The Journal of Family Practice

The FP considered the diagnoses of vitiligo and tinea versicolor. He performed a potassium hydroxide (KOH) preparation and saw the “spaghetti and meatballs” pattern of Malassezia furfur. (See a video on how to perform a KOH preparation.) The “spaghetti” or “ziti” is the short mycelial form of M furfur and the “meatballs” are the round yeast form (Pityrosporum).

This was definitive proof that the patient had tinea versicolor caused by M furfur, a lipophilic yeast that can be found on healthy skin. Tinea versicolor starts when the yeast that normally colonizes the skin changes from the round form to the pathologic mycelial form and then invades the stratum corneum. M furfur thrives on sebum and moisture and tends to grow on the skin in areas where there are sebaceous follicles secreting sebum. Patients with tinea versicolor present with skin discolorations that are white, pink, or brown.

The patient in this case chose a single oral dose of 400 mg fluconazole to be repeated one week later. The condition cleared and the patient's skin color returned to normal in the following months.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Tinea versicolor. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:566-569.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP considered the diagnoses of vitiligo and tinea versicolor. He performed a potassium hydroxide (KOH) preparation and saw the “spaghetti and meatballs” pattern of Malassezia furfur. (See a video on how to perform a KOH preparation.) The “spaghetti” or “ziti” is the short mycelial form of M furfur and the “meatballs” are the round yeast form (Pityrosporum).

This was definitive proof that the patient had tinea versicolor caused by M furfur, a lipophilic yeast that can be found on healthy skin. Tinea versicolor starts when the yeast that normally colonizes the skin changes from the round form to the pathologic mycelial form and then invades the stratum corneum. M furfur thrives on sebum and moisture and tends to grow on the skin in areas where there are sebaceous follicles secreting sebum. Patients with tinea versicolor present with skin discolorations that are white, pink, or brown.

The patient in this case chose a single oral dose of 400 mg fluconazole to be repeated one week later. The condition cleared and the patient's skin color returned to normal in the following months.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Tinea versicolor. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:566-569.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The FP considered the diagnoses of vitiligo and tinea versicolor. He performed a potassium hydroxide (KOH) preparation and saw the “spaghetti and meatballs” pattern of Malassezia furfur. (See a video on how to perform a KOH preparation.) The “spaghetti” or “ziti” is the short mycelial form of M furfur and the “meatballs” are the round yeast form (Pityrosporum).

This was definitive proof that the patient had tinea versicolor caused by M furfur, a lipophilic yeast that can be found on healthy skin. Tinea versicolor starts when the yeast that normally colonizes the skin changes from the round form to the pathologic mycelial form and then invades the stratum corneum. M furfur thrives on sebum and moisture and tends to grow on the skin in areas where there are sebaceous follicles secreting sebum. Patients with tinea versicolor present with skin discolorations that are white, pink, or brown.

The patient in this case chose a single oral dose of 400 mg fluconazole to be repeated one week later. The condition cleared and the patient's skin color returned to normal in the following months.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Usatine R. Tinea versicolor. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:566-569.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

EVIDENCE SUMMARY

A systematic review and meta-analysis identified 26 studies evaluating activity and health outcomes with the use of pedometers.¹ The studies included 8 RCTs and 18 observational studies with 2767 patients (mean body mass index [BMI]: 30 kg/m²; mean age: 49 years; 85% women). The studies ranged from 3 to 104 weeks. From the RCT data, patients using pedometers had an increase of 2491 steps per day (about one mile) more than control group patients (8 trials, n=305; 95% confidence interval [CI], 1098-3885 steps/day; P<.001).

Across all of the observational studies, pedometer users had a 26.9% increase from their baseline physical activity (P=.001). When data from all of the studies were combined, the researchers found a decrease from baseline BMI (18 studies, n=562; mean difference [MD]=0.38 kg/m²; 95% CI, 0.05-0.72; P=.03) and a decrease in systolic BP (12 studies, n=468; MD=3.8 mm Hg; 95% CI, 1.7-5.9 mm Hg; P<.001). No statistically significant change was noted in cholesterol or fasting glucose levels. Weaknesses of this review include the heterogeneity of the interventions, relatively small study sizes, and short study durations.

Reduced weight, BMI in patients with type 2 diabetes

A systematic review and meta-analysis of 11 RCTs (N=1258) evaluated pedometer effects in overweight patients with type 2 diabetes.² (One RCT was included in the above meta-analysis.) Studies ran from 6 to 48 weeks, and mean enrollment BMI (where reported) was 30 kg/m² or more in at least one treatment arm. Compared to controls, patients using pedometers had greater reductions in weight (weighted mean difference [WMD]= -0.65 kg; 95% CI, -1.12 to -0.17 kg) and BMI (WMD= -0.15 kg/m²; 95% CI, -0.29 to -0.02 kg/m²). The effect persisted in the subset of studies in which the intervention and control groups both received dietary counseling (WMD weight= -0.86 kg; 95% CI, -1.45 to -0.27 kg; WMD BMI= -0.30 kg/m²; 95% CI, -0.50 to -0.10 kg/m²). Study quality was low to moderate, and 5 studies used per-protocol analysis instead of intention-to-treat analysis.

Pedometer use benefits patients with musculoskeletal diseases, too

A systematic review and meta-analysis examined the use of pedometers in patients with musculoskeletal diseases.³ It included 7 RCTs lasting 4 weeks to one year with 484 adults, 40 to 82 years of age, with musculoskeletal disorders (eg, back pain, knee pain, hip pain). (One RCT was also included in the diabetes meta-analysis.) Pedometer use resulted in a mean increase in physical activity of 1950 steps per day above baseline (range=818-2829 steps/day; P<.05). The authors noted that 4 of the 7 studies also demonstrated significant improvement in pain scores and physical function. BMI data were not tracked in this review.

Pedometers increase walking in older patients

A RCT compared the effects of pedometer-based activity prescriptions with standard time-based activity prescriptions in 330 patients ≥65 years of age with baseline low activity levels.⁴ All patients received an initial physician visit followed by 3 telephone counseling sessions encouraging increased activity. The pedometer group was counseled on increasing steps (without specific targets), while the standard activity prescription group received time-related activity goals.

At one year, “leisure walking” had increased more for the pedometer group than for the standard group (mean 50 minutes/week vs 28 minutes/week; P=.03), although both groups equally increased their amount of “total activity.” Blood pressure decreased equally in both groups, while BMI was unchanged in either.

EVIDENCE SUMMARY

A systematic review and meta-analysis identified 26 studies evaluating activity and health outcomes with the use of pedometers.¹ The studies included 8 RCTs and 18 observational studies with 2767 patients (mean body mass index [BMI]: 30 kg/m²; mean age: 49 years; 85% women). The studies ranged from 3 to 104 weeks. From the RCT data, patients using pedometers had an increase of 2491 steps per day (about one mile) more than control group patients (8 trials, n=305; 95% confidence interval [CI], 1098-3885 steps/day; P<.001).

Across all of the observational studies, pedometer users had a 26.9% increase from their baseline physical activity (P=.001). When data from all of the studies were combined, the researchers found a decrease from baseline BMI (18 studies, n=562; mean difference [MD]=0.38 kg/m²; 95% CI, 0.05-0.72; P=.03) and a decrease in systolic BP (12 studies, n=468; MD=3.8 mm Hg; 95% CI, 1.7-5.9 mm Hg; P<.001). No statistically significant change was noted in cholesterol or fasting glucose levels. Weaknesses of this review include the heterogeneity of the interventions, relatively small study sizes, and short study durations.

Reduced weight, BMI in patients with type 2 diabetes

A systematic review and meta-analysis of 11 RCTs (N=1258) evaluated pedometer effects in overweight patients with type 2 diabetes.² (One RCT was included in the above meta-analysis.) Studies ran from 6 to 48 weeks, and mean enrollment BMI (where reported) was 30 kg/m² or more in at least one treatment arm. Compared to controls, patients using pedometers had greater reductions in weight (weighted mean difference [WMD]= -0.65 kg; 95% CI, -1.12 to -0.17 kg) and BMI (WMD= -0.15 kg/m²; 95% CI, -0.29 to -0.02 kg/m²). The effect persisted in the subset of studies in which the intervention and control groups both received dietary counseling (WMD weight= -0.86 kg; 95% CI, -1.45 to -0.27 kg; WMD BMI= -0.30 kg/m²; 95% CI, -0.50 to -0.10 kg/m²). Study quality was low to moderate, and 5 studies used per-protocol analysis instead of intention-to-treat analysis.

Pedometer use benefits patients with musculoskeletal diseases, too

A systematic review and meta-analysis examined the use of pedometers in patients with musculoskeletal diseases.³ It included 7 RCTs lasting 4 weeks to one year with 484 adults, 40 to 82 years of age, with musculoskeletal disorders (eg, back pain, knee pain, hip pain). (One RCT was also included in the diabetes meta-analysis.) Pedometer use resulted in a mean increase in physical activity of 1950 steps per day above baseline (range=818-2829 steps/day; P<.05). The authors noted that 4 of the 7 studies also demonstrated significant improvement in pain scores and physical function. BMI data were not tracked in this review.

Pedometers increase walking in older patients

A RCT compared the effects of pedometer-based activity prescriptions with standard time-based activity prescriptions in 330 patients ≥65 years of age with baseline low activity levels.⁴ All patients received an initial physician visit followed by 3 telephone counseling sessions encouraging increased activity. The pedometer group was counseled on increasing steps (without specific targets), while the standard activity prescription group received time-related activity goals.

At one year, “leisure walking” had increased more for the pedometer group than for the standard group (mean 50 minutes/week vs 28 minutes/week; P=.03), although both groups equally increased their amount of “total activity.” Blood pressure decreased equally in both groups, while BMI was unchanged in either.

EVIDENCE SUMMARY

A systematic review and meta-analysis identified 26 studies evaluating activity and health outcomes with the use of pedometers.¹ The studies included 8 RCTs and 18 observational studies with 2767 patients (mean body mass index [BMI]: 30 kg/m²; mean age: 49 years; 85% women). The studies ranged from 3 to 104 weeks. From the RCT data, patients using pedometers had an increase of 2491 steps per day (about one mile) more than control group patients (8 trials, n=305; 95% confidence interval [CI], 1098-3885 steps/day; P<.001).

Across all of the observational studies, pedometer users had a 26.9% increase from their baseline physical activity (P=.001). When data from all of the studies were combined, the researchers found a decrease from baseline BMI (18 studies, n=562; mean difference [MD]=0.38 kg/m²; 95% CI, 0.05-0.72; P=.03) and a decrease in systolic BP (12 studies, n=468; MD=3.8 mm Hg; 95% CI, 1.7-5.9 mm Hg; P<.001). No statistically significant change was noted in cholesterol or fasting glucose levels. Weaknesses of this review include the heterogeneity of the interventions, relatively small study sizes, and short study durations.

