The Journal of Family Practice

EVIDENCE SUMMARY

Mixed results, quality issues do not support screening asymptomatic patients

A meta-analysis (12 observational studies; n = 1002) compared the diagnostic accuracy of panoramic radiography (PR) to Doppler ultrasonography (11 studies) or angiography (1 study) in detecting calcified carotid artery atheroma (CCAA).¹ The studies, conducted in 8 countries, were published after 2006. Patients were 29 to 71 years old without history of stroke, endarterectomy, angioplasty, or renal disease. In a pooled analysis, the sensitivity of PR to detect CCAA was 73% (range, 31%-95%; 95% CI, 69%-77%), and the specificity was 72% (range, 19%-99%; 95% CI, 68%-76%). The pooled positive predictive value was 70% (range, 37%-95%; 95% CI, 66%-74%), and negative predictive value was 75% (range, 43%-93%; 95% CI, 71%-79%). Pooled positive likelihood ratio was 2.32 (95% CI, 1.49-3.60) and negative likelihood ratio was 0.40 (95% CI, 0.25-0.63). Seven studies had high risk of patient selection bias, and most had methodologic limitations.

In a retrospective cohort study (n = 778) from the United States, researchers identified carotid artery calcifications on routine dental radiographs in patients ≥ 55 years old and prospectively performed duplex ultrasound (DUS) to assess for significant carotid stenosis (≥ 50%).² Twenty-seven patients (3.5%) had carotid artery calcifications on radiographs, and 20 of those patients underwent DUS of bilateral carotid arteries (40 sides). Of 26 sides with calcifications on radiograph, 13 (50%) had stenosis confirmed with DUS. Of the 14 sides without calcification on radiograph, 3 (21%) had stenosis on DUS. The positive predictive value for calcification on PR predicting significant carotid stenosis was between 40% and 80%.

In a cross-sectional study from Sweden, investigators sought surgical candidates for asymptomatic carotid endarterectomy and performed PRs of 1182 patients.³ Calcifications were found in 176 people; 117 of them were eligible for asymptomatic carotid endarterectomy (ages 18-74; no cancer or other serious comorbidity; and no prior stroke or transient ischemic attack) and underwent ultrasound to assess for significant carotid stenosis (≥ 50%). Of the 117 participants who underwent ultrasound, 8 (6.8%; 95% CI, 2.2%-11.5%), all men, were found to have significant carotid stenosis. Compared to a sex- and age-matched reference group (n = 119) with no calcifications on PR, the prevalence of carotid stenosis was significantly higher in men (12.5%; 95% CI, 4.2%-20.8%) and in patients who were current smokers (19%; 95% CI, 0.7%-37.4%), were taking cholesterol medications (13.1%; 95% CI 4.4%-21.8%), and had a cardiovascular event history (15.9%; 95% CI, 7%-27.2%).

Recommendations from others

The US Preventive Services Task Force ­(USPSTF) and the American Academy of Family Physicians do not mention carotid screening with radiographs but recommend against screening for carotid artery stenosis in asymptomatic adults because the risks of screening outweigh the potential benefits (USPSTF grade D; the harms outweigh the benefits).^4,5

Editor’s takeaway

If you see calcification of the carotid artery on an x-ray of an asymptomatic patient, ignore it. The positive and negative predictive values for carotid stenosis are poor, and you should not pursue further testing.

EVIDENCE SUMMARY

Mixed results, quality issues do not support screening asymptomatic patients

A meta-analysis (12 observational studies; n = 1002) compared the diagnostic accuracy of panoramic radiography (PR) to Doppler ultrasonography (11 studies) or angiography (1 study) in detecting calcified carotid artery atheroma (CCAA).¹ The studies, conducted in 8 countries, were published after 2006. Patients were 29 to 71 years old without history of stroke, endarterectomy, angioplasty, or renal disease. In a pooled analysis, the sensitivity of PR to detect CCAA was 73% (range, 31%-95%; 95% CI, 69%-77%), and the specificity was 72% (range, 19%-99%; 95% CI, 68%-76%). The pooled positive predictive value was 70% (range, 37%-95%; 95% CI, 66%-74%), and negative predictive value was 75% (range, 43%-93%; 95% CI, 71%-79%). Pooled positive likelihood ratio was 2.32 (95% CI, 1.49-3.60) and negative likelihood ratio was 0.40 (95% CI, 0.25-0.63). Seven studies had high risk of patient selection bias, and most had methodologic limitations.

In a retrospective cohort study (n = 778) from the United States, researchers identified carotid artery calcifications on routine dental radiographs in patients ≥ 55 years old and prospectively performed duplex ultrasound (DUS) to assess for significant carotid stenosis (≥ 50%).² Twenty-seven patients (3.5%) had carotid artery calcifications on radiographs, and 20 of those patients underwent DUS of bilateral carotid arteries (40 sides). Of 26 sides with calcifications on radiograph, 13 (50%) had stenosis confirmed with DUS. Of the 14 sides without calcification on radiograph, 3 (21%) had stenosis on DUS. The positive predictive value for calcification on PR predicting significant carotid stenosis was between 40% and 80%.

In a cross-sectional study from Sweden, investigators sought surgical candidates for asymptomatic carotid endarterectomy and performed PRs of 1182 patients.³ Calcifications were found in 176 people; 117 of them were eligible for asymptomatic carotid endarterectomy (ages 18-74; no cancer or other serious comorbidity; and no prior stroke or transient ischemic attack) and underwent ultrasound to assess for significant carotid stenosis (≥ 50%). Of the 117 participants who underwent ultrasound, 8 (6.8%; 95% CI, 2.2%-11.5%), all men, were found to have significant carotid stenosis. Compared to a sex- and age-matched reference group (n = 119) with no calcifications on PR, the prevalence of carotid stenosis was significantly higher in men (12.5%; 95% CI, 4.2%-20.8%) and in patients who were current smokers (19%; 95% CI, 0.7%-37.4%), were taking cholesterol medications (13.1%; 95% CI 4.4%-21.8%), and had a cardiovascular event history (15.9%; 95% CI, 7%-27.2%).

Recommendations from others

The US Preventive Services Task Force ­(USPSTF) and the American Academy of Family Physicians do not mention carotid screening with radiographs but recommend against screening for carotid artery stenosis in asymptomatic adults because the risks of screening outweigh the potential benefits (USPSTF grade D; the harms outweigh the benefits).^4,5

Editor’s takeaway

If you see calcification of the carotid artery on an x-ray of an asymptomatic patient, ignore it. The positive and negative predictive values for carotid stenosis are poor, and you should not pursue further testing.

EVIDENCE SUMMARY

Mixed results, quality issues do not support screening asymptomatic patients

A meta-analysis (12 observational studies; n = 1002) compared the diagnostic accuracy of panoramic radiography (PR) to Doppler ultrasonography (11 studies) or angiography (1 study) in detecting calcified carotid artery atheroma (CCAA).¹ The studies, conducted in 8 countries, were published after 2006. Patients were 29 to 71 years old without history of stroke, endarterectomy, angioplasty, or renal disease. In a pooled analysis, the sensitivity of PR to detect CCAA was 73% (range, 31%-95%; 95% CI, 69%-77%), and the specificity was 72% (range, 19%-99%; 95% CI, 68%-76%). The pooled positive predictive value was 70% (range, 37%-95%; 95% CI, 66%-74%), and negative predictive value was 75% (range, 43%-93%; 95% CI, 71%-79%). Pooled positive likelihood ratio was 2.32 (95% CI, 1.49-3.60) and negative likelihood ratio was 0.40 (95% CI, 0.25-0.63). Seven studies had high risk of patient selection bias, and most had methodologic limitations.

In a retrospective cohort study (n = 778) from the United States, researchers identified carotid artery calcifications on routine dental radiographs in patients ≥ 55 years old and prospectively performed duplex ultrasound (DUS) to assess for significant carotid stenosis (≥ 50%).² Twenty-seven patients (3.5%) had carotid artery calcifications on radiographs, and 20 of those patients underwent DUS of bilateral carotid arteries (40 sides). Of 26 sides with calcifications on radiograph, 13 (50%) had stenosis confirmed with DUS. Of the 14 sides without calcification on radiograph, 3 (21%) had stenosis on DUS. The positive predictive value for calcification on PR predicting significant carotid stenosis was between 40% and 80%.

In a cross-sectional study from Sweden, investigators sought surgical candidates for asymptomatic carotid endarterectomy and performed PRs of 1182 patients.³ Calcifications were found in 176 people; 117 of them were eligible for asymptomatic carotid endarterectomy (ages 18-74; no cancer or other serious comorbidity; and no prior stroke or transient ischemic attack) and underwent ultrasound to assess for significant carotid stenosis (≥ 50%). Of the 117 participants who underwent ultrasound, 8 (6.8%; 95% CI, 2.2%-11.5%), all men, were found to have significant carotid stenosis. Compared to a sex- and age-matched reference group (n = 119) with no calcifications on PR, the prevalence of carotid stenosis was significantly higher in men (12.5%; 95% CI, 4.2%-20.8%) and in patients who were current smokers (19%; 95% CI, 0.7%-37.4%), were taking cholesterol medications (13.1%; 95% CI 4.4%-21.8%), and had a cardiovascular event history (15.9%; 95% CI, 7%-27.2%).

Recommendations from others

The US Preventive Services Task Force ­(USPSTF) and the American Academy of Family Physicians do not mention carotid screening with radiographs but recommend against screening for carotid artery stenosis in asymptomatic adults because the risks of screening outweigh the potential benefits (USPSTF grade D; the harms outweigh the benefits).^4,5

Editor’s takeaway

If you see calcification of the carotid artery on an x-ray of an asymptomatic patient, ignore it. The positive and negative predictive values for carotid stenosis are poor, and you should not pursue further testing.

A solitary dark lesion on the back of an adult is worrisome for melanoma. A scoop-shave biopsy was ordered with the aim of achieving a 1- to 3-mm margin. The biopsy identified the lesion as a benign pigmented seborrheic keratosis (SK).

SKs are a group of common, keratinocyte neoplasms that can occur in large numbers on a patient. They may meet many of the ABCDE criteria (Asymmetry, Border irregularity, Color [varying shades or deep black color], Diameter > 6 mm, or Evolving/changing) used to grossly identify potential melanomas. It is worth noting that not all dark-pigmented lesions arise from melanocytes. In this instance, the dark SK is made of keratinocytes that had accumulated melanin.

