices needing to be implanted to save a life.

“Our results should help patients to make decisions about their treatment that take into account individual circumstances and preferences,” the researchers noted.

SOURCE: Bauer A et al. Lancet. 2019 Sep 2. doi: 10.1016/S0140-6736(19)31996-8.

Here are 5 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. No birth rate gains from levothyroxine in pregnancy

To take the posttest, go to: https://bit.ly/2ZoXzK8
Expires March 23, 2020

2. Simple screening for risk of falling in elderly can guide prevention

To take the posttest, go to: https://bit.ly/2NKXxu3
Expires March 24, 2020

3. Time to revisit fasting rules for surgery patients

To take the posttest, go to: https://bit.ly/2HHwHiD
Expires March 26, 2020

4. Four biomarkers could distinguish psoriatic arthritis from osteoarthritis

To take the posttest, go to: https://bit.ly/344WPNS
Expires March 28, 2020

5. More chest compression–only CPR leads to increased survival rates

To take the posttest, go to: https://bit.ly/30CahGF
Expires April 1, 2020

Here are 5 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. No birth rate gains from levothyroxine in pregnancy

To take the posttest, go to: https://bit.ly/2ZoXzK8
Expires March 23, 2020

2. Simple screening for risk of falling in elderly can guide prevention

To take the posttest, go to: https://bit.ly/2NKXxu3
Expires March 24, 2020

3. Time to revisit fasting rules for surgery patients

To take the posttest, go to: https://bit.ly/2HHwHiD
Expires March 26, 2020

4. Four biomarkers could distinguish psoriatic arthritis from osteoarthritis

To take the posttest, go to: https://bit.ly/344WPNS
Expires March 28, 2020

5. More chest compression–only CPR leads to increased survival rates

To take the posttest, go to: https://bit.ly/30CahGF
Expires April 1, 2020

Here are 5 articles from the September issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. No birth rate gains from levothyroxine in pregnancy

To take the posttest, go to: https://bit.ly/2ZoXzK8
Expires March 23, 2020

2. Simple screening for risk of falling in elderly can guide prevention

To take the posttest, go to: https://bit.ly/2NKXxu3
Expires March 24, 2020

3. Time to revisit fasting rules for surgery patients

To take the posttest, go to: https://bit.ly/2HHwHiD
Expires March 26, 2020

4. Four biomarkers could distinguish psoriatic arthritis from osteoarthritis

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PARIS – Patients with stable coronary artery disease and type 2 diabetes saw fewer ischemic cardiovascular events when they received dual antiplatelet therapy with ticagrelor plus aspirin, though they also had more major bleeding events than patients receiving placebo plus aspirin.

The subset of patients who had received prior percutaneous coronary intervention (PCI) stood to benefit more from extended dual antiplatelet therapy (DAPT), according to clinical trial results presented to an overflow crowd at the annual congress of the European Society of Cardiology.

Findings from the full study, named The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS), and from the PCI subgroup analysis were published concurrently with the presentation (N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2).

“This strategy of long-term dual antiplatelet therapy may be beneficial in selected patients at low risk of bleeding, but at high risk of ischemic events,” said the study’s co-principal investigator Deepak Bhatt, MD, professor of medicine at Harvard Medical School, Boston, and executive director of interventional cardiology programs at Boston’s Brigham and Women’s Hospital. In a video interview, he hypothesized that “prior PCI may serve as a sort of ‘stress test’ for bleeding,” thus identifying a subset of patients who might benefit from long-term DAPT.

Ischemic events, the primary efficacy outcome of THEMIS, occurred in 7.7% of patients taking the P2Y12 receptor antagonist ticagrelor and 8.5% of those receiving placebo, for a hazard ratio of 0.90 favoring ticagrelor (P = .04). Ischemic events included cardiovascular deaths, myocardial infarctions (MIs), and stroke.

Looking at secondary endpoints, Dr. Bhatt said that there was no difference in cardiovascular deaths between study arms, but that ischemic strokes, all MIs, and ST segment elevation MIs were all less common for patients taking ticagrelor. All-cause mortality was similar between study groups.

Though ischemic events dropped, “This benefit was achieved at the expense of more bleeding,” said Dr. Bhatt. Major bleeding, the primary safety outcome, was seen in 2.2% of those taking ticagrelor and 1.0% of the placebo group, for a hazard ratio of 2.32 (P less than .001). Dr. Bhatt and his collaborators used the Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding for ascertainment of this outcome.

Intracranial hemorrhage was also more common for patients on ticagrelor, though incidence was low and the absolute difference was small between groups. This complication occurred in 0.7% of ticagrelor patients and 0.5% of placebo patients, yielding a hazard ratio of 1.71 (P = .0005). “This excess wasn’t in spontaneous or procedural intracranial bleeding, but rather in traumatic intracranial hemorrhage,” said Dr. Bhatt.

Fatal bleeds affected just 0.2% of those on ticagrelor and 0.1% of those receiving placebo; this difference wasn’t statistically significant.

koakes@mdedgecom

Source: Steg PG et al. N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Bhatt DL et al.Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2)

PARIS – Patients with stable coronary artery disease and type 2 diabetes saw fewer ischemic cardiovascular events when they received dual antiplatelet therapy with ticagrelor plus aspirin, though they also had more major bleeding events than patients receiving placebo plus aspirin.

The subset of patients who had received prior percutaneous coronary intervention (PCI) stood to benefit more from extended dual antiplatelet therapy (DAPT), according to clinical trial results presented to an overflow crowd at the annual congress of the European Society of Cardiology.

Findings from the full study, named The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS), and from the PCI subgroup analysis were published concurrently with the presentation (N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2).

“This strategy of long-term dual antiplatelet therapy may be beneficial in selected patients at low risk of bleeding, but at high risk of ischemic events,” said the study’s co-principal investigator Deepak Bhatt, MD, professor of medicine at Harvard Medical School, Boston, and executive director of interventional cardiology programs at Boston’s Brigham and Women’s Hospital. In a video interview, he hypothesized that “prior PCI may serve as a sort of ‘stress test’ for bleeding,” thus identifying a subset of patients who might benefit from long-term DAPT.

Ischemic events, the primary efficacy outcome of THEMIS, occurred in 7.7% of patients taking the P2Y12 receptor antagonist ticagrelor and 8.5% of those receiving placebo, for a hazard ratio of 0.90 favoring ticagrelor (P = .04). Ischemic events included cardiovascular deaths, myocardial infarctions (MIs), and stroke.

Looking at secondary endpoints, Dr. Bhatt said that there was no difference in cardiovascular deaths between study arms, but that ischemic strokes, all MIs, and ST segment elevation MIs were all less common for patients taking ticagrelor. All-cause mortality was similar between study groups.

Though ischemic events dropped, “This benefit was achieved at the expense of more bleeding,” said Dr. Bhatt. Major bleeding, the primary safety outcome, was seen in 2.2% of those taking ticagrelor and 1.0% of the placebo group, for a hazard ratio of 2.32 (P less than .001). Dr. Bhatt and his collaborators used the Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding for ascertainment of this outcome.

Intracranial hemorrhage was also more common for patients on ticagrelor, though incidence was low and the absolute difference was small between groups. This complication occurred in 0.7% of ticagrelor patients and 0.5% of placebo patients, yielding a hazard ratio of 1.71 (P = .0005). “This excess wasn’t in spontaneous or procedural intracranial bleeding, but rather in traumatic intracranial hemorrhage,” said Dr. Bhatt.

Fatal bleeds affected just 0.2% of those on ticagrelor and 0.1% of those receiving placebo; this difference wasn’t statistically significant.

koakes@mdedgecom

Source: Steg PG et al. N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Bhatt DL et al.Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2)

PARIS – Patients with stable coronary artery disease and type 2 diabetes saw fewer ischemic cardiovascular events when they received dual antiplatelet therapy with ticagrelor plus aspirin, though they also had more major bleeding events than patients receiving placebo plus aspirin.

The subset of patients who had received prior percutaneous coronary intervention (PCI) stood to benefit more from extended dual antiplatelet therapy (DAPT), according to clinical trial results presented to an overflow crowd at the annual congress of the European Society of Cardiology.

Findings from the full study, named The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS), and from the PCI subgroup analysis were published concurrently with the presentation (N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2).

“This strategy of long-term dual antiplatelet therapy may be beneficial in selected patients at low risk of bleeding, but at high risk of ischemic events,” said the study’s co-principal investigator Deepak Bhatt, MD, professor of medicine at Harvard Medical School, Boston, and executive director of interventional cardiology programs at Boston’s Brigham and Women’s Hospital. In a video interview, he hypothesized that “prior PCI may serve as a sort of ‘stress test’ for bleeding,” thus identifying a subset of patients who might benefit from long-term DAPT.

Ischemic events, the primary efficacy outcome of THEMIS, occurred in 7.7% of patients taking the P2Y12 receptor antagonist ticagrelor and 8.5% of those receiving placebo, for a hazard ratio of 0.90 favoring ticagrelor (P = .04). Ischemic events included cardiovascular deaths, myocardial infarctions (MIs), and stroke.

Looking at secondary endpoints, Dr. Bhatt said that there was no difference in cardiovascular deaths between study arms, but that ischemic strokes, all MIs, and ST segment elevation MIs were all less common for patients taking ticagrelor. All-cause mortality was similar between study groups.

Though ischemic events dropped, “This benefit was achieved at the expense of more bleeding,” said Dr. Bhatt. Major bleeding, the primary safety outcome, was seen in 2.2% of those taking ticagrelor and 1.0% of the placebo group, for a hazard ratio of 2.32 (P less than .001). Dr. Bhatt and his collaborators used the Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding for ascertainment of this outcome.

Intracranial hemorrhage was also more common for patients on ticagrelor, though incidence was low and the absolute difference was small between groups. This complication occurred in 0.7% of ticagrelor patients and 0.5% of placebo patients, yielding a hazard ratio of 1.71 (P = .0005). “This excess wasn’t in spontaneous or procedural intracranial bleeding, but rather in traumatic intracranial hemorrhage,” said Dr. Bhatt.

Fatal bleeds affected just 0.2% of those on ticagrelor and 0.1% of those receiving placebo; this difference wasn’t statistically significant.

koakes@mdedgecom

Source: Steg PG et al. N Engl J Med. 2019 Sep 1: DOI: 10.1056/NEJMoa1908077; Bhatt DL et al.Lancet. 2019 Sep 1: DOI:https://doi.org/10.1016/S0140-6736(19)31887-2)

PARIS – Bleeding after acute coronary syndrome is associated with an increased risk for a new diagnosis of cancer, according to work presented at the annual congress of the European Society of Cardiology.

Of 3,644 patients discharged with dual-antiplatelet therapy after acute coronary syndrome (ACS), 1,215 (33%) had postdischarge bleeding. Taken together, patients who bled had a hazard ratio (HR) of 3.43 for a new cancer diagnosis (P less than .001).

Of the patients in the post-ACS cohort, 227 were newly diagnosed with cancer after discharge, making up 1% of the patients who did not bleed after discharge, and 3.9% of the patients who experienced postdischarge bleeding. Put another way, “[t]he positive predictive value for cancer diagnosis of post-discharge bleeding was 7.7%,” wrote Isabel Muñoz Pousa, MD, and her colleagues in the poster accompanying the presentation.

This elevated risk for cancer diagnosis was driven primarily by the 827 incidents of spontaneous bleeding; here, the HR was 4.38 (P less than .001). The 389 bleeds occuring after trauma, such as bladder catheterization or a fall, did not carry an increased risk for a new cancer diagnosis.

“Spontaneous post-discharge bleeding in ACS patients is strongly associated with subsequent cancer diagnosis within the first 6 months,” wrote Dr. Muñoz Pousa and her colleagues of the Hospital Universitario Alvaro Cunqueiro, Vigo, Spain. The investigators found a median time of 4.6 months from the bleeding episode to cancer diagnosis.

Of all anatomic locations, genitourinary bleeds were the most strongly associated with new cancer: 228 patients saw a HR of 8.63 for a new cancer diagnosis (P less than .001). Bronchopulmonary bleeds, sustained by 56 patients, carried a HR of 4.26 for new cancer diagnosis, and gastrointestinal bleeds a HR of 3.78 (P = .001 and P less than .001, respectively). Dr. Muñoz Pousa and her coinvestigators aggregated data from patients who had bleeding at other sites and saw no significant association with new cancers in this group of patients.

Though patients were initially discharged on dual-antiplatelet therapy, many patients stopped taking the medication over the mean 56.2 months of follow-up. The risk of bleeding did not differ significantly between those who were taking DAPT and those off DAPT, wrote Dr. Muñoz Pousa and her colleagues, adding: “We found a higher incidence of cancer in the first six months after discharge regardless of whether patients were taking dual-antiplatelet therapy or not.”

In their statistical analysis, Dr. Muñoz Pousa and colleagues adjusted for potential confounders, and looked at the effect of bleeding as a time-varying covariate on subsequent cancer diagnosis, using Cox regression models.

“Most of the bleeding episodes in the study were mild,” noted Dr. Munoz Pousa in a press statement. However, she said, “The bleeding events more strongly related with a new cancer diagnosis were severe hemorrhages of unknown cause requiring surgery – for example digestive bleeding needing endoscopic treatment.”

Breaking bleeding severity down by Bleeding Academic Research Consortium (BARC) criteria, the investigators found that most patients had relatively mild bleeding episodes categorized as BARC 1 or 2, with about half of all bleeding falling into the BARC 1 category.

Still, the 436 patients who had BARC 2 bleeding had a hazard ratio of 4.88 for cancer diagnosis, and the 71 BARC 3A patients saw the HR climb to 7.30. The risk for cancer subsequent to bleeding peaked at BARC 3B, with a HR of 12.29 for these 46 individuals (P less than .001 for all). Just 37 patients experienced BARC 3C bleeds, which were associated with a nonsignificant HR of 3.17 for new cancer diagnosis.

Although it’s not known why the post ACS–cancer bleeding association exists, Dr. Munoz Pousa put forward a plausible reason for the link. “A possible explanation is that there is a preexisting subclinical lesion in an organ that is triggered to become cancer by antiplatelet drugs or a stressful situation such as heart attack,” she said in the press release.

Antiplatelet therapy should be taken as prescribed post-ACS, and the physician threshold for further evaluation should be low when a significant spontaneous bleed is seen soon after ACS. “A prompt evaluation of bleeding could be useful for enabling an early detection of cancer in these patients,” said Dr. Munoz Pousa and her colleagues. “Our results suggest that patients should seek medical advice if they experience bleeding after discharge for a heart attack.”

The authors reported no conflicts of interest.
 

[email protected]

SOURCE: Munoz Pousa, I. et al. ESC Congress 2019, Abstract P677.

PARIS – Bleeding after acute coronary syndrome is associated with an increased risk for a new diagnosis of cancer, according to work presented at the annual congress of the European Society of Cardiology.

Of 3,644 patients discharged with dual-antiplatelet therapy after acute coronary syndrome (ACS), 1,215 (33%) had postdischarge bleeding. Taken together, patients who bled had a hazard ratio (HR) of 3.43 for a new cancer diagnosis (P less than .001).

Of the patients in the post-ACS cohort, 227 were newly diagnosed with cancer after discharge, making up 1% of the patients who did not bleed after discharge, and 3.9% of the patients who experienced postdischarge bleeding. Put another way, “[t]he positive predictive value for cancer diagnosis of post-discharge bleeding was 7.7%,” wrote Isabel Muñoz Pousa, MD, and her colleagues in the poster accompanying the presentation.