Reduced weight, BMI in patients with type 2 diabetes

A systematic review and meta-analysis of 11 RCTs (N=1258) evaluated pedometer effects in overweight patients with type 2 diabetes.² (One RCT was included in the above meta-analysis.) Studies ran from 6 to 48 weeks, and mean enrollment BMI (where reported) was 30 kg/m² or more in at least one treatment arm. Compared to controls, patients using pedometers had greater reductions in weight (weighted mean difference [WMD]= -0.65 kg; 95% CI, -1.12 to -0.17 kg) and BMI (WMD= -0.15 kg/m²; 95% CI, -0.29 to -0.02 kg/m²). The effect persisted in the subset of studies in which the intervention and control groups both received dietary counseling (WMD weight= -0.86 kg; 95% CI, -1.45 to -0.27 kg; WMD BMI= -0.30 kg/m²; 95% CI, -0.50 to -0.10 kg/m²). Study quality was low to moderate, and 5 studies used per-protocol analysis instead of intention-to-treat analysis.

Pedometer use benefits patients with musculoskeletal diseases, too

A systematic review and meta-analysis examined the use of pedometers in patients with musculoskeletal diseases.³ It included 7 RCTs lasting 4 weeks to one year with 484 adults, 40 to 82 years of age, with musculoskeletal disorders (eg, back pain, knee pain, hip pain). (One RCT was also included in the diabetes meta-analysis.) Pedometer use resulted in a mean increase in physical activity of 1950 steps per day above baseline (range=818-2829 steps/day; P<.05). The authors noted that 4 of the 7 studies also demonstrated significant improvement in pain scores and physical function. BMI data were not tracked in this review.

Pedometers increase walking in older patients

A RCT compared the effects of pedometer-based activity prescriptions with standard time-based activity prescriptions in 330 patients ≥65 years of age with baseline low activity levels.⁴ All patients received an initial physician visit followed by 3 telephone counseling sessions encouraging increased activity. The pedometer group was counseled on increasing steps (without specific targets), while the standard activity prescription group received time-related activity goals.

At one year, “leisure walking” had increased more for the pedometer group than for the standard group (mean 50 minutes/week vs 28 minutes/week; P=.03), although both groups equally increased their amount of “total activity.” Blood pressure decreased equally in both groups, while BMI was unchanged in either.

Nearly 80 people die every day in America from an opioid overdose.¹ At the same time, sales of prescription painkillers have increased 4-fold since 1999.² My own medical assistant was given an unsolicited prescription for 40 oxycodone after a wisdom tooth extraction.

Meanwhile, about 80% of the country’s 2 million opioid-dependent patients are not receiving the treatment they need.^3,4 In Vermont, for example, more than 500 patients are on waiting lists to receive buprenorphine (the partial opioid agonist used to treat opioid addiction)—a wait that for many of them will last for more than a year and may cost them their life.⁵

Buprenorphine makes good sense. Fortunately, buprenorphine can reverse opioid cravings within minutes. Medication-assisted treatment with buprenorphine derivatives allows patients to lead normal, productive, and stable lives. Every dollar invested in treating opioid addiction saves society $7 in drug-related crime and criminal justice costs.⁶ In addition, 50% to 80% of opioid-dependent patients remain opioid-free for 12 months while taking buprenorphine.⁷

My medical assistant was given a prescription for 40 oxycodone after a tooth extraction.

Steps we can take. As family physicians (FPs), we are frequently overwhelmed by regulatory concerns, overhead expenses, and providing meaningful use data to third-party payers. And we sometimes take the easy route of simply prescribing or refilling scheduled drugs. Instead, we should educate ourselves and our patients about alternative therapeutic interventions for pain control and addiction.

To that end, I encourage all FPs to take the 8-hour online course provided by the American Society of Addiction Medicine to obtain a US Drug Enforcement Administration waiver for prescribing buprenorphine (available at: http://www.asam.org/education/live-online-cme/buprenorphine-course). It costs less than $200 and successful completion of this CME program allows FPs to deliver office-based opioid dependency interventions as per the Drug Addiction Treatment Act of 2000.

Right now, monthly patient censuses indicate that there are about 3234 buprenorphine prescribers providing care for 245,016 opioid-dependent patients, and fewer than 20% of those prescribers are FPs.⁸ We need to change that. We have an opportunity to invest in the future of these high-risk patients. Let’s not let them down.

Nearly 80 people die every day in America from an opioid overdose.¹ At the same time, sales of prescription painkillers have increased 4-fold since 1999.² My own medical assistant was given an unsolicited prescription for 40 oxycodone after a wisdom tooth extraction.

Meanwhile, about 80% of the country’s 2 million opioid-dependent patients are not receiving the treatment they need.^3,4 In Vermont, for example, more than 500 patients are on waiting lists to receive buprenorphine (the partial opioid agonist used to treat opioid addiction)—a wait that for many of them will last for more than a year and may cost them their life.⁵

Buprenorphine makes good sense. Fortunately, buprenorphine can reverse opioid cravings within minutes. Medication-assisted treatment with buprenorphine derivatives allows patients to lead normal, productive, and stable lives. Every dollar invested in treating opioid addiction saves society $7 in drug-related crime and criminal justice costs.⁶ In addition, 50% to 80% of opioid-dependent patients remain opioid-free for 12 months while taking buprenorphine.⁷

My medical assistant was given a prescription for 40 oxycodone after a tooth extraction.

Steps we can take. As family physicians (FPs), we are frequently overwhelmed by regulatory concerns, overhead expenses, and providing meaningful use data to third-party payers. And we sometimes take the easy route of simply prescribing or refilling scheduled drugs. Instead, we should educate ourselves and our patients about alternative therapeutic interventions for pain control and addiction.

To that end, I encourage all FPs to take the 8-hour online course provided by the American Society of Addiction Medicine to obtain a US Drug Enforcement Administration waiver for prescribing buprenorphine (available at: http://www.asam.org/education/live-online-cme/buprenorphine-course). It costs less than $200 and successful completion of this CME program allows FPs to deliver office-based opioid dependency interventions as per the Drug Addiction Treatment Act of 2000.

Right now, monthly patient censuses indicate that there are about 3234 buprenorphine prescribers providing care for 245,016 opioid-dependent patients, and fewer than 20% of those prescribers are FPs.⁸ We need to change that. We have an opportunity to invest in the future of these high-risk patients. Let’s not let them down.

Nearly 80 people die every day in America from an opioid overdose.¹ At the same time, sales of prescription painkillers have increased 4-fold since 1999.² My own medical assistant was given an unsolicited prescription for 40 oxycodone after a wisdom tooth extraction.

Meanwhile, about 80% of the country’s 2 million opioid-dependent patients are not receiving the treatment they need.^3,4 In Vermont, for example, more than 500 patients are on waiting lists to receive buprenorphine (the partial opioid agonist used to treat opioid addiction)—a wait that for many of them will last for more than a year and may cost them their life.⁵

Buprenorphine makes good sense. Fortunately, buprenorphine can reverse opioid cravings within minutes. Medication-assisted treatment with buprenorphine derivatives allows patients to lead normal, productive, and stable lives. Every dollar invested in treating opioid addiction saves society $7 in drug-related crime and criminal justice costs.⁶ In addition, 50% to 80% of opioid-dependent patients remain opioid-free for 12 months while taking buprenorphine.⁷

My medical assistant was given a prescription for 40 oxycodone after a tooth extraction.

Steps we can take. As family physicians (FPs), we are frequently overwhelmed by regulatory concerns, overhead expenses, and providing meaningful use data to third-party payers. And we sometimes take the easy route of simply prescribing or refilling scheduled drugs. Instead, we should educate ourselves and our patients about alternative therapeutic interventions for pain control and addiction.

To that end, I encourage all FPs to take the 8-hour online course provided by the American Society of Addiction Medicine to obtain a US Drug Enforcement Administration waiver for prescribing buprenorphine (available at: http://www.asam.org/education/live-online-cme/buprenorphine-course). It costs less than $200 and successful completion of this CME program allows FPs to deliver office-based opioid dependency interventions as per the Drug Addiction Treatment Act of 2000.

Right now, monthly patient censuses indicate that there are about 3234 buprenorphine prescribers providing care for 245,016 opioid-dependent patients, and fewer than 20% of those prescribers are FPs.⁸ We need to change that. We have an opportunity to invest in the future of these high-risk patients. Let’s not let them down.

ILLUSTRATIVE CASE

A 58-year-old woman with type 2 diabetes mellitus (T2DM) and heart failure returns to your office for follow-up of her T2DM. She has been on the maximum dose of metformin alone for the past 6 months, but her HbA1c is now 7.8%. She is keen to avoid injections. What do you recommend next?

There is surprisingly little consensus about what to add to metformin for patients with T2DM who require a second agent to achieve their glycemic goal. Attainment of glycemic control earlier in the course of the disease may lead to reduced overall cardiovascular risk, so the choice of a second drug is an important one.² While metformin is well established as initial pharmacotherapy because of its proven mortality benefit, wide availability, and low cost, no second-choice drug has amassed enough evidence of benefit to emerge as the add-on therapy of choice.

Furthermore, the professional societies and associations are of little assistance. Dual therapy recommendations from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes do not denote a specific preference, and while the American Association of Clinical Endocrinologists/American College of Endocrinology do suggest a hierarchy of choices, it is based upon expert consensus recommendation.^3,4

Sulfonylureas can cause hypoglycemia and weight gain

Options for add-on therapy include sulfonylureas, thiazolidines, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and insulin. Providers have frequently prescribed a sulfonylurea after metformin because such agents are low in cost, have long-term safety data, and are effective at lowering HbA1c. Sulfonylureas work by directly stimulating insulin secretion by pancreatic beta cells in a glucose-independent manner. But as a 2010 meta-analysis revealed, they carry significant risks of hypoglycemia (relative risk [RR]=4.57; 95% confidence interval [CI], 2.11-11.45) and weight gain (2.06 kg; 95% CI, 1.15-2.96) compared to placebo.⁵

DPP-4 inhibitors, on the other hand, work by inducing insulin secretion in a glucose-dependent manner through an incretin mechanism. Combined with metformin, they provide glucose control similar to that achieved with the combination of a sulfonylurea and metformin.⁶ DPP-4 inhibitors were initially found to be associated with fewer cardiovascular events and less hypoglycemia than sulfonylureas, but were subsequently linked to an increased risk of hospitalization for heart failure.⁷

This latest large observational study provides more evidence on the effects of DPP-4s when added to metformin.¹

STUDY SUMMARY

DPP-4s as effective as sulfonylureas with no increased risks

This population-based observational cohort study compared DPP-4 inhibitors and sulfonylureas when added to metformin for the treatment of T2DM.¹ Outcomes were all-cause mortality, major adverse cardiovascular events (MACEs; defined as hospitalization for ischemic stroke or myocardial infarction [MI]), and hospitalizations for either heart failure or hypoglycemia. Using the National Health Insurance Research Database in Taiwan, the study included data on over 70,000 patients ages 20 years and older with a diagnosis of T2DM. Individuals adherent to metformin were considered to be enrolled into the cohort on the day they began using either a DPP-4 inhibitor or a sulfonylurea, in addition to metformin.