Dermoscopy usually helps distinguish SKs from melanocytic neoplasm, which would include nevi and melanoma. Melanocytic lesions (whether benign nevi or malignant melanoma) will display a pigment network, globules, streaks, homogeneous blue or tan color, or characteristic vascular findings. SKs, on the other hand, often demonstrate sharply demarcated borders, milia-like cysts or comedo-like openings, and hairpin vessels.

Both the clinical and dermoscopic photos in this case showed a sharply demarcated border, lack of network, and an absence of any vascular markings. The central scale crust did not exclude a melanocytic lesion and there were peripheral small black dots that could have been asymmetrical globules; however, the biopsy negated those clinical concerns.

Dermoscopy improves diagnostic specificity, but not perfectly. The number of benign lesions biopsied for every malignant lesion confirmed decreases from about 18 without dermoscopy to 8 or fewer for the most experienced dermoscopy practitioners.¹ This case highlights one of many instances of a clinically and dermoscopically suspicious lesion that ultimately was benign.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

A solitary dark lesion on the back of an adult is worrisome for melanoma. A scoop-shave biopsy was ordered with the aim of achieving a 1- to 3-mm margin. The biopsy identified the lesion as a benign pigmented seborrheic keratosis (SK).

SKs are a group of common, keratinocyte neoplasms that can occur in large numbers on a patient. They may meet many of the ABCDE criteria (Asymmetry, Border irregularity, Color [varying shades or deep black color], Diameter > 6 mm, or Evolving/changing) used to grossly identify potential melanomas. It is worth noting that not all dark-pigmented lesions arise from melanocytes. In this instance, the dark SK is made of keratinocytes that had accumulated melanin.

Dermoscopy usually helps distinguish SKs from melanocytic neoplasm, which would include nevi and melanoma. Melanocytic lesions (whether benign nevi or malignant melanoma) will display a pigment network, globules, streaks, homogeneous blue or tan color, or characteristic vascular findings. SKs, on the other hand, often demonstrate sharply demarcated borders, milia-like cysts or comedo-like openings, and hairpin vessels.

Both the clinical and dermoscopic photos in this case showed a sharply demarcated border, lack of network, and an absence of any vascular markings. The central scale crust did not exclude a melanocytic lesion and there were peripheral small black dots that could have been asymmetrical globules; however, the biopsy negated those clinical concerns.

Dermoscopy improves diagnostic specificity, but not perfectly. The number of benign lesions biopsied for every malignant lesion confirmed decreases from about 18 without dermoscopy to 8 or fewer for the most experienced dermoscopy practitioners.¹ This case highlights one of many instances of a clinically and dermoscopically suspicious lesion that ultimately was benign.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

A solitary dark lesion on the back of an adult is worrisome for melanoma. A scoop-shave biopsy was ordered with the aim of achieving a 1- to 3-mm margin. The biopsy identified the lesion as a benign pigmented seborrheic keratosis (SK).

SKs are a group of common, keratinocyte neoplasms that can occur in large numbers on a patient. They may meet many of the ABCDE criteria (Asymmetry, Border irregularity, Color [varying shades or deep black color], Diameter > 6 mm, or Evolving/changing) used to grossly identify potential melanomas. It is worth noting that not all dark-pigmented lesions arise from melanocytes. In this instance, the dark SK is made of keratinocytes that had accumulated melanin.

Dermoscopy usually helps distinguish SKs from melanocytic neoplasm, which would include nevi and melanoma. Melanocytic lesions (whether benign nevi or malignant melanoma) will display a pigment network, globules, streaks, homogeneous blue or tan color, or characteristic vascular findings. SKs, on the other hand, often demonstrate sharply demarcated borders, milia-like cysts or comedo-like openings, and hairpin vessels.

Both the clinical and dermoscopic photos in this case showed a sharply demarcated border, lack of network, and an absence of any vascular markings. The central scale crust did not exclude a melanocytic lesion and there were peripheral small black dots that could have been asymmetrical globules; however, the biopsy negated those clinical concerns.

Dermoscopy improves diagnostic specificity, but not perfectly. The number of benign lesions biopsied for every malignant lesion confirmed decreases from about 18 without dermoscopy to 8 or fewer for the most experienced dermoscopy practitioners.¹ This case highlights one of many instances of a clinically and dermoscopically suspicious lesion that ultimately was benign.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

THE CASE

A 75-year-old man with a history of osteoarthritis presented to our clinic with worsening weakness over the previous month. His signs and symptoms included profound fatigue, subjective fevers, a 10-pound weight loss, ankle swelling, myalgias in his legs and back, shortness of breath, and a persistent cough. The patient was otherwise previously healthy.

The patient’s heart and lung exams were normal. Initial outpatient labs showed significantly elevated inflammatory markers, with an erythrocyte sedimentation rate (ESR) of 102 mm/h (normal range for men ≥ 50 years, 0-20 mm/h) and a C-reactive protein (CRP) level of 11.1 mg/L (normal range, < 3 mg/L). The patient also had an elevated white blood cell count of 12,000/mcL (normal range, 4500-11,000/mcL). His hemoglobin was low (11 g/dL; normal range, 13.5-17.5 g/dL) and so was his albumin level (2.9 g/dL; normal range, 3.4-5.4 g/dL). The results of his prostate-specific antigen and brain natriuretic peptide tests were both normal. The results of a computed tomography scan of his thorax, abdomen, and pelvis were negative for malignancy.

The patient returned to our clinic 3 days later with severe weakness, which inhibited him from walking. He complained of a severe spasmodic pain between his shoulder blades. He denied joint stiffness, headaches, vision changes, or jaw claudication. The patient’s son had noted an overall increase in his father’s baseline heart rate, with readings increasing from the 50 beats/min range to the 70 beats/min range; this raised concern for a ­catecholamine-secreting tumor. There was also concern for occult infection and malignancy, or an autoimmune process, such as polymyalgia rheumatica. Due to his extreme weakness, the patient was directly admitted to the hospital for further work-up.

THE DIAGNOSIS

Concern for a smoldering infection prompted an order for a ­transthoracic echocardiogram. Images revealed a large mass on the mitral valve (FIGURE 1). Blood cultures quickly grew Streptococcus sanguinis. Additional work-up with a transesophageal echocardiogram (TEE) showed a “windsock” deformity (thinning and ballooning of the mitral valve), a known sequela of infective endocarditis (FIGURE 2).¹ Further history obtained after the TEE revealed the patient had had a routine dental cleaning the month before his symptoms began. A murmur was then also detected.

DISCUSSION

Infective endocarditis (IE) is uncommon and difficult to diagnose; it has a high early-­mortality rate of 30%.² TEE is the recommended imaging study for IE, because it is more sensitive than a transthoracic echocardiogram for identifying vegetations on the valves and it is more cost effective.³

The modified Duke Criteria provide guidance for diagnosis of endocarditis. Major criteria focus on positive blood cultures and evidence of endocardial involvement. Minor criteria include predisposing heart conditions, intravenous drug use (IVDU), fever, and vascular and immunologic phenomena. As many as 90% of patients have a fever and often experience weight loss.⁴ Murmurs are auscultated in up to 85% of patients, and embolic features are present in up to 25% of patients at the time of diagnosis.⁴ In the developed world, Janeway lesions, Osler nodes, and splinter hemorrhages are increasingly rare, as patients usually present earlier in the disease course.⁴ While ESR and CRP are generally elevated in cases of IE, they are not part of the Duke Criteria.⁴

A closer look at risk factors

In 2007, guidelines for the prevention, treatment, and management of endocarditis were given significant categorical revision by the American Heart Association for the first time in 50 years.⁵ Recommendations for antibiotic prophylaxis prior to dental procedures became more restrictive, to include only 4 groups of high-risk patients: those with prosthetic cardiac valves, those with a history of IE, those with congenital heart disease, and cardiac transplant recipients.⁴ The rationale for these restrictions included the small risk for anaphylaxis and potential increase in risk for bacterial resistance associated with antibiotic prophylaxis.⁴ A review published in 2021 noted no increase in the frequency of, nor the morbidity and mortality from, viridans group streptococcal IE since the guideline updates.⁵

Continue to: There is an emerging consensus...

There is an emerging consensus that poor oral hygiene and gingival bleeding after tooth brushing promote a chronic low-grade bacteremia that may be more strongly associated with IE than an isolated dental extraction.⁶ Poor dental hygiene, defined as dental plaque and calculus, is especially common in the elderly, who are known to let their dental hygiene lapse.⁶ In our patient’s case, his generally poor oral hygiene was more likely the cause of his IE than his routine dental cleaning.

Other risk factors include IV drug use. At our tertiary care hospital in western North Carolina, 48% of patients with endocarditis had an additional diagnosis of opiate or narcotic dependence (Ryan Tilton, PharmD, email communication, June 7, 2018). Interestingly, though, only 16% of patients in North America with endocarditis were found to be currently using IV drugs.⁷

Our patient was treated with IV antibiotics for 4 weeks and underwent rehabilitation at a skilled nursing facility. Four weeks after diagnosis, he underwent an endoscopic porcine mitral valve replacement. Two months after that, he returned to his previously active lifestyle and began riding his stationary bike. The patient also began taking a daily aspirin. Consistent with current guidelines, he now gets antibiotic prophylaxis prior to dental procedures.

THE TAKEAWAY

This patient, without any history of IVDU or cardiac valvular abnormalities, presented with symptoms classic for a developing malignancy or possible rheumatologic condition. Subacute IE may manifest similarly, with vague symptoms such as myalgias, fatigue, chills, and/or anemia. In non-drug users, suspicion for endocarditis should be highest in men older than age 60. Also, it’s important to auscultate for a new heart murmur. In our patient’s case, no murmur was auscultated until after his TEE. JFP

CORRESPONDENCE
Ginger Poulton, MD, 123 Hendersonville Road, Asheville, NC 28803; [email protected]

THE CASE

A 75-year-old man with a history of osteoarthritis presented to our clinic with worsening weakness over the previous month. His signs and symptoms included profound fatigue, subjective fevers, a 10-pound weight loss, ankle swelling, myalgias in his legs and back, shortness of breath, and a persistent cough. The patient was otherwise previously healthy.

The patient’s heart and lung exams were normal. Initial outpatient labs showed significantly elevated inflammatory markers, with an erythrocyte sedimentation rate (ESR) of 102 mm/h (normal range for men ≥ 50 years, 0-20 mm/h) and a C-reactive protein (CRP) level of 11.1 mg/L (normal range, < 3 mg/L). The patient also had an elevated white blood cell count of 12,000/mcL (normal range, 4500-11,000/mcL). His hemoglobin was low (11 g/dL; normal range, 13.5-17.5 g/dL) and so was his albumin level (2.9 g/dL; normal range, 3.4-5.4 g/dL). The results of his prostate-specific antigen and brain natriuretic peptide tests were both normal. The results of a computed tomography scan of his thorax, abdomen, and pelvis were negative for malignancy.