This elevated risk for cancer diagnosis was driven primarily by the 827 incidents of spontaneous bleeding; here, the HR was 4.38 (P less than .001). The 389 bleeds occuring after trauma, such as bladder catheterization or a fall, did not carry an increased risk for a new cancer diagnosis.

“Spontaneous post-discharge bleeding in ACS patients is strongly associated with subsequent cancer diagnosis within the first 6 months,” wrote Dr. Muñoz Pousa and her colleagues of the Hospital Universitario Alvaro Cunqueiro, Vigo, Spain. The investigators found a median time of 4.6 months from the bleeding episode to cancer diagnosis.

Of all anatomic locations, genitourinary bleeds were the most strongly associated with new cancer: 228 patients saw a HR of 8.63 for a new cancer diagnosis (P less than .001). Bronchopulmonary bleeds, sustained by 56 patients, carried a HR of 4.26 for new cancer diagnosis, and gastrointestinal bleeds a HR of 3.78 (P = .001 and P less than .001, respectively). Dr. Muñoz Pousa and her coinvestigators aggregated data from patients who had bleeding at other sites and saw no significant association with new cancers in this group of patients.

Though patients were initially discharged on dual-antiplatelet therapy, many patients stopped taking the medication over the mean 56.2 months of follow-up. The risk of bleeding did not differ significantly between those who were taking DAPT and those off DAPT, wrote Dr. Muñoz Pousa and her colleagues, adding: “We found a higher incidence of cancer in the first six months after discharge regardless of whether patients were taking dual-antiplatelet therapy or not.”

In their statistical analysis, Dr. Muñoz Pousa and colleagues adjusted for potential confounders, and looked at the effect of bleeding as a time-varying covariate on subsequent cancer diagnosis, using Cox regression models.

“Most of the bleeding episodes in the study were mild,” noted Dr. Munoz Pousa in a press statement. However, she said, “The bleeding events more strongly related with a new cancer diagnosis were severe hemorrhages of unknown cause requiring surgery – for example digestive bleeding needing endoscopic treatment.”

Breaking bleeding severity down by Bleeding Academic Research Consortium (BARC) criteria, the investigators found that most patients had relatively mild bleeding episodes categorized as BARC 1 or 2, with about half of all bleeding falling into the BARC 1 category.

Still, the 436 patients who had BARC 2 bleeding had a hazard ratio of 4.88 for cancer diagnosis, and the 71 BARC 3A patients saw the HR climb to 7.30. The risk for cancer subsequent to bleeding peaked at BARC 3B, with a HR of 12.29 for these 46 individuals (P less than .001 for all). Just 37 patients experienced BARC 3C bleeds, which were associated with a nonsignificant HR of 3.17 for new cancer diagnosis.

Although it’s not known why the post ACS–cancer bleeding association exists, Dr. Munoz Pousa put forward a plausible reason for the link. “A possible explanation is that there is a preexisting subclinical lesion in an organ that is triggered to become cancer by antiplatelet drugs or a stressful situation such as heart attack,” she said in the press release.

Antiplatelet therapy should be taken as prescribed post-ACS, and the physician threshold for further evaluation should be low when a significant spontaneous bleed is seen soon after ACS. “A prompt evaluation of bleeding could be useful for enabling an early detection of cancer in these patients,” said Dr. Munoz Pousa and her colleagues. “Our results suggest that patients should seek medical advice if they experience bleeding after discharge for a heart attack.”

The authors reported no conflicts of interest.
 

[email protected]

SOURCE: Munoz Pousa, I. et al. ESC Congress 2019, Abstract P677.

PARIS – Bleeding after acute coronary syndrome is associated with an increased risk for a new diagnosis of cancer, according to work presented at the annual congress of the European Society of Cardiology.

Of 3,644 patients discharged with dual-antiplatelet therapy after acute coronary syndrome (ACS), 1,215 (33%) had postdischarge bleeding. Taken together, patients who bled had a hazard ratio (HR) of 3.43 for a new cancer diagnosis (P less than .001).

Of the patients in the post-ACS cohort, 227 were newly diagnosed with cancer after discharge, making up 1% of the patients who did not bleed after discharge, and 3.9% of the patients who experienced postdischarge bleeding. Put another way, “[t]he positive predictive value for cancer diagnosis of post-discharge bleeding was 7.7%,” wrote Isabel Muñoz Pousa, MD, and her colleagues in the poster accompanying the presentation.

This elevated risk for cancer diagnosis was driven primarily by the 827 incidents of spontaneous bleeding; here, the HR was 4.38 (P less than .001). The 389 bleeds occuring after trauma, such as bladder catheterization or a fall, did not carry an increased risk for a new cancer diagnosis.

“Spontaneous post-discharge bleeding in ACS patients is strongly associated with subsequent cancer diagnosis within the first 6 months,” wrote Dr. Muñoz Pousa and her colleagues of the Hospital Universitario Alvaro Cunqueiro, Vigo, Spain. The investigators found a median time of 4.6 months from the bleeding episode to cancer diagnosis.

Of all anatomic locations, genitourinary bleeds were the most strongly associated with new cancer: 228 patients saw a HR of 8.63 for a new cancer diagnosis (P less than .001). Bronchopulmonary bleeds, sustained by 56 patients, carried a HR of 4.26 for new cancer diagnosis, and gastrointestinal bleeds a HR of 3.78 (P = .001 and P less than .001, respectively). Dr. Muñoz Pousa and her coinvestigators aggregated data from patients who had bleeding at other sites and saw no significant association with new cancers in this group of patients.

Though patients were initially discharged on dual-antiplatelet therapy, many patients stopped taking the medication over the mean 56.2 months of follow-up. The risk of bleeding did not differ significantly between those who were taking DAPT and those off DAPT, wrote Dr. Muñoz Pousa and her colleagues, adding: “We found a higher incidence of cancer in the first six months after discharge regardless of whether patients were taking dual-antiplatelet therapy or not.”

In their statistical analysis, Dr. Muñoz Pousa and colleagues adjusted for potential confounders, and looked at the effect of bleeding as a time-varying covariate on subsequent cancer diagnosis, using Cox regression models.

“Most of the bleeding episodes in the study were mild,” noted Dr. Munoz Pousa in a press statement. However, she said, “The bleeding events more strongly related with a new cancer diagnosis were severe hemorrhages of unknown cause requiring surgery – for example digestive bleeding needing endoscopic treatment.”

Breaking bleeding severity down by Bleeding Academic Research Consortium (BARC) criteria, the investigators found that most patients had relatively mild bleeding episodes categorized as BARC 1 or 2, with about half of all bleeding falling into the BARC 1 category.

Still, the 436 patients who had BARC 2 bleeding had a hazard ratio of 4.88 for cancer diagnosis, and the 71 BARC 3A patients saw the HR climb to 7.30. The risk for cancer subsequent to bleeding peaked at BARC 3B, with a HR of 12.29 for these 46 individuals (P less than .001 for all). Just 37 patients experienced BARC 3C bleeds, which were associated with a nonsignificant HR of 3.17 for new cancer diagnosis.

Although it’s not known why the post ACS–cancer bleeding association exists, Dr. Munoz Pousa put forward a plausible reason for the link. “A possible explanation is that there is a preexisting subclinical lesion in an organ that is triggered to become cancer by antiplatelet drugs or a stressful situation such as heart attack,” she said in the press release.

Antiplatelet therapy should be taken as prescribed post-ACS, and the physician threshold for further evaluation should be low when a significant spontaneous bleed is seen soon after ACS. “A prompt evaluation of bleeding could be useful for enabling an early detection of cancer in these patients,” said Dr. Munoz Pousa and her colleagues. “Our results suggest that patients should seek medical advice if they experience bleeding after discharge for a heart attack.”

The authors reported no conflicts of interest.
 

[email protected]

SOURCE: Munoz Pousa, I. et al. ESC Congress 2019, Abstract P677.

PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.

“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.

This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.

Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.

“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.

The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.

The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.

The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.

In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.

“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.

POP AGE is hailed as ‘a wake up call’

In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”

“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.

Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.

“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”

So is POP AGE a practice-changing study?

“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”

“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.

Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
 

[email protected]

SOURCE: Gimbel ME. ESC 2019, Abstract 84.


 

PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.

“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.

This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.

Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.

“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.

The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.

The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.

The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.

In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.

“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.

POP AGE is hailed as ‘a wake up call’

In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”

“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.

Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.

“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”

So is POP AGE a practice-changing study?

“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”

“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.

Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
 

[email protected]

SOURCE: Gimbel ME. ESC 2019, Abstract 84.


 

PARIS – Older patients with non-ST-elevation acute coronary syndrome who were assigned to 12 months of dual antiplatelet therapy with clopidogrel experienced significantly less major and minor bleeding than with ticagrelor or prasugrel and were similarly protected from thrombotic events in the prospective randomized POPular AGE trial, Marieke E. Gimbel, MD, reported at the annual congress of the European Society of Cardiology.

“Therefore, we consider clopidogrel the preferred treatment in patients age 70 or older with non-ST-elevation ACS,” said Dr. Gimbel, a cardiologist at St. Antonius Hospital in Nieuwegein, The Netherlands.

This stance is contrary to both the current ESC and U.S. guidelines on management of non-ST-elevation ACS, which preferentially recommend ticagrelor and prasugrel over clopidogrel, chiefly on the basis of the large PLATO (N Engl J Med 2009;361:1045-57) and TRITON TIMI 38 (N Engl J Med 2007;357:2001-15) randomized trials. Those studies from the previous decade reported significantly lower rates of the composite endpoint of cardiovascular death, acute MI, or stroke in patients on ticagrelor or prasugrel, respectively, than with clopidogrel. But this benefit came at a cost of significantly higher rates of TIMI major bleeding than with clopidogrel, and multiple studies have shown that major bleeding in ACS patients is associated with a sharply increased risk of death.

Bleeding is an issue of particular concern in the elderly. But older patients were greatly underrepresented in PLATO and TRITON, where they comprised just 13%-15% of participants, even though registry studies would suggest older individuals make up about 35% of all patients with non-ST-elevation ACS. Selective inclusion of elderly patients in the major trials means those study results can’t legitimately be extrapolated to the entire elderly patient population.

“The best course of action in the elderly has been unclear,” Dr. Gimbel argued.

The POPular AGE (POP AGE) trial was an open-label study featuring independent blinded adjudication of clinical events. The median age of participants was 77 years, and about one-quarter had a prior MI. It was basically an all-comers study in which 1,003 non-ST-elevation ACS patients age 70 or older at 11 Dutch medical centers were randomized within 3 days of hospital admission to 12 months of dual antiplatelet therapy with either ticagrelor or one of the two more potent antiplatelet agents. Although the choice of ticagrelor or prasugrel was left to the physician, it’s noteworthy that 94% of patients in the high-potency P2Y12 inhibitor study arm were discharged on ticagrelor. At 12 months, the adherence rate to the assigned regimen was 76% in the clopidogrel group and just 51% in what was essentially the ticagrelor arm. Bleeding was the number-one reason for the much higher discontinuation rate in the ticagrelor group, followed by initiation of oral anticoagulation and dyspnea.

The primary safety endpoint in POP AGE was the rate of major and minor bleeding as defined in the PLATO study. The rate was 17.6% with clopidogrel, compared with 23.1% in the ticagrelor group, for a highly significant 26% reduction in relative risk. Of note, the PLATO major bleeding rate was 4.4% with clopidogrel, versus 8% with ticagrelor/prasugrel.

The coprimary endpoint was net clinical benefit, defined as a composite of all-cause mortality, MI, stroke, and PLATO major and minor bleeding. The rate was 30.7% with ticagrelor and 27.3% in the clopidogrel group, for an absolute 3.4% risk difference favoring clopidogrel, which barely missed the prespecified cutoff for noninferiority. Indeed, even though the 12-month follow-up was 99.6% complete, Dr. Gimbel raised the possibility that when the results come in for the final 0.4% of the study population, the difference in net clinical benefit may reach significance.

In any case, she noted there was no between-group difference in the key secondary endpoint of death, MI, or stroke, with rates of 12.8% and 12.5% in the clopidogrel and ticagrelor groups, respectively.

“One might expect a higher ischemic event rate with clopidogrel compared to ticagrelor. However, in these elderly patients there was no difference between the two treatment strategies,” the cardiologist observed.

POP AGE is hailed as ‘a wake up call’

In an interview, Freek Verheugt, MD, PhD, professor emeritus of cardiology at Radboud University in Nijmegen, The Netherlands, called POP AGE “a very important study.”

“The problem with most studies in the elderly is that they are post hoc analyses from huge trials like PLATO and TRITON, and also the thrombolysis and primary PCI studies. The elderly do very well in those studies, because only the very fit elderly are included in the megatrials. It’s much more important to do a prospective randomized trial in the elderly only, and this is one of the very few done so far,” he observed.

Bleeding is a major problem in the elderly with ACS. It leads to more MIs, strokes, and increased mortality.

“Even minor bleeding is an issue,” Dr. Verheugt added. “Minor bleeding is a major problem, because patients who encounter minor bleeding – nose bleeds, gum bleeds, or even in their underwear – they do away with all drugs. They stop their antithrombotic, but they also stop their statin, their ACE inhibitor – their lifesavers – and that’s why they die.”

So is POP AGE a practice-changing study?

“No, of course not,” the cardiologist scoffed. “To be practice-changing you need several trials going in the same direction. But I think if there are more data prospectively accrued in the elderly alone, showing the same, then POP AGE would be practice-changing.”

“In my personal view, this study is a wake-up call. If you have an elderly, frail patient presenting with ACS, strongly consider good, old clopidogrel. Although people say that 30% of patients on clopidogrel don’t have appropriate platelet inhibition, that’s a laboratory finding. It’s not a clinical finding. POP AGE gave us a clinical finding showing that they do quite well,” he said.

Dr. Verheugt was on the independent data safety monitoring board for POP AGE, funded by ZonMw, a Dutch governmental research organization. Neither Dr. Verheugt nor Dr. Gimbel reported having any financial conflicts of interest.
 

[email protected]

SOURCE: Gimbel ME. ESC 2019, Abstract 84.


 

Initial management decisions for patients with community-acquired pneumonia (CAP) will depend on severity of infection, with need for hospitalization being one of the first decisions. Because empiric antibiotics are the mainstay of treatment and the causative organisms are seldom identified, underlying medical conditions and epidemiologic risk factors are considered when selecting an empiric regimen. As with other infections, duration of therapy is not standardized, but rather is guided by clinical improvement. Prevention of pneumonia centers around vaccination and smoking cessation. This article, the second in a 2-part review of CAP in adults, focuses on site of care decision, empiric and directed therapies, length of treatment, and prevention strategies. Evaluation and diagnosis of CAP are discussed in a separate article.

Site of Care Decision

For patients diagnosed with CAP, the clinician must decide whether treatment will be done in an outpatient or inpatient setting, and for those in the inpatient setting, whether they can safely be treated on the general medical ward or in the intensive care unit (ICU). Two common scoring systems that can be used to aid the clinician in determining severity of the infection and guide site-of-care decisions are the Pneumonia Severity Index (PSI) and CURB-65 scores.