Combined with metformin, DPP-4s provide glucose control similar to that achieved with the combination of a sulfonylurea and metformin.

The researchers collected additional data on the enrolled individuals regarding socioeconomic factors, urbanization, robustness of the local health care system, Charlson Comorbidity Index, adapted Diabetes Complications Severity Index, and other comorbidities and medications that could affect the outcomes of interest. Using these data, enrollees were matched by propensity score into 10,089 pairs consisting of a DPP-4 inhibitor user and a sulfonylurea user.

After a mean follow-up period of 2.8 years, the authors of the study used Cox regression analysis to evaluate the relative hazards of the outcomes. Subgroup analysis performed by age, sex, Charlson Comorbidity Index, hypertension, chronic kidney disease, hospitalization for heart failure, MI, and cerebrovascular disease yielded results similar to those of the primary analysis for each outcome. Additionally, similar results were obtained when the data were analyzed without propensity-score matching.

The researchers found that users of DPP-4 inhibitors—when compared to users of sulfonylureas—had a lower risk of all-cause mortality (366 vs 488 deaths; hazard ratio [HR]=0.63; 95% CI, 0.55-0.72; number needed to treat [NNT]=117), MACE (209 vs 282 events; HR=0.68; 95% CI, 0.55-0.83; NNT=191), ischemic stroke (144 vs 203 strokes; HR 0.64; 95% CI, 0.51-0.81; NNT=246), and hypoglycemia (89 vs 170 events; HR=0.43; 95% CI, 0.33-0.56; NNT=201). Further, there were no significant differences in either the number of MIs that occurred (69 vs 88 MIs; HR=0.75; 95% CI, 0.52-1.07) or in the number of hospitalizations for heart failure (100 vs 100 events; HR=0.78; 95% CI, 0.57-1.06) between users of DPP-4 inhibitors and those of sulfonylureas.

WHAT’S NEW

Lower risks of death, CV events, and hypoglycemia

This study found that when added to metformin, DPP-4 inhibitors were associated with lower risks for all-cause mortality, cardiovascular events, and hypoglycemia when compared to sulfonylureas. Additionally, DPP-4 inhibitors did not increase the risk of hospitalization for heart failure. A recent multicenter observational study of nearly 1.5 million patients on the effects of incretin-based treatments, including both DPP-4 inhibitors and GLP-1 agonists, similarly found no increased risk of hospitalization for heart failure, with DPP-4 inhibitors compared to other combinations of oral T2DM agents.⁸

CAVEATS

Did unmeasured confounders play a role?

Unmeasured confounders potentially bias all observational population cohort results. In this study, in particular, there may have been unmeasured, but significant, patient factors that providers used to choose diabetes medications. Also, the study did not evaluate diabetes control, although previous studies have shown similar glucose control between sulfonylureas and DPP-4 inhibitors when they were added to metformin.⁶

Another caveat is that the results from this study group may not be fully generalizable to other populations due to physiologic differences. People of Asian ancestry are at risk of developing T2DM at a lower body mass index than people of European ancestry, which could affect the outcomes of interest.⁹

Use of DPP-4s appears to have a lower risk of all-cause mortality, major adverse cardiovascular events, ischemic stroke, and hypoglycemia, compared to use of sulfonylureas.

Furthermore, the study did not evaluate outcomes based on whether patients were taking first-, second-, or third-generation sulfonylureas. Some sulfonylureas, such as glyburide, carry a higher risk of hypoglycemia, which could bias the results if a large number of patients were taking them.¹⁰

Lastly, the study only provides guidance when choosing between a sulfonylurea and a DPP-4 inhibitor for second-line pharmacotherapy. The GRADE trial, due to be completed in 2023, is comparing sulfonylureas, DPP-4 inhibitors, GLP-1 agonists, and insulin as add-on medications to metformin, and may provide more data on which to base treatment decisions.¹¹

CHALLENGES TO IMPLEMENTATION

DPP-4s have a higher price tag than sulfonylureas

Sulfonylureas and DPP-4 inhibitors are both available as generic medications, but the cost of DPP-4 inhibitors remains significantly higher.¹² Higher copays and deductibles could affect patient preference. Furthermore, for patients without health insurance, sulfonylureas are available on the discounted drug lists of many major retailers, while DPP-4 inhibitors are not.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A 58-year-old woman with type 2 diabetes mellitus (T2DM) and heart failure returns to your office for follow-up of her T2DM. She has been on the maximum dose of metformin alone for the past 6 months, but her HbA1c is now 7.8%. She is keen to avoid injections. What do you recommend next?

There is surprisingly little consensus about what to add to metformin for patients with T2DM who require a second agent to achieve their glycemic goal. Attainment of glycemic control earlier in the course of the disease may lead to reduced overall cardiovascular risk, so the choice of a second drug is an important one.² While metformin is well established as initial pharmacotherapy because of its proven mortality benefit, wide availability, and low cost, no second-choice drug has amassed enough evidence of benefit to emerge as the add-on therapy of choice.

Furthermore, the professional societies and associations are of little assistance. Dual therapy recommendations from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes do not denote a specific preference, and while the American Association of Clinical Endocrinologists/American College of Endocrinology do suggest a hierarchy of choices, it is based upon expert consensus recommendation.^3,4

Sulfonylureas can cause hypoglycemia and weight gain

Options for add-on therapy include sulfonylureas, thiazolidines, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and insulin. Providers have frequently prescribed a sulfonylurea after metformin because such agents are low in cost, have long-term safety data, and are effective at lowering HbA1c. Sulfonylureas work by directly stimulating insulin secretion by pancreatic beta cells in a glucose-independent manner. But as a 2010 meta-analysis revealed, they carry significant risks of hypoglycemia (relative risk [RR]=4.57; 95% confidence interval [CI], 2.11-11.45) and weight gain (2.06 kg; 95% CI, 1.15-2.96) compared to placebo.⁵

DPP-4 inhibitors, on the other hand, work by inducing insulin secretion in a glucose-dependent manner through an incretin mechanism. Combined with metformin, they provide glucose control similar to that achieved with the combination of a sulfonylurea and metformin.⁶ DPP-4 inhibitors were initially found to be associated with fewer cardiovascular events and less hypoglycemia than sulfonylureas, but were subsequently linked to an increased risk of hospitalization for heart failure.⁷

This latest large observational study provides more evidence on the effects of DPP-4s when added to metformin.¹

STUDY SUMMARY

DPP-4s as effective as sulfonylureas with no increased risks

This population-based observational cohort study compared DPP-4 inhibitors and sulfonylureas when added to metformin for the treatment of T2DM.¹ Outcomes were all-cause mortality, major adverse cardiovascular events (MACEs; defined as hospitalization for ischemic stroke or myocardial infarction [MI]), and hospitalizations for either heart failure or hypoglycemia. Using the National Health Insurance Research Database in Taiwan, the study included data on over 70,000 patients ages 20 years and older with a diagnosis of T2DM. Individuals adherent to metformin were considered to be enrolled into the cohort on the day they began using either a DPP-4 inhibitor or a sulfonylurea, in addition to metformin.

Combined with metformin, DPP-4s provide glucose control similar to that achieved with the combination of a sulfonylurea and metformin.

The researchers collected additional data on the enrolled individuals regarding socioeconomic factors, urbanization, robustness of the local health care system, Charlson Comorbidity Index, adapted Diabetes Complications Severity Index, and other comorbidities and medications that could affect the outcomes of interest. Using these data, enrollees were matched by propensity score into 10,089 pairs consisting of a DPP-4 inhibitor user and a sulfonylurea user.

After a mean follow-up period of 2.8 years, the authors of the study used Cox regression analysis to evaluate the relative hazards of the outcomes. Subgroup analysis performed by age, sex, Charlson Comorbidity Index, hypertension, chronic kidney disease, hospitalization for heart failure, MI, and cerebrovascular disease yielded results similar to those of the primary analysis for each outcome. Additionally, similar results were obtained when the data were analyzed without propensity-score matching.

The researchers found that users of DPP-4 inhibitors—when compared to users of sulfonylureas—had a lower risk of all-cause mortality (366 vs 488 deaths; hazard ratio [HR]=0.63; 95% CI, 0.55-0.72; number needed to treat [NNT]=117), MACE (209 vs 282 events; HR=0.68; 95% CI, 0.55-0.83; NNT=191), ischemic stroke (144 vs 203 strokes; HR 0.64; 95% CI, 0.51-0.81; NNT=246), and hypoglycemia (89 vs 170 events; HR=0.43; 95% CI, 0.33-0.56; NNT=201). Further, there were no significant differences in either the number of MIs that occurred (69 vs 88 MIs; HR=0.75; 95% CI, 0.52-1.07) or in the number of hospitalizations for heart failure (100 vs 100 events; HR=0.78; 95% CI, 0.57-1.06) between users of DPP-4 inhibitors and those of sulfonylureas.

WHAT’S NEW

Lower risks of death, CV events, and hypoglycemia

This study found that when added to metformin, DPP-4 inhibitors were associated with lower risks for all-cause mortality, cardiovascular events, and hypoglycemia when compared to sulfonylureas. Additionally, DPP-4 inhibitors did not increase the risk of hospitalization for heart failure. A recent multicenter observational study of nearly 1.5 million patients on the effects of incretin-based treatments, including both DPP-4 inhibitors and GLP-1 agonists, similarly found no increased risk of hospitalization for heart failure, with DPP-4 inhibitors compared to other combinations of oral T2DM agents.⁸

CAVEATS

Did unmeasured confounders play a role?

Unmeasured confounders potentially bias all observational population cohort results. In this study, in particular, there may have been unmeasured, but significant, patient factors that providers used to choose diabetes medications. Also, the study did not evaluate diabetes control, although previous studies have shown similar glucose control between sulfonylureas and DPP-4 inhibitors when they were added to metformin.⁶

Another caveat is that the results from this study group may not be fully generalizable to other populations due to physiologic differences. People of Asian ancestry are at risk of developing T2DM at a lower body mass index than people of European ancestry, which could affect the outcomes of interest.⁹

Use of DPP-4s appears to have a lower risk of all-cause mortality, major adverse cardiovascular events, ischemic stroke, and hypoglycemia, compared to use of sulfonylureas.

