Case Reports

A cute colonic pseudo-obstruction, or Ogilvie syndrome, is dilatation of the colon without mechanical obstruction. It is often seen postoperatively after cesarean section , pelvic , spinal, or other orthopedic surgery, such as knee arthroplasty. ¹ One study demonstrated an incidence of acute colonic pseudo-obstruction of 1.3% following hip replacement surgery. ²

The most common symptoms are abdominal distension, pain, nausea, vomiting, constipation, or diarrhea. Bowel sounds are present in the majority of cases.³ It is important to recognize the varied presentations of ileus in the postoperative setting. The most serious complications of acute colonic pseudo-obstruction are colonic ischemia and bowel perforation.

Case Presentation

An 84-year-old man underwent a total left hip arthroplasty revision. The evening after his surgery, his blood pressure (BP) decreased from 93/54 to 71/47 mm Hg, and his heart rate was 73 beats per minute. He was awake, in no acute distress, but reported loose stools. Results of cardiac and pulmonary examinations were normal, showing a regular rate and rhythm with no murmurs and clear lungs. There was normal jugular venous pressure and chronic pitting edema of the lower extremities bilaterally.

An abdominal examination revealed positive bowel sounds, a large ventral hernia, which was easily reducible, and a distended abdomen. His BP remained unchanged after IV normal saline 4 L, and urine output was 200 cc over 4 hours, which the care team determined represented adequate resuscitation. An infection workup, including chest X-ray, urinalysis, and blood and urine cultures, was unrevealing. Hemoglobin was stable at 8.5 g/dL (normal range 14-18), and creatinine level 0.66 mg/dL (normal range 0.7-1.2) at baseline. A transthoracic echocardiogram showed impaired diastolic filling suggestive of extrinsic compression of the left ventricle by mediastinal contents (Figure 1). An abdominal X-ray revealed diffuse dilatation of large bowel loops up to 10 cm, causing elevation and rightward shift of the heart (Figure 2A). A computed tomography scan of the abdomen showed total colonic dilatation without obstruction (Figure 2B).

Discussion

We present an unusual case of left ventricular compression leading to hypotension due to acute colonic pseudo-obstruction. Our patient presented with the rare complication of hypotension due to cardiac compression, which we have not previously seen reported in the literature. Analogous instance of cardiac compression may arise from hiatal hernias and diaphragmatic paralysis. ^4-6

Management of acute colonic pseudo-obstruction is through nothing by mouth status and abdominal decompression. For more severe cases, neostigmine, colonoscopic decompression, and surgery can be considered.

This surgical complication was diagnosed by internal medicine hospitalist consultants on a surgical comanagement service. In the comanagement model, the surgical specialties of orthopedic surgery, neurosurgery, and podiatry at San Francisco Veterans Affairs Medical Center in California have hospitalists who work with the team as active consultants for the medical care of the patients. Hospitalists develop a unique skill set in which they can anticipate new diagnoses, prevent or identify early complications, and individualize a patient’s postoperative care.⁷ One study found that a surgical comanagement service was associated with a decrease in the number of patients with at least 1 surgical complication, decrease in length of stay and 30-day readmissions for a medical cause, decreased consultant use, and an average cost savings per patient of about $2,600 to $4,300.⁸

Conclusions

With the increasing prevalence of hospitalist comanagement services, it is important for surgeons and nonsurgeons alike to recognize acute colonic pseudo-obstruction as a possible surgical complication.

A cute colonic pseudo-obstruction, or Ogilvie syndrome, is dilatation of the colon without mechanical obstruction. It is often seen postoperatively after cesarean section , pelvic , spinal, or other orthopedic surgery, such as knee arthroplasty. ¹ One study demonstrated an incidence of acute colonic pseudo-obstruction of 1.3% following hip replacement surgery. ²

The most common symptoms are abdominal distension, pain, nausea, vomiting, constipation, or diarrhea. Bowel sounds are present in the majority of cases.³ It is important to recognize the varied presentations of ileus in the postoperative setting. The most serious complications of acute colonic pseudo-obstruction are colonic ischemia and bowel perforation.

Case Presentation

An 84-year-old man underwent a total left hip arthroplasty revision. The evening after his surgery, his blood pressure (BP) decreased from 93/54 to 71/47 mm Hg, and his heart rate was 73 beats per minute. He was awake, in no acute distress, but reported loose stools. Results of cardiac and pulmonary examinations were normal, showing a regular rate and rhythm with no murmurs and clear lungs. There was normal jugular venous pressure and chronic pitting edema of the lower extremities bilaterally.

An abdominal examination revealed positive bowel sounds, a large ventral hernia, which was easily reducible, and a distended abdomen. His BP remained unchanged after IV normal saline 4 L, and urine output was 200 cc over 4 hours, which the care team determined represented adequate resuscitation. An infection workup, including chest X-ray, urinalysis, and blood and urine cultures, was unrevealing. Hemoglobin was stable at 8.5 g/dL (normal range 14-18), and creatinine level 0.66 mg/dL (normal range 0.7-1.2) at baseline. A transthoracic echocardiogram showed impaired diastolic filling suggestive of extrinsic compression of the left ventricle by mediastinal contents (Figure 1). An abdominal X-ray revealed diffuse dilatation of large bowel loops up to 10 cm, causing elevation and rightward shift of the heart (Figure 2A). A computed tomography scan of the abdomen showed total colonic dilatation without obstruction (Figure 2B).

Discussion

We present an unusual case of left ventricular compression leading to hypotension due to acute colonic pseudo-obstruction. Our patient presented with the rare complication of hypotension due to cardiac compression, which we have not previously seen reported in the literature. Analogous instance of cardiac compression may arise from hiatal hernias and diaphragmatic paralysis. ^4-6

Management of acute colonic pseudo-obstruction is through nothing by mouth status and abdominal decompression. For more severe cases, neostigmine, colonoscopic decompression, and surgery can be considered.

This surgical complication was diagnosed by internal medicine hospitalist consultants on a surgical comanagement service. In the comanagement model, the surgical specialties of orthopedic surgery, neurosurgery, and podiatry at San Francisco Veterans Affairs Medical Center in California have hospitalists who work with the team as active consultants for the medical care of the patients. Hospitalists develop a unique skill set in which they can anticipate new diagnoses, prevent or identify early complications, and individualize a patient’s postoperative care.⁷ One study found that a surgical comanagement service was associated with a decrease in the number of patients with at least 1 surgical complication, decrease in length of stay and 30-day readmissions for a medical cause, decreased consultant use, and an average cost savings per patient of about $2,600 to $4,300.⁸

Conclusions

With the increasing prevalence of hospitalist comanagement services, it is important for surgeons and nonsurgeons alike to recognize acute colonic pseudo-obstruction as a possible surgical complication.

A cute colonic pseudo-obstruction, or Ogilvie syndrome, is dilatation of the colon without mechanical obstruction. It is often seen postoperatively after cesarean section , pelvic , spinal, or other orthopedic surgery, such as knee arthroplasty. ¹ One study demonstrated an incidence of acute colonic pseudo-obstruction of 1.3% following hip replacement surgery. ²

The most common symptoms are abdominal distension, pain, nausea, vomiting, constipation, or diarrhea. Bowel sounds are present in the majority of cases.³ It is important to recognize the varied presentations of ileus in the postoperative setting. The most serious complications of acute colonic pseudo-obstruction are colonic ischemia and bowel perforation.

Case Presentation

An 84-year-old man underwent a total left hip arthroplasty revision. The evening after his surgery, his blood pressure (BP) decreased from 93/54 to 71/47 mm Hg, and his heart rate was 73 beats per minute. He was awake, in no acute distress, but reported loose stools. Results of cardiac and pulmonary examinations were normal, showing a regular rate and rhythm with no murmurs and clear lungs. There was normal jugular venous pressure and chronic pitting edema of the lower extremities bilaterally.

An abdominal examination revealed positive bowel sounds, a large ventral hernia, which was easily reducible, and a distended abdomen. His BP remained unchanged after IV normal saline 4 L, and urine output was 200 cc over 4 hours, which the care team determined represented adequate resuscitation. An infection workup, including chest X-ray, urinalysis, and blood and urine cultures, was unrevealing. Hemoglobin was stable at 8.5 g/dL (normal range 14-18), and creatinine level 0.66 mg/dL (normal range 0.7-1.2) at baseline. A transthoracic echocardiogram showed impaired diastolic filling suggestive of extrinsic compression of the left ventricle by mediastinal contents (Figure 1). An abdominal X-ray revealed diffuse dilatation of large bowel loops up to 10 cm, causing elevation and rightward shift of the heart (Figure 2A). A computed tomography scan of the abdomen showed total colonic dilatation without obstruction (Figure 2B).

Discussion

We present an unusual case of left ventricular compression leading to hypotension due to acute colonic pseudo-obstruction. Our patient presented with the rare complication of hypotension due to cardiac compression, which we have not previously seen reported in the literature. Analogous instance of cardiac compression may arise from hiatal hernias and diaphragmatic paralysis. ^4-6

Management of acute colonic pseudo-obstruction is through nothing by mouth status and abdominal decompression. For more severe cases, neostigmine, colonoscopic decompression, and surgery can be considered.

This surgical complication was diagnosed by internal medicine hospitalist consultants on a surgical comanagement service. In the comanagement model, the surgical specialties of orthopedic surgery, neurosurgery, and podiatry at San Francisco Veterans Affairs Medical Center in California have hospitalists who work with the team as active consultants for the medical care of the patients. Hospitalists develop a unique skill set in which they can anticipate new diagnoses, prevent or identify early complications, and individualize a patient’s postoperative care.⁷ One study found that a surgical comanagement service was associated with a decrease in the number of patients with at least 1 surgical complication, decrease in length of stay and 30-day readmissions for a medical cause, decreased consultant use, and an average cost savings per patient of about $2,600 to $4,300.⁸

Conclusions

With the increasing prevalence of hospitalist comanagement services, it is important for surgeons and nonsurgeons alike to recognize acute colonic pseudo-obstruction as a possible surgical complication.

Leptospirosis (LS) is considered the most common and widespread zoonotic disease in the world. Numerous outbreaks have occurred in the past 10 years. Due to its technically difficult diagnosis, LS is severely underrecognized, underdiagnosed, and therefore, underreported.^1,2 The Centers for Disease Control and Prevention (CDC) estimate 100 to 150 cases of LS are identified annually in the US, with about 50% of those cases occurring in Puerto Rico (PR).³ Specifically in PR, about 15 to 100 cases of suspected LS were reported annually between 2000 and 2009, with 59 cases and 1 death reported in 2010. The data are thought to be severely underreported due to a lack of widespread diagnostic testing availability in PR and no formal veterinary and environmental surveillance programs to monitor the incidence of animal cases and actual circulating serovars.⁴

A recent systematic review of 80 studies from 34 countries on morbidity and mortality of LS revealed that the global incidence and mortality is about 1.03 million cases and 58,900 deaths every year. Almost half of the reported deaths were adult males aged 20 to 49 years.⁵ Although mild cases of LS are not associated with an elevated mortality, icteric LS with renal failure (Weil disease) carries a mortality rate of 10%.⁶ In patients who develop hemorrhagic pneumonitis, mortality may be as high as 50 to 70%.⁷ Therefore, it is pivotal that clinicians recognize the disease early, that novel modalities of treatment continue to be developed, and that their impact on patient morbidity and mortality are studied and documented.

Case Presentation

A 43-year-old man with a medical history of schizophrenia presented to the emergency department at the US Department of Veterans Affairs (VA) Caribbean Healthcare System in San Juan, PR, after experiencing 1 week of intermittent fever, myalgia, and general weakness. Emergency medical services had found him disheveled and in a rodent-infested swamp area several days before admission. Initial vital signs were within normal limits.

On physical examination, the patient was afebrile, without acute distress, but he had diffuse jaundice and mild epigastric tenderness without evidence of peritoneal irritation. His complete blood count was remarkable for leukocytosis with left shifting, adequate hemoglobin levels but with 9 × 10³ U/L platelets. The complete metabolic panel demonstrated an aspartate aminotransferase level of 564 U/L, alanine transaminase level of 462 U/L, total bilirubin of 12 mg/dL, which 10.2 mg/dL were direct bilirubin, and an alkaline phosphate of 345 U/L. Lipase levels were measured at 626 U/L. Marked coagulopathy also was present. The toxicology panel, including acetaminophen and salicylate acid levels, did not reveal the presence of any of the tested substances, and chest imaging did not demonstrate any infiltrates.

An abdominal ultrasound was negative for acute cholestatic pathologies, such as cholelithiasis, cholecystitis, or choledocholithiasis. Nonetheless, a noncontrast abdominopelvic computed tomography was remarkable for peripancreatic fat stranding, which raised suspicion for a diagnosis of pancreatitis.

Once the patient was transferred to the intensive care unit, he developed several episodes of hematemesis, leading to hemodynamical instability and severe respiratory distress. Due to anticipated respiratory failure and need for airway securement, endotracheal intubation was performed. Multiple packed red blood cells were transfused, and the patient was started in vasopressor support.

Diagnosis

A presumptive diagnosis of LS was made due to a considerable history of rodent exposure. The patient was started on broad-spectrum parenteral antibiotics, vancomycin 750 mg every 24 hours, metronidazole 500 mg every 8 hours, and ceftriaxone 2 g IV daily for adequate coverage against Leptospira spp. Despite 72 hours of antibiotic treatment, the patient’s clinical state deteriorated. He required high dosages of norepinephrine (1.5 mcg/kg/min) and vasopressin (0.03 U/min) to maintain adequate organ perfusion. Despite lung protective settings with low tidal volume and a high positive end-expiratory pressure, there was difficulty maintaining adequate oxygenation. Chest imaging was remarkable for bilateral infiltrates concerning for acute respiratory distress syndrome (ARDS).

The coagulopathy and cholestasis continued to worsen, and the renal failure progressed from nonoliguric to anuric. Because of this progression, the patient was started on continuous renal replacement therapy (CRRT) by hemodialysis. Within 24 hours of initiating CRRT, the patient’s clinical status improved dramatically. Vasopressor support was weaned, the coagulopathy resolved, and the cholestasis was improving. The patient’s respiratory status improved in such a manner that he was extubated by the seventh day after being placed on mechanical ventilation. The urine and blood samples sent for identification of Leptospira spp. through polymerase chain reaction (PCR) returned positive by the ninth day of admission. While on CRRT, the patient’s renal function eventually returned to baseline, and he was discharged 12 days after admission.

Discussion

The spirochetes of the genus Leptospira include both saprophytic and pathogenic species. These pathogenic Leptospira spp. have adapted to a grand variety of zoonotic hosts, the most important being rodents. They serve as vectors for the contraction of the disease by humans. Initial infection in rodents by Leptospira spp. causes a systemic illness followed by a persistent colonization of renal tubules from which they are excreted in the urine and into the environment. Humans, in turn, are an incidental host unable to induce a carrier state for the transmission of the pathogenic organism.¹ The time from exposure to onset of symptoms, or incubation phase, averages 7 to 12 days but may range from 3 to 30 days.⁸

LS has been described as having 2 discernable but often coexisting phases. The first, an acute febrile bacteremic phase, has been noted to last about 9 days in about 85% of patients, although a minority have persistent fever from 2 weeks to > 30 days. A second phase, the immune or inflammatory phase, is characterized by a second fever spike preceded by 1 to 5 afebrile days in which there is presence of IgM antibodies and resolution of leptospiremia but positive urine cultures.⁹ Weil disease may present as the second phase of the disease or as a single, progressive illness from its first manifestation. It is characterized by a triad of jaundice, renal failure, and hemorrhage or coagulopathy.¹⁰ Weil disease is of great concern and importance due to its associated higher mortality than that found with the mildest form of the disease.

There are studies that advocate for RRT as an intricate part of the treatment regimen in LS to remove the inflammatory cytokines produced as a reaction to the spirochete.¹¹ In tropical countries with a higher incidence of the disease, leptospirosis is an important cause of acute kidney injury (AKI), depending on multiple factors, including the AKI definition that is used.¹² Renal invasion by Leptospira spp. produces acute tubular necrosis (ATN) and cell edema during the first week and then could progress to acute interstitial nephritis (AIN) in 2 to 3 weeks. It is believed that the mechanism for the Leptospira spp. invasion of the tubules that results in damage is associated with the antigenic components in its outer membrane; the most important outer membrane protein expressed during infection is LipL32. This protein increases the production of proinflammatory proteins, such as inducible nitric oxide synthase, monocyte chemotactic protein-1 (CCL2/MCP-1), T cells, and tumor necrosis factor.¹³

Although doxycycline has been recommended for the prophylaxis and treatment of mild LS, the preferred agent and the conferred benefits of antibiotic treatment overall for the severe form of the disease has been controversial. Traditionally, penicillin G sodium has been recommended as the first-line antibiotic treatment for moderate-to-severe LS.¹⁴ Nonetheless, there has been an increasing pattern of penicillin resistance among Leptospira spp. that has prompted the study and use of alternative agents.