The patient returned to our clinic 3 days later with severe weakness, which inhibited him from walking. He complained of a severe spasmodic pain between his shoulder blades. He denied joint stiffness, headaches, vision changes, or jaw claudication. The patient’s son had noted an overall increase in his father’s baseline heart rate, with readings increasing from the 50 beats/min range to the 70 beats/min range; this raised concern for a ­catecholamine-secreting tumor. There was also concern for occult infection and malignancy, or an autoimmune process, such as polymyalgia rheumatica. Due to his extreme weakness, the patient was directly admitted to the hospital for further work-up.

THE DIAGNOSIS

Concern for a smoldering infection prompted an order for a ­transthoracic echocardiogram. Images revealed a large mass on the mitral valve (FIGURE 1). Blood cultures quickly grew Streptococcus sanguinis. Additional work-up with a transesophageal echocardiogram (TEE) showed a “windsock” deformity (thinning and ballooning of the mitral valve), a known sequela of infective endocarditis (FIGURE 2).¹ Further history obtained after the TEE revealed the patient had had a routine dental cleaning the month before his symptoms began. A murmur was then also detected.

DISCUSSION

Infective endocarditis (IE) is uncommon and difficult to diagnose; it has a high early-­mortality rate of 30%.² TEE is the recommended imaging study for IE, because it is more sensitive than a transthoracic echocardiogram for identifying vegetations on the valves and it is more cost effective.³

The modified Duke Criteria provide guidance for diagnosis of endocarditis. Major criteria focus on positive blood cultures and evidence of endocardial involvement. Minor criteria include predisposing heart conditions, intravenous drug use (IVDU), fever, and vascular and immunologic phenomena. As many as 90% of patients have a fever and often experience weight loss.⁴ Murmurs are auscultated in up to 85% of patients, and embolic features are present in up to 25% of patients at the time of diagnosis.⁴ In the developed world, Janeway lesions, Osler nodes, and splinter hemorrhages are increasingly rare, as patients usually present earlier in the disease course.⁴ While ESR and CRP are generally elevated in cases of IE, they are not part of the Duke Criteria.⁴

A closer look at risk factors

In 2007, guidelines for the prevention, treatment, and management of endocarditis were given significant categorical revision by the American Heart Association for the first time in 50 years.⁵ Recommendations for antibiotic prophylaxis prior to dental procedures became more restrictive, to include only 4 groups of high-risk patients: those with prosthetic cardiac valves, those with a history of IE, those with congenital heart disease, and cardiac transplant recipients.⁴ The rationale for these restrictions included the small risk for anaphylaxis and potential increase in risk for bacterial resistance associated with antibiotic prophylaxis.⁴ A review published in 2021 noted no increase in the frequency of, nor the morbidity and mortality from, viridans group streptococcal IE since the guideline updates.⁵

Continue to: There is an emerging consensus...

There is an emerging consensus that poor oral hygiene and gingival bleeding after tooth brushing promote a chronic low-grade bacteremia that may be more strongly associated with IE than an isolated dental extraction.⁶ Poor dental hygiene, defined as dental plaque and calculus, is especially common in the elderly, who are known to let their dental hygiene lapse.⁶ In our patient’s case, his generally poor oral hygiene was more likely the cause of his IE than his routine dental cleaning.

Other risk factors include IV drug use. At our tertiary care hospital in western North Carolina, 48% of patients with endocarditis had an additional diagnosis of opiate or narcotic dependence (Ryan Tilton, PharmD, email communication, June 7, 2018). Interestingly, though, only 16% of patients in North America with endocarditis were found to be currently using IV drugs.⁷

Our patient was treated with IV antibiotics for 4 weeks and underwent rehabilitation at a skilled nursing facility. Four weeks after diagnosis, he underwent an endoscopic porcine mitral valve replacement. Two months after that, he returned to his previously active lifestyle and began riding his stationary bike. The patient also began taking a daily aspirin. Consistent with current guidelines, he now gets antibiotic prophylaxis prior to dental procedures.

THE TAKEAWAY

This patient, without any history of IVDU or cardiac valvular abnormalities, presented with symptoms classic for a developing malignancy or possible rheumatologic condition. Subacute IE may manifest similarly, with vague symptoms such as myalgias, fatigue, chills, and/or anemia. In non-drug users, suspicion for endocarditis should be highest in men older than age 60. Also, it’s important to auscultate for a new heart murmur. In our patient’s case, no murmur was auscultated until after his TEE. JFP

CORRESPONDENCE
Ginger Poulton, MD, 123 Hendersonville Road, Asheville, NC 28803; [email protected]

THE CASE

A 75-year-old man with a history of osteoarthritis presented to our clinic with worsening weakness over the previous month. His signs and symptoms included profound fatigue, subjective fevers, a 10-pound weight loss, ankle swelling, myalgias in his legs and back, shortness of breath, and a persistent cough. The patient was otherwise previously healthy.

The patient’s heart and lung exams were normal. Initial outpatient labs showed significantly elevated inflammatory markers, with an erythrocyte sedimentation rate (ESR) of 102 mm/h (normal range for men ≥ 50 years, 0-20 mm/h) and a C-reactive protein (CRP) level of 11.1 mg/L (normal range, < 3 mg/L). The patient also had an elevated white blood cell count of 12,000/mcL (normal range, 4500-11,000/mcL). His hemoglobin was low (11 g/dL; normal range, 13.5-17.5 g/dL) and so was his albumin level (2.9 g/dL; normal range, 3.4-5.4 g/dL). The results of his prostate-specific antigen and brain natriuretic peptide tests were both normal. The results of a computed tomography scan of his thorax, abdomen, and pelvis were negative for malignancy.

The patient returned to our clinic 3 days later with severe weakness, which inhibited him from walking. He complained of a severe spasmodic pain between his shoulder blades. He denied joint stiffness, headaches, vision changes, or jaw claudication. The patient’s son had noted an overall increase in his father’s baseline heart rate, with readings increasing from the 50 beats/min range to the 70 beats/min range; this raised concern for a ­catecholamine-secreting tumor. There was also concern for occult infection and malignancy, or an autoimmune process, such as polymyalgia rheumatica. Due to his extreme weakness, the patient was directly admitted to the hospital for further work-up.

THE DIAGNOSIS

Concern for a smoldering infection prompted an order for a ­transthoracic echocardiogram. Images revealed a large mass on the mitral valve (FIGURE 1). Blood cultures quickly grew Streptococcus sanguinis. Additional work-up with a transesophageal echocardiogram (TEE) showed a “windsock” deformity (thinning and ballooning of the mitral valve), a known sequela of infective endocarditis (FIGURE 2).¹ Further history obtained after the TEE revealed the patient had had a routine dental cleaning the month before his symptoms began. A murmur was then also detected.

DISCUSSION

Infective endocarditis (IE) is uncommon and difficult to diagnose; it has a high early-­mortality rate of 30%.² TEE is the recommended imaging study for IE, because it is more sensitive than a transthoracic echocardiogram for identifying vegetations on the valves and it is more cost effective.³

The modified Duke Criteria provide guidance for diagnosis of endocarditis. Major criteria focus on positive blood cultures and evidence of endocardial involvement. Minor criteria include predisposing heart conditions, intravenous drug use (IVDU), fever, and vascular and immunologic phenomena. As many as 90% of patients have a fever and often experience weight loss.⁴ Murmurs are auscultated in up to 85% of patients, and embolic features are present in up to 25% of patients at the time of diagnosis.⁴ In the developed world, Janeway lesions, Osler nodes, and splinter hemorrhages are increasingly rare, as patients usually present earlier in the disease course.⁴ While ESR and CRP are generally elevated in cases of IE, they are not part of the Duke Criteria.⁴

A closer look at risk factors

In 2007, guidelines for the prevention, treatment, and management of endocarditis were given significant categorical revision by the American Heart Association for the first time in 50 years.⁵ Recommendations for antibiotic prophylaxis prior to dental procedures became more restrictive, to include only 4 groups of high-risk patients: those with prosthetic cardiac valves, those with a history of IE, those with congenital heart disease, and cardiac transplant recipients.⁴ The rationale for these restrictions included the small risk for anaphylaxis and potential increase in risk for bacterial resistance associated with antibiotic prophylaxis.⁴ A review published in 2021 noted no increase in the frequency of, nor the morbidity and mortality from, viridans group streptococcal IE since the guideline updates.⁵

Continue to: There is an emerging consensus...

There is an emerging consensus that poor oral hygiene and gingival bleeding after tooth brushing promote a chronic low-grade bacteremia that may be more strongly associated with IE than an isolated dental extraction.⁶ Poor dental hygiene, defined as dental plaque and calculus, is especially common in the elderly, who are known to let their dental hygiene lapse.⁶ In our patient’s case, his generally poor oral hygiene was more likely the cause of his IE than his routine dental cleaning.

Other risk factors include IV drug use. At our tertiary care hospital in western North Carolina, 48% of patients with endocarditis had an additional diagnosis of opiate or narcotic dependence (Ryan Tilton, PharmD, email communication, June 7, 2018). Interestingly, though, only 16% of patients in North America with endocarditis were found to be currently using IV drugs.⁷

Our patient was treated with IV antibiotics for 4 weeks and underwent rehabilitation at a skilled nursing facility. Four weeks after diagnosis, he underwent an endoscopic porcine mitral valve replacement. Two months after that, he returned to his previously active lifestyle and began riding his stationary bike. The patient also began taking a daily aspirin. Consistent with current guidelines, he now gets antibiotic prophylaxis prior to dental procedures.

THE TAKEAWAY

This patient, without any history of IVDU or cardiac valvular abnormalities, presented with symptoms classic for a developing malignancy or possible rheumatologic condition. Subacute IE may manifest similarly, with vague symptoms such as myalgias, fatigue, chills, and/or anemia. In non-drug users, suspicion for endocarditis should be highest in men older than age 60. Also, it’s important to auscultate for a new heart murmur. In our patient’s case, no murmur was auscultated until after his TEE. JFP

CORRESPONDENCE
Ginger Poulton, MD, 123 Hendersonville Road, Asheville, NC 28803; [email protected]

A 2-YEAR-OLD BOY presented to the emergency room with a 1-day history of a diffuse, mildly pruritic rash and swelling of his knees, ankles, and feet following treatment of acute otitis media with amoxicillin for the previous 8 days. He was mildly febrile and consolable, but he was refusing to walk. His medical history was unremarkable.