Furthermore, the study did not evaluate outcomes based on whether patients were taking first-, second-, or third-generation sulfonylureas. Some sulfonylureas, such as glyburide, carry a higher risk of hypoglycemia, which could bias the results if a large number of patients were taking them.¹⁰

Lastly, the study only provides guidance when choosing between a sulfonylurea and a DPP-4 inhibitor for second-line pharmacotherapy. The GRADE trial, due to be completed in 2023, is comparing sulfonylureas, DPP-4 inhibitors, GLP-1 agonists, and insulin as add-on medications to metformin, and may provide more data on which to base treatment decisions.¹¹

CHALLENGES TO IMPLEMENTATION

DPP-4s have a higher price tag than sulfonylureas

Sulfonylureas and DPP-4 inhibitors are both available as generic medications, but the cost of DPP-4 inhibitors remains significantly higher.¹² Higher copays and deductibles could affect patient preference. Furthermore, for patients without health insurance, sulfonylureas are available on the discounted drug lists of many major retailers, while DPP-4 inhibitors are not.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A 58-year-old woman with type 2 diabetes mellitus (T2DM) and heart failure returns to your office for follow-up of her T2DM. She has been on the maximum dose of metformin alone for the past 6 months, but her HbA1c is now 7.8%. She is keen to avoid injections. What do you recommend next?

There is surprisingly little consensus about what to add to metformin for patients with T2DM who require a second agent to achieve their glycemic goal. Attainment of glycemic control earlier in the course of the disease may lead to reduced overall cardiovascular risk, so the choice of a second drug is an important one.² While metformin is well established as initial pharmacotherapy because of its proven mortality benefit, wide availability, and low cost, no second-choice drug has amassed enough evidence of benefit to emerge as the add-on therapy of choice.

Furthermore, the professional societies and associations are of little assistance. Dual therapy recommendations from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes do not denote a specific preference, and while the American Association of Clinical Endocrinologists/American College of Endocrinology do suggest a hierarchy of choices, it is based upon expert consensus recommendation.^3,4

Sulfonylureas can cause hypoglycemia and weight gain

Options for add-on therapy include sulfonylureas, thiazolidines, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and insulin. Providers have frequently prescribed a sulfonylurea after metformin because such agents are low in cost, have long-term safety data, and are effective at lowering HbA1c. Sulfonylureas work by directly stimulating insulin secretion by pancreatic beta cells in a glucose-independent manner. But as a 2010 meta-analysis revealed, they carry significant risks of hypoglycemia (relative risk [RR]=4.57; 95% confidence interval [CI], 2.11-11.45) and weight gain (2.06 kg; 95% CI, 1.15-2.96) compared to placebo.⁵

DPP-4 inhibitors, on the other hand, work by inducing insulin secretion in a glucose-dependent manner through an incretin mechanism. Combined with metformin, they provide glucose control similar to that achieved with the combination of a sulfonylurea and metformin.⁶ DPP-4 inhibitors were initially found to be associated with fewer cardiovascular events and less hypoglycemia than sulfonylureas, but were subsequently linked to an increased risk of hospitalization for heart failure.⁷

This latest large observational study provides more evidence on the effects of DPP-4s when added to metformin.¹

STUDY SUMMARY

DPP-4s as effective as sulfonylureas with no increased risks

This population-based observational cohort study compared DPP-4 inhibitors and sulfonylureas when added to metformin for the treatment of T2DM.¹ Outcomes were all-cause mortality, major adverse cardiovascular events (MACEs; defined as hospitalization for ischemic stroke or myocardial infarction [MI]), and hospitalizations for either heart failure or hypoglycemia. Using the National Health Insurance Research Database in Taiwan, the study included data on over 70,000 patients ages 20 years and older with a diagnosis of T2DM. Individuals adherent to metformin were considered to be enrolled into the cohort on the day they began using either a DPP-4 inhibitor or a sulfonylurea, in addition to metformin.

Combined with metformin, DPP-4s provide glucose control similar to that achieved with the combination of a sulfonylurea and metformin.

The researchers collected additional data on the enrolled individuals regarding socioeconomic factors, urbanization, robustness of the local health care system, Charlson Comorbidity Index, adapted Diabetes Complications Severity Index, and other comorbidities and medications that could affect the outcomes of interest. Using these data, enrollees were matched by propensity score into 10,089 pairs consisting of a DPP-4 inhibitor user and a sulfonylurea user.

After a mean follow-up period of 2.8 years, the authors of the study used Cox regression analysis to evaluate the relative hazards of the outcomes. Subgroup analysis performed by age, sex, Charlson Comorbidity Index, hypertension, chronic kidney disease, hospitalization for heart failure, MI, and cerebrovascular disease yielded results similar to those of the primary analysis for each outcome. Additionally, similar results were obtained when the data were analyzed without propensity-score matching.

The researchers found that users of DPP-4 inhibitors—when compared to users of sulfonylureas—had a lower risk of all-cause mortality (366 vs 488 deaths; hazard ratio [HR]=0.63; 95% CI, 0.55-0.72; number needed to treat [NNT]=117), MACE (209 vs 282 events; HR=0.68; 95% CI, 0.55-0.83; NNT=191), ischemic stroke (144 vs 203 strokes; HR 0.64; 95% CI, 0.51-0.81; NNT=246), and hypoglycemia (89 vs 170 events; HR=0.43; 95% CI, 0.33-0.56; NNT=201). Further, there were no significant differences in either the number of MIs that occurred (69 vs 88 MIs; HR=0.75; 95% CI, 0.52-1.07) or in the number of hospitalizations for heart failure (100 vs 100 events; HR=0.78; 95% CI, 0.57-1.06) between users of DPP-4 inhibitors and those of sulfonylureas.

WHAT’S NEW

Lower risks of death, CV events, and hypoglycemia

This study found that when added to metformin, DPP-4 inhibitors were associated with lower risks for all-cause mortality, cardiovascular events, and hypoglycemia when compared to sulfonylureas. Additionally, DPP-4 inhibitors did not increase the risk of hospitalization for heart failure. A recent multicenter observational study of nearly 1.5 million patients on the effects of incretin-based treatments, including both DPP-4 inhibitors and GLP-1 agonists, similarly found no increased risk of hospitalization for heart failure, with DPP-4 inhibitors compared to other combinations of oral T2DM agents.⁸

CAVEATS

Did unmeasured confounders play a role?

Unmeasured confounders potentially bias all observational population cohort results. In this study, in particular, there may have been unmeasured, but significant, patient factors that providers used to choose diabetes medications. Also, the study did not evaluate diabetes control, although previous studies have shown similar glucose control between sulfonylureas and DPP-4 inhibitors when they were added to metformin.⁶

Another caveat is that the results from this study group may not be fully generalizable to other populations due to physiologic differences. People of Asian ancestry are at risk of developing T2DM at a lower body mass index than people of European ancestry, which could affect the outcomes of interest.⁹

Use of DPP-4s appears to have a lower risk of all-cause mortality, major adverse cardiovascular events, ischemic stroke, and hypoglycemia, compared to use of sulfonylureas.

Furthermore, the study did not evaluate outcomes based on whether patients were taking first-, second-, or third-generation sulfonylureas. Some sulfonylureas, such as glyburide, carry a higher risk of hypoglycemia, which could bias the results if a large number of patients were taking them.¹⁰

Lastly, the study only provides guidance when choosing between a sulfonylurea and a DPP-4 inhibitor for second-line pharmacotherapy. The GRADE trial, due to be completed in 2023, is comparing sulfonylureas, DPP-4 inhibitors, GLP-1 agonists, and insulin as add-on medications to metformin, and may provide more data on which to base treatment decisions.¹¹

CHALLENGES TO IMPLEMENTATION

DPP-4s have a higher price tag than sulfonylureas

Sulfonylureas and DPP-4 inhibitors are both available as generic medications, but the cost of DPP-4 inhibitors remains significantly higher.¹² Higher copays and deductibles could affect patient preference. Furthermore, for patients without health insurance, sulfonylureas are available on the discounted drug lists of many major retailers, while DPP-4 inhibitors are not.

ACKNOWLEDGEMENT

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

THE CASE

A 44-year-old woman with a 15-year history of type 2 diabetes sought care for a firm, non-tender mass in the medial lower quadrant of her right breast. She hadn’t experienced any skin changes or axillary lymphadenopathy. The patient had immigrated to California from Afghanistan 22 years earlier, at which time she was briefly married to an Afghan man suffering from a chronic cough.

Mammography revealed a 3.5 x 4 x 4 cm lesion at the chest wall, which was highly suspicious for carcinoma (FIGURES 1A AND 1B). Sonography showed a heterogenous hypoechoic and isoechoic mass with posterior acoustic enhancement (FIGURE 1C). An excisional biopsy was performed.

One week postoperatively, the patient presented to the emergency department for a worsening nonproductive cough that intensified when supine, and was associated with subscapular pleuritic pain. She denied fever or weight loss. Biopsy results were pending.

THE DIAGNOSIS

Chest x-rays revealed a large right pleural effusion that was presumed to be malignant (FIGURES 1D AND 1E). Thoracentesis yielded 1.5 liters of tea-colored exudate containing 2800 nucleated cells/mL—63% lymphocytes and 37% neutrophils—and a pleural fluid to serum protein ratio >0.5. Adenosine deaminase was <1 U/L. Fluid Gram stain, acid-fast bacillus (AFB) fluorescent antibody testing, AFB cultures, and cytology were negative. Computed tomography (CT) subsequently demonstrated recurrent effusion without hilar or mediastinal lymphadenopathy or pleural enhancement (FIGURE 1F).

Histologically, the breast mass showed caseating granulomatous inflammation (FIGURES 1G AND 1H). An AFB stain was negative. Polymerase chain reaction (PCR) performed on DNA extracted from the formalin-fixed, paraffin-embedded biopsy material was positive for Mycobacterium tuberculosis.¹ A CT-guided pleural biopsy showed only normal tissue. A follow-up tuberculin skin test (purified protein derivative [PPD]) yielded a 10-mm indurated reaction.