An open-label, randomized comparison of parenteral cefotaxime, penicillin G sodium, and doxycycline for the treatment of suspected severe leptospirosis conducted by Suputtamongkol and colleagues showed no difference in mortality, defervescence, or time to resolution of abnormal laboratory findings.¹⁵ Current CDC recommendations include the use of parenteral penicillin 1.5 MU every 6 hours as the drug of choice, with ceftriaxone 1 g administered IV every 24 hours equally as effective.³

In addition to antimicrobial therapy, supportive care has shifted to include hemodialysis in those patients who develop AKI as part of the disease. Andrade and colleagues conducted a study of 33 patients with LS in Brazil that was set to compare the impact of door-to-dialysis time and dosage of hemodialysis on mortality. In patients with a quicker door-to-dialysis time and daily hemodialysis sessions, there was a 50% (16.7% vs 66.7%) absolute mortality reduction when compared with those with delayed initiation and alternate-day hemodialysis sessions.¹¹ A follow-up prospective study compared the use of traditional sustained low-efficiency dialysis (SLED) with the use of extended SLED via hemodiafiltration in patients with LS presenting with ARDS and AKI. Although hemodiafiltration resulted in a relative decrease in serum levels of interleukin (IL)-17, IL-7, and CCL2/MCP-1, there was no significant difference in mortality.¹⁶ The most important prognostic factor in severe LS presenting with AKI and relating to RRT is a shorter door-to-dialysis time and increased dose, not the mode of dialysis clearance. Nonetheless, both RRT methods resulted in a progressive decrease in inflammatory mediators that have been associated with ATN and AIN in the context of LS.¹⁶ The authors argue that using CRRT instead of SLED via hemodiafiltration could have accentuated the effects of the reduction that inflammatory mediators may have on mortality in patients with severe LS.

Conclusions

LS continues to be of interest due to its current status as the most common zoonotic disease and its widespread prevalence throughout the globe. Novel treatment modalities for LS, specifically for Weil disease, continue to be developed with the goal of reducing the current mortality rate associated with the disease.

In endemic areas, prompt recognition is essential to initiate the recommended therapy. Parenteral antibiotics, such as penicillin G sodium and ceftriaxone, continue to be the mainstay of treatment and constitute the current CDC recommendations. Nonetheless, early initiation of CRRT has been shown to greatly reduce the mortality associated with Weil disease and, when available, should be considered in these patients.

Our patient failed to improve while receiving parenteral antibiotics alone but showed marked improvement after being placed on CRRT. Furthermore, initiation of CRRT resulted in near-complete resolution of his organ dysfunction and eventual discharge from the hospital. This case serves to further support the use of early CRRT as part of the standard of care in severe LS.

Leptospirosis (LS) is considered the most common and widespread zoonotic disease in the world. Numerous outbreaks have occurred in the past 10 years. Due to its technically difficult diagnosis, LS is severely underrecognized, underdiagnosed, and therefore, underreported.^1,2 The Centers for Disease Control and Prevention (CDC) estimate 100 to 150 cases of LS are identified annually in the US, with about 50% of those cases occurring in Puerto Rico (PR).³ Specifically in PR, about 15 to 100 cases of suspected LS were reported annually between 2000 and 2009, with 59 cases and 1 death reported in 2010. The data are thought to be severely underreported due to a lack of widespread diagnostic testing availability in PR and no formal veterinary and environmental surveillance programs to monitor the incidence of animal cases and actual circulating serovars.⁴

A recent systematic review of 80 studies from 34 countries on morbidity and mortality of LS revealed that the global incidence and mortality is about 1.03 million cases and 58,900 deaths every year. Almost half of the reported deaths were adult males aged 20 to 49 years.⁵ Although mild cases of LS are not associated with an elevated mortality, icteric LS with renal failure (Weil disease) carries a mortality rate of 10%.⁶ In patients who develop hemorrhagic pneumonitis, mortality may be as high as 50 to 70%.⁷ Therefore, it is pivotal that clinicians recognize the disease early, that novel modalities of treatment continue to be developed, and that their impact on patient morbidity and mortality are studied and documented.

Case Presentation

A 43-year-old man with a medical history of schizophrenia presented to the emergency department at the US Department of Veterans Affairs (VA) Caribbean Healthcare System in San Juan, PR, after experiencing 1 week of intermittent fever, myalgia, and general weakness. Emergency medical services had found him disheveled and in a rodent-infested swamp area several days before admission. Initial vital signs were within normal limits.

On physical examination, the patient was afebrile, without acute distress, but he had diffuse jaundice and mild epigastric tenderness without evidence of peritoneal irritation. His complete blood count was remarkable for leukocytosis with left shifting, adequate hemoglobin levels but with 9 × 10³ U/L platelets. The complete metabolic panel demonstrated an aspartate aminotransferase level of 564 U/L, alanine transaminase level of 462 U/L, total bilirubin of 12 mg/dL, which 10.2 mg/dL were direct bilirubin, and an alkaline phosphate of 345 U/L. Lipase levels were measured at 626 U/L. Marked coagulopathy also was present. The toxicology panel, including acetaminophen and salicylate acid levels, did not reveal the presence of any of the tested substances, and chest imaging did not demonstrate any infiltrates.

An abdominal ultrasound was negative for acute cholestatic pathologies, such as cholelithiasis, cholecystitis, or choledocholithiasis. Nonetheless, a noncontrast abdominopelvic computed tomography was remarkable for peripancreatic fat stranding, which raised suspicion for a diagnosis of pancreatitis.

Once the patient was transferred to the intensive care unit, he developed several episodes of hematemesis, leading to hemodynamical instability and severe respiratory distress. Due to anticipated respiratory failure and need for airway securement, endotracheal intubation was performed. Multiple packed red blood cells were transfused, and the patient was started in vasopressor support.

Diagnosis

A presumptive diagnosis of LS was made due to a considerable history of rodent exposure. The patient was started on broad-spectrum parenteral antibiotics, vancomycin 750 mg every 24 hours, metronidazole 500 mg every 8 hours, and ceftriaxone 2 g IV daily for adequate coverage against Leptospira spp. Despite 72 hours of antibiotic treatment, the patient’s clinical state deteriorated. He required high dosages of norepinephrine (1.5 mcg/kg/min) and vasopressin (0.03 U/min) to maintain adequate organ perfusion. Despite lung protective settings with low tidal volume and a high positive end-expiratory pressure, there was difficulty maintaining adequate oxygenation. Chest imaging was remarkable for bilateral infiltrates concerning for acute respiratory distress syndrome (ARDS).

The coagulopathy and cholestasis continued to worsen, and the renal failure progressed from nonoliguric to anuric. Because of this progression, the patient was started on continuous renal replacement therapy (CRRT) by hemodialysis. Within 24 hours of initiating CRRT, the patient’s clinical status improved dramatically. Vasopressor support was weaned, the coagulopathy resolved, and the cholestasis was improving. The patient’s respiratory status improved in such a manner that he was extubated by the seventh day after being placed on mechanical ventilation. The urine and blood samples sent for identification of Leptospira spp. through polymerase chain reaction (PCR) returned positive by the ninth day of admission. While on CRRT, the patient’s renal function eventually returned to baseline, and he was discharged 12 days after admission.

Discussion

The spirochetes of the genus Leptospira include both saprophytic and pathogenic species. These pathogenic Leptospira spp. have adapted to a grand variety of zoonotic hosts, the most important being rodents. They serve as vectors for the contraction of the disease by humans. Initial infection in rodents by Leptospira spp. causes a systemic illness followed by a persistent colonization of renal tubules from which they are excreted in the urine and into the environment. Humans, in turn, are an incidental host unable to induce a carrier state for the transmission of the pathogenic organism.¹ The time from exposure to onset of symptoms, or incubation phase, averages 7 to 12 days but may range from 3 to 30 days.⁸

LS has been described as having 2 discernable but often coexisting phases. The first, an acute febrile bacteremic phase, has been noted to last about 9 days in about 85% of patients, although a minority have persistent fever from 2 weeks to > 30 days. A second phase, the immune or inflammatory phase, is characterized by a second fever spike preceded by 1 to 5 afebrile days in which there is presence of IgM antibodies and resolution of leptospiremia but positive urine cultures.⁹ Weil disease may present as the second phase of the disease or as a single, progressive illness from its first manifestation. It is characterized by a triad of jaundice, renal failure, and hemorrhage or coagulopathy.¹⁰ Weil disease is of great concern and importance due to its associated higher mortality than that found with the mildest form of the disease.

There are studies that advocate for RRT as an intricate part of the treatment regimen in LS to remove the inflammatory cytokines produced as a reaction to the spirochete.¹¹ In tropical countries with a higher incidence of the disease, leptospirosis is an important cause of acute kidney injury (AKI), depending on multiple factors, including the AKI definition that is used.¹² Renal invasion by Leptospira spp. produces acute tubular necrosis (ATN) and cell edema during the first week and then could progress to acute interstitial nephritis (AIN) in 2 to 3 weeks. It is believed that the mechanism for the Leptospira spp. invasion of the tubules that results in damage is associated with the antigenic components in its outer membrane; the most important outer membrane protein expressed during infection is LipL32. This protein increases the production of proinflammatory proteins, such as inducible nitric oxide synthase, monocyte chemotactic protein-1 (CCL2/MCP-1), T cells, and tumor necrosis factor.¹³

Although doxycycline has been recommended for the prophylaxis and treatment of mild LS, the preferred agent and the conferred benefits of antibiotic treatment overall for the severe form of the disease has been controversial. Traditionally, penicillin G sodium has been recommended as the first-line antibiotic treatment for moderate-to-severe LS.¹⁴ Nonetheless, there has been an increasing pattern of penicillin resistance among Leptospira spp. that has prompted the study and use of alternative agents.

An open-label, randomized comparison of parenteral cefotaxime, penicillin G sodium, and doxycycline for the treatment of suspected severe leptospirosis conducted by Suputtamongkol and colleagues showed no difference in mortality, defervescence, or time to resolution of abnormal laboratory findings.¹⁵ Current CDC recommendations include the use of parenteral penicillin 1.5 MU every 6 hours as the drug of choice, with ceftriaxone 1 g administered IV every 24 hours equally as effective.³

In addition to antimicrobial therapy, supportive care has shifted to include hemodialysis in those patients who develop AKI as part of the disease. Andrade and colleagues conducted a study of 33 patients with LS in Brazil that was set to compare the impact of door-to-dialysis time and dosage of hemodialysis on mortality. In patients with a quicker door-to-dialysis time and daily hemodialysis sessions, there was a 50% (16.7% vs 66.7%) absolute mortality reduction when compared with those with delayed initiation and alternate-day hemodialysis sessions.¹¹ A follow-up prospective study compared the use of traditional sustained low-efficiency dialysis (SLED) with the use of extended SLED via hemodiafiltration in patients with LS presenting with ARDS and AKI. Although hemodiafiltration resulted in a relative decrease in serum levels of interleukin (IL)-17, IL-7, and CCL2/MCP-1, there was no significant difference in mortality.¹⁶ The most important prognostic factor in severe LS presenting with AKI and relating to RRT is a shorter door-to-dialysis time and increased dose, not the mode of dialysis clearance. Nonetheless, both RRT methods resulted in a progressive decrease in inflammatory mediators that have been associated with ATN and AIN in the context of LS.¹⁶ The authors argue that using CRRT instead of SLED via hemodiafiltration could have accentuated the effects of the reduction that inflammatory mediators may have on mortality in patients with severe LS.

Conclusions

LS continues to be of interest due to its current status as the most common zoonotic disease and its widespread prevalence throughout the globe. Novel treatment modalities for LS, specifically for Weil disease, continue to be developed with the goal of reducing the current mortality rate associated with the disease.

In endemic areas, prompt recognition is essential to initiate the recommended therapy. Parenteral antibiotics, such as penicillin G sodium and ceftriaxone, continue to be the mainstay of treatment and constitute the current CDC recommendations. Nonetheless, early initiation of CRRT has been shown to greatly reduce the mortality associated with Weil disease and, when available, should be considered in these patients.

Our patient failed to improve while receiving parenteral antibiotics alone but showed marked improvement after being placed on CRRT. Furthermore, initiation of CRRT resulted in near-complete resolution of his organ dysfunction and eventual discharge from the hospital. This case serves to further support the use of early CRRT as part of the standard of care in severe LS.

Leptospirosis (LS) is considered the most common and widespread zoonotic disease in the world. Numerous outbreaks have occurred in the past 10 years. Due to its technically difficult diagnosis, LS is severely underrecognized, underdiagnosed, and therefore, underreported.^1,2 The Centers for Disease Control and Prevention (CDC) estimate 100 to 150 cases of LS are identified annually in the US, with about 50% of those cases occurring in Puerto Rico (PR).³ Specifically in PR, about 15 to 100 cases of suspected LS were reported annually between 2000 and 2009, with 59 cases and 1 death reported in 2010. The data are thought to be severely underreported due to a lack of widespread diagnostic testing availability in PR and no formal veterinary and environmental surveillance programs to monitor the incidence of animal cases and actual circulating serovars.⁴

A recent systematic review of 80 studies from 34 countries on morbidity and mortality of LS revealed that the global incidence and mortality is about 1.03 million cases and 58,900 deaths every year. Almost half of the reported deaths were adult males aged 20 to 49 years.⁵ Although mild cases of LS are not associated with an elevated mortality, icteric LS with renal failure (Weil disease) carries a mortality rate of 10%.⁶ In patients who develop hemorrhagic pneumonitis, mortality may be as high as 50 to 70%.⁷ Therefore, it is pivotal that clinicians recognize the disease early, that novel modalities of treatment continue to be developed, and that their impact on patient morbidity and mortality are studied and documented.

Case Presentation

A 43-year-old man with a medical history of schizophrenia presented to the emergency department at the US Department of Veterans Affairs (VA) Caribbean Healthcare System in San Juan, PR, after experiencing 1 week of intermittent fever, myalgia, and general weakness. Emergency medical services had found him disheveled and in a rodent-infested swamp area several days before admission. Initial vital signs were within normal limits.

On physical examination, the patient was afebrile, without acute distress, but he had diffuse jaundice and mild epigastric tenderness without evidence of peritoneal irritation. His complete blood count was remarkable for leukocytosis with left shifting, adequate hemoglobin levels but with 9 × 10³ U/L platelets. The complete metabolic panel demonstrated an aspartate aminotransferase level of 564 U/L, alanine transaminase level of 462 U/L, total bilirubin of 12 mg/dL, which 10.2 mg/dL were direct bilirubin, and an alkaline phosphate of 345 U/L. Lipase levels were measured at 626 U/L. Marked coagulopathy also was present. The toxicology panel, including acetaminophen and salicylate acid levels, did not reveal the presence of any of the tested substances, and chest imaging did not demonstrate any infiltrates.

An abdominal ultrasound was negative for acute cholestatic pathologies, such as cholelithiasis, cholecystitis, or choledocholithiasis. Nonetheless, a noncontrast abdominopelvic computed tomography was remarkable for peripancreatic fat stranding, which raised suspicion for a diagnosis of pancreatitis.

Once the patient was transferred to the intensive care unit, he developed several episodes of hematemesis, leading to hemodynamical instability and severe respiratory distress. Due to anticipated respiratory failure and need for airway securement, endotracheal intubation was performed. Multiple packed red blood cells were transfused, and the patient was started in vasopressor support.

Diagnosis

A presumptive diagnosis of LS was made due to a considerable history of rodent exposure. The patient was started on broad-spectrum parenteral antibiotics, vancomycin 750 mg every 24 hours, metronidazole 500 mg every 8 hours, and ceftriaxone 2 g IV daily for adequate coverage against Leptospira spp. Despite 72 hours of antibiotic treatment, the patient’s clinical state deteriorated. He required high dosages of norepinephrine (1.5 mcg/kg/min) and vasopressin (0.03 U/min) to maintain adequate organ perfusion. Despite lung protective settings with low tidal volume and a high positive end-expiratory pressure, there was difficulty maintaining adequate oxygenation. Chest imaging was remarkable for bilateral infiltrates concerning for acute respiratory distress syndrome (ARDS).

The coagulopathy and cholestasis continued to worsen, and the renal failure progressed from nonoliguric to anuric. Because of this progression, the patient was started on continuous renal replacement therapy (CRRT) by hemodialysis. Within 24 hours of initiating CRRT, the patient’s clinical status improved dramatically. Vasopressor support was weaned, the coagulopathy resolved, and the cholestasis was improving. The patient’s respiratory status improved in such a manner that he was extubated by the seventh day after being placed on mechanical ventilation. The urine and blood samples sent for identification of Leptospira spp. through polymerase chain reaction (PCR) returned positive by the ninth day of admission. While on CRRT, the patient’s renal function eventually returned to baseline, and he was discharged 12 days after admission.

Discussion

The spirochetes of the genus Leptospira include both saprophytic and pathogenic species. These pathogenic Leptospira spp. have adapted to a grand variety of zoonotic hosts, the most important being rodents. They serve as vectors for the contraction of the disease by humans. Initial infection in rodents by Leptospira spp. causes a systemic illness followed by a persistent colonization of renal tubules from which they are excreted in the urine and into the environment. Humans, in turn, are an incidental host unable to induce a carrier state for the transmission of the pathogenic organism.¹ The time from exposure to onset of symptoms, or incubation phase, averages 7 to 12 days but may range from 3 to 30 days.⁸

LS has been described as having 2 discernable but often coexisting phases. The first, an acute febrile bacteremic phase, has been noted to last about 9 days in about 85% of patients, although a minority have persistent fever from 2 weeks to > 30 days. A second phase, the immune or inflammatory phase, is characterized by a second fever spike preceded by 1 to 5 afebrile days in which there is presence of IgM antibodies and resolution of leptospiremia but positive urine cultures.⁹ Weil disease may present as the second phase of the disease or as a single, progressive illness from its first manifestation. It is characterized by a triad of jaundice, renal failure, and hemorrhage or coagulopathy.¹⁰ Weil disease is of great concern and importance due to its associated higher mortality than that found with the mildest form of the disease.