Physical examination revealed erythematous annular wheals on his chest, face, back, and extremities. Lymphadenopathy and mucous membrane involvement were not present. A complete blood count (CBC) with differential, inflammatory marker tests, and a comprehensive metabolic panel were ordered. Given the joint swelling and rash, the patient was admitted for observation.

During his second day in the hospital, his skin lesions enlarged and several formed dusky blue centers (FIGURE 1A). He also developed swelling of his hands (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s lab work came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Children with urticaria multiforme may have significant edema of the feet and may find walking difficult; this should not be confused with arthritis or arthralgias.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. The incidence and prevalence are not known. Urticaria multiforme is considered common, but it is frequently misdiagnosed.¹ It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 Individual lesions last less than 24 hours, but new ones may appear. The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Dermatographism due to mast cell–mediated cutaneous hypersensitivity at sites of minor skin trauma is common (44%).¹ Patients often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias. Generally, patients are nontoxic in appearance, and systemic symptoms are limited to a low-grade fever.^1-3

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing.When performed, laboratory studies, including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis are routinely normal.

Erythema multiforme and urticarial vasculitis are part of the differential

The differential diagnosis in this case includes erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis (TABLE^1,2,4).

Continue to: Erythema multiforme

Erythema multiforme is a common misdiagnosis in patients with urticaria multiforme.^1,2 The erythema multiforme rash has a “target” lesion with outer erythema and central ecchymosis, which may develop blisters or necrosis. Lesions are fixed and last 2 to 3 weeks. Unlike urticaria multiforme, patients with erythema multiforme commonly have mucous membrane erosions and occasionally ulcerations. Facial and acral edema is rare. Treatment is largely symptomatic and can include glucocorticoids. Antiviral medications may be used to treat recurrences.^1,2

Henoch-Schönlein purpura is an immunoglobulin A–mediated vasculitis that affects the skin, gastrointestinal tract, and joints.^4,5 Patients often present with arthralgias, gastrointestinal symptoms such as abdominal pain and bleeding, and a nonpruritic, erythematous rash that progresses to palpable purpura in dependent areas of the body. Treatment is generally symptomatic, but steroids may be used in severe cases.^4,5

Serum sickness-like reaction can manifest with angioedema and a similar urticarial rash (with central clearing) that lasts 1 to 6 weeks.^1,2,6,7 However, patients tend to have a high-grade fever, arthralgias, myalgias, and lymphadenopathy while dermatographism is absent. Treatment includes discontinuing the offending agent and the use of H1 and H2 antihistamines and steroids, in severe cases.

Urticarial vasculitis manifests as plaques or wheals lasting 1 to 7 days that may cause burning and pain but not pruritis.^2,5 Purpura or hypopigmentation may develop as the hives resolve. Angioedema and arthralgias are common, but dermatographism is not present. Triggers include infections, autoimmune disease, malignancy, and the use of certain medications. H1 and H2 blockers and nonsteroidal anti-inflammatory agents are first-line therapy.²

Step 1: Discontinue offending agents; Step 2: Recommend antihistamines

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Continue to: Our patient's amoxicillin

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

A 2-YEAR-OLD BOY presented to the emergency room with a 1-day history of a diffuse, mildly pruritic rash and swelling of his knees, ankles, and feet following treatment of acute otitis media with amoxicillin for the previous 8 days. He was mildly febrile and consolable, but he was refusing to walk. His medical history was unremarkable.

Physical examination revealed erythematous annular wheals on his chest, face, back, and extremities. Lymphadenopathy and mucous membrane involvement were not present. A complete blood count (CBC) with differential, inflammatory marker tests, and a comprehensive metabolic panel were ordered. Given the joint swelling and rash, the patient was admitted for observation.

During his second day in the hospital, his skin lesions enlarged and several formed dusky blue centers (FIGURE 1A). He also developed swelling of his hands (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s lab work came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Children with urticaria multiforme may have significant edema of the feet and may find walking difficult; this should not be confused with arthritis or arthralgias.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. The incidence and prevalence are not known. Urticaria multiforme is considered common, but it is frequently misdiagnosed.¹ It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 Individual lesions last less than 24 hours, but new ones may appear. The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Dermatographism due to mast cell–mediated cutaneous hypersensitivity at sites of minor skin trauma is common (44%).¹ Patients often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias. Generally, patients are nontoxic in appearance, and systemic symptoms are limited to a low-grade fever.^1-3

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing.When performed, laboratory studies, including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis are routinely normal.

Erythema multiforme and urticarial vasculitis are part of the differential

The differential diagnosis in this case includes erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis (TABLE^1,2,4).

Continue to: Erythema multiforme

Erythema multiforme is a common misdiagnosis in patients with urticaria multiforme.^1,2 The erythema multiforme rash has a “target” lesion with outer erythema and central ecchymosis, which may develop blisters or necrosis. Lesions are fixed and last 2 to 3 weeks. Unlike urticaria multiforme, patients with erythema multiforme commonly have mucous membrane erosions and occasionally ulcerations. Facial and acral edema is rare. Treatment is largely symptomatic and can include glucocorticoids. Antiviral medications may be used to treat recurrences.^1,2

Henoch-Schönlein purpura is an immunoglobulin A–mediated vasculitis that affects the skin, gastrointestinal tract, and joints.^4,5 Patients often present with arthralgias, gastrointestinal symptoms such as abdominal pain and bleeding, and a nonpruritic, erythematous rash that progresses to palpable purpura in dependent areas of the body. Treatment is generally symptomatic, but steroids may be used in severe cases.^4,5

Serum sickness-like reaction can manifest with angioedema and a similar urticarial rash (with central clearing) that lasts 1 to 6 weeks.^1,2,6,7 However, patients tend to have a high-grade fever, arthralgias, myalgias, and lymphadenopathy while dermatographism is absent. Treatment includes discontinuing the offending agent and the use of H1 and H2 antihistamines and steroids, in severe cases.

Urticarial vasculitis manifests as plaques or wheals lasting 1 to 7 days that may cause burning and pain but not pruritis.^2,5 Purpura or hypopigmentation may develop as the hives resolve. Angioedema and arthralgias are common, but dermatographism is not present. Triggers include infections, autoimmune disease, malignancy, and the use of certain medications. H1 and H2 blockers and nonsteroidal anti-inflammatory agents are first-line therapy.²

Step 1: Discontinue offending agents; Step 2: Recommend antihistamines

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Continue to: Our patient's amoxicillin

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

A 2-YEAR-OLD BOY presented to the emergency room with a 1-day history of a diffuse, mildly pruritic rash and swelling of his knees, ankles, and feet following treatment of acute otitis media with amoxicillin for the previous 8 days. He was mildly febrile and consolable, but he was refusing to walk. His medical history was unremarkable.

Physical examination revealed erythematous annular wheals on his chest, face, back, and extremities. Lymphadenopathy and mucous membrane involvement were not present. A complete blood count (CBC) with differential, inflammatory marker tests, and a comprehensive metabolic panel were ordered. Given the joint swelling and rash, the patient was admitted for observation.

During his second day in the hospital, his skin lesions enlarged and several formed dusky blue centers (FIGURE 1A). He also developed swelling of his hands (FIGURE 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s lab work came back within normal range, except for an elevated white blood cell count (19,700/mm³; reference range, 4500-13,500/mm³). His mild systemic symptoms, skin lesions without blistering or necrosis, acral edema, and the absence of lymphadenopathy pointed to a diagnosis of urticaria multiforme.

Children with urticaria multiforme may have significant edema of the feet and may find walking difficult; this should not be confused with arthritis or arthralgias.

Urticaria multiforme, also called acute annular urticaria or acute urticarial hypersensitivity syndrome, is a histamine-mediated hypersensitivity reaction characterized by transient annular, polycyclic, urticarial lesions with central ecchymosis. The incidence and prevalence are not known. Urticaria multiforme is considered common, but it is frequently misdiagnosed.¹ It typically manifests in children ages 4 months to 4 years and begins with small erythematous macules, papules, and plaques that progress to large blanchable wheals with dusky blue centers.^1-3 Lesions are usually located on the face, trunk, and extremities and are often pruritic (60%-94%).^1-3 Individual lesions last less than 24 hours, but new ones may appear. The rash generally lasts 2 to 12 days.^1,3

Patients often report a preceding viral illness, otitis media, recent use of antibiotics, or recent immunizations. Dermatographism due to mast cell–mediated cutaneous hypersensitivity at sites of minor skin trauma is common (44%).¹ Patients often have associated facial or acral edema (72%).¹ Children with significant edema of the feet may find walking difficult, which should not be confused with arthritis or arthralgias. Generally, patients are nontoxic in appearance, and systemic symptoms are limited to a low-grade fever.^1-3

The diagnosis is made clinically and should not require a skin biopsy or extensive laboratory testing.When performed, laboratory studies, including CBC, erythrocyte sedimentation rate, C-reactive protein, and urinalysis are routinely normal.

Erythema multiforme and urticarial vasculitis are part of the differential

The differential diagnosis in this case includes erythema multiforme, Henoch-Schönlein purpura, serum sickness-like reaction, and urticarial vasculitis (TABLE^1,2,4).

Continue to: Erythema multiforme

Erythema multiforme is a common misdiagnosis in patients with urticaria multiforme.^1,2 The erythema multiforme rash has a “target” lesion with outer erythema and central ecchymosis, which may develop blisters or necrosis. Lesions are fixed and last 2 to 3 weeks. Unlike urticaria multiforme, patients with erythema multiforme commonly have mucous membrane erosions and occasionally ulcerations. Facial and acral edema is rare. Treatment is largely symptomatic and can include glucocorticoids. Antiviral medications may be used to treat recurrences.^1,2

Henoch-Schönlein purpura is an immunoglobulin A–mediated vasculitis that affects the skin, gastrointestinal tract, and joints.^4,5 Patients often present with arthralgias, gastrointestinal symptoms such as abdominal pain and bleeding, and a nonpruritic, erythematous rash that progresses to palpable purpura in dependent areas of the body. Treatment is generally symptomatic, but steroids may be used in severe cases.^4,5

Serum sickness-like reaction can manifest with angioedema and a similar urticarial rash (with central clearing) that lasts 1 to 6 weeks.^1,2,6,7 However, patients tend to have a high-grade fever, arthralgias, myalgias, and lymphadenopathy while dermatographism is absent. Treatment includes discontinuing the offending agent and the use of H1 and H2 antihistamines and steroids, in severe cases.