DISCUSSION

Granulomatous lesions, such as foreign body granuloma, idiopathic granulomatous mastitis (IGM), and sarcoidosis can mimic breast carcinoma.^2,3 IGM is associated with elevated prolactin (eg, pregnancy or oral contraceptive use) and is usually subareolar.² Infection, however, is also commonly subareolar. Sarcoidosis rarely exhibits unilateral pleural effusion and usually manifests with bilateral interstitial lung disease, hilar lymphadenopathy, and non-necrotizing granulomas.^3,4

M tuberculosis and other granulomatous infections may also feign breast cancer.^5-13 Breast TB, which is highly uncommon in the developed world, often demonstrates imaging similar to that which was seen in this case. Breast TB may appear nodular with ill-defined contours. Masses are sometimes attached to the chest wall and usually lack microcalcifications on mammography; they are also typically hypoechoic and heterogenous on ultrasound, often showing posterior enhancement.^5,7,8 Like other breast infections, tuberculosis may show cutaneous sinus tract formation, which is seen in about one-third of patients.^6,7 Alternatively, it may manifest as a diffuse mastitis with skin thickening and axillary lymphadenopathy.⁸

Primary breast TB without chest disease comprises up to 86% of mammary tuberculosis.^6,7 Infection may occur via contamination of the skin or nipple.^5-7 Lactation, pregnancy, and other causes of immunosuppression (especially human immunodeficiency virus) have been associated with an increased risk of breast infection.^6-8 This patient was at risk for immunosuppression from longstanding diabetes.¹⁴

Many patients from TB-endemic areas have received the bacille Calmette-Guerin (BCG) vaccine and may exhibit equivocal or false-positive PPD results. Because interferon-gamma release assay TB blood tests (eg, QuantiFERON-TB Gold or T-SPOT.TB) are not affected by BCG, they are not associated with false-positive repeat testing results.¹⁵

Biopsy is necessary to rule out malignancy and diagnose breast TB

A pleural fluid to serum protein ratio >0.5 is consistent with infection, but also with sarcoidosis or malignancy.^3,16 Elevated pleural fluid adenosine deaminase (>40 U/L) is sensitive, albeit nonspecific, for the presence of TB microorganisms. If a lymphocyte-dominant exudate is also present, however, its reliability greatly increases.^16,17 Increased pleural fluid interferon-gamma is also sensitive and specific for TB pleurisy.¹⁸ Culture, along with drug sensitivity testing, should be performed on all unexplained pleural effusions.

This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

A biopsy is often required to diagnose breast TB and should be performed on all suspicious lesions to exclude malignancy.^5-7,9 AFB stains and cultures of aspirate fluids or tissue are often negative.^7,9 PCR or other nucleic acid amplification tests of sputum, body fluids, or biopsy material may be positive in culture-negative cases and can rapidly confirm M tuberculosis infection.^17,19 No testing modality offers 100% sensitivity or specificity; therefore, an additional confirmatory test is desirable.

Possible routes of transmission include activation of latent pulmonary tuberculosis and direct, lymphatic, or hematologic extension to the chest wall and breast.^5-7 In this patient, we believe that activation of a latent breast granuloma may have resulted in a secondary or “sympathetic” pleural effusion, possibly triggered by surgical manipulation. This is compatible with her negative pleural adenosine deaminase result, negative culture, absence of pulmonary parenchymal disease, and negative pleural biopsy. Although we conducted a PubMed search, reviewing material as far back as 1966, we were unable to find a previous case of apparent sympathetic effusion associated with breast TB.

Our patient was treated with daily oral isoniazid, rifabutin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifabutin for 4 months. She has been disease-free for over 10 years.

THE TAKEAWAY

We describe a rare case of breast TB mimicking carcinoma that was associated with unilateral pleural effusion in a woman who had emigrated from Afghanistan. Patients at particular risk for breast TB include immigrants from endemic regions—especially parous females,^6,7 those with a history of TB contacts, and those who are immunosuppressed.⁸ This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

ACKNOWLEDGEMENTS
The authors thank Drs. Margie Scott, Harpreet Dhillon, Samir Vora, Todd Williams, Jeffrey Hawley, and Mr. Sergio Landeros. This report is dedicated to the memory of our friend and colleague in medicine, Dr. Jeanie Care Gillinta.

THE CASE

A 44-year-old woman with a 15-year history of type 2 diabetes sought care for a firm, non-tender mass in the medial lower quadrant of her right breast. She hadn’t experienced any skin changes or axillary lymphadenopathy. The patient had immigrated to California from Afghanistan 22 years earlier, at which time she was briefly married to an Afghan man suffering from a chronic cough.

Mammography revealed a 3.5 x 4 x 4 cm lesion at the chest wall, which was highly suspicious for carcinoma (FIGURES 1A AND 1B). Sonography showed a heterogenous hypoechoic and isoechoic mass with posterior acoustic enhancement (FIGURE 1C). An excisional biopsy was performed.

One week postoperatively, the patient presented to the emergency department for a worsening nonproductive cough that intensified when supine, and was associated with subscapular pleuritic pain. She denied fever or weight loss. Biopsy results were pending.

THE DIAGNOSIS

Chest x-rays revealed a large right pleural effusion that was presumed to be malignant (FIGURES 1D AND 1E). Thoracentesis yielded 1.5 liters of tea-colored exudate containing 2800 nucleated cells/mL—63% lymphocytes and 37% neutrophils—and a pleural fluid to serum protein ratio >0.5. Adenosine deaminase was <1 U/L. Fluid Gram stain, acid-fast bacillus (AFB) fluorescent antibody testing, AFB cultures, and cytology were negative. Computed tomography (CT) subsequently demonstrated recurrent effusion without hilar or mediastinal lymphadenopathy or pleural enhancement (FIGURE 1F).

Histologically, the breast mass showed caseating granulomatous inflammation (FIGURES 1G AND 1H). An AFB stain was negative. Polymerase chain reaction (PCR) performed on DNA extracted from the formalin-fixed, paraffin-embedded biopsy material was positive for Mycobacterium tuberculosis.¹ A CT-guided pleural biopsy showed only normal tissue. A follow-up tuberculin skin test (purified protein derivative [PPD]) yielded a 10-mm indurated reaction.

DISCUSSION

Granulomatous lesions, such as foreign body granuloma, idiopathic granulomatous mastitis (IGM), and sarcoidosis can mimic breast carcinoma.^2,3 IGM is associated with elevated prolactin (eg, pregnancy or oral contraceptive use) and is usually subareolar.² Infection, however, is also commonly subareolar. Sarcoidosis rarely exhibits unilateral pleural effusion and usually manifests with bilateral interstitial lung disease, hilar lymphadenopathy, and non-necrotizing granulomas.^3,4

M tuberculosis and other granulomatous infections may also feign breast cancer.^5-13 Breast TB, which is highly uncommon in the developed world, often demonstrates imaging similar to that which was seen in this case. Breast TB may appear nodular with ill-defined contours. Masses are sometimes attached to the chest wall and usually lack microcalcifications on mammography; they are also typically hypoechoic and heterogenous on ultrasound, often showing posterior enhancement.^5,7,8 Like other breast infections, tuberculosis may show cutaneous sinus tract formation, which is seen in about one-third of patients.^6,7 Alternatively, it may manifest as a diffuse mastitis with skin thickening and axillary lymphadenopathy.⁸

Primary breast TB without chest disease comprises up to 86% of mammary tuberculosis.^6,7 Infection may occur via contamination of the skin or nipple.^5-7 Lactation, pregnancy, and other causes of immunosuppression (especially human immunodeficiency virus) have been associated with an increased risk of breast infection.^6-8 This patient was at risk for immunosuppression from longstanding diabetes.¹⁴

Many patients from TB-endemic areas have received the bacille Calmette-Guerin (BCG) vaccine and may exhibit equivocal or false-positive PPD results. Because interferon-gamma release assay TB blood tests (eg, QuantiFERON-TB Gold or T-SPOT.TB) are not affected by BCG, they are not associated with false-positive repeat testing results.¹⁵

Biopsy is necessary to rule out malignancy and diagnose breast TB

A pleural fluid to serum protein ratio >0.5 is consistent with infection, but also with sarcoidosis or malignancy.^3,16 Elevated pleural fluid adenosine deaminase (>40 U/L) is sensitive, albeit nonspecific, for the presence of TB microorganisms. If a lymphocyte-dominant exudate is also present, however, its reliability greatly increases.^16,17 Increased pleural fluid interferon-gamma is also sensitive and specific for TB pleurisy.¹⁸ Culture, along with drug sensitivity testing, should be performed on all unexplained pleural effusions.

This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

A biopsy is often required to diagnose breast TB and should be performed on all suspicious lesions to exclude malignancy.^5-7,9 AFB stains and cultures of aspirate fluids or tissue are often negative.^7,9 PCR or other nucleic acid amplification tests of sputum, body fluids, or biopsy material may be positive in culture-negative cases and can rapidly confirm M tuberculosis infection.^17,19 No testing modality offers 100% sensitivity or specificity; therefore, an additional confirmatory test is desirable.

Possible routes of transmission include activation of latent pulmonary tuberculosis and direct, lymphatic, or hematologic extension to the chest wall and breast.^5-7 In this patient, we believe that activation of a latent breast granuloma may have resulted in a secondary or “sympathetic” pleural effusion, possibly triggered by surgical manipulation. This is compatible with her negative pleural adenosine deaminase result, negative culture, absence of pulmonary parenchymal disease, and negative pleural biopsy. Although we conducted a PubMed search, reviewing material as far back as 1966, we were unable to find a previous case of apparent sympathetic effusion associated with breast TB.

Our patient was treated with daily oral isoniazid, rifabutin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifabutin for 4 months. She has been disease-free for over 10 years.

THE TAKEAWAY

We describe a rare case of breast TB mimicking carcinoma that was associated with unilateral pleural effusion in a woman who had emigrated from Afghanistan. Patients at particular risk for breast TB include immigrants from endemic regions—especially parous females,^6,7 those with a history of TB contacts, and those who are immunosuppressed.⁸ This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

ACKNOWLEDGEMENTS
The authors thank Drs. Margie Scott, Harpreet Dhillon, Samir Vora, Todd Williams, Jeffrey Hawley, and Mr. Sergio Landeros. This report is dedicated to the memory of our friend and colleague in medicine, Dr. Jeanie Care Gillinta.

THE CASE

A 44-year-old woman with a 15-year history of type 2 diabetes sought care for a firm, non-tender mass in the medial lower quadrant of her right breast. She hadn’t experienced any skin changes or axillary lymphadenopathy. The patient had immigrated to California from Afghanistan 22 years earlier, at which time she was briefly married to an Afghan man suffering from a chronic cough.

Mammography revealed a 3.5 x 4 x 4 cm lesion at the chest wall, which was highly suspicious for carcinoma (FIGURES 1A AND 1B). Sonography showed a heterogenous hypoechoic and isoechoic mass with posterior acoustic enhancement (FIGURE 1C). An excisional biopsy was performed.

One week postoperatively, the patient presented to the emergency department for a worsening nonproductive cough that intensified when supine, and was associated with subscapular pleuritic pain. She denied fever or weight loss. Biopsy results were pending.