There are studies that advocate for RRT as an intricate part of the treatment regimen in LS to remove the inflammatory cytokines produced as a reaction to the spirochete.¹¹ In tropical countries with a higher incidence of the disease, leptospirosis is an important cause of acute kidney injury (AKI), depending on multiple factors, including the AKI definition that is used.¹² Renal invasion by Leptospira spp. produces acute tubular necrosis (ATN) and cell edema during the first week and then could progress to acute interstitial nephritis (AIN) in 2 to 3 weeks. It is believed that the mechanism for the Leptospira spp. invasion of the tubules that results in damage is associated with the antigenic components in its outer membrane; the most important outer membrane protein expressed during infection is LipL32. This protein increases the production of proinflammatory proteins, such as inducible nitric oxide synthase, monocyte chemotactic protein-1 (CCL2/MCP-1), T cells, and tumor necrosis factor.¹³

Although doxycycline has been recommended for the prophylaxis and treatment of mild LS, the preferred agent and the conferred benefits of antibiotic treatment overall for the severe form of the disease has been controversial. Traditionally, penicillin G sodium has been recommended as the first-line antibiotic treatment for moderate-to-severe LS.¹⁴ Nonetheless, there has been an increasing pattern of penicillin resistance among Leptospira spp. that has prompted the study and use of alternative agents.

An open-label, randomized comparison of parenteral cefotaxime, penicillin G sodium, and doxycycline for the treatment of suspected severe leptospirosis conducted by Suputtamongkol and colleagues showed no difference in mortality, defervescence, or time to resolution of abnormal laboratory findings.¹⁵ Current CDC recommendations include the use of parenteral penicillin 1.5 MU every 6 hours as the drug of choice, with ceftriaxone 1 g administered IV every 24 hours equally as effective.³

In addition to antimicrobial therapy, supportive care has shifted to include hemodialysis in those patients who develop AKI as part of the disease. Andrade and colleagues conducted a study of 33 patients with LS in Brazil that was set to compare the impact of door-to-dialysis time and dosage of hemodialysis on mortality. In patients with a quicker door-to-dialysis time and daily hemodialysis sessions, there was a 50% (16.7% vs 66.7%) absolute mortality reduction when compared with those with delayed initiation and alternate-day hemodialysis sessions.¹¹ A follow-up prospective study compared the use of traditional sustained low-efficiency dialysis (SLED) with the use of extended SLED via hemodiafiltration in patients with LS presenting with ARDS and AKI. Although hemodiafiltration resulted in a relative decrease in serum levels of interleukin (IL)-17, IL-7, and CCL2/MCP-1, there was no significant difference in mortality.¹⁶ The most important prognostic factor in severe LS presenting with AKI and relating to RRT is a shorter door-to-dialysis time and increased dose, not the mode of dialysis clearance. Nonetheless, both RRT methods resulted in a progressive decrease in inflammatory mediators that have been associated with ATN and AIN in the context of LS.¹⁶ The authors argue that using CRRT instead of SLED via hemodiafiltration could have accentuated the effects of the reduction that inflammatory mediators may have on mortality in patients with severe LS.

Conclusions

LS continues to be of interest due to its current status as the most common zoonotic disease and its widespread prevalence throughout the globe. Novel treatment modalities for LS, specifically for Weil disease, continue to be developed with the goal of reducing the current mortality rate associated with the disease.

In endemic areas, prompt recognition is essential to initiate the recommended therapy. Parenteral antibiotics, such as penicillin G sodium and ceftriaxone, continue to be the mainstay of treatment and constitute the current CDC recommendations. Nonetheless, early initiation of CRRT has been shown to greatly reduce the mortality associated with Weil disease and, when available, should be considered in these patients.

Our patient failed to improve while receiving parenteral antibiotics alone but showed marked improvement after being placed on CRRT. Furthermore, initiation of CRRT resulted in near-complete resolution of his organ dysfunction and eventual discharge from the hospital. This case serves to further support the use of early CRRT as part of the standard of care in severe LS.

More than 34 million adults in the US have type 2 diabetes mellitus (T2DM), a chronic progressive disease identified by worsening hyperglycemia and micro- and macrovascular complications.¹ Consequently, 12.2% of the US adult population is currently at risk for macrovascular diseases, such as stroke and coronary artery disease (CAD) and microvascular diseases, such as neuropathy and diabetic nephropathy.¹

T2DM is the most common comorbid risk factor for chronic kidney disease (CKD) and the leading cause of end-stage renal disease (ESRD). As of 2017, about 750,000 Americans have CKD stage 5 requiring dialysis, and 50% of these patients have preexisting diabetic nephropathy.² Rates of mortality and morbidity are observed to be higher in patients with both CKD and T2DM compared with patients with CKD without T2DM.² Previous clinical trials, including the United Kingdom Prospective Diabetes Study of 1998, have proven that optimal glycemic control decreases the risk of complications of T2DM (ie, nephropathy) in the general population.³ Conversely, tight glycemic control that targets hemoglobin A_1c (HbA_1c) < 7%, in patients with T2DM with ESRD has not shown the same benefits and may lead to worse outcomes. It is postulated that this may be due to the increased incidence of hypoglycemia in this patient population.⁴

Dialysis has varying effects on patients both with and without T2DM. While patients with ESRD without T2DM have the potential to develop impaired glucose tolerance and T2DM, about 33% of patients with T2DM on dialysis actually have HbA_1c < 6%.⁵ In these patients, glycemic control improves spontaneously as their disease progresses, leading to a decrease or cessation of insulin or other antidiabetic medications. This phenomenon, known as burnt-out diabetes, is characterized by (1) alterations in glucose homeostasis and normoglycemia without antidiabetic treatment; (2) HbA_1c levels < 6% despite having established T2DM; (3) decline in insulin requirements or cessation of insulin altogether; and (4) spontaneous hypoglycemia.

There is a misconception that burnt-out diabetes is a favorable condition due to the alteration of the natural course of T2DM. Although this may be true, patients with this condition are prone to develop hypoglycemic episodes and may be linked to poor survival outcomes due to low HbA_1c.^6,7

Since Kalantar-Zadeh and colleagues presented a 2009 case study, there has been a lack of research regarding this unique condition.⁸ The purpose of this case study is to shed further light on burnt-out diabetes and present a patient case pertaining to the challenges of glycemic control in ESRD.

Case Presentation

Mr. A is a 49-year-old Hispanic male veteran with a history of ESRD on hemodialysis (HD) for 6 years, anemia of CKD, and T2DM for 22 years. The patient also has an extensive cardiovascular disease history, including hypertension, hyperlipidemia, and CAD status post-4-vessel coronary artery bypass graft in December 2014. The patient receives in-home HD Monday, Wednesday, and Friday and is on the wait list for kidney transplantation. The patient’s T2DM is managed by a primary care clinical pharmacy specialist (CPS) at the Michael E. DeBakey Veteran Affairs Medical Center (MEDVAMC) in Houston, Texas.

Mr. A’s antidiabetic regimen is 45 units of subcutaneous insulin glargine every morning; insulin aspart sliding scale (about 15-27 units) subcutaneous 3 times daily with meals; and saxagliptin 2.5 mg by mouth once daily.

At a follow-up visit with the CPS, Mr. A stated, “I feel fine except for the occasional low blood sugar episode.” The patient’s most recent HbA_1c was 6.1%, and he reported medication adherence and no signs or symptoms of hyperglycemia (ie, polydipsia, polyphagia, nocturia, visual disturbances). Mr. A reported no use of alcohol, tobacco, or illicit drugs. He walks 1 mile every other day and participates in self-monitoring blood glucose (SMBG) about 2 to 3 times daily (Table 1).

Analysis

Few articles on potential contributors to burnt-out diabetes have been published.^6,7 These articles discuss decreased renal and hepatic clearance of insulin (which increases its half-life) hypoglycemia during HD, and low HbA_1c due to preexisting anemia. Inappropriately low HbA_1c levels may be secondary to, but not limited to, hemolysis, recent blood transfusion, acute blood loss, and medications, such as erythropoietin-stimulating agents (ESAs).⁹ The conditions that affect red blood cell turnover are common in patients with advanced CKD and may result in discrepancies in HbA_1c levels.

Glycated hemoglobin is a series of minor hemoglobin components formed by the adduction of various carbohydrate molecules to hemoglobin. HbA_1c is the largest fraction formed and the most consistent index of the concentration of glucose in the blood.¹⁰ Hence, HbA_1c is the traditional indicator of overall glycemic control. The current HbA_1c goals recommended by the American Diabetes Association are derived from landmark trials conducted with patients in the general adult diabetic non-CKD population. However, hemoglobin measurements can be confounded by conditions present in ESRD and tend to underestimate glucose measurements in patients with T2DM on HD. Despite this, HbA_1c is still regarded as a reasonable measure of glycemic control even in patients with ESRD; however, alternative markers of glycemia may be preferable.¹¹

Although HbA_1c is the gold standard, there are other laboratory measures of average glycemic control available. Fructosamine is a ketoamine formed when glucose binds to serum proteins. When these proteins are exposed to high concentrations of glucose, they experience increased glycation. Fructosamine assays measure the total glycated serum proteins, of which albumin accounts for about 90%.¹¹ Because the half-life of serum proteins is about 20 days, fructosamine levels can reflect glycemic control over a 2- to 3-week period. This is advantageous in conditions that affect the average age of red blood cells, in pregnancy where frequent monitoring and measures of short-term glucose control are especially important, and in the evaluation of a medication adjustment in the management of T2DM. However, this test is not without its limitations. It is less reliable in settings of decreased protein levels (eg, liver disease), there is a lack of availability in routine practice, and reference levels have not been established.¹¹

Hypoglycemic Episodes

At the 2-month follow-up visit with the CPS, Mr. A reported having 5 hypoglycemic episodes in the past 30 days. He also stated he would forget to take his insulin aspart dose before dinner about 3 to 4 times a week but would take it 30 to 60 minutes after the meal. Mr. A did not bring his glucometer or SMBG readings to the visit, but he indicated that his blood glucose levels continued to fluctuate and were elevated when consuming carbohydrates.

Laboratory tests 1 month prior to the 2-month follow-up visit showed HbA_1c of 7.3%, which had increased from his previous level of 6.1%. He was counseled on the proper administration of insulin aspart and lifestyle modifications. A fructosamine level was ordered at this visit to further assess his glycemic control. A follow-up appointment and laboratory workup (fructosamine and HbA_1c) were scheduled for 2 months from the visit (Table 3).

Mr. A was educated on the unreliability of his HbA_1c levels secondary to his condition of ESRD on HD. He was counseled on the purpose of fructosamine and how it may be a better predictor of his glycemic control and morbidity. Mr. A continued to be followed closely by the primary care CPS for T2DM management.

Discussion

Management of T2DM in patients with ESRD presents challenges for clinicians in determining HbA_1c goals and selecting appropriate medication options. The 2012 Kidney Disease Outcomes Quality Initiative (KDOQI) diabetes guideline does not recommend treatment for patients with substantially reduced kidney function to a target HbA_1c < 7% due to risk of hypoglycemia.¹³ Although a target HbA_1c > 7% is suggested for these patients, little is known about appropriate glycemic control in these patients as there is a paucity of prospective, randomized clinical trials that include patients with advanced CKD.¹³

Moreover, many oral antidiabetic medications and their metabolites are cleared by the kidneys and, therefore, pose with potential harm for patients with CKD. Because of this, insulin is the medication of choice for patients with ESRD.⁷ Although insulin requirements may diminish with worsening kidney function, insulin provides the safest method of glycemic control. Insulin dosing can be individualized according to a patient’s renal status as there is no uniformity in renal dose adjustments. There are some noninsulin antidiabetic agents that can be used in ESRD, but use of these agents requires close monitoring and evaluation of the medication’s pharmacokinetics (Table 4). Overall, medication management can be a difficult task for patients with T2DM and ESRD, but antidiabetic regimens may be reduced or discontinued altogether in burnt-out diabetes.

Conclusions

Patients with T2DM and ESRD on dialysis may have higher morbidity and mortality rates than the rates of those without T2DM. It has been shown in various studies that very low HbA_1c (< 5%) and high HbA_1c (> 8%) are associated with poor survival. Some patients with T2DM on dialysis may experience burnt-out diabetes in which they may have normoglycemia and a HbA_1c below goal; despite these facts, this condition is not positive and can be linked to bad outcomes. In patients with T2DM and ESRD, insulin is the antidiabetic medication of choice, and we recommend a HbA_1c target of 6 to 8%. In this patient population, consider using fructosamine levels or other measures of glycemic control to supplement HbA_1c and glucose values to provide a better assessment of glycemic control, morbidity, and mortality. Larger clinical trials are needed to assist in answering questions regarding mortality and optimal HbA_1c targets in burnt-out diabetes.

More than 34 million adults in the US have type 2 diabetes mellitus (T2DM), a chronic progressive disease identified by worsening hyperglycemia and micro- and macrovascular complications.¹ Consequently, 12.2% of the US adult population is currently at risk for macrovascular diseases, such as stroke and coronary artery disease (CAD) and microvascular diseases, such as neuropathy and diabetic nephropathy.¹

T2DM is the most common comorbid risk factor for chronic kidney disease (CKD) and the leading cause of end-stage renal disease (ESRD). As of 2017, about 750,000 Americans have CKD stage 5 requiring dialysis, and 50% of these patients have preexisting diabetic nephropathy.² Rates of mortality and morbidity are observed to be higher in patients with both CKD and T2DM compared with patients with CKD without T2DM.² Previous clinical trials, including the United Kingdom Prospective Diabetes Study of 1998, have proven that optimal glycemic control decreases the risk of complications of T2DM (ie, nephropathy) in the general population.³ Conversely, tight glycemic control that targets hemoglobin A_1c (HbA_1c) < 7%, in patients with T2DM with ESRD has not shown the same benefits and may lead to worse outcomes. It is postulated that this may be due to the increased incidence of hypoglycemia in this patient population.⁴

Dialysis has varying effects on patients both with and without T2DM. While patients with ESRD without T2DM have the potential to develop impaired glucose tolerance and T2DM, about 33% of patients with T2DM on dialysis actually have HbA_1c < 6%.⁵ In these patients, glycemic control improves spontaneously as their disease progresses, leading to a decrease or cessation of insulin or other antidiabetic medications. This phenomenon, known as burnt-out diabetes, is characterized by (1) alterations in glucose homeostasis and normoglycemia without antidiabetic treatment; (2) HbA_1c levels < 6% despite having established T2DM; (3) decline in insulin requirements or cessation of insulin altogether; and (4) spontaneous hypoglycemia.

There is a misconception that burnt-out diabetes is a favorable condition due to the alteration of the natural course of T2DM. Although this may be true, patients with this condition are prone to develop hypoglycemic episodes and may be linked to poor survival outcomes due to low HbA_1c.^6,7

Since Kalantar-Zadeh and colleagues presented a 2009 case study, there has been a lack of research regarding this unique condition.⁸ The purpose of this case study is to shed further light on burnt-out diabetes and present a patient case pertaining to the challenges of glycemic control in ESRD.

Case Presentation

Mr. A is a 49-year-old Hispanic male veteran with a history of ESRD on hemodialysis (HD) for 6 years, anemia of CKD, and T2DM for 22 years. The patient also has an extensive cardiovascular disease history, including hypertension, hyperlipidemia, and CAD status post-4-vessel coronary artery bypass graft in December 2014. The patient receives in-home HD Monday, Wednesday, and Friday and is on the wait list for kidney transplantation. The patient’s T2DM is managed by a primary care clinical pharmacy specialist (CPS) at the Michael E. DeBakey Veteran Affairs Medical Center (MEDVAMC) in Houston, Texas.

Mr. A’s antidiabetic regimen is 45 units of subcutaneous insulin glargine every morning; insulin aspart sliding scale (about 15-27 units) subcutaneous 3 times daily with meals; and saxagliptin 2.5 mg by mouth once daily.

At a follow-up visit with the CPS, Mr. A stated, “I feel fine except for the occasional low blood sugar episode.” The patient’s most recent HbA_1c was 6.1%, and he reported medication adherence and no signs or symptoms of hyperglycemia (ie, polydipsia, polyphagia, nocturia, visual disturbances). Mr. A reported no use of alcohol, tobacco, or illicit drugs. He walks 1 mile every other day and participates in self-monitoring blood glucose (SMBG) about 2 to 3 times daily (Table 1).

Analysis

Few articles on potential contributors to burnt-out diabetes have been published.^6,7 These articles discuss decreased renal and hepatic clearance of insulin (which increases its half-life) hypoglycemia during HD, and low HbA_1c due to preexisting anemia. Inappropriately low HbA_1c levels may be secondary to, but not limited to, hemolysis, recent blood transfusion, acute blood loss, and medications, such as erythropoietin-stimulating agents (ESAs).⁹ The conditions that affect red blood cell turnover are common in patients with advanced CKD and may result in discrepancies in HbA_1c levels.