The PSI score uses 20 different parameters, including comorbidities, laboratory parameters, and radiographic findings, to stratify patients into 5 mortality risk classes.¹ On the basis of associated mortality rates, it has been suggested that risk class I and II patients should be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients should be treated as inpatients.¹

The CURB-65 method of risk stratification is based on 5 clinical parameters: confusion, urea level, respiratory rate, systolic blood pressure, and age ≥ 65 years (Table 1).^2,3 A modification to the CURB-65 algorithm tool was CRB-65, which excludes urea nitrogen, making it optimal for making determinations in a clinic-based setting. It should be emphasized that these tools do not take into account other factors that should be used in determining location of treatment, such as stable home, mental illness, or concerns about compliance with medications. In many instances, it is these factors that preclude low-risk patients from being treated as outpatients.^4,5 Similarly, these scoring systems have not been validated for immunocompromised patients or those who would qualify as having health care–associated pneumonia.

Patients with CURB-65 scores of 4 or 5 are considered to have severe pneumonia, and admission to the ICU should be considered for these patients. Aside from the CURB-65 score, anyone requiring vasopressor support or mechanical ventilation merits admission to the ICU.⁶ American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guidelines also recommend the use of “minor criteria” for making ICU admission decisions; these include respiratory rate ≥ 30 breaths/minute, PaO₂ fraction ≤ 250 mm Hg, multilobar infiltrates, confusion, blood urea nitrogen ≥ 20 mg/dL, leukopenia, thrombocytopenia, hypothermia, and hypotension.⁶ These factors are associated with increased mortality due to CAP, and ICU admission is indicated if 3 of the minor criteria for severe CAP are present.

Another clinical calculator that can be used for assessing severity of CAP is SMART-COP (systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation and arterial pH).⁷ This scoring system uses 8 weighted criteria to predict which patients will require intensive respiratory or vasopressor support. SMART-COP has a sensitivity of 79% and a specificity of 64% in predicting ICU admission, whereas CURB-65 has a pooled sensitivity of 57.2% and specificity of 77.2%.⁸

Antibiotic Therapy

Antibiotics are the mainstay of treatment for CAP, with the majority of patients with CAP treated empirically taking into account the site of care, likely pathogen, and antimicrobial resistance issues. Patients with pneumonia who are treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment of CAP usually receive empiric antibiotic on admission. Once the etiology has been determined by microbiologic or serologic means, antimicrobial therapy should be adjusted accordingly. A CDC study found that the burden of viral etiologies was higher than previously thought, with rhinovirus and influenza accounting for 15% of cases and Streptococcus pneumoniae for only 5%.⁹ This study highlighted the fact that despite advances in molecular techniques, no pathogen is identified for most patients with pneumonia.⁹ Given the lack of discernable pathogens in the majority of cases, patients should continue to be treated with antibiotics unless a nonbacterial etiology is found.

Outpatients without comorbidities or risk factors for drug-resistant S. pneumoniae (Table 2)¹⁰ can be treated with monotherapy. Hospitalized patients are usually treated with combination intravenous therapy, although non-ICU patients who receive a respiratory fluoroquinolone can be treated orally.

As previously mentioned, antibiotic therapy is typically empiric, since neither clinical features nor radiographic features are sufficient to include or exclude infectious etiologies. Epidemiologic risk factors should be considered and, in certain cases, antimicrobial coverage should be expanded to include those entities; for example, treatment of anaerobes in the setting of lung abscess and antipseudomonal antibiotics for patients with bronchiectasis.

Of concern in the treatment of CAP is the increased prevalence of antimicrobial resistance among S. pneumoniae. The IDSA guidelines report that drug-resistant S. pneumoniae is more common in persons aged < 2 or > 65 years, and those with β-lactam therapy within the previous 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, or exposure to a child who attends a day care center.⁶

Staphylococcus aureus should be considered during influenza outbreaks, with either vancomycin or linezolid being the recommended agents in the setting of methicillin-resistant S. aureus (MRSA). In a study comparing vancomycin versus linezolid for nosocomial pneumonia, the all-cause 60-day mortality was similar for both agents.¹¹ Daptomycin, another agent used against MRSA, is not indicated in the setting of pneumonia because daptomycin binds to surfactant, yielding it ineffective in the treatment of pneumonia.¹² Ceftaroline is a newer cephalosporin with activity against MRSA; its role in treatment of community-acquired MRSA pneumonia has not been fully elucidated, but it appears to be a useful agent for this indication.^13,14 Similarly, other agents known to have antibacterial properties against MRSA, such as trimethoprim/sulfamethoxazole and doxycycline, have not been studied for this indication. Clindamycin has been used to treat MRSA in children, and IDSA guidelines on the treatment of MRSA list clindamycin as an alternative¹⁵ if MRSA is known to be sensitive.

A summary of recommended empiric antibiotic therapy is presented in Table 3.¹⁶

Three antibiotics were approved by the US Food and Drug Administration (FDA) for the treatment of CAP after the release of the IDSA/ATS guidelines in 2007. Ceftaroline fosamil is a fifth-generation cephalosporin that has coverage for MRSA and was approved in November 2010.¹⁷ It can only be administered intravenously and needs dose adjustment for renal function. Omadacycline is a new tetracycline that was approved by the FDA in October 2018.¹⁸ It is available in both intravenous injectable and oral forms. No dose adjustment is needed for renal function. Lefamulin is a first-in-class novel pleuromutilin antibiotic which was FDA-approved in August 2019. It can be administered intravenously or orally, with no dosage adjustment necessary in patients with renal impairment.¹⁹

Antibiotic Therapy for Selected Pathogens

Streptococcus pneumoniae

Patients with pneumococcal pneumonia who have penicillin-susceptible strains can be treated with intravenous penicillin (2 or 3 million units every 4 hours) or ceftriaxone. Once a patient meets criteria of stability, they can then be transitioned to oral penicillin, amoxicillin, or clarithromycin. Those with strains with reduced susceptibility can still be treated with penicillin, but at a higher dose (4 million units intravenously [IV] every 4 hours), or a third-generation cephalosporin. Those whose pneumococcal pneumonia is complicated by bacteremia will benefit from dual therapy if severely ill, requiring ICU monitoring. Those not severely ill can be treated with monotherapy.²⁰

Staphylococcus aureus

Staphylococcus aureus is more commonly associated with hospital-acquired pneumonia, but it may also be seen during the influenza season and in those with severe necrotizing CAP. Both linezolid and vancomycin can be used to treat MRSA CAP. As noted, ceftaroline has activity against MRSA and is approved for treatment of CAP, but is not approved by the FDA for MRSA CAP treatment. Similarly, tigecycline is approved for CAP and has activity against MRSA, but is not approved for MRSA CAP. Moreover, the FDA has warned of increased risk of death with tigecycline and has a black box warning to that effect.²¹

Legionella

Legionellosis can be treated with tetra¬cyclines, macrolides, or fluoroquinolones. For non-immunocompromised patients with mild pneumonia, any of the listed antibiotics is considered appropriate. However, patients with severe infection or those with immunosuppression should be treated with either levofloxacin or azithromycin for 7 to 10 days.²²

Chlamydophila pneumoniae

As with other atypical organisms, Chlamydophila pneumoniae can be treated with doxycycline, a macrolide, or respiratory fluoroquinolones. However, length of therapy varies by regimen used; treating with doxycycline 100 mg twice daily generally requires 14 to 21 days, whereas moxifloxacin 400 mg daily requires 10 days.²³

Mycoplasma pneumoniae

As with C. pneumoniae, length of therapy of Mycoplasma pneumoniae varies by which antimicrobial regimen is used. Shortest courses are seen with the use of macrolides for 5 days, whereas 14 days is considered standard for doxycycline or a respiratory fluoroquinolone.²⁴ It should be noted that there has been increasingly documented resistance to macrolides, with known resistance of 8.2% in the United States.²⁵

Duration of Treatment

Most patients with CAP respond to appropriate therapy within 72 hours. IDSA/ATS guidelines recommend that patients with routine cases of CAP be treated for a minimum of 5 days. Despite this, many patients are treated for an excessive amount of time, with over 70% of patients reported to have received antibiotics for more than 10 days for uncomplicated CAP.²⁶ There are instances that require longer courses of antibiotics, including cases caused by Pseudomonas aeruginosa, S. aureus, and Legionella species and patients with lung abscesses or necrotizing infections, among others.²⁷

Hospitalized patients do not need to be monitored for an additional day once they have reached clinical stability (Table 4), are able to maintain oral intake, and have normal mentation, provided that other comorbidities are stable and social needs have been met.⁶ C-reactive protein (CRP) level has been postulated as an additional measure of stability, specifically monitoring for a greater than 50% reduction in CRP; however, this was validated only for those with complicated pneumonia.²⁸ Patients discharged from the hospital with instability have higher risk of readmission or death.²⁹

Transition to Oral Therapy

IDSA/ATS guidelines⁶ recommend that patients should be transitioned from intravenous to oral antibiotics when they are improving clinically, have stable vital signs, and are able to ingest food/fluids and medications.

Management of Nonresponders

Although the majority of patients respond to antibiotics within 72 hours, treatment failure occurs in up to 15% of patients.¹⁵ Nonresponding pneumonia is generally seen in 2 patterns: worsening of clinical status despite empiric antibiotics or delay in achieving clinical stability, as defined in Table 4, after 72 hours of treatment.³⁰ Risk factors associated with nonresponding pneumonia³¹ are:

• Radiographic: multilobar infiltrates, pleural effusion, cavitation
• Bacteriologic: MRSA, gram-negative or Legionella pneumonia
• Severity index: PSI > 90
• Pharmacologic: incorrect antibiotic choice based on susceptibility

Patients with acute deterioration of clinical status require prompt transfer to a higher level of care and may require mechanical ventilator support. In those with delay in achieving clinical stability, a question centers on whether the same antibiotics can be continued while doing further radiographic/microbiologic work-up and/or changing antibiotics. History should be reviewed, with particular attention to exposures, travel history, and microbiologic and radiographic data. Clinicians should recall that viruses account for up to 20% of pneumonias and that there are also noninfectious causes that can mimic pyogenic infections.³² If adequate initial cultures were not obtained, they should be obtained; however, care must be taken in reviewing new sets of cultures while on antibiotics, as they may reveal colonization selected out by antibiotics and not a true pathogen. If repeat evaluation is unrevealing, then further evaluation with computed tomography (CT) scan and bronchoscopy with bronchoalveolar lavage and biopsy is warranted. CT scans can show pleural effusions, bronchial obstructions, or a pattern suggestive of cryptogenic pneumonia. A bronchoscopy might yield a microbiologic diagnosis and, when combined with biopsy, can also evaluate for noninfectious causes.

As with other infections, if escalation of antibiotics is undertaken, clinicians should try to determine the reason for nonresponse. To simply broaden antimicrobial therapy without attempts at establishing a microbiologic or radiographic cause for nonresponse may lead to inappropriate treatment and recurrence of infection. Aside from patients who have bacteremic pneumococcal pneumonia in an ICU setting, there are no published reports pointing to superiority of combination antibiotics.²⁰

Other Treatment

Several agents have been evaluated as adjunctive treatment of pneumonia to decrease the inflammatory response associated with pneumonia; namely, steroids, macrolide antibiotics, and statins. To date, only the use of steroids (methylprednisolone 0.5 mg/kg every 12 hours for 5 days) in those with severe CAP and high initial anti-inflammatory response (CRP > 150) has been shown to decrease treatment failure, decrease risk of acute respiratory distress syndrome, and possibly reduce length of stay and duration of intravenous antibiotics, without effect on mortality or adverse side effects.^33,34 However, a recent double-blind randomized study conducted in Australia in which patients admitted with CAP were prescribed prednisolone acetate (50 mg/day for 7 days) and de-escalated from parenteral to oral antibiotics according to standardized criteria revealed no difference in mortality, length of stay, or readmission rates between the corticosteroids group and the control group at 90-day follow-up.³⁵ At this point, corticosteroid as an adjunctive treatment for CAP is still controversial and the new 2019 ATS/IDSA guidelines recommend not routinely using corticosteroids in all patients with CAP.³⁶ Other adjunctive methods have not been found to have significant impact.⁶

Prevention of Pneumonia

Prevention of pneumococcal pneumonia involves vaccinations to prevent infection caused by S. pneumoniae and influenza viruses. As influenza is a risk factor for bacterial infection, specifically with S. pneumoniae, influenza vaccination can help prevent bacterial pneumonia.³⁷ In their most recent recommendations, the CDC continues to recommend routine influenza vaccination for all persons older than age 6 months, unless otherwise contraindicated.³⁸

There are 2 vaccines for prevention of pneumococcal disease: the pneumococcal polysaccharide vaccine (PPSV23) and a conjugate vaccine (PCV13). Following vaccination with PPSV23, 80% of adults develop antibodies against at least 18 of the 23 serotypes.³⁹ PPSV23 is reported to be protective against invasive pneumococcal infection, although there is no consensus regarding whether PPSV23 leads to decreased rates of pneumonia.⁴⁰ On the other hand, PCV13 vaccination was associated with prevention of both invasive disease and CAP in adults aged 65 years or older.⁴¹ The CDC recommends that all children aged 2 years or younger receive PCV13, and those aged 65 or older receive PCV13 followed by a dose of PPSV23.^42,43 The dose of PPSV23 should be given at least 1 year after the dose of PCV13 is administered.⁴⁴ Persons younger than 65 years with immunocompromising and certain other conditions should also receive vaccination (Table 5).⁴⁴ Full recommendations, many scenarios, and details on timing of vaccinations can be found at the CDC’s website.

Cigarette smoking increases the risk of respiratory infections, as evidenced by smokers accounting for almost half of all patients with invasive pneumococcal disease.¹¹ As this is a modifiable risk factor, smoking cessation should be part of a comprehensive approach toward prevention of pneumonia.

Summary

Most patients with CAP are treated empirically with antibiotics, with therapy selection based on the site of care, likely pathogen, and antimicrobial resistance issues. Those treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment usually receive empiric antibiotic on admission, and antimicrobial therapy is adjusted accordingly once the etiology has been determined by microbiologic or serologic means. At this time, the use of corticosteroid as an adjunctive treatment for CAP is still controversial, so not all patients with CAP should routinely receive corticosteroids. Because vaccination (PPSV23, PCV13, and influenza vaccine) remains the most effective tool in preventing the development of CAP, clinicians should strive for 100% vaccination rates in persons without contraindications.

Initial management decisions for patients with community-acquired pneumonia (CAP) will depend on severity of infection, with need for hospitalization being one of the first decisions. Because empiric antibiotics are the mainstay of treatment and the causative organisms are seldom identified, underlying medical conditions and epidemiologic risk factors are considered when selecting an empiric regimen. As with other infections, duration of therapy is not standardized, but rather is guided by clinical improvement. Prevention of pneumonia centers around vaccination and smoking cessation. This article, the second in a 2-part review of CAP in adults, focuses on site of care decision, empiric and directed therapies, length of treatment, and prevention strategies. Evaluation and diagnosis of CAP are discussed in a separate article.

Site of Care Decision

For patients diagnosed with CAP, the clinician must decide whether treatment will be done in an outpatient or inpatient setting, and for those in the inpatient setting, whether they can safely be treated on the general medical ward or in the intensive care unit (ICU). Two common scoring systems that can be used to aid the clinician in determining severity of the infection and guide site-of-care decisions are the Pneumonia Severity Index (PSI) and CURB-65 scores.