THE DIAGNOSIS

Chest x-rays revealed a large right pleural effusion that was presumed to be malignant (FIGURES 1D AND 1E). Thoracentesis yielded 1.5 liters of tea-colored exudate containing 2800 nucleated cells/mL—63% lymphocytes and 37% neutrophils—and a pleural fluid to serum protein ratio >0.5. Adenosine deaminase was <1 U/L. Fluid Gram stain, acid-fast bacillus (AFB) fluorescent antibody testing, AFB cultures, and cytology were negative. Computed tomography (CT) subsequently demonstrated recurrent effusion without hilar or mediastinal lymphadenopathy or pleural enhancement (FIGURE 1F).

Histologically, the breast mass showed caseating granulomatous inflammation (FIGURES 1G AND 1H). An AFB stain was negative. Polymerase chain reaction (PCR) performed on DNA extracted from the formalin-fixed, paraffin-embedded biopsy material was positive for Mycobacterium tuberculosis.¹ A CT-guided pleural biopsy showed only normal tissue. A follow-up tuberculin skin test (purified protein derivative [PPD]) yielded a 10-mm indurated reaction.

DISCUSSION

Granulomatous lesions, such as foreign body granuloma, idiopathic granulomatous mastitis (IGM), and sarcoidosis can mimic breast carcinoma.^2,3 IGM is associated with elevated prolactin (eg, pregnancy or oral contraceptive use) and is usually subareolar.² Infection, however, is also commonly subareolar. Sarcoidosis rarely exhibits unilateral pleural effusion and usually manifests with bilateral interstitial lung disease, hilar lymphadenopathy, and non-necrotizing granulomas.^3,4

M tuberculosis and other granulomatous infections may also feign breast cancer.^5-13 Breast TB, which is highly uncommon in the developed world, often demonstrates imaging similar to that which was seen in this case. Breast TB may appear nodular with ill-defined contours. Masses are sometimes attached to the chest wall and usually lack microcalcifications on mammography; they are also typically hypoechoic and heterogenous on ultrasound, often showing posterior enhancement.^5,7,8 Like other breast infections, tuberculosis may show cutaneous sinus tract formation, which is seen in about one-third of patients.^6,7 Alternatively, it may manifest as a diffuse mastitis with skin thickening and axillary lymphadenopathy.⁸

Primary breast TB without chest disease comprises up to 86% of mammary tuberculosis.^6,7 Infection may occur via contamination of the skin or nipple.^5-7 Lactation, pregnancy, and other causes of immunosuppression (especially human immunodeficiency virus) have been associated with an increased risk of breast infection.^6-8 This patient was at risk for immunosuppression from longstanding diabetes.¹⁴

Many patients from TB-endemic areas have received the bacille Calmette-Guerin (BCG) vaccine and may exhibit equivocal or false-positive PPD results. Because interferon-gamma release assay TB blood tests (eg, QuantiFERON-TB Gold or T-SPOT.TB) are not affected by BCG, they are not associated with false-positive repeat testing results.¹⁵

Biopsy is necessary to rule out malignancy and diagnose breast TB

A pleural fluid to serum protein ratio >0.5 is consistent with infection, but also with sarcoidosis or malignancy.^3,16 Elevated pleural fluid adenosine deaminase (>40 U/L) is sensitive, albeit nonspecific, for the presence of TB microorganisms. If a lymphocyte-dominant exudate is also present, however, its reliability greatly increases.^16,17 Increased pleural fluid interferon-gamma is also sensitive and specific for TB pleurisy.¹⁸ Culture, along with drug sensitivity testing, should be performed on all unexplained pleural effusions.

This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

A biopsy is often required to diagnose breast TB and should be performed on all suspicious lesions to exclude malignancy.^5-7,9 AFB stains and cultures of aspirate fluids or tissue are often negative.^7,9 PCR or other nucleic acid amplification tests of sputum, body fluids, or biopsy material may be positive in culture-negative cases and can rapidly confirm M tuberculosis infection.^17,19 No testing modality offers 100% sensitivity or specificity; therefore, an additional confirmatory test is desirable.

Possible routes of transmission include activation of latent pulmonary tuberculosis and direct, lymphatic, or hematologic extension to the chest wall and breast.^5-7 In this patient, we believe that activation of a latent breast granuloma may have resulted in a secondary or “sympathetic” pleural effusion, possibly triggered by surgical manipulation. This is compatible with her negative pleural adenosine deaminase result, negative culture, absence of pulmonary parenchymal disease, and negative pleural biopsy. Although we conducted a PubMed search, reviewing material as far back as 1966, we were unable to find a previous case of apparent sympathetic effusion associated with breast TB.

Our patient was treated with daily oral isoniazid, rifabutin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifabutin for 4 months. She has been disease-free for over 10 years.

THE TAKEAWAY

We describe a rare case of breast TB mimicking carcinoma that was associated with unilateral pleural effusion in a woman who had emigrated from Afghanistan. Patients at particular risk for breast TB include immigrants from endemic regions—especially parous females,^6,7 those with a history of TB contacts, and those who are immunosuppressed.⁸ This case emphasizes the need for increased awareness of extrapulmonary TB by physicians in developed countries.

ACKNOWLEDGEMENTS
The authors thank Drs. Margie Scott, Harpreet Dhillon, Samir Vora, Todd Williams, Jeffrey Hawley, and Mr. Sergio Landeros. This report is dedicated to the memory of our friend and colleague in medicine, Dr. Jeanie Care Gillinta.

A 50-year-old man who worked in construction presented to a local urgent care facility complaining of 2 weeks of bilateral foot discomfort associated with local malodorous discharge, redness, and crusting. He had a past medical history of recurrent tinea pedis and had previously been treated with intravenous (IV) antibiotics for a severe episode of cellulitis. He denied recent fever, trauma, or swelling. Physical examination revealed extensive malodorous crusting of the interdigital webs of both feet, in addition to tenderness, erythema, and serous discharge. He was treated with topical clotrimazole and oral terbinafine for a presumed tinea pedis recurrence; cephalexin and triamcinolone were added a week later after minimal response. Two days later, he sought care at a local emergency department with progressive cellulitis, bullae formation, and extensive desquamation (FIGURES 1A AND 1B) and was hospitalized.

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

Diagnosis: Gram-negative foot intertrigo

Plain x-rays and computed tomography imaging did not reveal evidence of abscess formation, subcutaneous gas/air formation, or osteomyelitis. Laboratory testing was normal. The patient was empirically started on cefepime, clindamycin, and ketoconazole. Wound therapy, consisting of normal saline washes, use of xeroform gauze to cover the wound, and frequent absorbent dressing changes, was also initiated. Wound cultures were obtained, which later grew Pseudomonas aeruginosa and Enterococcus faecalis. (P aeruginosa was the predominant organism.) We made the diagnosis of gram-negative foot intertrigo.

It’s likely that sweating (and consequent skin maceration), tinea pedis, and perhaps even friction between the affected area and the patient’s shoes led to skin ulceration.

First described in 1973, researchers have found that P aeruginosa, as well as E faecalis and Staphylococcus aureus, are commonly associated with tinea pedis¹ and toe web intertrigo.² The infection usually involves the lateral 3 toe webs, and can present with malodorous discharge, itchy maceration, edema, and erythema of the surrounding tissue. Non-purulent lower extremity cellulitis is typically caused by beta-hemolytic streptococci residing in the toe webs, and is usually treated empirically with cephalexin or similar antibiotics.³ The presentation of foot intertrigo varies along a spectrum that includes tinea pedis, superinfected maceration, and infectious eczematoid dermatitis, all of which can encourage bacterial superinfections.

In this patient, it is likely that sweating (and consequent skin maceration), tinea pedis, and perhaps even friction between the affected area and the patient’s shoes led to skin ulceration. This then became colonized and infected with bacteria, including gram-negative varieties, which sometimes harbor at the edges of ulcerations. Addressing each of these factors is important to heal the infection.

Differential diagnosis includes other bacterial skin infections

The differential diagnosis includes erysipelas, cellulitis, lipodermatosclerosis, venous eczema, and burns. Erysipelas affects the superficial dermis with well demarcated borders, while cellulitis involves the subcutaneous fat.⁴ Both are more likely to be caused by beta-hemolytic streptococci, but at first may be difficult to differentiate from similar appearing gram-negative skin/soft tissue infection without microbiologic data.

Patients with lipodermatosclerosis and venous eczema often have a history of chronic venous insufficiency. Lipodermatosclerosis often presents with a subcutaneous panniculitis and hyperpigmentation; venous eczema is often associated with scaling of the involved areas. Although burns can become secondarily superinfected with bacteria, they can be differentiated from a primary bacterial infection by the history or presentation.

Gram-negative infections (especially those caused by Pseudomonas species) should be suspected if a toe web infection does not respond to empiric antimicrobial therapy with first- or second-generation cephalosporins, as their spectrum of antimicrobial activity does not include P aeruginosa. If the infection is severe, it may impact ambulation.² Predisposing factors for gram-negative toe web infections include obesity, diabetes, moist environments, tight interdigital spaces, and recurrent tinea pedis.⁴

Administer appropriate wound care and start antimicrobial therapy

Foot intertrigo provides an easy portal of entry for pathogenic organisms.⁵ Therefore, it is important to modify risk factors from the outset to help prevent superinfection (as occurred with this patient) and other complications. Aggressive treatment of tinea pedis and use of compression stockings to reduce lymphedema are vital for prevention of recurrent infections.³

Physicians should be aware of likely, as well as unlikely, causative pathogens; “typical” skin and soft tissue infections that do not resolve may be due to atypical or gram-negative organisms, and typical first-line antibiotics will do nothing to eradicate them. Antimicrobial susceptibilities and a bacterial culture will steer you to the appropriate antimicrobial therapy. Debridement of the edge of the ulceration is necessary to remove any lingering bacteria.⁶ And appropriate wound care is paramount and should include the use of techniques to keep the affected areas dry, such as the use of astringent powders along with avoidance of damp shoes and socks.

Our patient was switched from empiric therapy to culture-specific IV therapy with vancomycin 2 g every 12 hours, ciprofloxacin 400 mg every 12 hours, and fluconazole 400 mg daily. Two weeks later, he was discharged from the hospital on topical antifungals, oral fluconazole, and daily acetic acid soaks. He did, however, require further advanced topical treatments (miconazole 2% twice daily) due to recurrent flare-ups before complete resolution was achieved 6 weeks after presentation (FIGURES 2A AND 2B).

CORRESPONDENCE
Alberto Marcelin, MD, Department of Family Medicine, Mayo Clinic Health System, 1000 1st Dr NW, Austin, MN 55912; [email protected].