Urticarial vasculitis manifests as plaques or wheals lasting 1 to 7 days that may cause burning and pain but not pruritis.^2,5 Purpura or hypopigmentation may develop as the hives resolve. Angioedema and arthralgias are common, but dermatographism is not present. Triggers include infections, autoimmune disease, malignancy, and the use of certain medications. H1 and H2 blockers and nonsteroidal anti-inflammatory agents are first-line therapy.²

Step 1: Discontinue offending agents; Step 2: Recommend antihistamines

Treatment consists of discontinuing any offending agent (if suspected) and using systemic H1 or H2 antihistamines for symptom relief. Systemic steroids should only be given in refractory cases.

Continue to: Our patient's amoxicillin

Our patient’s amoxicillin was discontinued, and he was started on a 14-day course of cetirizine 5 mg bid and hydroxyzine 10 mg at bedtime. He was also started on triamcinolone 0.1% cream to be applied twice daily for 1 week. During his 3-day hospital stay, his fever resolved and his rash and edema improved.

During an outpatient follow-up visit with a pediatric dermatologist 2 weeks after discharge, the patient’s rash was still present and dermatographism was noted. In light of this, his parents were instructed to continue giving the cetirizine and hydroxyzine once daily for an additional 2 weeks and to return as needed.

Primary care clinicians care for the vast majority of the 34 million individuals in the United States with type 2 diabetes; these patients make up about 11% of visits in most practices.^1,2 Maximizing their health requires that we make the most of the ever-growing number of medications and devices that can be used to manage diabetes, while being sensitive to the health care inequities that limit patient access to the best care we have to offer.

A growing number of effective Tx options. In the past few years, we have seen the number of new drug classes for treating type 2 diabetes climb steadily. Within-class effects and adverse effects vary widely, demanding familiarity with the proven benefits of each individual drug. The advent of oral and injectable agents that include glucagon-like peptide 1 (GLP-1) receptor agonists and sodium glucose cotransporter 2 (SGLT2) inhibitors now supplement an expanding list of reliable basal insulins. Never before have we had such effective drugs with fewer adverse effects to manage glycemic control. New evidence supports adding selected medicines from these categories to reduce the risk of cardiovascular disease, heart failure, or chronic kidney dis­ease in patients at risk—regardless of the level of glucose control.

The benefit of more achievable goals. When the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial began in 1999, the UKPDS (United Kingdom Prospective Diabetes Study) had just demonstrated that lower blood sugars resulted in lower morbidity in patients with type 2 diabetes. Colleagues insisted that an extrapolation of UKPDS results suggested that low blood sugars were better, and that it would be unethical to allow a patient to maintain an A1C of 7.5% if less than 6.0% was possible.

We can expect amplified inequities in diabetes clinical outcomes to continue unless we develop a better system of distributing these life-changing medicines to Americans who need them.

By 2008, the ACCORD trial demonstrated that more lives were saved with a less aggressive approach, and family physicians could breathe a sigh of relief as they addressed other important comorbidities of diabetes. However, the tools we used in ACCORD were rudimentary compared to today’s approaches. As glycemic control becomes safer and more effective, demands for further normalizing glycemic control to minimize complications are inevitable.

Devices have transformed care, too. A wide variety of new continuous monitoring devices, delivery systems, and self-management tools provide more options for ensuring that treatment is less disruptive and more effective than ever before. Inevitably, the advent of these major advances also brings new and serious challenges. Practices will need to transform to support the demands and the needs of our patients.

Practice transformation is necessary if primary care is to continue the delivery of high-quality diabetes care. The link between practice diabetes performance measures and the introduction of enhanced patient-centered care teams providing proactive outreach is clear.³

Our biggest challenge. Despite advances in the science, perhaps the biggest challenge in diabetes care is the inevitable inequity in access to new medications. The average wholesale price of glargine has soared to $340 per month, while the most effective new GLP-1 receptor agonists are close to $1000 per month.⁴

Continue to: Although primary care doctors...

Although primary care doctors have always tried to accommodate the uninsured, the stark differences between new and old medicines now resembles a 2-tiered system. We can all celebrate advances in diabetes care and work hard to learn when and how to best use them, but those advances are accompanied by an uncomfortable awareness of the enormous inequity of prescribing regimens that haven't been considered best practice since the 1990s to patients who simply can’t afford better medicine.

We can expect amplified inequities in diabetes clinical outcomes to continue unless we develop a better system of distributing these life-changing medicines to those Americans who need them. Some state legislatures have made progress by supporting limited access to affordable insulin. However, ensuring that all patients with diabetes have access to modern insulin and effective medications is a national responsibility that needs a national response. Universal access to the modern tools of basic health care is a long-overdue treatment for an expanding epidemic of inequity.

Primary care clinicians care for the vast majority of the 34 million individuals in the United States with type 2 diabetes; these patients make up about 11% of visits in most practices.^1,2 Maximizing their health requires that we make the most of the ever-growing number of medications and devices that can be used to manage diabetes, while being sensitive to the health care inequities that limit patient access to the best care we have to offer.

A growing number of effective Tx options. In the past few years, we have seen the number of new drug classes for treating type 2 diabetes climb steadily. Within-class effects and adverse effects vary widely, demanding familiarity with the proven benefits of each individual drug. The advent of oral and injectable agents that include glucagon-like peptide 1 (GLP-1) receptor agonists and sodium glucose cotransporter 2 (SGLT2) inhibitors now supplement an expanding list of reliable basal insulins. Never before have we had such effective drugs with fewer adverse effects to manage glycemic control. New evidence supports adding selected medicines from these categories to reduce the risk of cardiovascular disease, heart failure, or chronic kidney dis­ease in patients at risk—regardless of the level of glucose control.

The benefit of more achievable goals. When the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial began in 1999, the UKPDS (United Kingdom Prospective Diabetes Study) had just demonstrated that lower blood sugars resulted in lower morbidity in patients with type 2 diabetes. Colleagues insisted that an extrapolation of UKPDS results suggested that low blood sugars were better, and that it would be unethical to allow a patient to maintain an A1C of 7.5% if less than 6.0% was possible.

We can expect amplified inequities in diabetes clinical outcomes to continue unless we develop a better system of distributing these life-changing medicines to Americans who need them.

By 2008, the ACCORD trial demonstrated that more lives were saved with a less aggressive approach, and family physicians could breathe a sigh of relief as they addressed other important comorbidities of diabetes. However, the tools we used in ACCORD were rudimentary compared to today’s approaches. As glycemic control becomes safer and more effective, demands for further normalizing glycemic control to minimize complications are inevitable.

Devices have transformed care, too. A wide variety of new continuous monitoring devices, delivery systems, and self-management tools provide more options for ensuring that treatment is less disruptive and more effective than ever before. Inevitably, the advent of these major advances also brings new and serious challenges. Practices will need to transform to support the demands and the needs of our patients.

Practice transformation is necessary if primary care is to continue the delivery of high-quality diabetes care. The link between practice diabetes performance measures and the introduction of enhanced patient-centered care teams providing proactive outreach is clear.³

Our biggest challenge. Despite advances in the science, perhaps the biggest challenge in diabetes care is the inevitable inequity in access to new medications. The average wholesale price of glargine has soared to $340 per month, while the most effective new GLP-1 receptor agonists are close to $1000 per month.⁴

Continue to: Although primary care doctors...

Although primary care doctors have always tried to accommodate the uninsured, the stark differences between new and old medicines now resembles a 2-tiered system. We can all celebrate advances in diabetes care and work hard to learn when and how to best use them, but those advances are accompanied by an uncomfortable awareness of the enormous inequity of prescribing regimens that haven't been considered best practice since the 1990s to patients who simply can’t afford better medicine.

We can expect amplified inequities in diabetes clinical outcomes to continue unless we develop a better system of distributing these life-changing medicines to those Americans who need them. Some state legislatures have made progress by supporting limited access to affordable insulin. However, ensuring that all patients with diabetes have access to modern insulin and effective medications is a national responsibility that needs a national response. Universal access to the modern tools of basic health care is a long-overdue treatment for an expanding epidemic of inequity.

Primary care clinicians care for the vast majority of the 34 million individuals in the United States with type 2 diabetes; these patients make up about 11% of visits in most practices.^1,2 Maximizing their health requires that we make the most of the ever-growing number of medications and devices that can be used to manage diabetes, while being sensitive to the health care inequities that limit patient access to the best care we have to offer.

A growing number of effective Tx options. In the past few years, we have seen the number of new drug classes for treating type 2 diabetes climb steadily. Within-class effects and adverse effects vary widely, demanding familiarity with the proven benefits of each individual drug. The advent of oral and injectable agents that include glucagon-like peptide 1 (GLP-1) receptor agonists and sodium glucose cotransporter 2 (SGLT2) inhibitors now supplement an expanding list of reliable basal insulins. Never before have we had such effective drugs with fewer adverse effects to manage glycemic control. New evidence supports adding selected medicines from these categories to reduce the risk of cardiovascular disease, heart failure, or chronic kidney dis­ease in patients at risk—regardless of the level of glucose control.

The benefit of more achievable goals. When the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial began in 1999, the UKPDS (United Kingdom Prospective Diabetes Study) had just demonstrated that lower blood sugars resulted in lower morbidity in patients with type 2 diabetes. Colleagues insisted that an extrapolation of UKPDS results suggested that low blood sugars were better, and that it would be unethical to allow a patient to maintain an A1C of 7.5% if less than 6.0% was possible.

We can expect amplified inequities in diabetes clinical outcomes to continue unless we develop a better system of distributing these life-changing medicines to Americans who need them.

By 2008, the ACCORD trial demonstrated that more lives were saved with a less aggressive approach, and family physicians could breathe a sigh of relief as they addressed other important comorbidities of diabetes. However, the tools we used in ACCORD were rudimentary compared to today’s approaches. As glycemic control becomes safer and more effective, demands for further normalizing glycemic control to minimize complications are inevitable.

Devices have transformed care, too. A wide variety of new continuous monitoring devices, delivery systems, and self-management tools provide more options for ensuring that treatment is less disruptive and more effective than ever before. Inevitably, the advent of these major advances also brings new and serious challenges. Practices will need to transform to support the demands and the needs of our patients.

Practice transformation is necessary if primary care is to continue the delivery of high-quality diabetes care. The link between practice diabetes performance measures and the introduction of enhanced patient-centered care teams providing proactive outreach is clear.³

Our biggest challenge. Despite advances in the science, perhaps the biggest challenge in diabetes care is the inevitable inequity in access to new medications. The average wholesale price of glargine has soared to $340 per month, while the most effective new GLP-1 receptor agonists are close to $1000 per month.⁴

Continue to: Although primary care doctors...