The PSI score uses 20 different parameters, including comorbidities, laboratory parameters, and radiographic findings, to stratify patients into 5 mortality risk classes.¹ On the basis of associated mortality rates, it has been suggested that risk class I and II patients should be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients should be treated as inpatients.¹

The CURB-65 method of risk stratification is based on 5 clinical parameters: confusion, urea level, respiratory rate, systolic blood pressure, and age ≥ 65 years (Table 1).^2,3 A modification to the CURB-65 algorithm tool was CRB-65, which excludes urea nitrogen, making it optimal for making determinations in a clinic-based setting. It should be emphasized that these tools do not take into account other factors that should be used in determining location of treatment, such as stable home, mental illness, or concerns about compliance with medications. In many instances, it is these factors that preclude low-risk patients from being treated as outpatients.^4,5 Similarly, these scoring systems have not been validated for immunocompromised patients or those who would qualify as having health care–associated pneumonia.

Patients with CURB-65 scores of 4 or 5 are considered to have severe pneumonia, and admission to the ICU should be considered for these patients. Aside from the CURB-65 score, anyone requiring vasopressor support or mechanical ventilation merits admission to the ICU.⁶ American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guidelines also recommend the use of “minor criteria” for making ICU admission decisions; these include respiratory rate ≥ 30 breaths/minute, PaO₂ fraction ≤ 250 mm Hg, multilobar infiltrates, confusion, blood urea nitrogen ≥ 20 mg/dL, leukopenia, thrombocytopenia, hypothermia, and hypotension.⁶ These factors are associated with increased mortality due to CAP, and ICU admission is indicated if 3 of the minor criteria for severe CAP are present.

Another clinical calculator that can be used for assessing severity of CAP is SMART-COP (systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation and arterial pH).⁷ This scoring system uses 8 weighted criteria to predict which patients will require intensive respiratory or vasopressor support. SMART-COP has a sensitivity of 79% and a specificity of 64% in predicting ICU admission, whereas CURB-65 has a pooled sensitivity of 57.2% and specificity of 77.2%.⁸

Antibiotic Therapy

Antibiotics are the mainstay of treatment for CAP, with the majority of patients with CAP treated empirically taking into account the site of care, likely pathogen, and antimicrobial resistance issues. Patients with pneumonia who are treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment of CAP usually receive empiric antibiotic on admission. Once the etiology has been determined by microbiologic or serologic means, antimicrobial therapy should be adjusted accordingly. A CDC study found that the burden of viral etiologies was higher than previously thought, with rhinovirus and influenza accounting for 15% of cases and Streptococcus pneumoniae for only 5%.⁹ This study highlighted the fact that despite advances in molecular techniques, no pathogen is identified for most patients with pneumonia.⁹ Given the lack of discernable pathogens in the majority of cases, patients should continue to be treated with antibiotics unless a nonbacterial etiology is found.

Outpatients without comorbidities or risk factors for drug-resistant S. pneumoniae (Table 2)¹⁰ can be treated with monotherapy. Hospitalized patients are usually treated with combination intravenous therapy, although non-ICU patients who receive a respiratory fluoroquinolone can be treated orally.

As previously mentioned, antibiotic therapy is typically empiric, since neither clinical features nor radiographic features are sufficient to include or exclude infectious etiologies. Epidemiologic risk factors should be considered and, in certain cases, antimicrobial coverage should be expanded to include those entities; for example, treatment of anaerobes in the setting of lung abscess and antipseudomonal antibiotics for patients with bronchiectasis.

Of concern in the treatment of CAP is the increased prevalence of antimicrobial resistance among S. pneumoniae. The IDSA guidelines report that drug-resistant S. pneumoniae is more common in persons aged < 2 or > 65 years, and those with β-lactam therapy within the previous 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, or exposure to a child who attends a day care center.⁶

Staphylococcus aureus should be considered during influenza outbreaks, with either vancomycin or linezolid being the recommended agents in the setting of methicillin-resistant S. aureus (MRSA). In a study comparing vancomycin versus linezolid for nosocomial pneumonia, the all-cause 60-day mortality was similar for both agents.¹¹ Daptomycin, another agent used against MRSA, is not indicated in the setting of pneumonia because daptomycin binds to surfactant, yielding it ineffective in the treatment of pneumonia.¹² Ceftaroline is a newer cephalosporin with activity against MRSA; its role in treatment of community-acquired MRSA pneumonia has not been fully elucidated, but it appears to be a useful agent for this indication.^13,14 Similarly, other agents known to have antibacterial properties against MRSA, such as trimethoprim/sulfamethoxazole and doxycycline, have not been studied for this indication. Clindamycin has been used to treat MRSA in children, and IDSA guidelines on the treatment of MRSA list clindamycin as an alternative¹⁵ if MRSA is known to be sensitive.

A summary of recommended empiric antibiotic therapy is presented in Table 3.¹⁶

Three antibiotics were approved by the US Food and Drug Administration (FDA) for the treatment of CAP after the release of the IDSA/ATS guidelines in 2007. Ceftaroline fosamil is a fifth-generation cephalosporin that has coverage for MRSA and was approved in November 2010.¹⁷ It can only be administered intravenously and needs dose adjustment for renal function. Omadacycline is a new tetracycline that was approved by the FDA in October 2018.¹⁸ It is available in both intravenous injectable and oral forms. No dose adjustment is needed for renal function. Lefamulin is a first-in-class novel pleuromutilin antibiotic which was FDA-approved in August 2019. It can be administered intravenously or orally, with no dosage adjustment necessary in patients with renal impairment.¹⁹

Antibiotic Therapy for Selected Pathogens

Streptococcus pneumoniae

Patients with pneumococcal pneumonia who have penicillin-susceptible strains can be treated with intravenous penicillin (2 or 3 million units every 4 hours) or ceftriaxone. Once a patient meets criteria of stability, they can then be transitioned to oral penicillin, amoxicillin, or clarithromycin. Those with strains with reduced susceptibility can still be treated with penicillin, but at a higher dose (4 million units intravenously [IV] every 4 hours), or a third-generation cephalosporin. Those whose pneumococcal pneumonia is complicated by bacteremia will benefit from dual therapy if severely ill, requiring ICU monitoring. Those not severely ill can be treated with monotherapy.²⁰

Staphylococcus aureus

Staphylococcus aureus is more commonly associated with hospital-acquired pneumonia, but it may also be seen during the influenza season and in those with severe necrotizing CAP. Both linezolid and vancomycin can be used to treat MRSA CAP. As noted, ceftaroline has activity against MRSA and is approved for treatment of CAP, but is not approved by the FDA for MRSA CAP treatment. Similarly, tigecycline is approved for CAP and has activity against MRSA, but is not approved for MRSA CAP. Moreover, the FDA has warned of increased risk of death with tigecycline and has a black box warning to that effect.²¹

Legionella

Legionellosis can be treated with tetra¬cyclines, macrolides, or fluoroquinolones. For non-immunocompromised patients with mild pneumonia, any of the listed antibiotics is considered appropriate. However, patients with severe infection or those with immunosuppression should be treated with either levofloxacin or azithromycin for 7 to 10 days.²²

Chlamydophila pneumoniae

As with other atypical organisms, Chlamydophila pneumoniae can be treated with doxycycline, a macrolide, or respiratory fluoroquinolones. However, length of therapy varies by regimen used; treating with doxycycline 100 mg twice daily generally requires 14 to 21 days, whereas moxifloxacin 400 mg daily requires 10 days.²³

Mycoplasma pneumoniae

As with C. pneumoniae, length of therapy of Mycoplasma pneumoniae varies by which antimicrobial regimen is used. Shortest courses are seen with the use of macrolides for 5 days, whereas 14 days is considered standard for doxycycline or a respiratory fluoroquinolone.²⁴ It should be noted that there has been increasingly documented resistance to macrolides, with known resistance of 8.2% in the United States.²⁵

Duration of Treatment

Most patients with CAP respond to appropriate therapy within 72 hours. IDSA/ATS guidelines recommend that patients with routine cases of CAP be treated for a minimum of 5 days. Despite this, many patients are treated for an excessive amount of time, with over 70% of patients reported to have received antibiotics for more than 10 days for uncomplicated CAP.²⁶ There are instances that require longer courses of antibiotics, including cases caused by Pseudomonas aeruginosa, S. aureus, and Legionella species and patients with lung abscesses or necrotizing infections, among others.²⁷

Hospitalized patients do not need to be monitored for an additional day once they have reached clinical stability (Table 4), are able to maintain oral intake, and have normal mentation, provided that other comorbidities are stable and social needs have been met.⁶ C-reactive protein (CRP) level has been postulated as an additional measure of stability, specifically monitoring for a greater than 50% reduction in CRP; however, this was validated only for those with complicated pneumonia.²⁸ Patients discharged from the hospital with instability have higher risk of readmission or death.²⁹

Transition to Oral Therapy

IDSA/ATS guidelines⁶ recommend that patients should be transitioned from intravenous to oral antibiotics when they are improving clinically, have stable vital signs, and are able to ingest food/fluids and medications.

Management of Nonresponders

Although the majority of patients respond to antibiotics within 72 hours, treatment failure occurs in up to 15% of patients.¹⁵ Nonresponding pneumonia is generally seen in 2 patterns: worsening of clinical status despite empiric antibiotics or delay in achieving clinical stability, as defined in Table 4, after 72 hours of treatment.³⁰ Risk factors associated with nonresponding pneumonia³¹ are:

• Radiographic: multilobar infiltrates, pleural effusion, cavitation
• Bacteriologic: MRSA, gram-negative or Legionella pneumonia
• Severity index: PSI > 90
• Pharmacologic: incorrect antibiotic choice based on susceptibility

Patients with acute deterioration of clinical status require prompt transfer to a higher level of care and may require mechanical ventilator support. In those with delay in achieving clinical stability, a question centers on whether the same antibiotics can be continued while doing further radiographic/microbiologic work-up and/or changing antibiotics. History should be reviewed, with particular attention to exposures, travel history, and microbiologic and radiographic data. Clinicians should recall that viruses account for up to 20% of pneumonias and that there are also noninfectious causes that can mimic pyogenic infections.³² If adequate initial cultures were not obtained, they should be obtained; however, care must be taken in reviewing new sets of cultures while on antibiotics, as they may reveal colonization selected out by antibiotics and not a true pathogen. If repeat evaluation is unrevealing, then further evaluation with computed tomography (CT) scan and bronchoscopy with bronchoalveolar lavage and biopsy is warranted. CT scans can show pleural effusions, bronchial obstructions, or a pattern suggestive of cryptogenic pneumonia. A bronchoscopy might yield a microbiologic diagnosis and, when combined with biopsy, can also evaluate for noninfectious causes.

As with other infections, if escalation of antibiotics is undertaken, clinicians should try to determine the reason for nonresponse. To simply broaden antimicrobial therapy without attempts at establishing a microbiologic or radiographic cause for nonresponse may lead to inappropriate treatment and recurrence of infection. Aside from patients who have bacteremic pneumococcal pneumonia in an ICU setting, there are no published reports pointing to superiority of combination antibiotics.²⁰

Other Treatment

Several agents have been evaluated as adjunctive treatment of pneumonia to decrease the inflammatory response associated with pneumonia; namely, steroids, macrolide antibiotics, and statins. To date, only the use of steroids (methylprednisolone 0.5 mg/kg every 12 hours for 5 days) in those with severe CAP and high initial anti-inflammatory response (CRP > 150) has been shown to decrease treatment failure, decrease risk of acute respiratory distress syndrome, and possibly reduce length of stay and duration of intravenous antibiotics, without effect on mortality or adverse side effects.^33,34 However, a recent double-blind randomized study conducted in Australia in which patients admitted with CAP were prescribed prednisolone acetate (50 mg/day for 7 days) and de-escalated from parenteral to oral antibiotics according to standardized criteria revealed no difference in mortality, length of stay, or readmission rates between the corticosteroids group and the control group at 90-day follow-up.³⁵ At this point, corticosteroid as an adjunctive treatment for CAP is still controversial and the new 2019 ATS/IDSA guidelines recommend not routinely using corticosteroids in all patients with CAP.³⁶ Other adjunctive methods have not been found to have significant impact.⁶

Prevention of Pneumonia

Prevention of pneumococcal pneumonia involves vaccinations to prevent infection caused by S. pneumoniae and influenza viruses. As influenza is a risk factor for bacterial infection, specifically with S. pneumoniae, influenza vaccination can help prevent bacterial pneumonia.³⁷ In their most recent recommendations, the CDC continues to recommend routine influenza vaccination for all persons older than age 6 months, unless otherwise contraindicated.³⁸

There are 2 vaccines for prevention of pneumococcal disease: the pneumococcal polysaccharide vaccine (PPSV23) and a conjugate vaccine (PCV13). Following vaccination with PPSV23, 80% of adults develop antibodies against at least 18 of the 23 serotypes.³⁹ PPSV23 is reported to be protective against invasive pneumococcal infection, although there is no consensus regarding whether PPSV23 leads to decreased rates of pneumonia.⁴⁰ On the other hand, PCV13 vaccination was associated with prevention of both invasive disease and CAP in adults aged 65 years or older.⁴¹ The CDC recommends that all children aged 2 years or younger receive PCV13, and those aged 65 or older receive PCV13 followed by a dose of PPSV23.^42,43 The dose of PPSV23 should be given at least 1 year after the dose of PCV13 is administered.⁴⁴ Persons younger than 65 years with immunocompromising and certain other conditions should also receive vaccination (Table 5).⁴⁴ Full recommendations, many scenarios, and details on timing of vaccinations can be found at the CDC’s website.

Cigarette smoking increases the risk of respiratory infections, as evidenced by smokers accounting for almost half of all patients with invasive pneumococcal disease.¹¹ As this is a modifiable risk factor, smoking cessation should be part of a comprehensive approach toward prevention of pneumonia.

Summary

Most patients with CAP are treated empirically with antibiotics, with therapy selection based on the site of care, likely pathogen, and antimicrobial resistance issues. Those treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment usually receive empiric antibiotic on admission, and antimicrobial therapy is adjusted accordingly once the etiology has been determined by microbiologic or serologic means. At this time, the use of corticosteroid as an adjunctive treatment for CAP is still controversial, so not all patients with CAP should routinely receive corticosteroids. Because vaccination (PPSV23, PCV13, and influenza vaccine) remains the most effective tool in preventing the development of CAP, clinicians should strive for 100% vaccination rates in persons without contraindications.

Initial management decisions for patients with community-acquired pneumonia (CAP) will depend on severity of infection, with need for hospitalization being one of the first decisions. Because empiric antibiotics are the mainstay of treatment and the causative organisms are seldom identified, underlying medical conditions and epidemiologic risk factors are considered when selecting an empiric regimen. As with other infections, duration of therapy is not standardized, but rather is guided by clinical improvement. Prevention of pneumonia centers around vaccination and smoking cessation. This article, the second in a 2-part review of CAP in adults, focuses on site of care decision, empiric and directed therapies, length of treatment, and prevention strategies. Evaluation and diagnosis of CAP are discussed in a separate article.

Site of Care Decision

For patients diagnosed with CAP, the clinician must decide whether treatment will be done in an outpatient or inpatient setting, and for those in the inpatient setting, whether they can safely be treated on the general medical ward or in the intensive care unit (ICU). Two common scoring systems that can be used to aid the clinician in determining severity of the infection and guide site-of-care decisions are the Pneumonia Severity Index (PSI) and CURB-65 scores.