Glycated hemoglobin is a series of minor hemoglobin components formed by the adduction of various carbohydrate molecules to hemoglobin. HbA_1c is the largest fraction formed and the most consistent index of the concentration of glucose in the blood.¹⁰ Hence, HbA_1c is the traditional indicator of overall glycemic control. The current HbA_1c goals recommended by the American Diabetes Association are derived from landmark trials conducted with patients in the general adult diabetic non-CKD population. However, hemoglobin measurements can be confounded by conditions present in ESRD and tend to underestimate glucose measurements in patients with T2DM on HD. Despite this, HbA_1c is still regarded as a reasonable measure of glycemic control even in patients with ESRD; however, alternative markers of glycemia may be preferable.¹¹

Although HbA_1c is the gold standard, there are other laboratory measures of average glycemic control available. Fructosamine is a ketoamine formed when glucose binds to serum proteins. When these proteins are exposed to high concentrations of glucose, they experience increased glycation. Fructosamine assays measure the total glycated serum proteins, of which albumin accounts for about 90%.¹¹ Because the half-life of serum proteins is about 20 days, fructosamine levels can reflect glycemic control over a 2- to 3-week period. This is advantageous in conditions that affect the average age of red blood cells, in pregnancy where frequent monitoring and measures of short-term glucose control are especially important, and in the evaluation of a medication adjustment in the management of T2DM. However, this test is not without its limitations. It is less reliable in settings of decreased protein levels (eg, liver disease), there is a lack of availability in routine practice, and reference levels have not been established.¹¹

Hypoglycemic Episodes

At the 2-month follow-up visit with the CPS, Mr. A reported having 5 hypoglycemic episodes in the past 30 days. He also stated he would forget to take his insulin aspart dose before dinner about 3 to 4 times a week but would take it 30 to 60 minutes after the meal. Mr. A did not bring his glucometer or SMBG readings to the visit, but he indicated that his blood glucose levels continued to fluctuate and were elevated when consuming carbohydrates.

Laboratory tests 1 month prior to the 2-month follow-up visit showed HbA_1c of 7.3%, which had increased from his previous level of 6.1%. He was counseled on the proper administration of insulin aspart and lifestyle modifications. A fructosamine level was ordered at this visit to further assess his glycemic control. A follow-up appointment and laboratory workup (fructosamine and HbA_1c) were scheduled for 2 months from the visit (Table 3).

Mr. A was educated on the unreliability of his HbA_1c levels secondary to his condition of ESRD on HD. He was counseled on the purpose of fructosamine and how it may be a better predictor of his glycemic control and morbidity. Mr. A continued to be followed closely by the primary care CPS for T2DM management.

Discussion

Management of T2DM in patients with ESRD presents challenges for clinicians in determining HbA_1c goals and selecting appropriate medication options. The 2012 Kidney Disease Outcomes Quality Initiative (KDOQI) diabetes guideline does not recommend treatment for patients with substantially reduced kidney function to a target HbA_1c < 7% due to risk of hypoglycemia.¹³ Although a target HbA_1c > 7% is suggested for these patients, little is known about appropriate glycemic control in these patients as there is a paucity of prospective, randomized clinical trials that include patients with advanced CKD.¹³

Moreover, many oral antidiabetic medications and their metabolites are cleared by the kidneys and, therefore, pose with potential harm for patients with CKD. Because of this, insulin is the medication of choice for patients with ESRD.⁷ Although insulin requirements may diminish with worsening kidney function, insulin provides the safest method of glycemic control. Insulin dosing can be individualized according to a patient’s renal status as there is no uniformity in renal dose adjustments. There are some noninsulin antidiabetic agents that can be used in ESRD, but use of these agents requires close monitoring and evaluation of the medication’s pharmacokinetics (Table 4). Overall, medication management can be a difficult task for patients with T2DM and ESRD, but antidiabetic regimens may be reduced or discontinued altogether in burnt-out diabetes.

Conclusions

Patients with T2DM and ESRD on dialysis may have higher morbidity and mortality rates than the rates of those without T2DM. It has been shown in various studies that very low HbA_1c (< 5%) and high HbA_1c (> 8%) are associated with poor survival. Some patients with T2DM on dialysis may experience burnt-out diabetes in which they may have normoglycemia and a HbA_1c below goal; despite these facts, this condition is not positive and can be linked to bad outcomes. In patients with T2DM and ESRD, insulin is the antidiabetic medication of choice, and we recommend a HbA_1c target of 6 to 8%. In this patient population, consider using fructosamine levels or other measures of glycemic control to supplement HbA_1c and glucose values to provide a better assessment of glycemic control, morbidity, and mortality. Larger clinical trials are needed to assist in answering questions regarding mortality and optimal HbA_1c targets in burnt-out diabetes.

More than 34 million adults in the US have type 2 diabetes mellitus (T2DM), a chronic progressive disease identified by worsening hyperglycemia and micro- and macrovascular complications.¹ Consequently, 12.2% of the US adult population is currently at risk for macrovascular diseases, such as stroke and coronary artery disease (CAD) and microvascular diseases, such as neuropathy and diabetic nephropathy.¹

T2DM is the most common comorbid risk factor for chronic kidney disease (CKD) and the leading cause of end-stage renal disease (ESRD). As of 2017, about 750,000 Americans have CKD stage 5 requiring dialysis, and 50% of these patients have preexisting diabetic nephropathy.² Rates of mortality and morbidity are observed to be higher in patients with both CKD and T2DM compared with patients with CKD without T2DM.² Previous clinical trials, including the United Kingdom Prospective Diabetes Study of 1998, have proven that optimal glycemic control decreases the risk of complications of T2DM (ie, nephropathy) in the general population.³ Conversely, tight glycemic control that targets hemoglobin A_1c (HbA_1c) < 7%, in patients with T2DM with ESRD has not shown the same benefits and may lead to worse outcomes. It is postulated that this may be due to the increased incidence of hypoglycemia in this patient population.⁴

Dialysis has varying effects on patients both with and without T2DM. While patients with ESRD without T2DM have the potential to develop impaired glucose tolerance and T2DM, about 33% of patients with T2DM on dialysis actually have HbA_1c < 6%.⁵ In these patients, glycemic control improves spontaneously as their disease progresses, leading to a decrease or cessation of insulin or other antidiabetic medications. This phenomenon, known as burnt-out diabetes, is characterized by (1) alterations in glucose homeostasis and normoglycemia without antidiabetic treatment; (2) HbA_1c levels < 6% despite having established T2DM; (3) decline in insulin requirements or cessation of insulin altogether; and (4) spontaneous hypoglycemia.

There is a misconception that burnt-out diabetes is a favorable condition due to the alteration of the natural course of T2DM. Although this may be true, patients with this condition are prone to develop hypoglycemic episodes and may be linked to poor survival outcomes due to low HbA_1c.^6,7

Since Kalantar-Zadeh and colleagues presented a 2009 case study, there has been a lack of research regarding this unique condition.⁸ The purpose of this case study is to shed further light on burnt-out diabetes and present a patient case pertaining to the challenges of glycemic control in ESRD.

Case Presentation

Mr. A is a 49-year-old Hispanic male veteran with a history of ESRD on hemodialysis (HD) for 6 years, anemia of CKD, and T2DM for 22 years. The patient also has an extensive cardiovascular disease history, including hypertension, hyperlipidemia, and CAD status post-4-vessel coronary artery bypass graft in December 2014. The patient receives in-home HD Monday, Wednesday, and Friday and is on the wait list for kidney transplantation. The patient’s T2DM is managed by a primary care clinical pharmacy specialist (CPS) at the Michael E. DeBakey Veteran Affairs Medical Center (MEDVAMC) in Houston, Texas.

Mr. A’s antidiabetic regimen is 45 units of subcutaneous insulin glargine every morning; insulin aspart sliding scale (about 15-27 units) subcutaneous 3 times daily with meals; and saxagliptin 2.5 mg by mouth once daily.

At a follow-up visit with the CPS, Mr. A stated, “I feel fine except for the occasional low blood sugar episode.” The patient’s most recent HbA_1c was 6.1%, and he reported medication adherence and no signs or symptoms of hyperglycemia (ie, polydipsia, polyphagia, nocturia, visual disturbances). Mr. A reported no use of alcohol, tobacco, or illicit drugs. He walks 1 mile every other day and participates in self-monitoring blood glucose (SMBG) about 2 to 3 times daily (Table 1).

Analysis

Few articles on potential contributors to burnt-out diabetes have been published.^6,7 These articles discuss decreased renal and hepatic clearance of insulin (which increases its half-life) hypoglycemia during HD, and low HbA_1c due to preexisting anemia. Inappropriately low HbA_1c levels may be secondary to, but not limited to, hemolysis, recent blood transfusion, acute blood loss, and medications, such as erythropoietin-stimulating agents (ESAs).⁹ The conditions that affect red blood cell turnover are common in patients with advanced CKD and may result in discrepancies in HbA_1c levels.

Glycated hemoglobin is a series of minor hemoglobin components formed by the adduction of various carbohydrate molecules to hemoglobin. HbA_1c is the largest fraction formed and the most consistent index of the concentration of glucose in the blood.¹⁰ Hence, HbA_1c is the traditional indicator of overall glycemic control. The current HbA_1c goals recommended by the American Diabetes Association are derived from landmark trials conducted with patients in the general adult diabetic non-CKD population. However, hemoglobin measurements can be confounded by conditions present in ESRD and tend to underestimate glucose measurements in patients with T2DM on HD. Despite this, HbA_1c is still regarded as a reasonable measure of glycemic control even in patients with ESRD; however, alternative markers of glycemia may be preferable.¹¹

Although HbA_1c is the gold standard, there are other laboratory measures of average glycemic control available. Fructosamine is a ketoamine formed when glucose binds to serum proteins. When these proteins are exposed to high concentrations of glucose, they experience increased glycation. Fructosamine assays measure the total glycated serum proteins, of which albumin accounts for about 90%.¹¹ Because the half-life of serum proteins is about 20 days, fructosamine levels can reflect glycemic control over a 2- to 3-week period. This is advantageous in conditions that affect the average age of red blood cells, in pregnancy where frequent monitoring and measures of short-term glucose control are especially important, and in the evaluation of a medication adjustment in the management of T2DM. However, this test is not without its limitations. It is less reliable in settings of decreased protein levels (eg, liver disease), there is a lack of availability in routine practice, and reference levels have not been established.¹¹

Hypoglycemic Episodes

At the 2-month follow-up visit with the CPS, Mr. A reported having 5 hypoglycemic episodes in the past 30 days. He also stated he would forget to take his insulin aspart dose before dinner about 3 to 4 times a week but would take it 30 to 60 minutes after the meal. Mr. A did not bring his glucometer or SMBG readings to the visit, but he indicated that his blood glucose levels continued to fluctuate and were elevated when consuming carbohydrates.

Laboratory tests 1 month prior to the 2-month follow-up visit showed HbA_1c of 7.3%, which had increased from his previous level of 6.1%. He was counseled on the proper administration of insulin aspart and lifestyle modifications. A fructosamine level was ordered at this visit to further assess his glycemic control. A follow-up appointment and laboratory workup (fructosamine and HbA_1c) were scheduled for 2 months from the visit (Table 3).

Mr. A was educated on the unreliability of his HbA_1c levels secondary to his condition of ESRD on HD. He was counseled on the purpose of fructosamine and how it may be a better predictor of his glycemic control and morbidity. Mr. A continued to be followed closely by the primary care CPS for T2DM management.

Discussion

Management of T2DM in patients with ESRD presents challenges for clinicians in determining HbA_1c goals and selecting appropriate medication options. The 2012 Kidney Disease Outcomes Quality Initiative (KDOQI) diabetes guideline does not recommend treatment for patients with substantially reduced kidney function to a target HbA_1c < 7% due to risk of hypoglycemia.¹³ Although a target HbA_1c > 7% is suggested for these patients, little is known about appropriate glycemic control in these patients as there is a paucity of prospective, randomized clinical trials that include patients with advanced CKD.¹³

Moreover, many oral antidiabetic medications and their metabolites are cleared by the kidneys and, therefore, pose with potential harm for patients with CKD. Because of this, insulin is the medication of choice for patients with ESRD.⁷ Although insulin requirements may diminish with worsening kidney function, insulin provides the safest method of glycemic control. Insulin dosing can be individualized according to a patient’s renal status as there is no uniformity in renal dose adjustments. There are some noninsulin antidiabetic agents that can be used in ESRD, but use of these agents requires close monitoring and evaluation of the medication’s pharmacokinetics (Table 4). Overall, medication management can be a difficult task for patients with T2DM and ESRD, but antidiabetic regimens may be reduced or discontinued altogether in burnt-out diabetes.

Conclusions

Patients with T2DM and ESRD on dialysis may have higher morbidity and mortality rates than the rates of those without T2DM. It has been shown in various studies that very low HbA_1c (< 5%) and high HbA_1c (> 8%) are associated with poor survival. Some patients with T2DM on dialysis may experience burnt-out diabetes in which they may have normoglycemia and a HbA_1c below goal; despite these facts, this condition is not positive and can be linked to bad outcomes. In patients with T2DM and ESRD, insulin is the antidiabetic medication of choice, and we recommend a HbA_1c target of 6 to 8%. In this patient population, consider using fructosamine levels or other measures of glycemic control to supplement HbA_1c and glucose values to provide a better assessment of glycemic control, morbidity, and mortality. Larger clinical trials are needed to assist in answering questions regarding mortality and optimal HbA_1c targets in burnt-out diabetes.

THE CASE

An obese 90-year-old White man presented for a 1-month follow-up with his family physician after being hospitalized for an acute exacerbation of heart failure (HF). In addition to New York Heart Association (NYHA) Class III heart failure with reduced ejection fraction (HFrEF), he had a history of tobacco abuse, hyperlipidemia, atrial fibrillation, coronary artery disease, stage 3 chronic kidney disease, and benign prostatic hyperplasia. The patient’s family accompanied him during the visit to discuss hospice care.

The patient complained of persistent shortness of breath that limited his activities of daily living (ADLs) and lower extremity and scrotal edema. He denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, ascites, nocturia, and nocturnal cough.

The patient had undergone a coronary artery bypass graft 23 years earlier. His HF was being managed with metoprolol tartrate 25 mg bid, spironolactone 25 mg/d, and furosemide 80 mg/d.

Examination revealed bilateral 3+ pitting edema in the lower extremities midway up the shin, crackles to the inferior scapula bilaterally, and a 3/6 systolic murmur with regular rate and rhythm. The remainder of the physical exam was normal. The patient’s vitals were within normal limits, with an oxygen saturation of 90%.

The patient’s most recent chest x-ray demonstrated mild cardiomegaly. An echocardiogram showed an ejection fraction of 44% with severe bi-atrial enlargement, moderate-to-severe mitral regurgitation, and mild-to-moderate aortic insufficiency. His brain natriuretic peptide (BNP) was 915 pg/mL (normal range for patients ages 75-99 years, < 450 pg/mL).

THE DIAGNOSIS

The differential diagnosis for the patient’s shortness of breath included chronic obstructive pulmonary disease secondary to his smoking history, pulmonary embolus, respiratory infection, anemia, and medication-related adverse effects. The patient’s history of renal disease merited consideration of a nephrotic syndrome causing low albumin, which could explain his edema. Another possible cause of the edema was venous insufficiency. However, given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to the current diuretic regimen.

Several changes to the patient’s medications were made. Lisinopril 2.5 mg/d was started due to the mortality benefit of angiotensin-converting enzyme inhibitors in the treatment of HFrEF.¹ Metoprolol tartrate 25 mg/d was transitioned to metoprolol succinate 50 mg/d, as only the longer-acting succinate version has shown mortality benefit in HFrEF.¹ (Other beta-blockers with mortality benefit include carvedilol and bisoprolol.¹) The furosemide 80 mg/d was replaced with torsemide 100 mg/d to provide an enhanced diuretic effect for symptomatic relief. The spironolactone dose was not increased due to concerns about the patient’s renal function. Of note, spironolactone was included in the patient’s regimen based on his NYHA classification, as well as the potential mortality benefits and improvement in edema seen in HFrEF patients.¹ Spironolactone can be used with loop and/or thiazide diuretics in the treatment of HF.

Continue to: Within 5 days...

Within 5 days, the patient had lost 6 lb and his oxygen saturation had improved from 90% to 95%. He reported improvements in his breathing and was able to move around more easily.

DISCUSSION

There are several possible explanations for torsemide’s superior diuretic effect in this patient. Unlike furosemide, torsemide absorption is not influenced by intestinal edema, which is commonly seen in patients with HF. It has a longer half-life and improved bioavailability that is not altered by food intake. Torsemide also inhibits the actions of aldosterone through its interaction with the renin-angiotensin-aldosterone system and aldosterone receptor, leading to further diuresis and reduced cardiac remodeling.²

What the evidence shows. The ­TORIC trial was an open-label, nonrandomized, post-marketing surveillance study of 1377 patients with NYHA Class II–III HF who received diuretic therapy with torsemide 10 mg/d, furosemide 40 mg/d, or another diuretic for 12 months.³ Significantly lower total mortality and cardiac mortality was found in the torsemide group; in addition, a significantly greater proportion of patients in the torsemide group showed improvement in NYHA classification.³ Murray et al reported a reduction in hospitalization rates with torsemide therapy vs furosemide therapy in a randomized trial of 234 HF patients (32% vs 17%, P = 0.01).⁴ The ASCEND-HF trial, a large international acute HF trial comparing torsemide with furosemide, demonstrated a nonsignificant reduction in 30-day and 180-day events (all-cause mortality or HF hospitalization) in those receiving torsemide, after risk adjustment.⁵ Torsemide has also been shown to improve quality of life compared to furosemide.⁶

Given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to his diuretic regimen.