A 50-year-old man who worked in construction presented to a local urgent care facility complaining of 2 weeks of bilateral foot discomfort associated with local malodorous discharge, redness, and crusting. He had a past medical history of recurrent tinea pedis and had previously been treated with intravenous (IV) antibiotics for a severe episode of cellulitis. He denied recent fever, trauma, or swelling. Physical examination revealed extensive malodorous crusting of the interdigital webs of both feet, in addition to tenderness, erythema, and serous discharge. He was treated with topical clotrimazole and oral terbinafine for a presumed tinea pedis recurrence; cephalexin and triamcinolone were added a week later after minimal response. Two days later, he sought care at a local emergency department with progressive cellulitis, bullae formation, and extensive desquamation (FIGURES 1A AND 1B) and was hospitalized.

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

Diagnosis: Gram-negative foot intertrigo

Plain x-rays and computed tomography imaging did not reveal evidence of abscess formation, subcutaneous gas/air formation, or osteomyelitis. Laboratory testing was normal. The patient was empirically started on cefepime, clindamycin, and ketoconazole. Wound therapy, consisting of normal saline washes, use of xeroform gauze to cover the wound, and frequent absorbent dressing changes, was also initiated. Wound cultures were obtained, which later grew Pseudomonas aeruginosa and Enterococcus faecalis. (P aeruginosa was the predominant organism.) We made the diagnosis of gram-negative foot intertrigo.

It’s likely that sweating (and consequent skin maceration), tinea pedis, and perhaps even friction between the affected area and the patient’s shoes led to skin ulceration.

First described in 1973, researchers have found that P aeruginosa, as well as E faecalis and Staphylococcus aureus, are commonly associated with tinea pedis¹ and toe web intertrigo.² The infection usually involves the lateral 3 toe webs, and can present with malodorous discharge, itchy maceration, edema, and erythema of the surrounding tissue. Non-purulent lower extremity cellulitis is typically caused by beta-hemolytic streptococci residing in the toe webs, and is usually treated empirically with cephalexin or similar antibiotics.³ The presentation of foot intertrigo varies along a spectrum that includes tinea pedis, superinfected maceration, and infectious eczematoid dermatitis, all of which can encourage bacterial superinfections.

In this patient, it is likely that sweating (and consequent skin maceration), tinea pedis, and perhaps even friction between the affected area and the patient’s shoes led to skin ulceration. This then became colonized and infected with bacteria, including gram-negative varieties, which sometimes harbor at the edges of ulcerations. Addressing each of these factors is important to heal the infection.

Differential diagnosis includes other bacterial skin infections

The differential diagnosis includes erysipelas, cellulitis, lipodermatosclerosis, venous eczema, and burns. Erysipelas affects the superficial dermis with well demarcated borders, while cellulitis involves the subcutaneous fat.⁴ Both are more likely to be caused by beta-hemolytic streptococci, but at first may be difficult to differentiate from similar appearing gram-negative skin/soft tissue infection without microbiologic data.

Patients with lipodermatosclerosis and venous eczema often have a history of chronic venous insufficiency. Lipodermatosclerosis often presents with a subcutaneous panniculitis and hyperpigmentation; venous eczema is often associated with scaling of the involved areas. Although burns can become secondarily superinfected with bacteria, they can be differentiated from a primary bacterial infection by the history or presentation.

Gram-negative infections (especially those caused by Pseudomonas species) should be suspected if a toe web infection does not respond to empiric antimicrobial therapy with first- or second-generation cephalosporins, as their spectrum of antimicrobial activity does not include P aeruginosa. If the infection is severe, it may impact ambulation.² Predisposing factors for gram-negative toe web infections include obesity, diabetes, moist environments, tight interdigital spaces, and recurrent tinea pedis.⁴

Administer appropriate wound care and start antimicrobial therapy

Foot intertrigo provides an easy portal of entry for pathogenic organisms.⁵ Therefore, it is important to modify risk factors from the outset to help prevent superinfection (as occurred with this patient) and other complications. Aggressive treatment of tinea pedis and use of compression stockings to reduce lymphedema are vital for prevention of recurrent infections.³

Physicians should be aware of likely, as well as unlikely, causative pathogens; “typical” skin and soft tissue infections that do not resolve may be due to atypical or gram-negative organisms, and typical first-line antibiotics will do nothing to eradicate them. Antimicrobial susceptibilities and a bacterial culture will steer you to the appropriate antimicrobial therapy. Debridement of the edge of the ulceration is necessary to remove any lingering bacteria.⁶ And appropriate wound care is paramount and should include the use of techniques to keep the affected areas dry, such as the use of astringent powders along with avoidance of damp shoes and socks.

Our patient was switched from empiric therapy to culture-specific IV therapy with vancomycin 2 g every 12 hours, ciprofloxacin 400 mg every 12 hours, and fluconazole 400 mg daily. Two weeks later, he was discharged from the hospital on topical antifungals, oral fluconazole, and daily acetic acid soaks. He did, however, require further advanced topical treatments (miconazole 2% twice daily) due to recurrent flare-ups before complete resolution was achieved 6 weeks after presentation (FIGURES 2A AND 2B).

CORRESPONDENCE
Alberto Marcelin, MD, Department of Family Medicine, Mayo Clinic Health System, 1000 1st Dr NW, Austin, MN 55912; [email protected].

A 50-year-old man who worked in construction presented to a local urgent care facility complaining of 2 weeks of bilateral foot discomfort associated with local malodorous discharge, redness, and crusting. He had a past medical history of recurrent tinea pedis and had previously been treated with intravenous (IV) antibiotics for a severe episode of cellulitis. He denied recent fever, trauma, or swelling. Physical examination revealed extensive malodorous crusting of the interdigital webs of both feet, in addition to tenderness, erythema, and serous discharge. He was treated with topical clotrimazole and oral terbinafine for a presumed tinea pedis recurrence; cephalexin and triamcinolone were added a week later after minimal response. Two days later, he sought care at a local emergency department with progressive cellulitis, bullae formation, and extensive desquamation (FIGURES 1A AND 1B) and was hospitalized.

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

Diagnosis: Gram-negative foot intertrigo

Plain x-rays and computed tomography imaging did not reveal evidence of abscess formation, subcutaneous gas/air formation, or osteomyelitis. Laboratory testing was normal. The patient was empirically started on cefepime, clindamycin, and ketoconazole. Wound therapy, consisting of normal saline washes, use of xeroform gauze to cover the wound, and frequent absorbent dressing changes, was also initiated. Wound cultures were obtained, which later grew Pseudomonas aeruginosa and Enterococcus faecalis. (P aeruginosa was the predominant organism.) We made the diagnosis of gram-negative foot intertrigo.

It’s likely that sweating (and consequent skin maceration), tinea pedis, and perhaps even friction between the affected area and the patient’s shoes led to skin ulceration.

First described in 1973, researchers have found that P aeruginosa, as well as E faecalis and Staphylococcus aureus, are commonly associated with tinea pedis¹ and toe web intertrigo.² The infection usually involves the lateral 3 toe webs, and can present with malodorous discharge, itchy maceration, edema, and erythema of the surrounding tissue. Non-purulent lower extremity cellulitis is typically caused by beta-hemolytic streptococci residing in the toe webs, and is usually treated empirically with cephalexin or similar antibiotics.³ The presentation of foot intertrigo varies along a spectrum that includes tinea pedis, superinfected maceration, and infectious eczematoid dermatitis, all of which can encourage bacterial superinfections.

In this patient, it is likely that sweating (and consequent skin maceration), tinea pedis, and perhaps even friction between the affected area and the patient’s shoes led to skin ulceration. This then became colonized and infected with bacteria, including gram-negative varieties, which sometimes harbor at the edges of ulcerations. Addressing each of these factors is important to heal the infection.

Differential diagnosis includes other bacterial skin infections

The differential diagnosis includes erysipelas, cellulitis, lipodermatosclerosis, venous eczema, and burns. Erysipelas affects the superficial dermis with well demarcated borders, while cellulitis involves the subcutaneous fat.⁴ Both are more likely to be caused by beta-hemolytic streptococci, but at first may be difficult to differentiate from similar appearing gram-negative skin/soft tissue infection without microbiologic data.

Patients with lipodermatosclerosis and venous eczema often have a history of chronic venous insufficiency. Lipodermatosclerosis often presents with a subcutaneous panniculitis and hyperpigmentation; venous eczema is often associated with scaling of the involved areas. Although burns can become secondarily superinfected with bacteria, they can be differentiated from a primary bacterial infection by the history or presentation.

Gram-negative infections (especially those caused by Pseudomonas species) should be suspected if a toe web infection does not respond to empiric antimicrobial therapy with first- or second-generation cephalosporins, as their spectrum of antimicrobial activity does not include P aeruginosa. If the infection is severe, it may impact ambulation.² Predisposing factors for gram-negative toe web infections include obesity, diabetes, moist environments, tight interdigital spaces, and recurrent tinea pedis.⁴

Administer appropriate wound care and start antimicrobial therapy

Foot intertrigo provides an easy portal of entry for pathogenic organisms.⁵ Therefore, it is important to modify risk factors from the outset to help prevent superinfection (as occurred with this patient) and other complications. Aggressive treatment of tinea pedis and use of compression stockings to reduce lymphedema are vital for prevention of recurrent infections.³

Physicians should be aware of likely, as well as unlikely, causative pathogens; “typical” skin and soft tissue infections that do not resolve may be due to atypical or gram-negative organisms, and typical first-line antibiotics will do nothing to eradicate them. Antimicrobial susceptibilities and a bacterial culture will steer you to the appropriate antimicrobial therapy. Debridement of the edge of the ulceration is necessary to remove any lingering bacteria.⁶ And appropriate wound care is paramount and should include the use of techniques to keep the affected areas dry, such as the use of astringent powders along with avoidance of damp shoes and socks.

Our patient was switched from empiric therapy to culture-specific IV therapy with vancomycin 2 g every 12 hours, ciprofloxacin 400 mg every 12 hours, and fluconazole 400 mg daily. Two weeks later, he was discharged from the hospital on topical antifungals, oral fluconazole, and daily acetic acid soaks. He did, however, require further advanced topical treatments (miconazole 2% twice daily) due to recurrent flare-ups before complete resolution was achieved 6 weeks after presentation (FIGURES 2A AND 2B).

CORRESPONDENCE
Alberto Marcelin, MD, Department of Family Medicine, Mayo Clinic Health System, 1000 1st Dr NW, Austin, MN 55912; [email protected].

An 8-year-old girl was brought to her family physician’s office (RU) because of a persistent rash on her lateral eyebrows and periumbilical region. The family indicated that she’d had the rash for more than 6 months. They also mentioned that the child had received a new pair of eyeglasses 8 months earlier. The child was otherwise in good health. The physical examination revealed erythematous scaling plaques near both lateral eyebrows and around the belly button (FIGURES 1 AND 2).

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

We recognized that this was a case of allergic contact dermatitis (ACD), based on the clinical presentation. The distribution of the erythema, scale, and postinflammatory hyperpigmentation was highly suggestive of an ACD to nickel. In this case, the nickel in the patient’s eyeglasses and the snaps found on her pants were the culprits.