The PSI score uses 20 different parameters, including comorbidities, laboratory parameters, and radiographic findings, to stratify patients into 5 mortality risk classes.¹ On the basis of associated mortality rates, it has been suggested that risk class I and II patients should be treated as outpatients, risk class III patients should be treated in an observation unit or with a short hospitalization, and risk class IV and V patients should be treated as inpatients.¹

The CURB-65 method of risk stratification is based on 5 clinical parameters: confusion, urea level, respiratory rate, systolic blood pressure, and age ≥ 65 years (Table 1).^2,3 A modification to the CURB-65 algorithm tool was CRB-65, which excludes urea nitrogen, making it optimal for making determinations in a clinic-based setting. It should be emphasized that these tools do not take into account other factors that should be used in determining location of treatment, such as stable home, mental illness, or concerns about compliance with medications. In many instances, it is these factors that preclude low-risk patients from being treated as outpatients.^4,5 Similarly, these scoring systems have not been validated for immunocompromised patients or those who would qualify as having health care–associated pneumonia.

Patients with CURB-65 scores of 4 or 5 are considered to have severe pneumonia, and admission to the ICU should be considered for these patients. Aside from the CURB-65 score, anyone requiring vasopressor support or mechanical ventilation merits admission to the ICU.⁶ American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guidelines also recommend the use of “minor criteria” for making ICU admission decisions; these include respiratory rate ≥ 30 breaths/minute, PaO₂ fraction ≤ 250 mm Hg, multilobar infiltrates, confusion, blood urea nitrogen ≥ 20 mg/dL, leukopenia, thrombocytopenia, hypothermia, and hypotension.⁶ These factors are associated with increased mortality due to CAP, and ICU admission is indicated if 3 of the minor criteria for severe CAP are present.

Another clinical calculator that can be used for assessing severity of CAP is SMART-COP (systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation and arterial pH).⁷ This scoring system uses 8 weighted criteria to predict which patients will require intensive respiratory or vasopressor support. SMART-COP has a sensitivity of 79% and a specificity of 64% in predicting ICU admission, whereas CURB-65 has a pooled sensitivity of 57.2% and specificity of 77.2%.⁸

Antibiotic Therapy

Antibiotics are the mainstay of treatment for CAP, with the majority of patients with CAP treated empirically taking into account the site of care, likely pathogen, and antimicrobial resistance issues. Patients with pneumonia who are treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment of CAP usually receive empiric antibiotic on admission. Once the etiology has been determined by microbiologic or serologic means, antimicrobial therapy should be adjusted accordingly. A CDC study found that the burden of viral etiologies was higher than previously thought, with rhinovirus and influenza accounting for 15% of cases and Streptococcus pneumoniae for only 5%.⁹ This study highlighted the fact that despite advances in molecular techniques, no pathogen is identified for most patients with pneumonia.⁹ Given the lack of discernable pathogens in the majority of cases, patients should continue to be treated with antibiotics unless a nonbacterial etiology is found.

Outpatients without comorbidities or risk factors for drug-resistant S. pneumoniae (Table 2)¹⁰ can be treated with monotherapy. Hospitalized patients are usually treated with combination intravenous therapy, although non-ICU patients who receive a respiratory fluoroquinolone can be treated orally.

As previously mentioned, antibiotic therapy is typically empiric, since neither clinical features nor radiographic features are sufficient to include or exclude infectious etiologies. Epidemiologic risk factors should be considered and, in certain cases, antimicrobial coverage should be expanded to include those entities; for example, treatment of anaerobes in the setting of lung abscess and antipseudomonal antibiotics for patients with bronchiectasis.

Of concern in the treatment of CAP is the increased prevalence of antimicrobial resistance among S. pneumoniae. The IDSA guidelines report that drug-resistant S. pneumoniae is more common in persons aged < 2 or > 65 years, and those with β-lactam therapy within the previous 3 months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, or exposure to a child who attends a day care center.⁶

Staphylococcus aureus should be considered during influenza outbreaks, with either vancomycin or linezolid being the recommended agents in the setting of methicillin-resistant S. aureus (MRSA). In a study comparing vancomycin versus linezolid for nosocomial pneumonia, the all-cause 60-day mortality was similar for both agents.¹¹ Daptomycin, another agent used against MRSA, is not indicated in the setting of pneumonia because daptomycin binds to surfactant, yielding it ineffective in the treatment of pneumonia.¹² Ceftaroline is a newer cephalosporin with activity against MRSA; its role in treatment of community-acquired MRSA pneumonia has not been fully elucidated, but it appears to be a useful agent for this indication.^13,14 Similarly, other agents known to have antibacterial properties against MRSA, such as trimethoprim/sulfamethoxazole and doxycycline, have not been studied for this indication. Clindamycin has been used to treat MRSA in children, and IDSA guidelines on the treatment of MRSA list clindamycin as an alternative¹⁵ if MRSA is known to be sensitive.

A summary of recommended empiric antibiotic therapy is presented in Table 3.¹⁶

Three antibiotics were approved by the US Food and Drug Administration (FDA) for the treatment of CAP after the release of the IDSA/ATS guidelines in 2007. Ceftaroline fosamil is a fifth-generation cephalosporin that has coverage for MRSA and was approved in November 2010.¹⁷ It can only be administered intravenously and needs dose adjustment for renal function. Omadacycline is a new tetracycline that was approved by the FDA in October 2018.¹⁸ It is available in both intravenous injectable and oral forms. No dose adjustment is needed for renal function. Lefamulin is a first-in-class novel pleuromutilin antibiotic which was FDA-approved in August 2019. It can be administered intravenously or orally, with no dosage adjustment necessary in patients with renal impairment.¹⁹

Antibiotic Therapy for Selected Pathogens

Streptococcus pneumoniae

Patients with pneumococcal pneumonia who have penicillin-susceptible strains can be treated with intravenous penicillin (2 or 3 million units every 4 hours) or ceftriaxone. Once a patient meets criteria of stability, they can then be transitioned to oral penicillin, amoxicillin, or clarithromycin. Those with strains with reduced susceptibility can still be treated with penicillin, but at a higher dose (4 million units intravenously [IV] every 4 hours), or a third-generation cephalosporin. Those whose pneumococcal pneumonia is complicated by bacteremia will benefit from dual therapy if severely ill, requiring ICU monitoring. Those not severely ill can be treated with monotherapy.²⁰

Staphylococcus aureus

Staphylococcus aureus is more commonly associated with hospital-acquired pneumonia, but it may also be seen during the influenza season and in those with severe necrotizing CAP. Both linezolid and vancomycin can be used to treat MRSA CAP. As noted, ceftaroline has activity against MRSA and is approved for treatment of CAP, but is not approved by the FDA for MRSA CAP treatment. Similarly, tigecycline is approved for CAP and has activity against MRSA, but is not approved for MRSA CAP. Moreover, the FDA has warned of increased risk of death with tigecycline and has a black box warning to that effect.²¹

Legionella

Legionellosis can be treated with tetra¬cyclines, macrolides, or fluoroquinolones. For non-immunocompromised patients with mild pneumonia, any of the listed antibiotics is considered appropriate. However, patients with severe infection or those with immunosuppression should be treated with either levofloxacin or azithromycin for 7 to 10 days.²²

Chlamydophila pneumoniae

As with other atypical organisms, Chlamydophila pneumoniae can be treated with doxycycline, a macrolide, or respiratory fluoroquinolones. However, length of therapy varies by regimen used; treating with doxycycline 100 mg twice daily generally requires 14 to 21 days, whereas moxifloxacin 400 mg daily requires 10 days.²³

Mycoplasma pneumoniae

As with C. pneumoniae, length of therapy of Mycoplasma pneumoniae varies by which antimicrobial regimen is used. Shortest courses are seen with the use of macrolides for 5 days, whereas 14 days is considered standard for doxycycline or a respiratory fluoroquinolone.²⁴ It should be noted that there has been increasingly documented resistance to macrolides, with known resistance of 8.2% in the United States.²⁵

Duration of Treatment

Most patients with CAP respond to appropriate therapy within 72 hours. IDSA/ATS guidelines recommend that patients with routine cases of CAP be treated for a minimum of 5 days. Despite this, many patients are treated for an excessive amount of time, with over 70% of patients reported to have received antibiotics for more than 10 days for uncomplicated CAP.²⁶ There are instances that require longer courses of antibiotics, including cases caused by Pseudomonas aeruginosa, S. aureus, and Legionella species and patients with lung abscesses or necrotizing infections, among others.²⁷

Hospitalized patients do not need to be monitored for an additional day once they have reached clinical stability (Table 4), are able to maintain oral intake, and have normal mentation, provided that other comorbidities are stable and social needs have been met.⁶ C-reactive protein (CRP) level has been postulated as an additional measure of stability, specifically monitoring for a greater than 50% reduction in CRP; however, this was validated only for those with complicated pneumonia.²⁸ Patients discharged from the hospital with instability have higher risk of readmission or death.²⁹

Transition to Oral Therapy

IDSA/ATS guidelines⁶ recommend that patients should be transitioned from intravenous to oral antibiotics when they are improving clinically, have stable vital signs, and are able to ingest food/fluids and medications.

Management of Nonresponders

Although the majority of patients respond to antibiotics within 72 hours, treatment failure occurs in up to 15% of patients.¹⁵ Nonresponding pneumonia is generally seen in 2 patterns: worsening of clinical status despite empiric antibiotics or delay in achieving clinical stability, as defined in Table 4, after 72 hours of treatment.³⁰ Risk factors associated with nonresponding pneumonia³¹ are:

• Radiographic: multilobar infiltrates, pleural effusion, cavitation
• Bacteriologic: MRSA, gram-negative or Legionella pneumonia
• Severity index: PSI > 90
• Pharmacologic: incorrect antibiotic choice based on susceptibility

Patients with acute deterioration of clinical status require prompt transfer to a higher level of care and may require mechanical ventilator support. In those with delay in achieving clinical stability, a question centers on whether the same antibiotics can be continued while doing further radiographic/microbiologic work-up and/or changing antibiotics. History should be reviewed, with particular attention to exposures, travel history, and microbiologic and radiographic data. Clinicians should recall that viruses account for up to 20% of pneumonias and that there are also noninfectious causes that can mimic pyogenic infections.³² If adequate initial cultures were not obtained, they should be obtained; however, care must be taken in reviewing new sets of cultures while on antibiotics, as they may reveal colonization selected out by antibiotics and not a true pathogen. If repeat evaluation is unrevealing, then further evaluation with computed tomography (CT) scan and bronchoscopy with bronchoalveolar lavage and biopsy is warranted. CT scans can show pleural effusions, bronchial obstructions, or a pattern suggestive of cryptogenic pneumonia. A bronchoscopy might yield a microbiologic diagnosis and, when combined with biopsy, can also evaluate for noninfectious causes.

As with other infections, if escalation of antibiotics is undertaken, clinicians should try to determine the reason for nonresponse. To simply broaden antimicrobial therapy without attempts at establishing a microbiologic or radiographic cause for nonresponse may lead to inappropriate treatment and recurrence of infection. Aside from patients who have bacteremic pneumococcal pneumonia in an ICU setting, there are no published reports pointing to superiority of combination antibiotics.²⁰

Other Treatment

Several agents have been evaluated as adjunctive treatment of pneumonia to decrease the inflammatory response associated with pneumonia; namely, steroids, macrolide antibiotics, and statins. To date, only the use of steroids (methylprednisolone 0.5 mg/kg every 12 hours for 5 days) in those with severe CAP and high initial anti-inflammatory response (CRP > 150) has been shown to decrease treatment failure, decrease risk of acute respiratory distress syndrome, and possibly reduce length of stay and duration of intravenous antibiotics, without effect on mortality or adverse side effects.^33,34 However, a recent double-blind randomized study conducted in Australia in which patients admitted with CAP were prescribed prednisolone acetate (50 mg/day for 7 days) and de-escalated from parenteral to oral antibiotics according to standardized criteria revealed no difference in mortality, length of stay, or readmission rates between the corticosteroids group and the control group at 90-day follow-up.³⁵ At this point, corticosteroid as an adjunctive treatment for CAP is still controversial and the new 2019 ATS/IDSA guidelines recommend not routinely using corticosteroids in all patients with CAP.³⁶ Other adjunctive methods have not been found to have significant impact.⁶

Prevention of Pneumonia

Prevention of pneumococcal pneumonia involves vaccinations to prevent infection caused by S. pneumoniae and influenza viruses. As influenza is a risk factor for bacterial infection, specifically with S. pneumoniae, influenza vaccination can help prevent bacterial pneumonia.³⁷ In their most recent recommendations, the CDC continues to recommend routine influenza vaccination for all persons older than age 6 months, unless otherwise contraindicated.³⁸

There are 2 vaccines for prevention of pneumococcal disease: the pneumococcal polysaccharide vaccine (PPSV23) and a conjugate vaccine (PCV13). Following vaccination with PPSV23, 80% of adults develop antibodies against at least 18 of the 23 serotypes.³⁹ PPSV23 is reported to be protective against invasive pneumococcal infection, although there is no consensus regarding whether PPSV23 leads to decreased rates of pneumonia.⁴⁰ On the other hand, PCV13 vaccination was associated with prevention of both invasive disease and CAP in adults aged 65 years or older.⁴¹ The CDC recommends that all children aged 2 years or younger receive PCV13, and those aged 65 or older receive PCV13 followed by a dose of PPSV23.^42,43 The dose of PPSV23 should be given at least 1 year after the dose of PCV13 is administered.⁴⁴ Persons younger than 65 years with immunocompromising and certain other conditions should also receive vaccination (Table 5).⁴⁴ Full recommendations, many scenarios, and details on timing of vaccinations can be found at the CDC’s website.

Cigarette smoking increases the risk of respiratory infections, as evidenced by smokers accounting for almost half of all patients with invasive pneumococcal disease.¹¹ As this is a modifiable risk factor, smoking cessation should be part of a comprehensive approach toward prevention of pneumonia.

Summary

Most patients with CAP are treated empirically with antibiotics, with therapy selection based on the site of care, likely pathogen, and antimicrobial resistance issues. Those treated as outpatients usually respond well to empiric antibiotic treatment, and a causative pathogen is not usually sought. Patients who are hospitalized for treatment usually receive empiric antibiotic on admission, and antimicrobial therapy is adjusted accordingly once the etiology has been determined by microbiologic or serologic means. At this time, the use of corticosteroid as an adjunctive treatment for CAP is still controversial, so not all patients with CAP should routinely receive corticosteroids. Because vaccination (PPSV23, PCV13, and influenza vaccine) remains the most effective tool in preventing the development of CAP, clinicians should strive for 100% vaccination rates in persons without contraindications.

Despite advances in medical science, pneumonia remains a major cause of morbidity and mortality. In 2017, 49,157 patients in the United States died from the disease.¹ Pneumonia can be classified as community-acquired, hospital-acquired, or ventilator-associated. Another category, healthcare-associated pneumonia, was included in an earlier Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) guideline but was removed from the 2016 guideline because there was no clear evidence that patients diagnosed with healthcare-associated pneumonia were at higher risk for harboring multidrug-resistant pathogens.² This review is the first of 2 articles focusing on the management of community-acquired pneumonia (CAP). Here, we review CAP epidemiology, microbiology, predisposing factors, and diagnosis; current treatment and prevention of CAP are reviewed in a separate article.