Preliminary results from the TORNADO trial,⁷ a multicenter randomized controlled trial, demonstrated superior symptom improvement in HF patients taking torsemide compared to those taking furosemide.⁸ The preliminary endpoint—a composite of improvement in NYHA class, improvement in distance of at least 50 m during a 6-minute walk test, and a decrease in fluid retention of at least 0.5 ohms at 3-month follow-up—was achieved by 94% and 58% of patients on torsemide and furosemide, respectively (P = 0.03).⁸ A total of 7 patients (3 in the torsemide and 4 in the furosemide group) were hospitalized for worsening HF during the follow-up period.⁸

A 2020 meta-analysis of more than 19,000 patients compared furosemide to torsemide and found a number needed to treat (NNT) of 23 to prevent a hospitalization due to HF; an NNT of 5 for improvement in NYHA functional status; and an NNT of 40 for reduction in cardiac mortality.⁹

Continue to: Our patient

Our patient reported feeling “great” at the 6-week follow-up appointment, with significant improvement in breathing and ability to perform his ADLs. His NYHA classification improved to Class II. He had lost 26 pounds (back to his weight 9 months prior), and his oxygen saturation was 97%.

On exam, the bilateral peripheral edema in his lower extremities had improved from 3+ to 1+, with the edema extending just distal to the mid-shin. Only mild crackles were present at the lung bases. The remainder of his physical examination was unchanged. His vital signs were within normal limits with no signs of hypotension. A basic metabolic panel was obtained to confirm his electrolytes were still within normal limits. His BNP had decreased to 230 pg/mL.

The patient declined the referral for hospice evaluation due to the significant improvement in his symptoms.

THE TAKEAWAY

A significant clinical improvement and improved quality of life were achieved with the transition from furosemide to torsemide. It is apparent that the patient’s furosemide had an inferior diuretic effect compared to torsemide, whether that be secondary to his dose or due to the unpredictable nature of furosemide’s bioavailability, especially in the setting of intestinal edema.

A growing body of literature^9-11 suggests torsemide’s superiority over furosemide with no signs of increased adverse effects. Although additional prospective, head-to-head trials are needed, at this point in time it is appropriate to consider the use of torsemide in a patient with HF who does not seem to be fully responding to furosemide.

CORRESPONDENCE
Ryan Paulus, DO, 590 Manning Drive, Chapel Hill, NC 27599; [email protected]

THE CASE

An obese 90-year-old White man presented for a 1-month follow-up with his family physician after being hospitalized for an acute exacerbation of heart failure (HF). In addition to New York Heart Association (NYHA) Class III heart failure with reduced ejection fraction (HFrEF), he had a history of tobacco abuse, hyperlipidemia, atrial fibrillation, coronary artery disease, stage 3 chronic kidney disease, and benign prostatic hyperplasia. The patient’s family accompanied him during the visit to discuss hospice care.

The patient complained of persistent shortness of breath that limited his activities of daily living (ADLs) and lower extremity and scrotal edema. He denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, ascites, nocturia, and nocturnal cough.

The patient had undergone a coronary artery bypass graft 23 years earlier. His HF was being managed with metoprolol tartrate 25 mg bid, spironolactone 25 mg/d, and furosemide 80 mg/d.

Examination revealed bilateral 3+ pitting edema in the lower extremities midway up the shin, crackles to the inferior scapula bilaterally, and a 3/6 systolic murmur with regular rate and rhythm. The remainder of the physical exam was normal. The patient’s vitals were within normal limits, with an oxygen saturation of 90%.

The patient’s most recent chest x-ray demonstrated mild cardiomegaly. An echocardiogram showed an ejection fraction of 44% with severe bi-atrial enlargement, moderate-to-severe mitral regurgitation, and mild-to-moderate aortic insufficiency. His brain natriuretic peptide (BNP) was 915 pg/mL (normal range for patients ages 75-99 years, < 450 pg/mL).

THE DIAGNOSIS

The differential diagnosis for the patient’s shortness of breath included chronic obstructive pulmonary disease secondary to his smoking history, pulmonary embolus, respiratory infection, anemia, and medication-related adverse effects. The patient’s history of renal disease merited consideration of a nephrotic syndrome causing low albumin, which could explain his edema. Another possible cause of the edema was venous insufficiency. However, given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to the current diuretic regimen.

Several changes to the patient’s medications were made. Lisinopril 2.5 mg/d was started due to the mortality benefit of angiotensin-converting enzyme inhibitors in the treatment of HFrEF.¹ Metoprolol tartrate 25 mg/d was transitioned to metoprolol succinate 50 mg/d, as only the longer-acting succinate version has shown mortality benefit in HFrEF.¹ (Other beta-blockers with mortality benefit include carvedilol and bisoprolol.¹) The furosemide 80 mg/d was replaced with torsemide 100 mg/d to provide an enhanced diuretic effect for symptomatic relief. The spironolactone dose was not increased due to concerns about the patient’s renal function. Of note, spironolactone was included in the patient’s regimen based on his NYHA classification, as well as the potential mortality benefits and improvement in edema seen in HFrEF patients.¹ Spironolactone can be used with loop and/or thiazide diuretics in the treatment of HF.

Continue to: Within 5 days...

Within 5 days, the patient had lost 6 lb and his oxygen saturation had improved from 90% to 95%. He reported improvements in his breathing and was able to move around more easily.

DISCUSSION

There are several possible explanations for torsemide’s superior diuretic effect in this patient. Unlike furosemide, torsemide absorption is not influenced by intestinal edema, which is commonly seen in patients with HF. It has a longer half-life and improved bioavailability that is not altered by food intake. Torsemide also inhibits the actions of aldosterone through its interaction with the renin-angiotensin-aldosterone system and aldosterone receptor, leading to further diuresis and reduced cardiac remodeling.²

What the evidence shows. The ­TORIC trial was an open-label, nonrandomized, post-marketing surveillance study of 1377 patients with NYHA Class II–III HF who received diuretic therapy with torsemide 10 mg/d, furosemide 40 mg/d, or another diuretic for 12 months.³ Significantly lower total mortality and cardiac mortality was found in the torsemide group; in addition, a significantly greater proportion of patients in the torsemide group showed improvement in NYHA classification.³ Murray et al reported a reduction in hospitalization rates with torsemide therapy vs furosemide therapy in a randomized trial of 234 HF patients (32% vs 17%, P = 0.01).⁴ The ASCEND-HF trial, a large international acute HF trial comparing torsemide with furosemide, demonstrated a nonsignificant reduction in 30-day and 180-day events (all-cause mortality or HF hospitalization) in those receiving torsemide, after risk adjustment.⁵ Torsemide has also been shown to improve quality of life compared to furosemide.⁶

Given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to his diuretic regimen.

Preliminary results from the TORNADO trial,⁷ a multicenter randomized controlled trial, demonstrated superior symptom improvement in HF patients taking torsemide compared to those taking furosemide.⁸ The preliminary endpoint—a composite of improvement in NYHA class, improvement in distance of at least 50 m during a 6-minute walk test, and a decrease in fluid retention of at least 0.5 ohms at 3-month follow-up—was achieved by 94% and 58% of patients on torsemide and furosemide, respectively (P = 0.03).⁸ A total of 7 patients (3 in the torsemide and 4 in the furosemide group) were hospitalized for worsening HF during the follow-up period.⁸

A 2020 meta-analysis of more than 19,000 patients compared furosemide to torsemide and found a number needed to treat (NNT) of 23 to prevent a hospitalization due to HF; an NNT of 5 for improvement in NYHA functional status; and an NNT of 40 for reduction in cardiac mortality.⁹

Continue to: Our patient

Our patient reported feeling “great” at the 6-week follow-up appointment, with significant improvement in breathing and ability to perform his ADLs. His NYHA classification improved to Class II. He had lost 26 pounds (back to his weight 9 months prior), and his oxygen saturation was 97%.

On exam, the bilateral peripheral edema in his lower extremities had improved from 3+ to 1+, with the edema extending just distal to the mid-shin. Only mild crackles were present at the lung bases. The remainder of his physical examination was unchanged. His vital signs were within normal limits with no signs of hypotension. A basic metabolic panel was obtained to confirm his electrolytes were still within normal limits. His BNP had decreased to 230 pg/mL.

The patient declined the referral for hospice evaluation due to the significant improvement in his symptoms.

THE TAKEAWAY

A significant clinical improvement and improved quality of life were achieved with the transition from furosemide to torsemide. It is apparent that the patient’s furosemide had an inferior diuretic effect compared to torsemide, whether that be secondary to his dose or due to the unpredictable nature of furosemide’s bioavailability, especially in the setting of intestinal edema.

A growing body of literature^9-11 suggests torsemide’s superiority over furosemide with no signs of increased adverse effects. Although additional prospective, head-to-head trials are needed, at this point in time it is appropriate to consider the use of torsemide in a patient with HF who does not seem to be fully responding to furosemide.

CORRESPONDENCE
Ryan Paulus, DO, 590 Manning Drive, Chapel Hill, NC 27599; [email protected]

THE CASE

An obese 90-year-old White man presented for a 1-month follow-up with his family physician after being hospitalized for an acute exacerbation of heart failure (HF). In addition to New York Heart Association (NYHA) Class III heart failure with reduced ejection fraction (HFrEF), he had a history of tobacco abuse, hyperlipidemia, atrial fibrillation, coronary artery disease, stage 3 chronic kidney disease, and benign prostatic hyperplasia. The patient’s family accompanied him during the visit to discuss hospice care.

The patient complained of persistent shortness of breath that limited his activities of daily living (ADLs) and lower extremity and scrotal edema. He denied chest pain, orthopnea, paroxysmal nocturnal dyspnea, ascites, nocturia, and nocturnal cough.

The patient had undergone a coronary artery bypass graft 23 years earlier. His HF was being managed with metoprolol tartrate 25 mg bid, spironolactone 25 mg/d, and furosemide 80 mg/d.

Examination revealed bilateral 3+ pitting edema in the lower extremities midway up the shin, crackles to the inferior scapula bilaterally, and a 3/6 systolic murmur with regular rate and rhythm. The remainder of the physical exam was normal. The patient’s vitals were within normal limits, with an oxygen saturation of 90%.

The patient’s most recent chest x-ray demonstrated mild cardiomegaly. An echocardiogram showed an ejection fraction of 44% with severe bi-atrial enlargement, moderate-to-severe mitral regurgitation, and mild-to-moderate aortic insufficiency. His brain natriuretic peptide (BNP) was 915 pg/mL (normal range for patients ages 75-99 years, < 450 pg/mL).

THE DIAGNOSIS

The differential diagnosis for the patient’s shortness of breath included chronic obstructive pulmonary disease secondary to his smoking history, pulmonary embolus, respiratory infection, anemia, and medication-related adverse effects. The patient’s history of renal disease merited consideration of a nephrotic syndrome causing low albumin, which could explain his edema. Another possible cause of the edema was venous insufficiency. However, given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to the current diuretic regimen.

Several changes to the patient’s medications were made. Lisinopril 2.5 mg/d was started due to the mortality benefit of angiotensin-converting enzyme inhibitors in the treatment of HFrEF.¹ Metoprolol tartrate 25 mg/d was transitioned to metoprolol succinate 50 mg/d, as only the longer-acting succinate version has shown mortality benefit in HFrEF.¹ (Other beta-blockers with mortality benefit include carvedilol and bisoprolol.¹) The furosemide 80 mg/d was replaced with torsemide 100 mg/d to provide an enhanced diuretic effect for symptomatic relief. The spironolactone dose was not increased due to concerns about the patient’s renal function. Of note, spironolactone was included in the patient’s regimen based on his NYHA classification, as well as the potential mortality benefits and improvement in edema seen in HFrEF patients.¹ Spironolactone can be used with loop and/or thiazide diuretics in the treatment of HF.

Continue to: Within 5 days...

Within 5 days, the patient had lost 6 lb and his oxygen saturation had improved from 90% to 95%. He reported improvements in his breathing and was able to move around more easily.

DISCUSSION

There are several possible explanations for torsemide’s superior diuretic effect in this patient. Unlike furosemide, torsemide absorption is not influenced by intestinal edema, which is commonly seen in patients with HF. It has a longer half-life and improved bioavailability that is not altered by food intake. Torsemide also inhibits the actions of aldosterone through its interaction with the renin-angiotensin-aldosterone system and aldosterone receptor, leading to further diuresis and reduced cardiac remodeling.²

What the evidence shows. The ­TORIC trial was an open-label, nonrandomized, post-marketing surveillance study of 1377 patients with NYHA Class II–III HF who received diuretic therapy with torsemide 10 mg/d, furosemide 40 mg/d, or another diuretic for 12 months.³ Significantly lower total mortality and cardiac mortality was found in the torsemide group; in addition, a significantly greater proportion of patients in the torsemide group showed improvement in NYHA classification.³ Murray et al reported a reduction in hospitalization rates with torsemide therapy vs furosemide therapy in a randomized trial of 234 HF patients (32% vs 17%, P = 0.01).⁴ The ASCEND-HF trial, a large international acute HF trial comparing torsemide with furosemide, demonstrated a nonsignificant reduction in 30-day and 180-day events (all-cause mortality or HF hospitalization) in those receiving torsemide, after risk adjustment.⁵ Torsemide has also been shown to improve quality of life compared to furosemide.⁶

Given the patient’s extensive cardiac history, the most likely explanation for his shortness of breath and edema was congestive HF that was unresponsive to his diuretic regimen.

Preliminary results from the TORNADO trial,⁷ a multicenter randomized controlled trial, demonstrated superior symptom improvement in HF patients taking torsemide compared to those taking furosemide.⁸ The preliminary endpoint—a composite of improvement in NYHA class, improvement in distance of at least 50 m during a 6-minute walk test, and a decrease in fluid retention of at least 0.5 ohms at 3-month follow-up—was achieved by 94% and 58% of patients on torsemide and furosemide, respectively (P = 0.03).⁸ A total of 7 patients (3 in the torsemide and 4 in the furosemide group) were hospitalized for worsening HF during the follow-up period.⁸

A 2020 meta-analysis of more than 19,000 patients compared furosemide to torsemide and found a number needed to treat (NNT) of 23 to prevent a hospitalization due to HF; an NNT of 5 for improvement in NYHA functional status; and an NNT of 40 for reduction in cardiac mortality.⁹

Continue to: Our patient

Our patient reported feeling “great” at the 6-week follow-up appointment, with significant improvement in breathing and ability to perform his ADLs. His NYHA classification improved to Class II. He had lost 26 pounds (back to his weight 9 months prior), and his oxygen saturation was 97%.

On exam, the bilateral peripheral edema in his lower extremities had improved from 3+ to 1+, with the edema extending just distal to the mid-shin. Only mild crackles were present at the lung bases. The remainder of his physical examination was unchanged. His vital signs were within normal limits with no signs of hypotension. A basic metabolic panel was obtained to confirm his electrolytes were still within normal limits. His BNP had decreased to 230 pg/mL.

The patient declined the referral for hospice evaluation due to the significant improvement in his symptoms.

THE TAKEAWAY

A significant clinical improvement and improved quality of life were achieved with the transition from furosemide to torsemide. It is apparent that the patient’s furosemide had an inferior diuretic effect compared to torsemide, whether that be secondary to his dose or due to the unpredictable nature of furosemide’s bioavailability, especially in the setting of intestinal edema.

A growing body of literature^9-11 suggests torsemide’s superiority over furosemide with no signs of increased adverse effects. Although additional prospective, head-to-head trials are needed, at this point in time it is appropriate to consider the use of torsemide in a patient with HF who does not seem to be fully responding to furosemide.

CORRESPONDENCE
Ryan Paulus, DO, 590 Manning Drive, Chapel Hill, NC 27599; [email protected]

THE CASE

A 67-year-old man with a history of gout, tobacco use, hypertension, hyperlipidemia, prediabetes, and newly diagnosed heart failure with reduced ejection fraction presented with a new concern for sudden-onset, atraumatic right upper extremity pain and swelling. The patient had awakened with these symptoms and on the following day went to the emergency department (ED) for evaluation. Review of the ED documentation highlighted that the patient was afebrile and was found to have a slight leukocytosis (11.7 x 10³/µL) and an elevated C-reactive protein level (4 mg/dL; normal range, 0.3 to 1 mg/dL). A right upper extremity x-ray was unremarkable. The patient was treated with cephalexin and colchicine for cellulitis and possible acute gout.

Three days after the ED visit, the patient presented to his primary care clinic, reporting adherence to the prescribed therapies (cephalexin and colchicine) but no improvement in symptoms. He was again afebrile, and his blood pressure was controlled to goal (118/80 mm Hg). On exam, he had significant nonpitting, unilateral edema extending from the elbow through the fingers without erythema, warmth, or rash (FIGURE). A right upper extremity ultrasound was obtained; results were negative for deep vein thrombosis.

Medication reconciliation completed during the clinic visit revealed that the patient had started and continued to take newly prescribed medications for the treatment of heart failure, including metoprolol succinate, lisinopril, and furosemide. The patient confirmed that these were started 7 days prior to symptom onset.

THE DIAGNOSIS

Given the clinical resemblance to angioedema and the recent initiation of lisinopril, the patient was asked to hold this medication. He was also advised to discontinue the cephalexin and colchicine, given low suspicion for cellulitis and gout. Six days later, he returned to clinic and reported significantly improved pain and swelling.

DISCUSSION

Angioedema is a common condition in the United States, affecting approximately 15% of the general population.¹ When associated with hypotension, respiratory compromise, and other end-organ dysfunction, it is treated as anaphylaxis. Angioedema without anaphylaxis can be categorized as either histaminergic or nonhistaminergic; the former is more common.²

Certain patient and disease characteristics are more prevalent in select subsets of angioedema, although there are no features that automatically identify an etiology. Here are some factors to consider:

Recent exposures. Within the histaminergic category, allergic angioedema has the longest list of potential causes, including medications (notably, antibiotics, nonsteroidal anti-inflammatory drugs, opiates, and perioperative medications), foods, latex, and insect stings and/or bites.² Nonhistaminergic subtypes, which include hereditary and acquired angioedema, are caused by deficiencies or mutations in complement or coagulation pathways, which can be more challenging to diagnose.