Although primary care doctors have always tried to accommodate the uninsured, the stark differences between new and old medicines now resembles a 2-tiered system. We can all celebrate advances in diabetes care and work hard to learn when and how to best use them, but those advances are accompanied by an uncomfortable awareness of the enormous inequity of prescribing regimens that haven't been considered best practice since the 1990s to patients who simply can’t afford better medicine.

We can expect amplified inequities in diabetes clinical outcomes to continue unless we develop a better system of distributing these life-changing medicines to those Americans who need them. Some state legislatures have made progress by supporting limited access to affordable insulin. However, ensuring that all patients with diabetes have access to modern insulin and effective medications is a national responsibility that needs a national response. Universal access to the modern tools of basic health care is a long-overdue treatment for an expanding epidemic of inequity.

THE CASE

A 78-year-old man with a history of diabetes and hypertension was referred to the outpatient surgical office with a chief complaint of “tail bone pain” that had started after a fall a year earlier. The patient complained that the pain was worse when sitting and at nighttime. He also admitted to a 7-lb weight loss over the past 2 months without change in diet or appetite. He denied symptoms of incontinence, urinary retention, sharp stabbing pains in the lower extremities, night sweats, or anorexia.

The patient first visited an urgent care facility on the day after the fall because he was experiencing pain in his “tail bone” region while riding his lawn mower. A pelvic x-ray was performed at that time and showed no coccyx fracture. He received a steroid injection in the right sacroiliac joint, which provided some relief for a month. Throughout the course of the year, he was given 6 steroid injections into his sacroiliac joint by his primary care provider (PCP) and clinicians at his local urgent care facility. One year after the fall, the patient’s PCP ordered a computed tomography (CT) scan of the abdomen and pelvis, which revealed a 4.6 x 7.5–cm soft-tissue mass with bony destruction of the lower sacrum and coccyx that extended into the sacral and coccygeal canal (FIGURE 1).

On exam in our surgical office, the patient was found to be alert and oriented. His neurologic exam was unremarkable, with an intact motor and sensory exam and no symptoms of cauda equina syndrome. During palpation over the lower sacrum and coccyx, both tenderness and a boggy, soft mass were observed. Nerve impingement was most likely caused by the size of the mass.

THE DIAGNOSIS

Biopsy revealed a large tan-gray, gelatinous, soft-tissue mass that was necrotizing through the lower sacrum. The diagnosis of a sacral chordoma was confirmed with magnetic resonance imaging of the pelvis, which demonstrated a 4.6 × 8.1–cm destructive expansile sacrococcygeal tumor with an exophytic soft-tissue component (FIGURE 2). The tumor also involved the piriformis and gluteus maximus muscles bilaterally.

DISCUSSION

Chordomas are rare, malignant bone tumors that grow slowly and originate from embryonic remnants of the notochord.¹ They are most commonly seen in the sacrococcygeal segment (50%) but are also seen in the ­spheno-occipital synchondrosis (30%-35%) and other spinal segments such as C2 and lumbar spine.² Chordomas are typically seen in middle-aged patients, with sacral chordomas occurring predominantly in men compared to women (3:1).²

Slow to grow, slow to diagnose

The difficulty with diagnosing sacral chordomas lies in the tendency for these tumors to grow extremely slowly, making detection challenging due to a lack of symptoms in the early clinical course. Once the tumors cause noticeable symptoms, they are usually large and extensively locally invasive. As a result, most patients experience delayed diagnosis, with an average symptom duration of 2.3 years prior to diagnosis.³

Reexamining a common problem as a symptom of a rare condition

The most commonly manifesting symptom of sacral chordomas is lower back pain that is typically dull and worse with sitting.^3,4 Since lower back pain is the leading cause of disability, it is difficult to determine when back pain is simply a benign consequence of aging or muscular pain and when it is, in fact, pathologic.⁵ A thorough history and physical are crucial in making the distinction.

Continue to: Clinical red flags...

Clinical red flags include pain with neurologic symptoms (including paresthesia, urinary or bowel disturbances, and weakness in the lower limbs), pain in the lower back with or without coccyx pain that persists and gradually worsens over time, and pain that fails to resolve.³ These symptoms are collectively strong indicators of underlying sacral pathology and should warrant further investigation, including a CT and MRI of the involved area.

Survival rate is improved by surgery

The gold standard for treatment of sacral chordomas is surgical resection with adequate margins, as these tumors are both radio- and chemo-insensitive.⁶ It is generally accepted that achieving a wide surgical margin is the most important predictor of survival and of reducing local recurrence in patients with sacrococcygeal chordoma.^7-9

The survival rate varies after a posterior-only surgical approach; some studies cite the 5-year survival rate as 100% and others state the 7-year survival rate as 5%.⁴ The wide variation is likely due to small trial size, a lack of evidence, and how invasive the disease is at the time of surgery.

The recurrence rate 5 years after surgery is approximately 20%.⁴ The rate of urinary and fecal incontinence after surgery using a posterior-only approach is between 20% and 100%; some of this variation may be due to which spinal level is involved.⁴ If S3 is affected, there is almost always perineal anesthesia along with bowel and bladder incontinence.⁴

This patient was referred to Neurosurgery and underwent resection. He recovered well from surgery but suffered from some residual urinary incontinence. The patient did not receive chemotherapy or radiation, and further work-up revealed no evidence of metastasis.

Continue to: THE TAKEAWAY

The diagnosis of sacral chordoma remains challenging. A history of clinical red flags, especially persistent lower back pain with neuropathy, should prompt an aggressive investigation to rule out underlying pathology. Other signs on physical exam could include urinary or bowel disturbances, weakness in the lower limbs, saddle anesthesia, new foot drop, and/or laxity of the anal sphincter.⁵ Early detection and surgical intervention are crucial for these patients to experience a better prognosis and preserve maximum function.

CORRESPONDENCE
Ginger Poulton, MD, 123 Hendersonville Road, Asheville, NC 28803; [email protected]

THE CASE

A 78-year-old man with a history of diabetes and hypertension was referred to the outpatient surgical office with a chief complaint of “tail bone pain” that had started after a fall a year earlier. The patient complained that the pain was worse when sitting and at nighttime. He also admitted to a 7-lb weight loss over the past 2 months without change in diet or appetite. He denied symptoms of incontinence, urinary retention, sharp stabbing pains in the lower extremities, night sweats, or anorexia.

The patient first visited an urgent care facility on the day after the fall because he was experiencing pain in his “tail bone” region while riding his lawn mower. A pelvic x-ray was performed at that time and showed no coccyx fracture. He received a steroid injection in the right sacroiliac joint, which provided some relief for a month. Throughout the course of the year, he was given 6 steroid injections into his sacroiliac joint by his primary care provider (PCP) and clinicians at his local urgent care facility. One year after the fall, the patient’s PCP ordered a computed tomography (CT) scan of the abdomen and pelvis, which revealed a 4.6 x 7.5–cm soft-tissue mass with bony destruction of the lower sacrum and coccyx that extended into the sacral and coccygeal canal (FIGURE 1).

On exam in our surgical office, the patient was found to be alert and oriented. His neurologic exam was unremarkable, with an intact motor and sensory exam and no symptoms of cauda equina syndrome. During palpation over the lower sacrum and coccyx, both tenderness and a boggy, soft mass were observed. Nerve impingement was most likely caused by the size of the mass.

THE DIAGNOSIS

Biopsy revealed a large tan-gray, gelatinous, soft-tissue mass that was necrotizing through the lower sacrum. The diagnosis of a sacral chordoma was confirmed with magnetic resonance imaging of the pelvis, which demonstrated a 4.6 × 8.1–cm destructive expansile sacrococcygeal tumor with an exophytic soft-tissue component (FIGURE 2). The tumor also involved the piriformis and gluteus maximus muscles bilaterally.

DISCUSSION

Chordomas are rare, malignant bone tumors that grow slowly and originate from embryonic remnants of the notochord.¹ They are most commonly seen in the sacrococcygeal segment (50%) but are also seen in the ­spheno-occipital synchondrosis (30%-35%) and other spinal segments such as C2 and lumbar spine.² Chordomas are typically seen in middle-aged patients, with sacral chordomas occurring predominantly in men compared to women (3:1).²

Slow to grow, slow to diagnose

The difficulty with diagnosing sacral chordomas lies in the tendency for these tumors to grow extremely slowly, making detection challenging due to a lack of symptoms in the early clinical course. Once the tumors cause noticeable symptoms, they are usually large and extensively locally invasive. As a result, most patients experience delayed diagnosis, with an average symptom duration of 2.3 years prior to diagnosis.³

Reexamining a common problem as a symptom of a rare condition

The most commonly manifesting symptom of sacral chordomas is lower back pain that is typically dull and worse with sitting.^3,4 Since lower back pain is the leading cause of disability, it is difficult to determine when back pain is simply a benign consequence of aging or muscular pain and when it is, in fact, pathologic.⁵ A thorough history and physical are crucial in making the distinction.

Continue to: Clinical red flags...

Clinical red flags include pain with neurologic symptoms (including paresthesia, urinary or bowel disturbances, and weakness in the lower limbs), pain in the lower back with or without coccyx pain that persists and gradually worsens over time, and pain that fails to resolve.³ These symptoms are collectively strong indicators of underlying sacral pathology and should warrant further investigation, including a CT and MRI of the involved area.

Survival rate is improved by surgery

The gold standard for treatment of sacral chordomas is surgical resection with adequate margins, as these tumors are both radio- and chemo-insensitive.⁶ It is generally accepted that achieving a wide surgical margin is the most important predictor of survival and of reducing local recurrence in patients with sacrococcygeal chordoma.^7-9

The survival rate varies after a posterior-only surgical approach; some studies cite the 5-year survival rate as 100% and others state the 7-year survival rate as 5%.⁴ The wide variation is likely due to small trial size, a lack of evidence, and how invasive the disease is at the time of surgery.

The recurrence rate 5 years after surgery is approximately 20%.⁴ The rate of urinary and fecal incontinence after surgery using a posterior-only approach is between 20% and 100%; some of this variation may be due to which spinal level is involved.⁴ If S3 is affected, there is almost always perineal anesthesia along with bowel and bladder incontinence.⁴

This patient was referred to Neurosurgery and underwent resection. He recovered well from surgery but suffered from some residual urinary incontinence. The patient did not receive chemotherapy or radiation, and further work-up revealed no evidence of metastasis.