The lichenification of the plaque near the umbilicus suggested that the dermatitis was not acute and that the patient had likely been scratching the area due to itching. The plaque near the patient’s eye was actually in the shape of the metal on the inside of her glasses.

Most prevalent contact allergens. Patch testing data indicate that the 5 most prevalent contact allergens out of more than 3700 that are known are: nickel (14.3% of patients tested), fragrance mix (14%), the topical antibiotic neomycin (11.6%), balsam of Peru (used in some perfumes, toiletries, and pharmaceutical items) (10.4%), and the mercury-based vaccine preservative thimerosal (10.4%).¹

The 5 most prevalent contact allergens are nickel, fragrance mix, neomycin, balsam of Peru, and thimerosal.

ACD is a delayed-type hypersensitivity reaction in which a foreign substance comes into contact with the skin and is linked to skin proteins forming an antigen complex that leads to sensitization. When the epidermis is re-exposed to the antigen, the sensitized T cells initiate an inflammatory cascade, leading to the skin changes seen in ACD.²

Silverberg et al reported that in 30 children with a personal history of umbilical or wrist dermatitis or a family history of nickel ACD, 100% demonstrated a positive reaction to nickel sulfate.³ Nickel continues to be used (and unregulated) in a wide range of products, including costume jewelry, piercing posts, belt buckles, eyeglasses, and personal electronics (eg, tablets, cell phones, and laptop computers).

Making the diagnosis. Contact dermatitis can sometimes be diagnosed clinically with a good history and physical exam. However, there are many cases in which patch testing is needed to find the offending allergens or confirm the suspicion regarding a specific allergen. The only convenient and ready-to-use patch test in the United States is the T.R.U.E. test.

The differential includes other superficial skin infections

ACD characteristically presents with eczematoid plaques that are primarily in the area(s) of cutaneous contact with an allergen. The condition typically appears within a few days of exposure.

The differential diagnosis for ACD includes cutaneous candidiasis, impetigo, plaque psoriasis, and seborrheic dermatitis.

Cutaneous candidiasis is a superficial infection of the skin with a candida species. It can present as beefy red erythematous plaques on the buttocks, lower abdomen, thighs, or in intertriginous areas or oral commissures. A hallmark sign is pinpoint pustulovesicular satellite lesions.

Impetigo is a superficial bacterial skin infection that presents with edema, erythema, tenderness on palpation, and possible purulent drainage. It appears as honey-colored crusts with erythema and occurs most often on the face—especially around a child’s nose and mouth—but can occur anywhere on the head and body.

Plaque psoriasis presents as erythematous silver-scaled plaques on extensor surfaces, including the elbows and knees. Inverse psoriasis may present as erythema and maceration in intertriginous areas.

Seborrheic dermatitis appears as well-circumscribed greasy scale overlying erythematous skin. It is commonly found on the scalp, eyebrows, nasolabial folds, chest, face, and in the ear canals. It is thought to be an inflammatory reaction to Malassezia furfur.

Cool compresses, topical steroids can relieve symptoms

Patients with ACD should avoid the allergen that is causing the reaction. In cases of nickel ACD, the patient may cover the metal tab of their jeans with an iron-on patch or a few coats of clear nail polish. A better option is to buy jeans and pants that do not have nickel in the metal tab. (Levi’s has removed nickel from their pants.) Cool compresses can soothe the symptoms of acute cases of ACD.⁴ Calamine and colloidal oatmeal baths may help to dry and soothe acute, oozing lesions. Localized acute ACD lesions respond best to mid-potency (eg, 0.1% triamcinolone) to high-potency (eg, 0.05% clobetasol) topical steroids.⁴

On areas of thinner skin (eg, flexural surfaces, eyelids, face, anogenital region), lower-potency steroids such as desonide ointment can minimize the risk of skin atrophy.^3,4 Be aware that some patients are actually allergic to topical steroids. This unfortunate situation can be diagnosed with patch testing.

We recommended that our patient get different glasses that were nickel-free. Fortunately, there are many frames for glasses that have no nickel in them. We also gave her advice on how to avoid the nickel that still exists in some pants. We gave her desonide 0.05% cream to apply to the affected area for symptomatic relief.

CORRESPONDENCE
Richard P. Usatine, MD, Skin clinic, University of Texas Health Science Center at San Antonio, 903 W. Martin, San Antonio, TX 78207; [email protected].

An 8-year-old girl was brought to her family physician’s office (RU) because of a persistent rash on her lateral eyebrows and periumbilical region. The family indicated that she’d had the rash for more than 6 months. They also mentioned that the child had received a new pair of eyeglasses 8 months earlier. The child was otherwise in good health. The physical examination revealed erythematous scaling plaques near both lateral eyebrows and around the belly button (FIGURES 1 AND 2).

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

We recognized that this was a case of allergic contact dermatitis (ACD), based on the clinical presentation. The distribution of the erythema, scale, and postinflammatory hyperpigmentation was highly suggestive of an ACD to nickel. In this case, the nickel in the patient’s eyeglasses and the snaps found on her pants were the culprits.

The lichenification of the plaque near the umbilicus suggested that the dermatitis was not acute and that the patient had likely been scratching the area due to itching. The plaque near the patient’s eye was actually in the shape of the metal on the inside of her glasses.

Most prevalent contact allergens. Patch testing data indicate that the 5 most prevalent contact allergens out of more than 3700 that are known are: nickel (14.3% of patients tested), fragrance mix (14%), the topical antibiotic neomycin (11.6%), balsam of Peru (used in some perfumes, toiletries, and pharmaceutical items) (10.4%), and the mercury-based vaccine preservative thimerosal (10.4%).¹

The 5 most prevalent contact allergens are nickel, fragrance mix, neomycin, balsam of Peru, and thimerosal.

ACD is a delayed-type hypersensitivity reaction in which a foreign substance comes into contact with the skin and is linked to skin proteins forming an antigen complex that leads to sensitization. When the epidermis is re-exposed to the antigen, the sensitized T cells initiate an inflammatory cascade, leading to the skin changes seen in ACD.²

Silverberg et al reported that in 30 children with a personal history of umbilical or wrist dermatitis or a family history of nickel ACD, 100% demonstrated a positive reaction to nickel sulfate.³ Nickel continues to be used (and unregulated) in a wide range of products, including costume jewelry, piercing posts, belt buckles, eyeglasses, and personal electronics (eg, tablets, cell phones, and laptop computers).

Making the diagnosis. Contact dermatitis can sometimes be diagnosed clinically with a good history and physical exam. However, there are many cases in which patch testing is needed to find the offending allergens or confirm the suspicion regarding a specific allergen. The only convenient and ready-to-use patch test in the United States is the T.R.U.E. test.

The differential includes other superficial skin infections

ACD characteristically presents with eczematoid plaques that are primarily in the area(s) of cutaneous contact with an allergen. The condition typically appears within a few days of exposure.

The differential diagnosis for ACD includes cutaneous candidiasis, impetigo, plaque psoriasis, and seborrheic dermatitis.

Cutaneous candidiasis is a superficial infection of the skin with a candida species. It can present as beefy red erythematous plaques on the buttocks, lower abdomen, thighs, or in intertriginous areas or oral commissures. A hallmark sign is pinpoint pustulovesicular satellite lesions.

Impetigo is a superficial bacterial skin infection that presents with edema, erythema, tenderness on palpation, and possible purulent drainage. It appears as honey-colored crusts with erythema and occurs most often on the face—especially around a child’s nose and mouth—but can occur anywhere on the head and body.

Plaque psoriasis presents as erythematous silver-scaled plaques on extensor surfaces, including the elbows and knees. Inverse psoriasis may present as erythema and maceration in intertriginous areas.

Seborrheic dermatitis appears as well-circumscribed greasy scale overlying erythematous skin. It is commonly found on the scalp, eyebrows, nasolabial folds, chest, face, and in the ear canals. It is thought to be an inflammatory reaction to Malassezia furfur.

Cool compresses, topical steroids can relieve symptoms

Patients with ACD should avoid the allergen that is causing the reaction. In cases of nickel ACD, the patient may cover the metal tab of their jeans with an iron-on patch or a few coats of clear nail polish. A better option is to buy jeans and pants that do not have nickel in the metal tab. (Levi’s has removed nickel from their pants.) Cool compresses can soothe the symptoms of acute cases of ACD.⁴ Calamine and colloidal oatmeal baths may help to dry and soothe acute, oozing lesions. Localized acute ACD lesions respond best to mid-potency (eg, 0.1% triamcinolone) to high-potency (eg, 0.05% clobetasol) topical steroids.⁴

On areas of thinner skin (eg, flexural surfaces, eyelids, face, anogenital region), lower-potency steroids such as desonide ointment can minimize the risk of skin atrophy.^3,4 Be aware that some patients are actually allergic to topical steroids. This unfortunate situation can be diagnosed with patch testing.

We recommended that our patient get different glasses that were nickel-free. Fortunately, there are many frames for glasses that have no nickel in them. We also gave her advice on how to avoid the nickel that still exists in some pants. We gave her desonide 0.05% cream to apply to the affected area for symptomatic relief.

CORRESPONDENCE
Richard P. Usatine, MD, Skin clinic, University of Texas Health Science Center at San Antonio, 903 W. Martin, San Antonio, TX 78207; [email protected].

An 8-year-old girl was brought to her family physician’s office (RU) because of a persistent rash on her lateral eyebrows and periumbilical region. The family indicated that she’d had the rash for more than 6 months. They also mentioned that the child had received a new pair of eyeglasses 8 months earlier. The child was otherwise in good health. The physical examination revealed erythematous scaling plaques near both lateral eyebrows and around the belly button (FIGURES 1 AND 2).

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

We recognized that this was a case of allergic contact dermatitis (ACD), based on the clinical presentation. The distribution of the erythema, scale, and postinflammatory hyperpigmentation was highly suggestive of an ACD to nickel. In this case, the nickel in the patient’s eyeglasses and the snaps found on her pants were the culprits.

The lichenification of the plaque near the umbilicus suggested that the dermatitis was not acute and that the patient had likely been scratching the area due to itching. The plaque near the patient’s eye was actually in the shape of the metal on the inside of her glasses.

Most prevalent contact allergens. Patch testing data indicate that the 5 most prevalent contact allergens out of more than 3700 that are known are: nickel (14.3% of patients tested), fragrance mix (14%), the topical antibiotic neomycin (11.6%), balsam of Peru (used in some perfumes, toiletries, and pharmaceutical items) (10.4%), and the mercury-based vaccine preservative thimerosal (10.4%).¹

The 5 most prevalent contact allergens are nickel, fragrance mix, neomycin, balsam of Peru, and thimerosal.