Definition and Epidemiology

CAP is defined as an acute infection of the lungs that develops in patients who have not been hospitalized recently and have not had regular exposure to the health care system.³ A previously ambulatory patient who is diagnosed with pneumonia within 48 hours after admission also meets the criteria for CAP. Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually.⁴ About 25% of CAP patients require hospitalization, and about 5% to 10% of these patients are admitted to the intensive care unit (ICU).⁵ In-hospital mortality is considerable (~10% in population-based studies),⁶ and 30-day mortality was found to be as high as 23% in a review by File and Marrie.⁷ CAP also confers a high risk of long-term morbidity and mortality compared with the general population who have never had CAP, irrespective of age.⁸

Causative Organisms

Numerous microorganisms can cause CAP. Common causes and less common causes are delineated in Table 1. Until recently, many studies had demonstrated that pneumococcus was the most common cause of CAP. However, in the CDC Etiology of Pneumonia in the Community (EPIC) study team’s 2015 prospective, multicenter, population-based study, no pathogen was detected in the majority of patients diagnosed with CAP requiring hospitalization. The most common pathogens they detected were rhinovirus (9%), followed by influenza virus (6%) and pneumococcus (5%).⁹ Factors considered to be contributing to the decrease in the percentage of pneumococcus in patients diagnosed with CAP are the widespread use of pneumococcal vaccine and reduced rates of smoking.^10,11

Predisposing Factors

Most people diagnosed with CAP have 1 or more predisposing factors (Table 2).^12,13 Patients who develop CAP typically have a combination of these predisposing factors rather than a single factor. Aging, in combination with other risk factors, increases the susceptibility of a person to pneumonia.

Clinical Signs and Symptoms

Symptoms of CAP include fever, chills, rigors, fatigue, anorexia, diaphoresis, dyspnea, cough (with or without sputum production), and pleuritic chest pain. There is no individual symptom or cluster of symptoms that can absolutely differentiate pneumonia from other acute respiratory diseases, including upper and lower respiratory infections. However, patients presenting with the constellation of symptoms of fever ≥ 100°F (37.8°C), productive cough, and tachycardia is more suggestive of pneumonia.¹⁴ Abnormal vital signs include fever, hypothermia, tachypnea, tachycardia, and oxygen desaturation. Auscultation of the chest reveals crackles or other adventitious breath sounds. Elderly patients with pneumonia report a significantly lower number of both respiratory and nonrespiratory symptoms compared with younger patients. Clinicians should be aware of this phenomenon to avoid delayed diagnosis and treatment.¹⁵

Imaging Evaluation

The presence of a pulmonary consolidation or an infiltrate on chest radiograph is required to diagnose CAP, and a chest radiograph should be obtained when CAP is suspected.¹⁶ However, there is no pattern of radiographic abnormalities reliable enough to differentiate infectious pneumonia from noninfectious causes.¹⁷

There are case reports and case series demonstrating false-negative plain chest radiographs in dehydrated patients¹⁸ or in patients in a neutropenic state. However, animal studies have shown that dogs challenged with pneumococcus showed abnormal pulmonary shadow, suggestive of pneumonia, regardless of hydration status.¹⁹ There is also no reliable scientific evidence to support the notion that severe neutropenia can cause false-negative radiographs because of the inability to develop an acute inflammatory reaction in the lungs.²⁰

A chest computed tomography (CT) scan is more sensitive than a plain chest radiograph in detecting pneumonia. Therefore, a chest CT should be performed in a patient with negative plain chest radiograph when pneumonia is still highly suspected.²¹ A chest CT scan is also more sensitive in detecting cavitation, adenopathy, interstitial disease, and empyema. It also has the advantage of better defining anatomical changes than plain films.²²

Because improvement of pulmonary opacities in patients with CAP lags behind clinical improvement, repeating chest imaging studies is not recommended in patients who demonstrate clinical improvement. Clearing of pulmonary infiltrate or consolidation sometimes can take 6 weeks or longer.²³

Laboratory Evaluation

Generally, the etiologic agent of CAP cannot be determined solely on the basis of clinical signs and symptoms or imaging studies. Although routine microbiological testing for patients suspicious for CAP is not necessary for empirical treatment, determining the etiologic agent of the pneumonia allows the clinician to narrow the antibiotics from a broad-spectrum empirical regimen to specific pathogen-directed therapy. Determination of certain etiologic agents causing the pneumonia can have important public health implications (eg, Mycobacterium tuberculosis and influenza virus).²⁴

Sputum Gram Stain and Culture

Sputum Gram stain is an inexpensive test that may identify pathogens that cause CAP (eg, Streptococcus pneumoniae and Haemophilus influenzae). A quality specimen is required. A sputum sample must contain more than 25 neutrophils and less than 10 squamous epithelial cells/low power field on Gram stain to be considered suitable for culture. The sensitivity and specificity of sputum Gram stain and culture are highly variable in different clinical settings (eg, outpatient setting, nursing home, ICU). Reed et al’s meta-analysis of patients diagnosed with CAP in the United States showed the sensitivity and specificity of sputum Gram stain (compared with sputum culture) ranged from 15% to 100% and 11% to 100%, respectively.²⁴ In cases of proven bacteremic pneumococcal pneumonia, positive cultures from sputum samples were positive less than 50% of the time.²⁵

For patients who cannot provide sputum samples or are intubated, deep-suction aspirate or bronchoalveolar lavage through a bronchoscopic procedure may be necessary to obtain pulmonary secretion for Gram stain and culture. Besides bacterial culture, sputum samples can also be sent for fungal and mycobacterial cultures and acid-fast stain, if deemed clinically necessary.

The 2019 ATS/IDSA guidelines for diagnosis and treatment of adults with CAP recommend sputum culture in patients with severe disease and in all inpatients empirically treated for MRSA or Pseudomonas aeruginosa.²⁶

Because the positivity rate of blood culture in patients who are suspected to have pneumonia but not exposed to antimicrobial agents is low (5%–14%), blood cultures are not recommended for all patients with CAP. Another reason for not recommending blood culture is positive culture rarely leads to changes in antibiotic regimen in patients without underlying diseases.²⁷ However, the 2019 ATS/IDSA guidelines recommend blood culture in patients with severe disease and in all inpatients treated empirically for MRSA or P. aeruginosa.²⁶

A multinational study published in 2008 examined 125 patients with pneumococcal bacteremic CAP versus 1847 patients with non-bacteremic CAP.²⁸ Analysis of the data demonstrated no association between pneumococcal bacteremic CAP and time to clinical stability, length of hospital stay, all-cause mortality, or CAP-related mortality. The authors concluded that pneumococcal bacteremia does not increase the risk of poor outcomes in patients with CAP compared to non-bacteremic patients, and the presence of pneumococcal bacteremia should not deter de-escalation of therapy in clinically stable patients.

Urinary Antigen Tests

Urinary antigen tests may assist clinicians in narrowing antibiotic therapy when test results are positive. There are 2 US Food and Drug Administration–approved tests available to clinicians for detecting pneumococcal and Legionella antigen in urine. The test for Legionella pneumophila detects disease due to serogroup 1 only, which accounts for 80% of community-acquired Legionnaires’ disease. The sensitivity and specificity of the Legionella urine antigen test are 90% and 99%, respectively. The pneumococcal urine antigen test is less sensitive and specific than the Legionella urine antigen test (sensitivity 80% and specificity > 90%).^29,30

Advantages of the urinary antigen tests are that they are easily performed, results are available in less than an hour if done in-house, and results are not affected by prior exposure to antibiotics. However, the tests do not meet Clinical Laboratory Improvements Amendments criteria for waiver and must be performed by a technician in the laboratory. A multicenter, prospective surveillance study of hospitalized patients with CAP showed that the 2007 IDSA/ATS guidelines’ recommended indications for S. pneumoniae and L. pneumophila urinary antigen tests do not have sufficient sensitivity and specificity to identify patients with positive tests.³¹

Polymerase Chain Reaction

There are several FDA-approved polymerase chain reaction (PCR) tests commercially available to assist clinicians in diagnosing pneumonia. PCR testing of nasopharyngeal swabs for diagnosis of influenza has become standard in many US medical facilities. The great advantages of using PCR to diagnose influenza are its high sensitivity and specificity and rapid turnaround time. PCR can also be used to detect Legionella species, S. pneumonia, Mycoplasma pneumoniae, Chlamydophila pneumonia, and mycobacterial species.²⁴

One limitation of using PCR tests on respiratory specimens is that specimens can be contaminated with oral or upper airway flora, so the results must be interpreted with caution, bearing in mind that some of the pathogens isolated may be colonizers of the oral or upper airway flora.³²

Biologic Markers

Two biologic markers—procalcitonin and C-reactive protein (CRP)—can be used in conjunction with history, physical examination, laboratory tests, and imaging studies to assist in the diagnosis and treatment of CAP.²⁴ Procalcitonin is a peptide precursor of the hormone calcitonin that is released by parenchymal cells into the bloodstream, resulting in increased serum level in patients with bacterial infections. In contrast, there is no remarkable procalcitonin level increase with viral or noninfectious inflammation. The reference value of procalcitonin in the blood of an adult individual without infection or inflammation is < 0.15 ng/mL. In the blood, procalcitonin has a half-life of 25 to 30 hours. The quantitative immunoluminometric method (LUMI test, Brahms PCT, Berlin, Germany) is the preferred test to use because of its high sensitivity.³³ A meta-analysis of 12 studies involving more than 2400 patients with CAP demonstrated that serum procalcitonin does not have sufficient sensitivity or specificity to distinguish between bacterial and nonbacterial pneumonia. The authors concluded that procalcitonin level cannot be used to decide whether an antibiotic should be administered.³⁴

A 2012 Cochrane meta-analysis that involved 4221 patients with acute respiratory infections (with half of the patients diagnosed with CAP) from 14 prospective trials found the use of procalcitonin test for antibiotic use significantly decreased median antibiotic exposure from 8 to 4 days without an increase in treatment failure, mortality rates in any clinical setting (eg, outpatient clinic, emergency room), or length of hospitalization.³⁵ An update of the 2012 Cochrane review that examined the safety and efficacy of using procalcitonin for starting or stopping antibiotics again demonstrated procalcitonin use was associated with a reduction of antibiotic use (2.4 days).³⁶ A prospective study conducted in France on 100 ICU patients showed that increased procalcitonin from day 1 to day 3 has a poor prognosis factor for severe CAP, whereas decreasing procalcitonin levels is associated with a favorable outcome.³⁷

Because of conflicting data, the 2019 ATS/IDSA guidelines do not recommend using procalcitonin to determine need for initial antibacterial therapy.²⁶

CRP is an acute phase protein produced by the liver. CRP level in the blood increases in response to acute infection or inflammation. Use of CRP in assisting diagnosis and guiding treatment of CAP is more limited in part due to its poor specificity. A prospective study conducted on 168 consecutive patients who presented with cough showed that a CRP level > 40 mg/L had a sensitivity and specificity of 70% and 90%, respectively.³⁸

Summary

CAP remains a leading cause of hospitalization and death in the 21st century. Traditionally, pneumococcus has been considered the major pathogen causing CAP; however, the 2015 EPIC study found that S. pneumoniae was detected in only 5% of patients diagnosed with CAP. Despite the new findings, it is still recommended that empiric treatment for CAP target common typical bacteria (pneumococcus, H. influenzae, Moraxella catarrhalis) and atypical bacteria (M. pneumonia, C. pneumoniae, L. pneumophila).

Because diagnosing pneumonia through history and clinical examination is less than 50% sensitive, a chest imaging study (a plain chest radiograph or a chest CT scan) is usually required to make the diagnosis. Laboratory tests, such as sputum Gram stain/culture, blood culture, urinary antigen tests, PCR test, procalcitonin, and CRP are important adjunctive diagnostic modalities to assist in the diagnosis and management of CAP. However, because no single test is sensitive and specific enough to be a stand-alone test, they should be used in conjunction with history, physical examination, and imaging studies.

Despite advances in medical science, pneumonia remains a major cause of morbidity and mortality. In 2017, 49,157 patients in the United States died from the disease.¹ Pneumonia can be classified as community-acquired, hospital-acquired, or ventilator-associated. Another category, healthcare-associated pneumonia, was included in an earlier Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) guideline but was removed from the 2016 guideline because there was no clear evidence that patients diagnosed with healthcare-associated pneumonia were at higher risk for harboring multidrug-resistant pathogens.² This review is the first of 2 articles focusing on the management of community-acquired pneumonia (CAP). Here, we review CAP epidemiology, microbiology, predisposing factors, and diagnosis; current treatment and prevention of CAP are reviewed in a separate article.

Definition and Epidemiology

CAP is defined as an acute infection of the lungs that develops in patients who have not been hospitalized recently and have not had regular exposure to the health care system.³ A previously ambulatory patient who is diagnosed with pneumonia within 48 hours after admission also meets the criteria for CAP. Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually.⁴ About 25% of CAP patients require hospitalization, and about 5% to 10% of these patients are admitted to the intensive care unit (ICU).⁵ In-hospital mortality is considerable (~10% in population-based studies),⁶ and 30-day mortality was found to be as high as 23% in a review by File and Marrie.⁷ CAP also confers a high risk of long-term morbidity and mortality compared with the general population who have never had CAP, irrespective of age.⁸

Causative Organisms

Numerous microorganisms can cause CAP. Common causes and less common causes are delineated in Table 1. Until recently, many studies had demonstrated that pneumococcus was the most common cause of CAP. However, in the CDC Etiology of Pneumonia in the Community (EPIC) study team’s 2015 prospective, multicenter, population-based study, no pathogen was detected in the majority of patients diagnosed with CAP requiring hospitalization. The most common pathogens they detected were rhinovirus (9%), followed by influenza virus (6%) and pneumococcus (5%).⁹ Factors considered to be contributing to the decrease in the percentage of pneumococcus in patients diagnosed with CAP are the widespread use of pneumococcal vaccine and reduced rates of smoking.^10,11

Predisposing Factors

Most people diagnosed with CAP have 1 or more predisposing factors (Table 2).^12,13 Patients who develop CAP typically have a combination of these predisposing factors rather than a single factor. Aging, in combination with other risk factors, increases the susceptibility of a person to pneumonia.