Continue to: THE TAKEAWAY

The diagnosis of sacral chordoma remains challenging. A history of clinical red flags, especially persistent lower back pain with neuropathy, should prompt an aggressive investigation to rule out underlying pathology. Other signs on physical exam could include urinary or bowel disturbances, weakness in the lower limbs, saddle anesthesia, new foot drop, and/or laxity of the anal sphincter.⁵ Early detection and surgical intervention are crucial for these patients to experience a better prognosis and preserve maximum function.

CORRESPONDENCE
Ginger Poulton, MD, 123 Hendersonville Road, Asheville, NC 28803; [email protected]

THE CASE

A 78-year-old man with a history of diabetes and hypertension was referred to the outpatient surgical office with a chief complaint of “tail bone pain” that had started after a fall a year earlier. The patient complained that the pain was worse when sitting and at nighttime. He also admitted to a 7-lb weight loss over the past 2 months without change in diet or appetite. He denied symptoms of incontinence, urinary retention, sharp stabbing pains in the lower extremities, night sweats, or anorexia.

The patient first visited an urgent care facility on the day after the fall because he was experiencing pain in his “tail bone” region while riding his lawn mower. A pelvic x-ray was performed at that time and showed no coccyx fracture. He received a steroid injection in the right sacroiliac joint, which provided some relief for a month. Throughout the course of the year, he was given 6 steroid injections into his sacroiliac joint by his primary care provider (PCP) and clinicians at his local urgent care facility. One year after the fall, the patient’s PCP ordered a computed tomography (CT) scan of the abdomen and pelvis, which revealed a 4.6 x 7.5–cm soft-tissue mass with bony destruction of the lower sacrum and coccyx that extended into the sacral and coccygeal canal (FIGURE 1).

On exam in our surgical office, the patient was found to be alert and oriented. His neurologic exam was unremarkable, with an intact motor and sensory exam and no symptoms of cauda equina syndrome. During palpation over the lower sacrum and coccyx, both tenderness and a boggy, soft mass were observed. Nerve impingement was most likely caused by the size of the mass.

THE DIAGNOSIS

Biopsy revealed a large tan-gray, gelatinous, soft-tissue mass that was necrotizing through the lower sacrum. The diagnosis of a sacral chordoma was confirmed with magnetic resonance imaging of the pelvis, which demonstrated a 4.6 × 8.1–cm destructive expansile sacrococcygeal tumor with an exophytic soft-tissue component (FIGURE 2). The tumor also involved the piriformis and gluteus maximus muscles bilaterally.

DISCUSSION

Chordomas are rare, malignant bone tumors that grow slowly and originate from embryonic remnants of the notochord.¹ They are most commonly seen in the sacrococcygeal segment (50%) but are also seen in the ­spheno-occipital synchondrosis (30%-35%) and other spinal segments such as C2 and lumbar spine.² Chordomas are typically seen in middle-aged patients, with sacral chordomas occurring predominantly in men compared to women (3:1).²

Slow to grow, slow to diagnose

The difficulty with diagnosing sacral chordomas lies in the tendency for these tumors to grow extremely slowly, making detection challenging due to a lack of symptoms in the early clinical course. Once the tumors cause noticeable symptoms, they are usually large and extensively locally invasive. As a result, most patients experience delayed diagnosis, with an average symptom duration of 2.3 years prior to diagnosis.³

Reexamining a common problem as a symptom of a rare condition

The most commonly manifesting symptom of sacral chordomas is lower back pain that is typically dull and worse with sitting.^3,4 Since lower back pain is the leading cause of disability, it is difficult to determine when back pain is simply a benign consequence of aging or muscular pain and when it is, in fact, pathologic.⁵ A thorough history and physical are crucial in making the distinction.

Continue to: Clinical red flags...

Clinical red flags include pain with neurologic symptoms (including paresthesia, urinary or bowel disturbances, and weakness in the lower limbs), pain in the lower back with or without coccyx pain that persists and gradually worsens over time, and pain that fails to resolve.³ These symptoms are collectively strong indicators of underlying sacral pathology and should warrant further investigation, including a CT and MRI of the involved area.

Survival rate is improved by surgery

The gold standard for treatment of sacral chordomas is surgical resection with adequate margins, as these tumors are both radio- and chemo-insensitive.⁶ It is generally accepted that achieving a wide surgical margin is the most important predictor of survival and of reducing local recurrence in patients with sacrococcygeal chordoma.^7-9

The survival rate varies after a posterior-only surgical approach; some studies cite the 5-year survival rate as 100% and others state the 7-year survival rate as 5%.⁴ The wide variation is likely due to small trial size, a lack of evidence, and how invasive the disease is at the time of surgery.

The recurrence rate 5 years after surgery is approximately 20%.⁴ The rate of urinary and fecal incontinence after surgery using a posterior-only approach is between 20% and 100%; some of this variation may be due to which spinal level is involved.⁴ If S3 is affected, there is almost always perineal anesthesia along with bowel and bladder incontinence.⁴

This patient was referred to Neurosurgery and underwent resection. He recovered well from surgery but suffered from some residual urinary incontinence. The patient did not receive chemotherapy or radiation, and further work-up revealed no evidence of metastasis.

Continue to: THE TAKEAWAY

The diagnosis of sacral chordoma remains challenging. A history of clinical red flags, especially persistent lower back pain with neuropathy, should prompt an aggressive investigation to rule out underlying pathology. Other signs on physical exam could include urinary or bowel disturbances, weakness in the lower limbs, saddle anesthesia, new foot drop, and/or laxity of the anal sphincter.⁵ Early detection and surgical intervention are crucial for these patients to experience a better prognosis and preserve maximum function.

CORRESPONDENCE
Ginger Poulton, MD, 123 Hendersonville Road, Asheville, NC 28803; [email protected]

The global prevalence of dyspepsia is approximately 20%,¹ and it is often associated with other comorbidities and overlapping gastrointestinal complaints. The effects on the patient’s quality of life, including societal impacts, are considerable. Symptoms and their response to treatment are highly variable, necessitating individualized management. While some patients’ symptoms may be refractory to standard medical treatment initially, evidence suggests that the strategies summarized in our guidance here—including the use of tricyclic antidepressants (TCAs), prokinetics, and adjunctive therapies—may alleviate symptoms and improve patients’ quality of life.

What dyspepsia is—and what it isn’t

Dyspepsia is a poorly characterized disorder often associated with nausea, heartburn, early satiety, and bloating. The American College of Gastroenterology (ACG) now advocates using a clinically relevant definition of dyspepsia as “predominant epigastric pain lasting at least a month” as long as epigastric pain is the patient's primary complaint.² Causes of dyspepsia are listed in TABLE 1.

Heartburn, a burning sensation in the chest, is not a dyspeptic symptom but the 2 may often coexist. In general, dyspepsia does not have a colicky or postural component. Symptoms that are relieved by evacuation of feces or gas generally should not be considered a part of dyspepsia.

Functional dyspepsia (FD) is a subset for which no structural pathology has been identified, accounting for up to 70% of all patients with dyspepsia.³ The Rome Foundation, in its recent update (Rome IV), has highlighted 4 key symptoms and 2 proposed subtypes (TABLE 2).⁴ The comorbidities of anxiety, depression, and somatization appear to be more prevalent in these dyspepsia patients than in those with organic issues. The incidence of gastric malignancy is low in this cohort.^3,5 Dyspepsia occurring after an acute infection is referred to as postinfectious functional dyspepsia.

Pathophysiology of functional dyspepsia. Dysmotility, visceral hypersensitivity, mucosal immune dysfunction, altered gut microbiota, and disturbed central nervous system processing contribute in varying degrees to the pathophysiology of FD. There is evidence that luminal factors have the potential to trigger local neuronal excitability.^6,7 Early life psychosocial factors may further influence illness behaviors, coping strategies, stress responses, and the intensity of symptoms perceived by the patient.⁸

Clues in the history and physical examination

Patients describe their discomfort using a variety of terms, including pain, gnawing, burning, gassiness, or queasiness. Although allergic reactions to food (swelling of lips and tongue with a rash) are rare in adults, food intolerances are common in patients with dyspepsia.⁹ Consumption of nonsteroidal ­anti-inflammatory drugs is a common cause of dyspepsia, even at over-the-counter strength, and may cause ulceration, gastrointestinal bleeding, and anemia. Narcotic and marijuana use and the anticholinergic effects of antidepressant medications are associated with gastrointestinal dysmotility, including gastroparesis.

Weight loss, night waking, and vomiting make functional dyspepsia less likely and deserve immediate consideration of abdominal imaging or endoscopic examination.

Patients with FD often exhibit symptoms of other functional abdominal disorders including irritable bowel syndrome, functional heartburn, bloating, or chronic nausea, and may have been previously diagnosed with overlapping conditions suggestive of visceral hypersensitivity, including depression, anxiety, fibromyalgia, migraine, and pelvic pain. During the patient’s office visit, be alert to any indication of an underlying psychological issue.

Continue to: The initial diagnostic challenge

The initial diagnostic challenge is to identify those patients who may have a structural disorder requiring expedited and targeted investigation. Weight loss, night waking, and vomiting are unusual in the setting of either FD or Helicobacter pylori gastritis. These and other features of concern (TABLE 3) make a diagnosis of a functional disorder less likely and should prompt immediate consideration of abdominal imaging or endoscopic examination. Epigastric tenderness on palpation is common in patients with FD and is not necessarily predictive of structural pathology—unless accompanied by other findings of concern. Abdominal scars or a history of trauma may be suggestive of abdominal wall pain. Abdominal pain that remains unchanged or increases when the muscles of the abdominal wall are tensed (Carnett sign) suggests abdominal wall pain.

Initial testing and Tx assessments focus on H pylori

All 3 of the major US gastroenterology organizations recommend a stepwise approach in patients without alarm symptoms, generally beginning (in those < 60 years) by testing for H pylori with either the stool antigen or urea breath test (UBT)—and initiating appropriate treatment if results are positive.^5,10 (The first step for those ≥ 60 years is discussed later.) Since the serum antibody test cannot differentiate between active and past infection, it is not recommended if other options are available.¹¹ The stool antigen test is preferred; it is a cost-effective option used for both diagnosis and confirmation of H pylori eradication.

The UBT identifies active infection with a sensitivity and specificity of > 95%¹² but is more labor intensive, employs an isotope, and is relatively expensive. Because proton pump inhibitors (PPIs), bismuth, and antibiotics may increase the false-negative rate for both the UBT and stool antigen test, we recommend that these medications be held for 2 to 4 weeks prior to testing.¹¹ H₂-receptor antagonists do not need to be restricted.