Continue to: Acquired angioedema may also...

Acquired angioedema may also be associated with the use of angiotensin-converting enzyme (ACE) inhibitors. Risk factors for ACE inhibitor–induced angioedema include history of smoking, increasing age, and female gender.³ African-American race has been correlated with increased incidence of angioedema, with rates 4 to 5 times that of Whites,¹ but race is now identified as a social and not a biological construct and should not be relied on to make medical decisions about prescribing.

The rate of occurrence for ACE inhibitor–induced angioedema is highest within the first 30 days of medication use²; however, it can occur anytime. The absolute risk has been estimated as 0.3% per year.⁴

Patient age. Histaminergic angioedema can occur at any age. The hereditary subtype of nonhistaminergic angioedema is more common in younger individuals, typically occurring in infancy to the second decade of life, and tends to run in families, while the acquired subtype often manifests in adults older than 40.²

Physical exam findings. The typical manifestation of nonhistaminergic angioedema is firm, nonpitting, nonpruritic swelling resulting from fluid shifts to the reticular dermis and subcutaneous or submucosal tissue. In comparison, histaminergic reactions commonly involve deeper dermal tissue.

The patient’s age, tobacco history, and recent initiation of an ACE inhibitor made acquired angioedema a more likely etiology.

Commonly affected anatomic sites also vary by angioedema type but do not directly distinguish a cause. Allergic and ACE inhibitor–induced subtypes more commonly involve the lips, tongue, larynx, and face, whereas hereditary and other acquired etiologies are more likely to affect the periphery, abdomen, face, larynx, and genitourinary systems.² So the way that this patient presented was a bit unusual.

Continue to: Symptom history

Symptom history. Allergic angioedema often has a rapid onset and resolution, whereas hereditary and acquired subtypes appear more gradually.² While the presence of urticaria distinguishes a histaminergic reaction, both histaminergic and nonhistaminergic angioedema may manifest without this symptom.

In our patient, the timeline of gradual symptom manifestation and the physical exam findings, as well as the patient’s age, tobacco history, and recent initiation of an ACE inhibitor, made acquired angioedema a more likely etiology.

Treatment for ACE inhibitor–induced angioedema, in addition to airway support, entails drug discontinuation. This typically leads to symptom resolution within 24 to 48 hours.² Treatment with corticosteroids, antihistamines, and epinephrine is usually ineffective. Switching to an alternative ACE inhibitor is not recommended, as other members of the class carry the same risk. Instead, angiotensin receptor blockers (ARBs) are an appropriate substitute, as the incidence of cross-reactivity in ACE inhibitor–intolerant patients is estimated to be 10% or less,⁵ and the risk for recurrence has been shown to be no different than with placebo.^3,4

Our patient was transitioned to losartan 25 mg/d without recurrence of his symptoms and with continued blood pressure control (125/60 mm Hg).

THE TAKEAWAY

Angioedema is a common condition. While many medications are associated with histaminergic angioedema, ACE inhibitors are a common cause of the acquired subtype of nonhistaminergic angioedema. Commonly affected sites include the lips, tongue, and face; however, this diagnosis is not dependent on location and may manifest at other sites, as seen in this case. Treatment involves medication discontinuation. When switching the patient’s medication, other members of the ACE inhibitor class should be avoided. ARBs are an appropriate alternative without increased risk for recurrence.

CORRESPONDENCE
Katherine Montag Schafer, University of Minnesota— Department of Family Medicine and Community Health, 1414 Maryland Avenue E, St Paul, MN 55106; [email protected]

THE CASE

A 67-year-old man with a history of gout, tobacco use, hypertension, hyperlipidemia, prediabetes, and newly diagnosed heart failure with reduced ejection fraction presented with a new concern for sudden-onset, atraumatic right upper extremity pain and swelling. The patient had awakened with these symptoms and on the following day went to the emergency department (ED) for evaluation. Review of the ED documentation highlighted that the patient was afebrile and was found to have a slight leukocytosis (11.7 x 10³/µL) and an elevated C-reactive protein level (4 mg/dL; normal range, 0.3 to 1 mg/dL). A right upper extremity x-ray was unremarkable. The patient was treated with cephalexin and colchicine for cellulitis and possible acute gout.

Three days after the ED visit, the patient presented to his primary care clinic, reporting adherence to the prescribed therapies (cephalexin and colchicine) but no improvement in symptoms. He was again afebrile, and his blood pressure was controlled to goal (118/80 mm Hg). On exam, he had significant nonpitting, unilateral edema extending from the elbow through the fingers without erythema, warmth, or rash (FIGURE). A right upper extremity ultrasound was obtained; results were negative for deep vein thrombosis.

Medication reconciliation completed during the clinic visit revealed that the patient had started and continued to take newly prescribed medications for the treatment of heart failure, including metoprolol succinate, lisinopril, and furosemide. The patient confirmed that these were started 7 days prior to symptom onset.

THE DIAGNOSIS

Given the clinical resemblance to angioedema and the recent initiation of lisinopril, the patient was asked to hold this medication. He was also advised to discontinue the cephalexin and colchicine, given low suspicion for cellulitis and gout. Six days later, he returned to clinic and reported significantly improved pain and swelling.

DISCUSSION

Angioedema is a common condition in the United States, affecting approximately 15% of the general population.¹ When associated with hypotension, respiratory compromise, and other end-organ dysfunction, it is treated as anaphylaxis. Angioedema without anaphylaxis can be categorized as either histaminergic or nonhistaminergic; the former is more common.²

Certain patient and disease characteristics are more prevalent in select subsets of angioedema, although there are no features that automatically identify an etiology. Here are some factors to consider:

Recent exposures. Within the histaminergic category, allergic angioedema has the longest list of potential causes, including medications (notably, antibiotics, nonsteroidal anti-inflammatory drugs, opiates, and perioperative medications), foods, latex, and insect stings and/or bites.² Nonhistaminergic subtypes, which include hereditary and acquired angioedema, are caused by deficiencies or mutations in complement or coagulation pathways, which can be more challenging to diagnose.

Continue to: Acquired angioedema may also...

Acquired angioedema may also be associated with the use of angiotensin-converting enzyme (ACE) inhibitors. Risk factors for ACE inhibitor–induced angioedema include history of smoking, increasing age, and female gender.³ African-American race has been correlated with increased incidence of angioedema, with rates 4 to 5 times that of Whites,¹ but race is now identified as a social and not a biological construct and should not be relied on to make medical decisions about prescribing.

The rate of occurrence for ACE inhibitor–induced angioedema is highest within the first 30 days of medication use²; however, it can occur anytime. The absolute risk has been estimated as 0.3% per year.⁴

Patient age. Histaminergic angioedema can occur at any age. The hereditary subtype of nonhistaminergic angioedema is more common in younger individuals, typically occurring in infancy to the second decade of life, and tends to run in families, while the acquired subtype often manifests in adults older than 40.²

Physical exam findings. The typical manifestation of nonhistaminergic angioedema is firm, nonpitting, nonpruritic swelling resulting from fluid shifts to the reticular dermis and subcutaneous or submucosal tissue. In comparison, histaminergic reactions commonly involve deeper dermal tissue.

The patient’s age, tobacco history, and recent initiation of an ACE inhibitor made acquired angioedema a more likely etiology.

Commonly affected anatomic sites also vary by angioedema type but do not directly distinguish a cause. Allergic and ACE inhibitor–induced subtypes more commonly involve the lips, tongue, larynx, and face, whereas hereditary and other acquired etiologies are more likely to affect the periphery, abdomen, face, larynx, and genitourinary systems.² So the way that this patient presented was a bit unusual.

Continue to: Symptom history

Symptom history. Allergic angioedema often has a rapid onset and resolution, whereas hereditary and acquired subtypes appear more gradually.² While the presence of urticaria distinguishes a histaminergic reaction, both histaminergic and nonhistaminergic angioedema may manifest without this symptom.

In our patient, the timeline of gradual symptom manifestation and the physical exam findings, as well as the patient’s age, tobacco history, and recent initiation of an ACE inhibitor, made acquired angioedema a more likely etiology.

Treatment for ACE inhibitor–induced angioedema, in addition to airway support, entails drug discontinuation. This typically leads to symptom resolution within 24 to 48 hours.² Treatment with corticosteroids, antihistamines, and epinephrine is usually ineffective. Switching to an alternative ACE inhibitor is not recommended, as other members of the class carry the same risk. Instead, angiotensin receptor blockers (ARBs) are an appropriate substitute, as the incidence of cross-reactivity in ACE inhibitor–intolerant patients is estimated to be 10% or less,⁵ and the risk for recurrence has been shown to be no different than with placebo.^3,4

Our patient was transitioned to losartan 25 mg/d without recurrence of his symptoms and with continued blood pressure control (125/60 mm Hg).

THE TAKEAWAY

Angioedema is a common condition. While many medications are associated with histaminergic angioedema, ACE inhibitors are a common cause of the acquired subtype of nonhistaminergic angioedema. Commonly affected sites include the lips, tongue, and face; however, this diagnosis is not dependent on location and may manifest at other sites, as seen in this case. Treatment involves medication discontinuation. When switching the patient’s medication, other members of the ACE inhibitor class should be avoided. ARBs are an appropriate alternative without increased risk for recurrence.

CORRESPONDENCE
Katherine Montag Schafer, University of Minnesota— Department of Family Medicine and Community Health, 1414 Maryland Avenue E, St Paul, MN 55106; [email protected]

THE CASE

A 67-year-old man with a history of gout, tobacco use, hypertension, hyperlipidemia, prediabetes, and newly diagnosed heart failure with reduced ejection fraction presented with a new concern for sudden-onset, atraumatic right upper extremity pain and swelling. The patient had awakened with these symptoms and on the following day went to the emergency department (ED) for evaluation. Review of the ED documentation highlighted that the patient was afebrile and was found to have a slight leukocytosis (11.7 x 10³/µL) and an elevated C-reactive protein level (4 mg/dL; normal range, 0.3 to 1 mg/dL). A right upper extremity x-ray was unremarkable. The patient was treated with cephalexin and colchicine for cellulitis and possible acute gout.

Three days after the ED visit, the patient presented to his primary care clinic, reporting adherence to the prescribed therapies (cephalexin and colchicine) but no improvement in symptoms. He was again afebrile, and his blood pressure was controlled to goal (118/80 mm Hg). On exam, he had significant nonpitting, unilateral edema extending from the elbow through the fingers without erythema, warmth, or rash (FIGURE). A right upper extremity ultrasound was obtained; results were negative for deep vein thrombosis.

Medication reconciliation completed during the clinic visit revealed that the patient had started and continued to take newly prescribed medications for the treatment of heart failure, including metoprolol succinate, lisinopril, and furosemide. The patient confirmed that these were started 7 days prior to symptom onset.

THE DIAGNOSIS

Given the clinical resemblance to angioedema and the recent initiation of lisinopril, the patient was asked to hold this medication. He was also advised to discontinue the cephalexin and colchicine, given low suspicion for cellulitis and gout. Six days later, he returned to clinic and reported significantly improved pain and swelling.

DISCUSSION

Angioedema is a common condition in the United States, affecting approximately 15% of the general population.¹ When associated with hypotension, respiratory compromise, and other end-organ dysfunction, it is treated as anaphylaxis. Angioedema without anaphylaxis can be categorized as either histaminergic or nonhistaminergic; the former is more common.²

Certain patient and disease characteristics are more prevalent in select subsets of angioedema, although there are no features that automatically identify an etiology. Here are some factors to consider:

Recent exposures. Within the histaminergic category, allergic angioedema has the longest list of potential causes, including medications (notably, antibiotics, nonsteroidal anti-inflammatory drugs, opiates, and perioperative medications), foods, latex, and insect stings and/or bites.² Nonhistaminergic subtypes, which include hereditary and acquired angioedema, are caused by deficiencies or mutations in complement or coagulation pathways, which can be more challenging to diagnose.

Continue to: Acquired angioedema may also...

Acquired angioedema may also be associated with the use of angiotensin-converting enzyme (ACE) inhibitors. Risk factors for ACE inhibitor–induced angioedema include history of smoking, increasing age, and female gender.³ African-American race has been correlated with increased incidence of angioedema, with rates 4 to 5 times that of Whites,¹ but race is now identified as a social and not a biological construct and should not be relied on to make medical decisions about prescribing.

The rate of occurrence for ACE inhibitor–induced angioedema is highest within the first 30 days of medication use²; however, it can occur anytime. The absolute risk has been estimated as 0.3% per year.⁴

Patient age. Histaminergic angioedema can occur at any age. The hereditary subtype of nonhistaminergic angioedema is more common in younger individuals, typically occurring in infancy to the second decade of life, and tends to run in families, while the acquired subtype often manifests in adults older than 40.²

Physical exam findings. The typical manifestation of nonhistaminergic angioedema is firm, nonpitting, nonpruritic swelling resulting from fluid shifts to the reticular dermis and subcutaneous or submucosal tissue. In comparison, histaminergic reactions commonly involve deeper dermal tissue.

The patient’s age, tobacco history, and recent initiation of an ACE inhibitor made acquired angioedema a more likely etiology.

Commonly affected anatomic sites also vary by angioedema type but do not directly distinguish a cause. Allergic and ACE inhibitor–induced subtypes more commonly involve the lips, tongue, larynx, and face, whereas hereditary and other acquired etiologies are more likely to affect the periphery, abdomen, face, larynx, and genitourinary systems.² So the way that this patient presented was a bit unusual.

Continue to: Symptom history

Symptom history. Allergic angioedema often has a rapid onset and resolution, whereas hereditary and acquired subtypes appear more gradually.² While the presence of urticaria distinguishes a histaminergic reaction, both histaminergic and nonhistaminergic angioedema may manifest without this symptom.

In our patient, the timeline of gradual symptom manifestation and the physical exam findings, as well as the patient’s age, tobacco history, and recent initiation of an ACE inhibitor, made acquired angioedema a more likely etiology.

Treatment for ACE inhibitor–induced angioedema, in addition to airway support, entails drug discontinuation. This typically leads to symptom resolution within 24 to 48 hours.² Treatment with corticosteroids, antihistamines, and epinephrine is usually ineffective. Switching to an alternative ACE inhibitor is not recommended, as other members of the class carry the same risk. Instead, angiotensin receptor blockers (ARBs) are an appropriate substitute, as the incidence of cross-reactivity in ACE inhibitor–intolerant patients is estimated to be 10% or less,⁵ and the risk for recurrence has been shown to be no different than with placebo.^3,4

Our patient was transitioned to losartan 25 mg/d without recurrence of his symptoms and with continued blood pressure control (125/60 mm Hg).

THE TAKEAWAY

Angioedema is a common condition. While many medications are associated with histaminergic angioedema, ACE inhibitors are a common cause of the acquired subtype of nonhistaminergic angioedema. Commonly affected sites include the lips, tongue, and face; however, this diagnosis is not dependent on location and may manifest at other sites, as seen in this case. Treatment involves medication discontinuation. When switching the patient’s medication, other members of the ACE inhibitor class should be avoided. ARBs are an appropriate alternative without increased risk for recurrence.

CORRESPONDENCE
Katherine Montag Schafer, University of Minnesota— Department of Family Medicine and Community Health, 1414 Maryland Avenue E, St Paul, MN 55106; [email protected]

Mercury poisoning affects multiple body systems, leading to variable clinical presentations. Mercury intoxication at low levels frequently presents with weakness, fatigue, weight loss, and abdominal pain. At higher levels of mercury intoxication, tremors and neurologic dysfunction are more prevalent.¹ Dermatologic manifestations of mercury exposure vary and include pink disease (acrodynia), mercury exanthem, contact dermatitis, and cutaneous granulomas. Untreated mercury poisoning may result in severe complications, including renal tubular necrosis, pneumonitis, persistent neurologic dysfunction, and fatality in some cases.^1,2

Pink disease is a rare disease that typically arises in infants and young children from chronic mercury exposure.³ We report a unique presentation of pink disease occurring in an 18-year-old woman following mercury exposure.

Case Report

An 18-year-old woman who was previously healthy presented to the hospital for evaluation of body aches and back pain. She reported a transient rash on the torso 2 weeks prior, but at the current presentation, only the distal upper and lower extremities were involved. A review of systems revealed myalgia, most severe in the lower back; muscle spasms; stiffness in the fingers; abdominal pain; constipation; paresthesia in the hands and feet; hyperhidrosis; and generalized weakness.

Vitals on admission revealed tachycardia (112 beats per minute). Physical examination revealed the patient was pale and fatigued; she appeared to be in pain, with observable facial grimacing and muscle spasms in the legs. She had poorly demarcated pink macules and papules scattered on the left palm (Figure 1), right forearm, right wrist, and dorsal aspects of the feet including the soles. A few pinpoint pustules were present on the left fifth digit.

A diagnosis of mercury poisoning was made along with a component of postinfectious reactive arthropathy due to Campylobacter. The myokymia and skin eruption were believed to be secondary to mercury poisoning. The patient was started on ciprofloxacin (750 mg twice daily), intravenous immunoglobulin for Campylobacter, a 2-week treatment regimen with the chelating agent succimer (500 mg twice daily) for mercury poisoning, and a 3-day regimen of pulse intravenous steroids (intravenous methylprednisolone 500 mg once daily) to reduce inflammation. Repeat mercury levels showed a downward trend, and the rash improved with time. All family members were advised to undergo testing for mercury exposure.