Clinical Signs and Symptoms

Symptoms of CAP include fever, chills, rigors, fatigue, anorexia, diaphoresis, dyspnea, cough (with or without sputum production), and pleuritic chest pain. There is no individual symptom or cluster of symptoms that can absolutely differentiate pneumonia from other acute respiratory diseases, including upper and lower respiratory infections. However, patients presenting with the constellation of symptoms of fever ≥ 100°F (37.8°C), productive cough, and tachycardia is more suggestive of pneumonia.¹⁴ Abnormal vital signs include fever, hypothermia, tachypnea, tachycardia, and oxygen desaturation. Auscultation of the chest reveals crackles or other adventitious breath sounds. Elderly patients with pneumonia report a significantly lower number of both respiratory and nonrespiratory symptoms compared with younger patients. Clinicians should be aware of this phenomenon to avoid delayed diagnosis and treatment.¹⁵

Imaging Evaluation

The presence of a pulmonary consolidation or an infiltrate on chest radiograph is required to diagnose CAP, and a chest radiograph should be obtained when CAP is suspected.¹⁶ However, there is no pattern of radiographic abnormalities reliable enough to differentiate infectious pneumonia from noninfectious causes.¹⁷

There are case reports and case series demonstrating false-negative plain chest radiographs in dehydrated patients¹⁸ or in patients in a neutropenic state. However, animal studies have shown that dogs challenged with pneumococcus showed abnormal pulmonary shadow, suggestive of pneumonia, regardless of hydration status.¹⁹ There is also no reliable scientific evidence to support the notion that severe neutropenia can cause false-negative radiographs because of the inability to develop an acute inflammatory reaction in the lungs.²⁰

A chest computed tomography (CT) scan is more sensitive than a plain chest radiograph in detecting pneumonia. Therefore, a chest CT should be performed in a patient with negative plain chest radiograph when pneumonia is still highly suspected.²¹ A chest CT scan is also more sensitive in detecting cavitation, adenopathy, interstitial disease, and empyema. It also has the advantage of better defining anatomical changes than plain films.²²

Because improvement of pulmonary opacities in patients with CAP lags behind clinical improvement, repeating chest imaging studies is not recommended in patients who demonstrate clinical improvement. Clearing of pulmonary infiltrate or consolidation sometimes can take 6 weeks or longer.²³

Laboratory Evaluation

Generally, the etiologic agent of CAP cannot be determined solely on the basis of clinical signs and symptoms or imaging studies. Although routine microbiological testing for patients suspicious for CAP is not necessary for empirical treatment, determining the etiologic agent of the pneumonia allows the clinician to narrow the antibiotics from a broad-spectrum empirical regimen to specific pathogen-directed therapy. Determination of certain etiologic agents causing the pneumonia can have important public health implications (eg, Mycobacterium tuberculosis and influenza virus).²⁴

Sputum Gram Stain and Culture

Sputum Gram stain is an inexpensive test that may identify pathogens that cause CAP (eg, Streptococcus pneumoniae and Haemophilus influenzae). A quality specimen is required. A sputum sample must contain more than 25 neutrophils and less than 10 squamous epithelial cells/low power field on Gram stain to be considered suitable for culture. The sensitivity and specificity of sputum Gram stain and culture are highly variable in different clinical settings (eg, outpatient setting, nursing home, ICU). Reed et al’s meta-analysis of patients diagnosed with CAP in the United States showed the sensitivity and specificity of sputum Gram stain (compared with sputum culture) ranged from 15% to 100% and 11% to 100%, respectively.²⁴ In cases of proven bacteremic pneumococcal pneumonia, positive cultures from sputum samples were positive less than 50% of the time.²⁵

For patients who cannot provide sputum samples or are intubated, deep-suction aspirate or bronchoalveolar lavage through a bronchoscopic procedure may be necessary to obtain pulmonary secretion for Gram stain and culture. Besides bacterial culture, sputum samples can also be sent for fungal and mycobacterial cultures and acid-fast stain, if deemed clinically necessary.

The 2019 ATS/IDSA guidelines for diagnosis and treatment of adults with CAP recommend sputum culture in patients with severe disease and in all inpatients empirically treated for MRSA or Pseudomonas aeruginosa.²⁶

Because the positivity rate of blood culture in patients who are suspected to have pneumonia but not exposed to antimicrobial agents is low (5%–14%), blood cultures are not recommended for all patients with CAP. Another reason for not recommending blood culture is positive culture rarely leads to changes in antibiotic regimen in patients without underlying diseases.²⁷ However, the 2019 ATS/IDSA guidelines recommend blood culture in patients with severe disease and in all inpatients treated empirically for MRSA or P. aeruginosa.²⁶

A multinational study published in 2008 examined 125 patients with pneumococcal bacteremic CAP versus 1847 patients with non-bacteremic CAP.²⁸ Analysis of the data demonstrated no association between pneumococcal bacteremic CAP and time to clinical stability, length of hospital stay, all-cause mortality, or CAP-related mortality. The authors concluded that pneumococcal bacteremia does not increase the risk of poor outcomes in patients with CAP compared to non-bacteremic patients, and the presence of pneumococcal bacteremia should not deter de-escalation of therapy in clinically stable patients.

Urinary Antigen Tests

Urinary antigen tests may assist clinicians in narrowing antibiotic therapy when test results are positive. There are 2 US Food and Drug Administration–approved tests available to clinicians for detecting pneumococcal and Legionella antigen in urine. The test for Legionella pneumophila detects disease due to serogroup 1 only, which accounts for 80% of community-acquired Legionnaires’ disease. The sensitivity and specificity of the Legionella urine antigen test are 90% and 99%, respectively. The pneumococcal urine antigen test is less sensitive and specific than the Legionella urine antigen test (sensitivity 80% and specificity > 90%).^29,30

Advantages of the urinary antigen tests are that they are easily performed, results are available in less than an hour if done in-house, and results are not affected by prior exposure to antibiotics. However, the tests do not meet Clinical Laboratory Improvements Amendments criteria for waiver and must be performed by a technician in the laboratory. A multicenter, prospective surveillance study of hospitalized patients with CAP showed that the 2007 IDSA/ATS guidelines’ recommended indications for S. pneumoniae and L. pneumophila urinary antigen tests do not have sufficient sensitivity and specificity to identify patients with positive tests.³¹

Polymerase Chain Reaction

There are several FDA-approved polymerase chain reaction (PCR) tests commercially available to assist clinicians in diagnosing pneumonia. PCR testing of nasopharyngeal swabs for diagnosis of influenza has become standard in many US medical facilities. The great advantages of using PCR to diagnose influenza are its high sensitivity and specificity and rapid turnaround time. PCR can also be used to detect Legionella species, S. pneumonia, Mycoplasma pneumoniae, Chlamydophila pneumonia, and mycobacterial species.²⁴

One limitation of using PCR tests on respiratory specimens is that specimens can be contaminated with oral or upper airway flora, so the results must be interpreted with caution, bearing in mind that some of the pathogens isolated may be colonizers of the oral or upper airway flora.³²

Biologic Markers

Two biologic markers—procalcitonin and C-reactive protein (CRP)—can be used in conjunction with history, physical examination, laboratory tests, and imaging studies to assist in the diagnosis and treatment of CAP.²⁴ Procalcitonin is a peptide precursor of the hormone calcitonin that is released by parenchymal cells into the bloodstream, resulting in increased serum level in patients with bacterial infections. In contrast, there is no remarkable procalcitonin level increase with viral or noninfectious inflammation. The reference value of procalcitonin in the blood of an adult individual without infection or inflammation is < 0.15 ng/mL. In the blood, procalcitonin has a half-life of 25 to 30 hours. The quantitative immunoluminometric method (LUMI test, Brahms PCT, Berlin, Germany) is the preferred test to use because of its high sensitivity.³³ A meta-analysis of 12 studies involving more than 2400 patients with CAP demonstrated that serum procalcitonin does not have sufficient sensitivity or specificity to distinguish between bacterial and nonbacterial pneumonia. The authors concluded that procalcitonin level cannot be used to decide whether an antibiotic should be administered.³⁴

A 2012 Cochrane meta-analysis that involved 4221 patients with acute respiratory infections (with half of the patients diagnosed with CAP) from 14 prospective trials found the use of procalcitonin test for antibiotic use significantly decreased median antibiotic exposure from 8 to 4 days without an increase in treatment failure, mortality rates in any clinical setting (eg, outpatient clinic, emergency room), or length of hospitalization.³⁵ An update of the 2012 Cochrane review that examined the safety and efficacy of using procalcitonin for starting or stopping antibiotics again demonstrated procalcitonin use was associated with a reduction of antibiotic use (2.4 days).³⁶ A prospective study conducted in France on 100 ICU patients showed that increased procalcitonin from day 1 to day 3 has a poor prognosis factor for severe CAP, whereas decreasing procalcitonin levels is associated with a favorable outcome.³⁷

Because of conflicting data, the 2019 ATS/IDSA guidelines do not recommend using procalcitonin to determine need for initial antibacterial therapy.²⁶

CRP is an acute phase protein produced by the liver. CRP level in the blood increases in response to acute infection or inflammation. Use of CRP in assisting diagnosis and guiding treatment of CAP is more limited in part due to its poor specificity. A prospective study conducted on 168 consecutive patients who presented with cough showed that a CRP level > 40 mg/L had a sensitivity and specificity of 70% and 90%, respectively.³⁸

Summary

CAP remains a leading cause of hospitalization and death in the 21st century. Traditionally, pneumococcus has been considered the major pathogen causing CAP; however, the 2015 EPIC study found that S. pneumoniae was detected in only 5% of patients diagnosed with CAP. Despite the new findings, it is still recommended that empiric treatment for CAP target common typical bacteria (pneumococcus, H. influenzae, Moraxella catarrhalis) and atypical bacteria (M. pneumonia, C. pneumoniae, L. pneumophila).

Because diagnosing pneumonia through history and clinical examination is less than 50% sensitive, a chest imaging study (a plain chest radiograph or a chest CT scan) is usually required to make the diagnosis. Laboratory tests, such as sputum Gram stain/culture, blood culture, urinary antigen tests, PCR test, procalcitonin, and CRP are important adjunctive diagnostic modalities to assist in the diagnosis and management of CAP. However, because no single test is sensitive and specific enough to be a stand-alone test, they should be used in conjunction with history, physical examination, and imaging studies.

Despite advances in medical science, pneumonia remains a major cause of morbidity and mortality. In 2017, 49,157 patients in the United States died from the disease.¹ Pneumonia can be classified as community-acquired, hospital-acquired, or ventilator-associated. Another category, healthcare-associated pneumonia, was included in an earlier Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) guideline but was removed from the 2016 guideline because there was no clear evidence that patients diagnosed with healthcare-associated pneumonia were at higher risk for harboring multidrug-resistant pathogens.² This review is the first of 2 articles focusing on the management of community-acquired pneumonia (CAP). Here, we review CAP epidemiology, microbiology, predisposing factors, and diagnosis; current treatment and prevention of CAP are reviewed in a separate article.

Definition and Epidemiology

CAP is defined as an acute infection of the lungs that develops in patients who have not been hospitalized recently and have not had regular exposure to the health care system.³ A previously ambulatory patient who is diagnosed with pneumonia within 48 hours after admission also meets the criteria for CAP. Approximately 4 to 5 million cases of CAP are diagnosed in the United States annually.⁴ About 25% of CAP patients require hospitalization, and about 5% to 10% of these patients are admitted to the intensive care unit (ICU).⁵ In-hospital mortality is considerable (~10% in population-based studies),⁶ and 30-day mortality was found to be as high as 23% in a review by File and Marrie.⁷ CAP also confers a high risk of long-term morbidity and mortality compared with the general population who have never had CAP, irrespective of age.⁸

Causative Organisms

Numerous microorganisms can cause CAP. Common causes and less common causes are delineated in Table 1. Until recently, many studies had demonstrated that pneumococcus was the most common cause of CAP. However, in the CDC Etiology of Pneumonia in the Community (EPIC) study team’s 2015 prospective, multicenter, population-based study, no pathogen was detected in the majority of patients diagnosed with CAP requiring hospitalization. The most common pathogens they detected were rhinovirus (9%), followed by influenza virus (6%) and pneumococcus (5%).⁹ Factors considered to be contributing to the decrease in the percentage of pneumococcus in patients diagnosed with CAP are the widespread use of pneumococcal vaccine and reduced rates of smoking.^10,11

Predisposing Factors

Most people diagnosed with CAP have 1 or more predisposing factors (Table 2).^12,13 Patients who develop CAP typically have a combination of these predisposing factors rather than a single factor. Aging, in combination with other risk factors, increases the susceptibility of a person to pneumonia.

Clinical Signs and Symptoms

Symptoms of CAP include fever, chills, rigors, fatigue, anorexia, diaphoresis, dyspnea, cough (with or without sputum production), and pleuritic chest pain. There is no individual symptom or cluster of symptoms that can absolutely differentiate pneumonia from other acute respiratory diseases, including upper and lower respiratory infections. However, patients presenting with the constellation of symptoms of fever ≥ 100°F (37.8°C), productive cough, and tachycardia is more suggestive of pneumonia.¹⁴ Abnormal vital signs include fever, hypothermia, tachypnea, tachycardia, and oxygen desaturation. Auscultation of the chest reveals crackles or other adventitious breath sounds. Elderly patients with pneumonia report a significantly lower number of both respiratory and nonrespiratory symptoms compared with younger patients. Clinicians should be aware of this phenomenon to avoid delayed diagnosis and treatment.¹⁵

Imaging Evaluation

The presence of a pulmonary consolidation or an infiltrate on chest radiograph is required to diagnose CAP, and a chest radiograph should be obtained when CAP is suspected.¹⁶ However, there is no pattern of radiographic abnormalities reliable enough to differentiate infectious pneumonia from noninfectious causes.¹⁷

There are case reports and case series demonstrating false-negative plain chest radiographs in dehydrated patients¹⁸ or in patients in a neutropenic state. However, animal studies have shown that dogs challenged with pneumococcus showed abnormal pulmonary shadow, suggestive of pneumonia, regardless of hydration status.¹⁹ There is also no reliable scientific evidence to support the notion that severe neutropenia can cause false-negative radiographs because of the inability to develop an acute inflammatory reaction in the lungs.²⁰

A chest computed tomography (CT) scan is more sensitive than a plain chest radiograph in detecting pneumonia. Therefore, a chest CT should be performed in a patient with negative plain chest radiograph when pneumonia is still highly suspected.²¹ A chest CT scan is also more sensitive in detecting cavitation, adenopathy, interstitial disease, and empyema. It also has the advantage of better defining anatomical changes than plain films.²²

Because improvement of pulmonary opacities in patients with CAP lags behind clinical improvement, repeating chest imaging studies is not recommended in patients who demonstrate clinical improvement. Clearing of pulmonary infiltrate or consolidation sometimes can take 6 weeks or longer.²³

Laboratory Evaluation

Generally, the etiologic agent of CAP cannot be determined solely on the basis of clinical signs and symptoms or imaging studies. Although routine microbiological testing for patients suspicious for CAP is not necessary for empirical treatment, determining the etiologic agent of the pneumonia allows the clinician to narrow the antibiotics from a broad-spectrum empirical regimen to specific pathogen-directed therapy. Determination of certain etiologic agents causing the pneumonia can have important public health implications (eg, Mycobacterium tuberculosis and influenza virus).²⁴

Sputum Gram Stain and Culture

Sputum Gram stain is an inexpensive test that may identify pathogens that cause CAP (eg, Streptococcus pneumoniae and Haemophilus influenzae). A quality specimen is required. A sputum sample must contain more than 25 neutrophils and less than 10 squamous epithelial cells/low power field on Gram stain to be considered suitable for culture. The sensitivity and specificity of sputum Gram stain and culture are highly variable in different clinical settings (eg, outpatient setting, nursing home, ICU). Reed et al’s meta-analysis of patients diagnosed with CAP in the United States showed the sensitivity and specificity of sputum Gram stain (compared with sputum culture) ranged from 15% to 100% and 11% to 100%, respectively.²⁴ In cases of proven bacteremic pneumococcal pneumonia, positive cultures from sputum samples were positive less than 50% of the time.²⁵

For patients who cannot provide sputum samples or are intubated, deep-suction aspirate or bronchoalveolar lavage through a bronchoscopic procedure may be necessary to obtain pulmonary secretion for Gram stain and culture. Besides bacterial culture, sputum samples can also be sent for fungal and mycobacterial cultures and acid-fast stain, if deemed clinically necessary.