Treatment regimens containing clarithromycin have fallen into disfavor given the high rates of resistance that are now encountered. Fourteen-day regimens that can be used empirically (without susceptibility testing) are bismuth quadruple therapy (bismuth, metronidazole, tetracycline, and PPI) or rifabutin triple therapy (rifabutin, amoxicillin, and PPI).¹³ To confirm eradication, perform repeat testing with either stool antigen or UBT no sooner than 4 weeks after completion of therapy. If the first treatment fails, try a second regimen using different antibiotics.¹⁴ Although the impact of H pylori eradication on dyspeptic symptoms is only modest, this strategy is recommended also to reduce the risk of peptic ulceration and gastric neoplasia.

Next-step testing and Tx considerations

Given the heterogeneity of presenting symptoms of dyspepsia, some clinicians may be hesitant to diagnose a functional disorder at the first visit, preferring instead to conduct a limited range of investigations in concert with initial medical management. In these circumstances it would be reasonable, in addition to testing for H pylori, to order a complete blood count (CBC) and to measure serum lipase and liver enzymes. Keep in mind that liver enzymes may not be elevated in uncomplicated biliary colic.

Continue to: Consider ultrasound imaging...

Consider ultrasound imaging if gallstones are a consideration. A computerized tomography scan may not exclude uncomplicated and noncalcified gallstones, but it is an excellent modality for detecting suspected retroperitoneal pathology. Consider working with a gastroenterologist if the patient exhibits alarm features.

Empiric PPI therapy. A trial of daily PPI use over 4 weeks is recommended for patients without H pylori and for those whose symptoms continue despite eradication of the bacterium. A Cochrane meta-analysis found that PPI therapy was more effective than placebo (31% vs 26%; risk ratio, 0.88; number needed to treat [NNT] = 11; 95% CI 0.82 to 0.94; P < .001).¹⁵ PPI therapy appears to be slightly more effective than treatment with H₂-receptor antagonists. Both are proposed in the United Kingdom guideline.¹⁶ Both are generally safe and well tolerated but are not without potential adverse effects when used long term.

Dietary modification. Patients with dyspepsia commonly report that meals exacerbate symptoms. This is likely due to a combination of gastric distension and underlying visceral hypersensitivity rather than food composition.

The stool antigen test is preferred for diagnosing and confirming eradication of H pylori. The serum antibody test cannot differentiate between active and past infection.

There is no reliable “dyspepsia diet,” although a systematic review implicated wheat and high-fat foods as the 2 most common contributors to symptom onset.¹⁷ Recommended dietary modifications would be to consume smaller, more frequent meals and to eliminate recognized trigger foods. Patients with postprandial distress syndrome, a subset of FD, may want to consider reducing fat intake to help alleviate discomfort. If symptoms continue, evaluate for lactose intolerance. Also, consider a trial of a gluten-free diet. The low-FODMAP diet (restricting fermentable oligo-, di- and monosaccharides, as well as polyols) has shown benefit in patients with irritable bowel syndrome and may be considered in those with intractable FD, given the overlap in physiology of the disorders.

Upper gastrointestinal endoscopy. The ACG has suggested that esophagogastroduodenoscopy (EGD) be performed as the first investigative step for patients ≥ 60 years, while testing for H pylori be considered as the first step in younger patients, even if alarm symptoms are present² (FIGURE). This decision must be individualized, particularly in patients of Asian, Central or South American, or Caribbean descent, in whom the incidence of gastric cancer is higher with earlier onset.¹⁸

Continue to: Also consider EGD...

Also consider EGD for patients whose symptoms have not improved despite eradication of H pylori or an adequate trial of PPI therapy. While some guidelines do not require EGD in low-risk patients at this stage, other authorities would consider this step prudent, particularly when quality of life has been significantly impaired. An underlying organic cause, mainly erosive esophagitis or peptic ulcer disease, is found in 20% to 30% of patients with dyspepsia.⁵

Most patients without alarm features, with normal findings on upper endoscopy, who do not have H pylori gastritis, and whose symptoms continue despite a trial of PPI therapy, will have FD (FIGURE).²

Offer patients with functional dyspepsia supportive therapy

Neuromodulators

TCAs are superior to placebo in reducing dyspeptic symptoms with an NNT of 6 and are recommended for patients with ongoing symptoms despite PPI therapy or H pylori eradication.² Begin with a low dose and increase as tolerated. It may take a few weeks for improvement to be seen. Exercise caution in the presence of cardiac arrhythmias.

Mirtazapine, 7.5 to 15 mg every night at bedtime, reduces fullness and bloating in postprandial distress syndrome and is useful for patients who have lost weight. It’s important to note that TCAs and mirtazapine both have the potential for QT prolongation, as well as depression and suicidality in younger patients.¹⁹ The anxiolytic buspirone, 10 mg before meals, augments fundic relaxation, improves overall symptom severity, and helps alleviate early satiety, postprandial fullness, and upper abdominal bloating.²⁰

Prokinetics

A recent meta-analysis demonstrated significant benefit in symptom control in dyspeptic patients treated with prokinetics (NNT = 7).²¹ However, the benefit was predominantly due to cisapride, a drug that was withdrawn from the US market due to adverse effects. There are no clinical trials of metoclopramide or domperidone (not available in the United States) in FD. Nonetheless, the ACG has given a conditional recommendation, based on low-quality evidence, for the use of prokinetics in patients with FD not responding to PPI therapy, H pylori eradication, or TCA therapy.²

Continue to: A shortcoming of the established guidelines

A shortcoming of the established guidelines is that they do not provide guidance as to long-term management of those patients who respond to prescription medications. Our practice has been to continue medications for a minimum of 3 months, then begin a slow taper in order to establish the lowest efficacious dose. Some patients may relapse and require full dosage for a longer period of time.

Adjunctive therapies are worth considering

Complementary and alternative medicines. Products containing ginger, carraway oil, artichoke leaf extract, turmeric, and red pepper are readily available without prescription and have long been used with variable results for dyspepsia.²² The 9-herb combination STW-5 has demonstrated superiority over placebo in a number of studies and has a favorable safety profile.²³ The recommended dose is 10 to 20 drops tid. The European manufacturer has recently modified the package insert noting rare cases of hepatotoxicity.²⁴

Because PPIs, bismuth, and antibiotics may increase the false-negative rate for both the UBT and stool antigen test, we recommend that these medications be held for 2 to 4 weeks prior to testing.

A commercially available formulation (FDgard) containing L-menthol (a key component of peppermint oil) and caraway has been found to reduce the intensity of symptoms in patients with FD. Potential adverse effects include nausea, contact dermatitis, bronchospasm, and atrial fibrillation. Cayenne, a red pepper extract, is available over the counter for the benefit for epigastric pain and bloating. Begin with a 500-mg dose before breakfast and a 1000-mg dose before dinner, increasing to 2500 mg/d as tolerated. Cayenne preparations may trigger drug toxicities and are best avoided in patients taking antihypertensives, theophylline, or anticoagulants.

Cognitive behavioral therapy, acupuncture, and hypnosis. These modalities are time consuming, are often expensive, are not always covered by insurance, and require significant motivation. A systematic review found no benefit.²⁵ Subsequent studies summarized in the ACG guidelines² reported benefit; however, a lack of blinding and significant heterogeneity among the groups detract from the quality of the data. It remains unclear whether these are effective strategies for FD, and therefore they cannot be recommended on a routine basis.

CORRESPONDENCE
Norman H. Gilinsky, MD, Division of Digestive Diseases, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0595; norman.gilinsky@ uc.edu

The global prevalence of dyspepsia is approximately 20%,¹ and it is often associated with other comorbidities and overlapping gastrointestinal complaints. The effects on the patient’s quality of life, including societal impacts, are considerable. Symptoms and their response to treatment are highly variable, necessitating individualized management. While some patients’ symptoms may be refractory to standard medical treatment initially, evidence suggests that the strategies summarized in our guidance here—including the use of tricyclic antidepressants (TCAs), prokinetics, and adjunctive therapies—may alleviate symptoms and improve patients’ quality of life.

What dyspepsia is—and what it isn’t

Dyspepsia is a poorly characterized disorder often associated with nausea, heartburn, early satiety, and bloating. The American College of Gastroenterology (ACG) now advocates using a clinically relevant definition of dyspepsia as “predominant epigastric pain lasting at least a month” as long as epigastric pain is the patient's primary complaint.² Causes of dyspepsia are listed in TABLE 1.

Heartburn, a burning sensation in the chest, is not a dyspeptic symptom but the 2 may often coexist. In general, dyspepsia does not have a colicky or postural component. Symptoms that are relieved by evacuation of feces or gas generally should not be considered a part of dyspepsia.

Functional dyspepsia (FD) is a subset for which no structural pathology has been identified, accounting for up to 70% of all patients with dyspepsia.³ The Rome Foundation, in its recent update (Rome IV), has highlighted 4 key symptoms and 2 proposed subtypes (TABLE 2).⁴ The comorbidities of anxiety, depression, and somatization appear to be more prevalent in these dyspepsia patients than in those with organic issues. The incidence of gastric malignancy is low in this cohort.^3,5 Dyspepsia occurring after an acute infection is referred to as postinfectious functional dyspepsia.

Pathophysiology of functional dyspepsia. Dysmotility, visceral hypersensitivity, mucosal immune dysfunction, altered gut microbiota, and disturbed central nervous system processing contribute in varying degrees to the pathophysiology of FD. There is evidence that luminal factors have the potential to trigger local neuronal excitability.^6,7 Early life psychosocial factors may further influence illness behaviors, coping strategies, stress responses, and the intensity of symptoms perceived by the patient.⁸

Clues in the history and physical examination

Patients describe their discomfort using a variety of terms, including pain, gnawing, burning, gassiness, or queasiness. Although allergic reactions to food (swelling of lips and tongue with a rash) are rare in adults, food intolerances are common in patients with dyspepsia.⁹ Consumption of nonsteroidal ­anti-inflammatory drugs is a common cause of dyspepsia, even at over-the-counter strength, and may cause ulceration, gastrointestinal bleeding, and anemia. Narcotic and marijuana use and the anticholinergic effects of antidepressant medications are associated with gastrointestinal dysmotility, including gastroparesis.

Weight loss, night waking, and vomiting make functional dyspepsia less likely and deserve immediate consideration of abdominal imaging or endoscopic examination.

Patients with FD often exhibit symptoms of other functional abdominal disorders including irritable bowel syndrome, functional heartburn, bloating, or chronic nausea, and may have been previously diagnosed with overlapping conditions suggestive of visceral hypersensitivity, including depression, anxiety, fibromyalgia, migraine, and pelvic pain. During the patient’s office visit, be alert to any indication of an underlying psychological issue.