Comment

Manifestations of Mercury Poisoning
Dermatologic manifestations of mercury exposure are varied. The most common—allergic contact dermatitis—presents after repeat systemic or topical exposure.⁴ Mercury exanthem is an acute systemic contact dermatitis most commonly triggered by mercury vapor inhalation. It manifests as an erythematous maculopapular eruption predominantly involving the flexural areas and the anterior thighs in a V-shaped distribution.⁵ Purpura may be seen in severe cases. Cutaneous granulomas after direct injection of mercury also have been reported as well as cutaneous hyperpigmentation after chronic mercury absorption.⁶

Presentation of Pink Disease
Pink disease occurs in children after chronic mercury exposure. It was a common pediatric disorder in the 19th century due to the presence of mercury in certain anthelmintics and teething powders.⁷ However, prevalence drastically decreased after the removal of mercury from these products.³ Although pink disease classically was associated with mercury ingestion, cases also occurred secondary to external application of mercury.⁷ Additionally, in 1988 a case was reported in a 14-month-old girl after inhalation of mercury vapor from a spilled bottle of mercury.³

Pink disease begins with pink discoloration of the fingertips, nose, and toes, and later progresses to involvement of the hands and feet. Erythema, edema, and desquamation of the hands and feet are seen, along with irritability and autonomic dysfunction that manifests as profuse perspiration, tachycardia, and hypertension.³

Diagnosis of Pink Disease
The differential diagnosis of palmoplantar rash is broad and includes rickettsial disease; syphilis; scabies; toxic shock syndrome; infective endocarditis; meningococcal infection; hand-foot-and-mouth disease; dermatophytosis; and palmoplantar keratodermas. The involvement of the hands and feet in our patient, along with hyperhidrosis, tachycardia, and paresthesia, led us to believe that her condition was a variation of pink disease. The patient’s age at presentation (18 years) was unique, as it is atypical for pink disease. Although the polyarthropathy was attributed to Campylobacter, it is important to note that high levels of mercury exposure also have been associated with polyarthritis,⁸ polyneuropathy,⁴ and neuromuscular abnormalities on electromyography.⁴ Therefore, it is possible that the presence of these symptoms in our patient was either secondary to or compounded by mercury exposure.

Mercury Poisoning
Diagnosis of mercury poisoning can be made by assessing blood, urine, hair, or nail concentrations. However, as mercury deposits in multiple organs, individual concentrations do not correlate with total-body mercury levels.¹ Currently, no universal diagnostic criteria for mercury toxicity exist, though a provocation test with the chelating agent 2,3-dimercaptopropanesulfonate is considered reliable in assessing total-body mercury burden.¹

Elemental mercury, as found in some thermometers, dental amalgams, and electrical appliances (eg, certain switches, fluorescent light bulbs), can be converted to inorganic mercury in the body.⁹ Elemental mercury is vaporized at room temperature; the predominant route of exposure is by subsequent inhalation and lung absorbtion.¹⁰ Cutaneous absorption of high concentrations of elementary mercury in either liquid or vapor form may occur, though the rate is slow and absorption is poor. In cases of accidental exposure, contaminated clothing should be removed and immediately decontaminated or disposed. Exposed skin should be washed with a mild soap and water and rinsed thoroughly.¹⁰

The treatment of inorganic mercury poisoning is accomplished with the chelating agents succimer, dimercaptopropanesulfonate, dimercaprol, or D-penicillamine.¹ In symptomatic cases with high clinical suspicion, the first dose of chelation treatment should be initiated early without delay for laboratory confirmation, as treatment efficacy decreases with an increased interim between exposure and onset of chelation.¹¹ Combination chelation therapy also may be used in treatment. Plasma exchange or hemodialysis are treatment options for extreme, life-threatening cases.¹

Conclusion

Mercury exposure should be included in the differential diagnosis of patients presenting with a rash on the palms and soles, especially in young patients with systemic symptoms. A high level of suspicion and a thorough history can prevent a delay in treatment and an unnecessarily extensive and expensive workup. An emphasis on early diagnosis and treatment is important for optimal outcomes and can prevent the severe and potentially devastating consequences of mercury toxicity.

Mercury poisoning affects multiple body systems, leading to variable clinical presentations. Mercury intoxication at low levels frequently presents with weakness, fatigue, weight loss, and abdominal pain. At higher levels of mercury intoxication, tremors and neurologic dysfunction are more prevalent.¹ Dermatologic manifestations of mercury exposure vary and include pink disease (acrodynia), mercury exanthem, contact dermatitis, and cutaneous granulomas. Untreated mercury poisoning may result in severe complications, including renal tubular necrosis, pneumonitis, persistent neurologic dysfunction, and fatality in some cases.^1,2

Pink disease is a rare disease that typically arises in infants and young children from chronic mercury exposure.³ We report a unique presentation of pink disease occurring in an 18-year-old woman following mercury exposure.

Case Report

An 18-year-old woman who was previously healthy presented to the hospital for evaluation of body aches and back pain. She reported a transient rash on the torso 2 weeks prior, but at the current presentation, only the distal upper and lower extremities were involved. A review of systems revealed myalgia, most severe in the lower back; muscle spasms; stiffness in the fingers; abdominal pain; constipation; paresthesia in the hands and feet; hyperhidrosis; and generalized weakness.

Vitals on admission revealed tachycardia (112 beats per minute). Physical examination revealed the patient was pale and fatigued; she appeared to be in pain, with observable facial grimacing and muscle spasms in the legs. She had poorly demarcated pink macules and papules scattered on the left palm (Figure 1), right forearm, right wrist, and dorsal aspects of the feet including the soles. A few pinpoint pustules were present on the left fifth digit.

A diagnosis of mercury poisoning was made along with a component of postinfectious reactive arthropathy due to Campylobacter. The myokymia and skin eruption were believed to be secondary to mercury poisoning. The patient was started on ciprofloxacin (750 mg twice daily), intravenous immunoglobulin for Campylobacter, a 2-week treatment regimen with the chelating agent succimer (500 mg twice daily) for mercury poisoning, and a 3-day regimen of pulse intravenous steroids (intravenous methylprednisolone 500 mg once daily) to reduce inflammation. Repeat mercury levels showed a downward trend, and the rash improved with time. All family members were advised to undergo testing for mercury exposure.

Comment

Manifestations of Mercury Poisoning
Dermatologic manifestations of mercury exposure are varied. The most common—allergic contact dermatitis—presents after repeat systemic or topical exposure.⁴ Mercury exanthem is an acute systemic contact dermatitis most commonly triggered by mercury vapor inhalation. It manifests as an erythematous maculopapular eruption predominantly involving the flexural areas and the anterior thighs in a V-shaped distribution.⁵ Purpura may be seen in severe cases. Cutaneous granulomas after direct injection of mercury also have been reported as well as cutaneous hyperpigmentation after chronic mercury absorption.⁶

Presentation of Pink Disease
Pink disease occurs in children after chronic mercury exposure. It was a common pediatric disorder in the 19th century due to the presence of mercury in certain anthelmintics and teething powders.⁷ However, prevalence drastically decreased after the removal of mercury from these products.³ Although pink disease classically was associated with mercury ingestion, cases also occurred secondary to external application of mercury.⁷ Additionally, in 1988 a case was reported in a 14-month-old girl after inhalation of mercury vapor from a spilled bottle of mercury.³

Pink disease begins with pink discoloration of the fingertips, nose, and toes, and later progresses to involvement of the hands and feet. Erythema, edema, and desquamation of the hands and feet are seen, along with irritability and autonomic dysfunction that manifests as profuse perspiration, tachycardia, and hypertension.³

Diagnosis of Pink Disease
The differential diagnosis of palmoplantar rash is broad and includes rickettsial disease; syphilis; scabies; toxic shock syndrome; infective endocarditis; meningococcal infection; hand-foot-and-mouth disease; dermatophytosis; and palmoplantar keratodermas. The involvement of the hands and feet in our patient, along with hyperhidrosis, tachycardia, and paresthesia, led us to believe that her condition was a variation of pink disease. The patient’s age at presentation (18 years) was unique, as it is atypical for pink disease. Although the polyarthropathy was attributed to Campylobacter, it is important to note that high levels of mercury exposure also have been associated with polyarthritis,⁸ polyneuropathy,⁴ and neuromuscular abnormalities on electromyography.⁴ Therefore, it is possible that the presence of these symptoms in our patient was either secondary to or compounded by mercury exposure.

Mercury Poisoning
Diagnosis of mercury poisoning can be made by assessing blood, urine, hair, or nail concentrations. However, as mercury deposits in multiple organs, individual concentrations do not correlate with total-body mercury levels.¹ Currently, no universal diagnostic criteria for mercury toxicity exist, though a provocation test with the chelating agent 2,3-dimercaptopropanesulfonate is considered reliable in assessing total-body mercury burden.¹

Elemental mercury, as found in some thermometers, dental amalgams, and electrical appliances (eg, certain switches, fluorescent light bulbs), can be converted to inorganic mercury in the body.⁹ Elemental mercury is vaporized at room temperature; the predominant route of exposure is by subsequent inhalation and lung absorbtion.¹⁰ Cutaneous absorption of high concentrations of elementary mercury in either liquid or vapor form may occur, though the rate is slow and absorption is poor. In cases of accidental exposure, contaminated clothing should be removed and immediately decontaminated or disposed. Exposed skin should be washed with a mild soap and water and rinsed thoroughly.¹⁰

The treatment of inorganic mercury poisoning is accomplished with the chelating agents succimer, dimercaptopropanesulfonate, dimercaprol, or D-penicillamine.¹ In symptomatic cases with high clinical suspicion, the first dose of chelation treatment should be initiated early without delay for laboratory confirmation, as treatment efficacy decreases with an increased interim between exposure and onset of chelation.¹¹ Combination chelation therapy also may be used in treatment. Plasma exchange or hemodialysis are treatment options for extreme, life-threatening cases.¹

Conclusion

Mercury exposure should be included in the differential diagnosis of patients presenting with a rash on the palms and soles, especially in young patients with systemic symptoms. A high level of suspicion and a thorough history can prevent a delay in treatment and an unnecessarily extensive and expensive workup. An emphasis on early diagnosis and treatment is important for optimal outcomes and can prevent the severe and potentially devastating consequences of mercury toxicity.

Mercury poisoning affects multiple body systems, leading to variable clinical presentations. Mercury intoxication at low levels frequently presents with weakness, fatigue, weight loss, and abdominal pain. At higher levels of mercury intoxication, tremors and neurologic dysfunction are more prevalent.¹ Dermatologic manifestations of mercury exposure vary and include pink disease (acrodynia), mercury exanthem, contact dermatitis, and cutaneous granulomas. Untreated mercury poisoning may result in severe complications, including renal tubular necrosis, pneumonitis, persistent neurologic dysfunction, and fatality in some cases.^1,2

Pink disease is a rare disease that typically arises in infants and young children from chronic mercury exposure.³ We report a unique presentation of pink disease occurring in an 18-year-old woman following mercury exposure.

Case Report

An 18-year-old woman who was previously healthy presented to the hospital for evaluation of body aches and back pain. She reported a transient rash on the torso 2 weeks prior, but at the current presentation, only the distal upper and lower extremities were involved. A review of systems revealed myalgia, most severe in the lower back; muscle spasms; stiffness in the fingers; abdominal pain; constipation; paresthesia in the hands and feet; hyperhidrosis; and generalized weakness.

Vitals on admission revealed tachycardia (112 beats per minute). Physical examination revealed the patient was pale and fatigued; she appeared to be in pain, with observable facial grimacing and muscle spasms in the legs. She had poorly demarcated pink macules and papules scattered on the left palm (Figure 1), right forearm, right wrist, and dorsal aspects of the feet including the soles. A few pinpoint pustules were present on the left fifth digit.

A diagnosis of mercury poisoning was made along with a component of postinfectious reactive arthropathy due to Campylobacter. The myokymia and skin eruption were believed to be secondary to mercury poisoning. The patient was started on ciprofloxacin (750 mg twice daily), intravenous immunoglobulin for Campylobacter, a 2-week treatment regimen with the chelating agent succimer (500 mg twice daily) for mercury poisoning, and a 3-day regimen of pulse intravenous steroids (intravenous methylprednisolone 500 mg once daily) to reduce inflammation. Repeat mercury levels showed a downward trend, and the rash improved with time. All family members were advised to undergo testing for mercury exposure.

Comment

Manifestations of Mercury Poisoning
Dermatologic manifestations of mercury exposure are varied. The most common—allergic contact dermatitis—presents after repeat systemic or topical exposure.⁴ Mercury exanthem is an acute systemic contact dermatitis most commonly triggered by mercury vapor inhalation. It manifests as an erythematous maculopapular eruption predominantly involving the flexural areas and the anterior thighs in a V-shaped distribution.⁵ Purpura may be seen in severe cases. Cutaneous granulomas after direct injection of mercury also have been reported as well as cutaneous hyperpigmentation after chronic mercury absorption.⁶

Presentation of Pink Disease
Pink disease occurs in children after chronic mercury exposure. It was a common pediatric disorder in the 19th century due to the presence of mercury in certain anthelmintics and teething powders.⁷ However, prevalence drastically decreased after the removal of mercury from these products.³ Although pink disease classically was associated with mercury ingestion, cases also occurred secondary to external application of mercury.⁷ Additionally, in 1988 a case was reported in a 14-month-old girl after inhalation of mercury vapor from a spilled bottle of mercury.³

Pink disease begins with pink discoloration of the fingertips, nose, and toes, and later progresses to involvement of the hands and feet. Erythema, edema, and desquamation of the hands and feet are seen, along with irritability and autonomic dysfunction that manifests as profuse perspiration, tachycardia, and hypertension.³

Diagnosis of Pink Disease
The differential diagnosis of palmoplantar rash is broad and includes rickettsial disease; syphilis; scabies; toxic shock syndrome; infective endocarditis; meningococcal infection; hand-foot-and-mouth disease; dermatophytosis; and palmoplantar keratodermas. The involvement of the hands and feet in our patient, along with hyperhidrosis, tachycardia, and paresthesia, led us to believe that her condition was a variation of pink disease. The patient’s age at presentation (18 years) was unique, as it is atypical for pink disease. Although the polyarthropathy was attributed to Campylobacter, it is important to note that high levels of mercury exposure also have been associated with polyarthritis,⁸ polyneuropathy,⁴ and neuromuscular abnormalities on electromyography.⁴ Therefore, it is possible that the presence of these symptoms in our patient was either secondary to or compounded by mercury exposure.

Mercury Poisoning
Diagnosis of mercury poisoning can be made by assessing blood, urine, hair, or nail concentrations. However, as mercury deposits in multiple organs, individual concentrations do not correlate with total-body mercury levels.¹ Currently, no universal diagnostic criteria for mercury toxicity exist, though a provocation test with the chelating agent 2,3-dimercaptopropanesulfonate is considered reliable in assessing total-body mercury burden.¹

Elemental mercury, as found in some thermometers, dental amalgams, and electrical appliances (eg, certain switches, fluorescent light bulbs), can be converted to inorganic mercury in the body.⁹ Elemental mercury is vaporized at room temperature; the predominant route of exposure is by subsequent inhalation and lung absorbtion.¹⁰ Cutaneous absorption of high concentrations of elementary mercury in either liquid or vapor form may occur, though the rate is slow and absorption is poor. In cases of accidental exposure, contaminated clothing should be removed and immediately decontaminated or disposed. Exposed skin should be washed with a mild soap and water and rinsed thoroughly.¹⁰

The treatment of inorganic mercury poisoning is accomplished with the chelating agents succimer, dimercaptopropanesulfonate, dimercaprol, or D-penicillamine.¹ In symptomatic cases with high clinical suspicion, the first dose of chelation treatment should be initiated early without delay for laboratory confirmation, as treatment efficacy decreases with an increased interim between exposure and onset of chelation.¹¹ Combination chelation therapy also may be used in treatment. Plasma exchange or hemodialysis are treatment options for extreme, life-threatening cases.¹

Conclusion

Mercury exposure should be included in the differential diagnosis of patients presenting with a rash on the palms and soles, especially in young patients with systemic symptoms. A high level of suspicion and a thorough history can prevent a delay in treatment and an unnecessarily extensive and expensive workup. An emphasis on early diagnosis and treatment is important for optimal outcomes and can prevent the severe and potentially devastating consequences of mercury toxicity.

Case Report

A 50-year-old woman presented with a sore, tender, red lump on the right superior buttock of 5 months’ duration. Five months prior to presentation the patient used this area to attach the infusion set for an insulin pump, which was left in place for 7 days as opposed to the 2 or 3 days recommended by the device manufacturer. A firm, slightly tender lump formed, similar to prior scars that had developed from use of the insulin pump. However, the lump began to grow and get softer. It was intermittently warm and red. Although the area was sore and tender, she never had any major pain. She also denied any fever, malaise, or other systemic symptoms.

The patient indicated a medical history of type 1 diabetes mellitus diagnosed at 9 years of age; hypertension; asthma; gastroesophageal reflux disease; allergic rhinitis; migraine headaches; depression; hidradenitis suppurativa that resolved after surgical excision; and recurrent vaginal yeast infections, especially when taking antibiotics. She had a surgical history of hidradenitis suppurativa excision at the inguinal folds, bilateral carpal tunnel release, tubal ligation, abdominoplasty, and cholecystectomy. The patient’s current medications included insulin aspart, mometasone furoate, inhaled fluticasone, pantoprazole, cetirizine, spironolactone, duloxetine, sumatriptan, fluconazole, topiramate, and enalapril.