The 2019 ATS/IDSA guidelines for diagnosis and treatment of adults with CAP recommend sputum culture in patients with severe disease and in all inpatients empirically treated for MRSA or Pseudomonas aeruginosa.²⁶

Because the positivity rate of blood culture in patients who are suspected to have pneumonia but not exposed to antimicrobial agents is low (5%–14%), blood cultures are not recommended for all patients with CAP. Another reason for not recommending blood culture is positive culture rarely leads to changes in antibiotic regimen in patients without underlying diseases.²⁷ However, the 2019 ATS/IDSA guidelines recommend blood culture in patients with severe disease and in all inpatients treated empirically for MRSA or P. aeruginosa.²⁶

A multinational study published in 2008 examined 125 patients with pneumococcal bacteremic CAP versus 1847 patients with non-bacteremic CAP.²⁸ Analysis of the data demonstrated no association between pneumococcal bacteremic CAP and time to clinical stability, length of hospital stay, all-cause mortality, or CAP-related mortality. The authors concluded that pneumococcal bacteremia does not increase the risk of poor outcomes in patients with CAP compared to non-bacteremic patients, and the presence of pneumococcal bacteremia should not deter de-escalation of therapy in clinically stable patients.

Urinary Antigen Tests

Urinary antigen tests may assist clinicians in narrowing antibiotic therapy when test results are positive. There are 2 US Food and Drug Administration–approved tests available to clinicians for detecting pneumococcal and Legionella antigen in urine. The test for Legionella pneumophila detects disease due to serogroup 1 only, which accounts for 80% of community-acquired Legionnaires’ disease. The sensitivity and specificity of the Legionella urine antigen test are 90% and 99%, respectively. The pneumococcal urine antigen test is less sensitive and specific than the Legionella urine antigen test (sensitivity 80% and specificity > 90%).^29,30

Advantages of the urinary antigen tests are that they are easily performed, results are available in less than an hour if done in-house, and results are not affected by prior exposure to antibiotics. However, the tests do not meet Clinical Laboratory Improvements Amendments criteria for waiver and must be performed by a technician in the laboratory. A multicenter, prospective surveillance study of hospitalized patients with CAP showed that the 2007 IDSA/ATS guidelines’ recommended indications for S. pneumoniae and L. pneumophila urinary antigen tests do not have sufficient sensitivity and specificity to identify patients with positive tests.³¹

Polymerase Chain Reaction

There are several FDA-approved polymerase chain reaction (PCR) tests commercially available to assist clinicians in diagnosing pneumonia. PCR testing of nasopharyngeal swabs for diagnosis of influenza has become standard in many US medical facilities. The great advantages of using PCR to diagnose influenza are its high sensitivity and specificity and rapid turnaround time. PCR can also be used to detect Legionella species, S. pneumonia, Mycoplasma pneumoniae, Chlamydophila pneumonia, and mycobacterial species.²⁴

One limitation of using PCR tests on respiratory specimens is that specimens can be contaminated with oral or upper airway flora, so the results must be interpreted with caution, bearing in mind that some of the pathogens isolated may be colonizers of the oral or upper airway flora.³²

Biologic Markers

Two biologic markers—procalcitonin and C-reactive protein (CRP)—can be used in conjunction with history, physical examination, laboratory tests, and imaging studies to assist in the diagnosis and treatment of CAP.²⁴ Procalcitonin is a peptide precursor of the hormone calcitonin that is released by parenchymal cells into the bloodstream, resulting in increased serum level in patients with bacterial infections. In contrast, there is no remarkable procalcitonin level increase with viral or noninfectious inflammation. The reference value of procalcitonin in the blood of an adult individual without infection or inflammation is < 0.15 ng/mL. In the blood, procalcitonin has a half-life of 25 to 30 hours. The quantitative immunoluminometric method (LUMI test, Brahms PCT, Berlin, Germany) is the preferred test to use because of its high sensitivity.³³ A meta-analysis of 12 studies involving more than 2400 patients with CAP demonstrated that serum procalcitonin does not have sufficient sensitivity or specificity to distinguish between bacterial and nonbacterial pneumonia. The authors concluded that procalcitonin level cannot be used to decide whether an antibiotic should be administered.³⁴

A 2012 Cochrane meta-analysis that involved 4221 patients with acute respiratory infections (with half of the patients diagnosed with CAP) from 14 prospective trials found the use of procalcitonin test for antibiotic use significantly decreased median antibiotic exposure from 8 to 4 days without an increase in treatment failure, mortality rates in any clinical setting (eg, outpatient clinic, emergency room), or length of hospitalization.³⁵ An update of the 2012 Cochrane review that examined the safety and efficacy of using procalcitonin for starting or stopping antibiotics again demonstrated procalcitonin use was associated with a reduction of antibiotic use (2.4 days).³⁶ A prospective study conducted in France on 100 ICU patients showed that increased procalcitonin from day 1 to day 3 has a poor prognosis factor for severe CAP, whereas decreasing procalcitonin levels is associated with a favorable outcome.³⁷

Because of conflicting data, the 2019 ATS/IDSA guidelines do not recommend using procalcitonin to determine need for initial antibacterial therapy.²⁶

CRP is an acute phase protein produced by the liver. CRP level in the blood increases in response to acute infection or inflammation. Use of CRP in assisting diagnosis and guiding treatment of CAP is more limited in part due to its poor specificity. A prospective study conducted on 168 consecutive patients who presented with cough showed that a CRP level > 40 mg/L had a sensitivity and specificity of 70% and 90%, respectively.³⁸

Summary

CAP remains a leading cause of hospitalization and death in the 21st century. Traditionally, pneumococcus has been considered the major pathogen causing CAP; however, the 2015 EPIC study found that S. pneumoniae was detected in only 5% of patients diagnosed with CAP. Despite the new findings, it is still recommended that empiric treatment for CAP target common typical bacteria (pneumococcus, H. influenzae, Moraxella catarrhalis) and atypical bacteria (M. pneumonia, C. pneumoniae, L. pneumophila).

Because diagnosing pneumonia through history and clinical examination is less than 50% sensitive, a chest imaging study (a plain chest radiograph or a chest CT scan) is usually required to make the diagnosis. Laboratory tests, such as sputum Gram stain/culture, blood culture, urinary antigen tests, PCR test, procalcitonin, and CRP are important adjunctive diagnostic modalities to assist in the diagnosis and management of CAP. However, because no single test is sensitive and specific enough to be a stand-alone test, they should be used in conjunction with history, physical examination, and imaging studies.

Revascularization of more than just the culprit lesion in patients with ST-elevation myocardial infarctions could significantly reduce their risk of cardiovascular death or myocardial infarction, according to results of the COMPLETE trial, presented at the annual congress of the European Society of Cardiology.

The report, simultaneously published online in the New England Journal of Medicine, detailed the outcomes of COMPLETE (the Complete versus Culprit-Only Revascularization Strategies to Treat Multivessel Disease after Early PCI for STEMI), a study in 4,041 patients who had experienced an ST-elevation myocardial infarction (STEMI), who had multi-vessel coronary artery disease, and who had undergone successful percutaneous coronary intervention of the culprit lesion.

Participants were randomized either to complete revascularization of all angiographically significant nonculprit lesions, or to no further revascularization, and were followed for a median of 3 years.

Of the patients who underwent complete revascularization, 7.8% experienced either cardiovascular death or another myocardial infarction, compared with 10.5% of those who only had revascularization of the culprit lesion, representing a significant 26% reduction (P = .004) in the incidence of this composite coprimary outcome.

The decrease in events was driven by a significant 32% reduction in the incidence of new myocardial infarction – particularly non-STEMI, new STEMI, and myocardial infarction type 1 – in the complete revascularization group, with only a 7% reduction in the incidence of death from cardiovascular causes.

With the second coprimary outcome of a composite of cardiovascular death, myocardial infarction, or ischemia-driven revascularization, this was seen in 8.9% of patients in the complete revascularization group compared with 16.7% of patients with the culprit-lesion-only group; a significant 49% reduction in incidence (P less than .001).

The authors calculated that 37 complete revascularizations would need to be performed to prevent one incidence of cardiovascular death or myocardial infarction. To prevent cardiovascular death, myocardial infarction, or ischemia-driven revascularization, the number needed to treat was 13.

The timing of complete revascularization did not appear to affect the benefits of the procedure, which were consistent among patients who underwent complete revascularization during their index hospitalization and in those who underwent the procedure after hospital discharge. Investigators had to specify before randomization whether the patient would undergo complete revascularization during the index hospitalization or after discharge but within 45 days.

The study also did not find any significant differences between the two groups in the risks of major bleeding, stroke, or stent thrombosis. However, the complete revascularization group did experience a nonsignificant 59% higher odds of contrast-associated acute kidney injury, which was attributed to the nonculprit lesion revascularization in seven patients in the complete revascularization group.

Dr. Shamir R. Mehta, of the Population Health Research Institute at McMaster University, Ontario, and coauthors noted that previous trials of complete-revascularization strategies in patients with STEMI were smaller and had included revascularization as part of a composite primary outcome.

“In the absence of a reduction in irreversible events such as cardiovascular death or new myocardial infarction, the clinical relevance of performing early nonculprit-lesion PCI in all patients with multivessel coronary artery disease to prevent later PCI in a smaller number of those patients is debatable,” they wrote. “We have now found that routine nonculprit-lesion PCI with the goal of complete revascularization confers a reduction in the long-term risk of cardiovascular death or myocardial infarction.”

No patients with cardiogenic shock were enrolled in the study, so the results could not be extrapolated to that patient group.

SOURCE: Mehta S et al. N Engl J Med. 2019 Sep. 1. doi: 10.1056/NEJMoa1907775.

Revascularization of more than just the culprit lesion in patients with ST-elevation myocardial infarctions could significantly reduce their risk of cardiovascular death or myocardial infarction, according to results of the COMPLETE trial, presented at the annual congress of the European Society of Cardiology.

The report, simultaneously published online in the New England Journal of Medicine, detailed the outcomes of COMPLETE (the Complete versus Culprit-Only Revascularization Strategies to Treat Multivessel Disease after Early PCI for STEMI), a study in 4,041 patients who had experienced an ST-elevation myocardial infarction (STEMI), who had multi-vessel coronary artery disease, and who had undergone successful percutaneous coronary intervention of the culprit lesion.

Participants were randomized either to complete revascularization of all angiographically significant nonculprit lesions, or to no further revascularization, and were followed for a median of 3 years.

Of the patients who underwent complete revascularization, 7.8% experienced either cardiovascular death or another myocardial infarction, compared with 10.5% of those who only had revascularization of the culprit lesion, representing a significant 26% reduction (P = .004) in the incidence of this composite coprimary outcome.

The decrease in events was driven by a significant 32% reduction in the incidence of new myocardial infarction – particularly non-STEMI, new STEMI, and myocardial infarction type 1 – in the complete revascularization group, with only a 7% reduction in the incidence of death from cardiovascular causes.

With the second coprimary outcome of a composite of cardiovascular death, myocardial infarction, or ischemia-driven revascularization, this was seen in 8.9% of patients in the complete revascularization group compared with 16.7% of patients with the culprit-lesion-only group; a significant 49% reduction in incidence (P less than .001).

The authors calculated that 37 complete revascularizations would need to be performed to prevent one incidence of cardiovascular death or myocardial infarction. To prevent cardiovascular death, myocardial infarction, or ischemia-driven revascularization, the number needed to treat was 13.

The timing of complete revascularization did not appear to affect the benefits of the procedure, which were consistent among patients who underwent complete revascularization during their index hospitalization and in those who underwent the procedure after hospital discharge. Investigators had to specify before randomization whether the patient would undergo complete revascularization during the index hospitalization or after discharge but within 45 days.

The study also did not find any significant differences between the two groups in the risks of major bleeding, stroke, or stent thrombosis. However, the complete revascularization group did experience a nonsignificant 59% higher odds of contrast-associated acute kidney injury, which was attributed to the nonculprit lesion revascularization in seven patients in the complete revascularization group.

Dr. Shamir R. Mehta, of the Population Health Research Institute at McMaster University, Ontario, and coauthors noted that previous trials of complete-revascularization strategies in patients with STEMI were smaller and had included revascularization as part of a composite primary outcome.

“In the absence of a reduction in irreversible events such as cardiovascular death or new myocardial infarction, the clinical relevance of performing early nonculprit-lesion PCI in all patients with multivessel coronary artery disease to prevent later PCI in a smaller number of those patients is debatable,” they wrote. “We have now found that routine nonculprit-lesion PCI with the goal of complete revascularization confers a reduction in the long-term risk of cardiovascular death or myocardial infarction.”

No patients with cardiogenic shock were enrolled in the study, so the results could not be extrapolated to that patient group.

SOURCE: Mehta S et al. N Engl J Med. 2019 Sep. 1. doi: 10.1056/NEJMoa1907775.

Revascularization of more than just the culprit lesion in patients with ST-elevation myocardial infarctions could significantly reduce their risk of cardiovascular death or myocardial infarction, according to results of the COMPLETE trial, presented at the annual congress of the European Society of Cardiology.

The report, simultaneously published online in the New England Journal of Medicine, detailed the outcomes of COMPLETE (the Complete versus Culprit-Only Revascularization Strategies to Treat Multivessel Disease after Early PCI for STEMI), a study in 4,041 patients who had experienced an ST-elevation myocardial infarction (STEMI), who had multi-vessel coronary artery disease, and who had undergone successful percutaneous coronary intervention of the culprit lesion.

Participants were randomized either to complete revascularization of all angiographically significant nonculprit lesions, or to no further revascularization, and were followed for a median of 3 years.

Of the patients who underwent complete revascularization, 7.8% experienced either cardiovascular death or another myocardial infarction, compared with 10.5% of those who only had revascularization of the culprit lesion, representing a significant 26% reduction (P = .004) in the incidence of this composite coprimary outcome.

The decrease in events was driven by a significant 32% reduction in the incidence of new myocardial infarction – particularly non-STEMI, new STEMI, and myocardial infarction type 1 – in the complete revascularization group, with only a 7% reduction in the incidence of death from cardiovascular causes.

With the second coprimary outcome of a composite of cardiovascular death, myocardial infarction, or ischemia-driven revascularization, this was seen in 8.9% of patients in the complete revascularization group compared with 16.7% of patients with the culprit-lesion-only group; a significant 49% reduction in incidence (P less than .001).

The authors calculated that 37 complete revascularizations would need to be performed to prevent one incidence of cardiovascular death or myocardial infarction. To prevent cardiovascular death, myocardial infarction, or ischemia-driven revascularization, the number needed to treat was 13.

The timing of complete revascularization did not appear to affect the benefits of the procedure, which were consistent among patients who underwent complete revascularization during their index hospitalization and in those who underwent the procedure after hospital discharge. Investigators had to specify before randomization whether the patient would undergo complete revascularization during the index hospitalization or after discharge but within 45 days.

The study also did not find any significant differences between the two groups in the risks of major bleeding, stroke, or stent thrombosis. However, the complete revascularization group did experience a nonsignificant 59% higher odds of contrast-associated acute kidney injury, which was attributed to the nonculprit lesion revascularization in seven patients in the complete revascularization group.

Dr. Shamir R. Mehta, of the Population Health Research Institute at McMaster University, Ontario, and coauthors noted that previous trials of complete-revascularization strategies in patients with STEMI were smaller and had included revascularization as part of a composite primary outcome.

“In the absence of a reduction in irreversible events such as cardiovascular death or new myocardial infarction, the clinical relevance of performing early nonculprit-lesion PCI in all patients with multivessel coronary artery disease to prevent later PCI in a smaller number of those patients is debatable,” they wrote. “We have now found that routine nonculprit-lesion PCI with the goal of complete revascularization confers a reduction in the long-term risk of cardiovascular death or myocardial infarction.”

No patients with cardiogenic shock were enrolled in the study, so the results could not be extrapolated to that patient group.

SOURCE: Mehta S et al. N Engl J Med. 2019 Sep. 1. doi: 10.1056/NEJMoa1907775.