Physical examination revealed normal vital signs and the patient was afebrile. She had no swollen or tender lymph nodes. There was a 5.5×7.0-cm, soft, tender, erythematous subcutaneous mass with no visible punctum or overlying epidermal change on the right superior buttock (Figure 1). Based on the history and physical examination, the differential diagnosis included subcutaneous fat necrosis, epidermal inclusion cyst, and an abscess.

Comment

Achromobacter xylosoxidans is a nonfermentative, non–spore-forming, motile, gram-negative, aerobic, catalase-positive and oxidase-positive flagellate bacterium. It is an emerging pathogen that was first isolated in 1971 from patients with chronic otitis media.¹ Since its recognition, it has been documented to cause a variety of infections, including pneumonia, meningitis, osteomyelitis, endocarditis, and bacteremia, as well as abdominal, urinary tract, ocular, and skin and soft tissue infections.^2,3 Those affected usually are immunocompromised, have hematologic disorders, or have indwelling catheters.⁴ Strains of A xylosoxidans have shown resistance to multiple antibiotics including penicillins, cephalosporins, carbapenems, aminoglycosides, macrolides, fluoroquinolones, and TMP-SMX. Achromobacter xylosoxidans has been documented to form biofilms on plastics, including on contact lenses, urinary and intravenous catheters, and reusable tissue dispensers treated with disinfectant solution.^4-6 One study demonstrated that A xylosoxidans is even capable of biodegradation of plastic, using the plastic as its sole source of carbon.⁷

Our case illustrates an indolent infection with A xylosoxidans forming a granulomatous abscess at the site of an insulin pump that was left in place for 7 days in an immunocompetent patient. Although infections with A xylosoxidans in patients with urinary or intravenous catheters have been reported,⁴ our case is unique, as the insulin pump was the source of such an infection. It is possible that the subcutaneous focus of acellular material described on the pathology report represented a partially biodegraded piece of the insulin pump catheter that broke off and was serving as a nidus of infection for A xylosoxidans. Although multidrug resistance is common, the culture grown from our patient was susceptible to TMP-SMX, among other antibiotics. Our patient was treated successfully with surgical excision, drainage, and a 10-day course of TMP-SMX.

Conclusion

Health care providers should recognize A xylosoxidans as an emerging pathogen that is capable of forming biofilms on “disinfected” surfaces and medical products, especially plastics. Achromobacter xylosoxidans may be resistant to multiple antibiotics and can cause infections with various presentations.

Case Report

A 50-year-old woman presented with a sore, tender, red lump on the right superior buttock of 5 months’ duration. Five months prior to presentation the patient used this area to attach the infusion set for an insulin pump, which was left in place for 7 days as opposed to the 2 or 3 days recommended by the device manufacturer. A firm, slightly tender lump formed, similar to prior scars that had developed from use of the insulin pump. However, the lump began to grow and get softer. It was intermittently warm and red. Although the area was sore and tender, she never had any major pain. She also denied any fever, malaise, or other systemic symptoms.

The patient indicated a medical history of type 1 diabetes mellitus diagnosed at 9 years of age; hypertension; asthma; gastroesophageal reflux disease; allergic rhinitis; migraine headaches; depression; hidradenitis suppurativa that resolved after surgical excision; and recurrent vaginal yeast infections, especially when taking antibiotics. She had a surgical history of hidradenitis suppurativa excision at the inguinal folds, bilateral carpal tunnel release, tubal ligation, abdominoplasty, and cholecystectomy. The patient’s current medications included insulin aspart, mometasone furoate, inhaled fluticasone, pantoprazole, cetirizine, spironolactone, duloxetine, sumatriptan, fluconazole, topiramate, and enalapril.

Physical examination revealed normal vital signs and the patient was afebrile. She had no swollen or tender lymph nodes. There was a 5.5×7.0-cm, soft, tender, erythematous subcutaneous mass with no visible punctum or overlying epidermal change on the right superior buttock (Figure 1). Based on the history and physical examination, the differential diagnosis included subcutaneous fat necrosis, epidermal inclusion cyst, and an abscess.

Comment

Achromobacter xylosoxidans is a nonfermentative, non–spore-forming, motile, gram-negative, aerobic, catalase-positive and oxidase-positive flagellate bacterium. It is an emerging pathogen that was first isolated in 1971 from patients with chronic otitis media.¹ Since its recognition, it has been documented to cause a variety of infections, including pneumonia, meningitis, osteomyelitis, endocarditis, and bacteremia, as well as abdominal, urinary tract, ocular, and skin and soft tissue infections.^2,3 Those affected usually are immunocompromised, have hematologic disorders, or have indwelling catheters.⁴ Strains of A xylosoxidans have shown resistance to multiple antibiotics including penicillins, cephalosporins, carbapenems, aminoglycosides, macrolides, fluoroquinolones, and TMP-SMX. Achromobacter xylosoxidans has been documented to form biofilms on plastics, including on contact lenses, urinary and intravenous catheters, and reusable tissue dispensers treated with disinfectant solution.^4-6 One study demonstrated that A xylosoxidans is even capable of biodegradation of plastic, using the plastic as its sole source of carbon.⁷

Our case illustrates an indolent infection with A xylosoxidans forming a granulomatous abscess at the site of an insulin pump that was left in place for 7 days in an immunocompetent patient. Although infections with A xylosoxidans in patients with urinary or intravenous catheters have been reported,⁴ our case is unique, as the insulin pump was the source of such an infection. It is possible that the subcutaneous focus of acellular material described on the pathology report represented a partially biodegraded piece of the insulin pump catheter that broke off and was serving as a nidus of infection for A xylosoxidans. Although multidrug resistance is common, the culture grown from our patient was susceptible to TMP-SMX, among other antibiotics. Our patient was treated successfully with surgical excision, drainage, and a 10-day course of TMP-SMX.

Conclusion

Health care providers should recognize A xylosoxidans as an emerging pathogen that is capable of forming biofilms on “disinfected” surfaces and medical products, especially plastics. Achromobacter xylosoxidans may be resistant to multiple antibiotics and can cause infections with various presentations.

Case Report

A 50-year-old woman presented with a sore, tender, red lump on the right superior buttock of 5 months’ duration. Five months prior to presentation the patient used this area to attach the infusion set for an insulin pump, which was left in place for 7 days as opposed to the 2 or 3 days recommended by the device manufacturer. A firm, slightly tender lump formed, similar to prior scars that had developed from use of the insulin pump. However, the lump began to grow and get softer. It was intermittently warm and red. Although the area was sore and tender, she never had any major pain. She also denied any fever, malaise, or other systemic symptoms.

The patient indicated a medical history of type 1 diabetes mellitus diagnosed at 9 years of age; hypertension; asthma; gastroesophageal reflux disease; allergic rhinitis; migraine headaches; depression; hidradenitis suppurativa that resolved after surgical excision; and recurrent vaginal yeast infections, especially when taking antibiotics. She had a surgical history of hidradenitis suppurativa excision at the inguinal folds, bilateral carpal tunnel release, tubal ligation, abdominoplasty, and cholecystectomy. The patient’s current medications included insulin aspart, mometasone furoate, inhaled fluticasone, pantoprazole, cetirizine, spironolactone, duloxetine, sumatriptan, fluconazole, topiramate, and enalapril.

Physical examination revealed normal vital signs and the patient was afebrile. She had no swollen or tender lymph nodes. There was a 5.5×7.0-cm, soft, tender, erythematous subcutaneous mass with no visible punctum or overlying epidermal change on the right superior buttock (Figure 1). Based on the history and physical examination, the differential diagnosis included subcutaneous fat necrosis, epidermal inclusion cyst, and an abscess.

Comment

Achromobacter xylosoxidans is a nonfermentative, non–spore-forming, motile, gram-negative, aerobic, catalase-positive and oxidase-positive flagellate bacterium. It is an emerging pathogen that was first isolated in 1971 from patients with chronic otitis media.¹ Since its recognition, it has been documented to cause a variety of infections, including pneumonia, meningitis, osteomyelitis, endocarditis, and bacteremia, as well as abdominal, urinary tract, ocular, and skin and soft tissue infections.^2,3 Those affected usually are immunocompromised, have hematologic disorders, or have indwelling catheters.⁴ Strains of A xylosoxidans have shown resistance to multiple antibiotics including penicillins, cephalosporins, carbapenems, aminoglycosides, macrolides, fluoroquinolones, and TMP-SMX. Achromobacter xylosoxidans has been documented to form biofilms on plastics, including on contact lenses, urinary and intravenous catheters, and reusable tissue dispensers treated with disinfectant solution.^4-6 One study demonstrated that A xylosoxidans is even capable of biodegradation of plastic, using the plastic as its sole source of carbon.⁷

Our case illustrates an indolent infection with A xylosoxidans forming a granulomatous abscess at the site of an insulin pump that was left in place for 7 days in an immunocompetent patient. Although infections with A xylosoxidans in patients with urinary or intravenous catheters have been reported,⁴ our case is unique, as the insulin pump was the source of such an infection. It is possible that the subcutaneous focus of acellular material described on the pathology report represented a partially biodegraded piece of the insulin pump catheter that broke off and was serving as a nidus of infection for A xylosoxidans. Although multidrug resistance is common, the culture grown from our patient was susceptible to TMP-SMX, among other antibiotics. Our patient was treated successfully with surgical excision, drainage, and a 10-day course of TMP-SMX.

Conclusion

Health care providers should recognize A xylosoxidans as an emerging pathogen that is capable of forming biofilms on “disinfected” surfaces and medical products, especially plastics. Achromobacter xylosoxidans may be resistant to multiple antibiotics and can cause infections with various presentations.

Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.¹ The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.² Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.³ We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.

Case Reports

Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.

Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.

Comment

Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.⁴ Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.³ Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.⁴

Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.⁴ Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.⁵

Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.⁶ The macules expand into papules and plaques that reach maximum size over at least 1 week⁴ and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.⁶

Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.⁴

Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.⁷

Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.⁷ The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.⁸ To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.

Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include pentavalent antimonials, amphotericin B deoxycholate, and pentamidine isethionate, each with known toxicity or limited data on efficacy.⁶ Pentavalent antimonials can cause life-threatening cardiotoxicity and are more difficult to administer.⁹ Furthermore, they are not approved by the US Food and Drug Administration or commercially available in the United States, with only sodium stibogluconate available through the CDC.⁶

Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.¹⁰

Conclusion

Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.

Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.¹ The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.² Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.³ We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.

Case Reports

Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.

Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.

Comment

Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.⁴ Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.³ Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.⁴

Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.⁴ Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.⁵

Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.⁶ The macules expand into papules and plaques that reach maximum size over at least 1 week⁴ and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.⁶

Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.⁴

Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.⁷

Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.⁷ The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.⁸ To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.

Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include pentavalent antimonials, amphotericin B deoxycholate, and pentamidine isethionate, each with known toxicity or limited data on efficacy.⁶ Pentavalent antimonials can cause life-threatening cardiotoxicity and are more difficult to administer.⁹ Furthermore, they are not approved by the US Food and Drug Administration or commercially available in the United States, with only sodium stibogluconate available through the CDC.⁶

Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.¹⁰

Conclusion

Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.

Leishmaniasis is a neglected parasitic disease with an estimated annual incidence of 1.3 million cases, the majority of which manifest as cutaneous leishmaniasis.¹ The cutaneous and mucosal forms demonstrate substantial global burden with morbidity and socioeconomic repercussions, while the visceral form is responsible for up to 30,000 deaths annually.² Despite increasing prevalence in the United States, awareness and diagnosis remain relatively low.³ We describe 2 cases of cutaneous leishmaniasis in New England, United States, in travelers returning from Central America, both successfully treated with miltefosine. We also review prevention, diagnosis, and treatment options.

Case Reports

Patient 1
A 47-year-old woman presented with an enlarging, 2-cm, erythematous, ulcerated nodule on the right dorsal hand of 2 weeks’ duration with accompanying right epitrochlear lymphadenopathy (Figure 1A). She noticed the lesion 10 weeks after returning from Panama, where she had been photographing the jungle. Prior to the initial presentation to dermatology, salicylic acid wart remover, intramuscular ceftriaxone, and oral trimethoprim had failed to alleviate the lesion. Her laboratory results were notable for an elevated C-reactive protein level of 5.4 mg/L (reference range, ≤4.9 mg/L). A punch biopsy demonstrated pseudoepitheliomatous hyperplasia with diffuse dermal lymphohistiocytic inflammation and small intracytoplasmic structures within histiocytes consistent with leishmaniasis (Figure 2). Immunohistochemistry was consistent with leishmaniasis (Figure 3), and polymerase chain reaction performed by the Centers for Disease Control and Prevention (CDC) identified the pathogen as Leishmania braziliensis.

Patient 2
An 18-year-old man presented with an enlarging, well-delineated, tender ulcer of 6 weeks’ duration measuring 2.5×2 cm with an erythematous and edematous border on the right medial forearm with associated epitrochlear lymphadenopathy (Figure 4). Nine weeks prior to initial presentation, he had returned from a 3-month outdoor adventure trip to the Florida Keys, Costa Rica, and Panama. He had used bug repellent intermittently, slept under a bug net, and did not recall any trauma or bite at the ulcer site. Biopsy and tissue culture were obtained, and histopathology demonstrated an ulcer with a dense dermal lymphogranulomatous infiltrate and intracytoplasmic organisms consistent with leishmaniasis. Polymerase chain reaction by the CDC identified the pathogen as Leishmania panamensis.

Comment

Epidemiology and Prevention
Risk factors for leishmaniasis include weak immunity, poverty, poor housing, poor sanitation, malnutrition, urbanization, climate change, and human migration.⁴ Our patients were most directly affected by travel to locations where leishmaniasis is endemic. Despite an increasing prevalence of endemic leishmaniasis and new animal hosts in the southern United States, most patients diagnosed in the United States are infected abroad by Leishmania mexicana and L braziliensis, both cutaneous New World species.³ Our patients were infected by species within the New World subgenus Viannia that have potential for mucocutaneous spread.⁴

Because there is no chemoprophylaxis or acquired active immunity such as vaccines that can mitigate the risk for leishmaniasis, public health efforts focus on preventive measures. Although difficult to achieve, avoidance of the phlebotomine sand fly species that transmit the obligate intracellular Leishmania parasite is a most effective measure.⁴ Travelers entering geographic regions with higher risk for leishmaniasis should be aware of the inherent risk and determine which methods of prevention, such as N,N-diethyl-meta-toluamide (DEET) insecticides or permethrin-treated protective clothing, are most feasible. Although higher concentrations of DEET provide longer protection, the effectiveness tends to plateau at approximately 50%.⁵

Presentation and Prognosis
For patients who develop leishmaniasis, the disease course and prognosis depend greatly on the species and manifestation. The most common form of leishmaniasis is localized cutaneous leishmaniasis, which has an annual incidence of up to 1 million cases. It initially presents as macules, usually at the site of inoculation within several months to years of infection.⁶ The macules expand into papules and plaques that reach maximum size over at least 1 week⁴ and then progress into crusted ulcers up to 5 cm in diameter with raised edges. Although usually painless and self-limited, these lesions can take years to spontaneously heal, with the risk for atrophic scarring and altered pigmentation. Lymphatic involvement manifests as lymphadenitis or regional lymphadenopathy and is common with lesions caused by the subgenus Viannia.⁶

Leishmania braziliensis and L panamensis, the species that infected our patients, can uniquely cause cutaneous leishmaniasis that metastasizes into mucocutaneous leishmaniasis, which always affects the nasal mucosa. Risk factors for transformation include a primary lesion site above the waist, multiple or large primary lesions, and delayed healing of primary cutaneous leishmaniasis. Mucocutaneous leishmaniasis can result in notable morbidity and even mortality from invasion and destruction of nasal and oropharyngeal mucosa, as well as intercurrent pneumonia, especially if treatment is insufficient or delayed.⁴

Diagnosis
Prompt treatment relies on accurate and timely diagnosis, which is complicated by the relative unfamiliarity with leishmaniasis in the United States. The differential diagnosis for cutaneous leishmaniasis is broad, including deep fungal infection, Mycobacterium infection, cutaneous granulomatous conditions, nonmelanoma cutaneous neoplasms, and trauma. Taking a thorough patient history, including potential exposures and travels; having high clinical suspicion; and being aware of classic presentation allows for identification of leishmaniasis and subsequent stratification by manifestation.⁷

Diagnosis is made by detecting Leishmania organisms or DNA using light microscopy and staining to visualize the kinetoplast in an amastigote, molecular methods, or specialized culturing.⁷ The CDC is a valuable diagnostic partner for confirmation and speciation. Specific instructions for specimen collection and transportation can be found by contacting the CDC or reading their guide.⁸ To provide prompt care and reassurance to patients, it is important to be aware of the coordination effort that may be needed to send samples, receive results, and otherwise correspond with a separate institution.

Treatment
Treatment of cutaneous leishmaniasis is indicated to decrease the risk for mucosal dissemination and clinical reactivation of lesions, accelerate healing of lesions, decrease local morbidity caused by large or persistent lesions, and decrease the reservoir of infection in places where infected humans serve as reservoir hosts. Oral treatments include ketoconazole, itraconazole, and fluconazole, recommended at doses ranging from 200 to 600 mg daily for at least 28 days. For severe, refractory, or visceral leishmaniasis, parenteral choices include pentavalent antimonials, amphotericin B deoxycholate, and pentamidine isethionate, each with known toxicity or limited data on efficacy.⁶ Pentavalent antimonials can cause life-threatening cardiotoxicity and are more difficult to administer.⁹ Furthermore, they are not approved by the US Food and Drug Administration or commercially available in the United States, with only sodium stibogluconate available through the CDC.⁶

Miltefosine is becoming a more common treatment of leishmaniasis because of its oral route, tolerability in nonpregnant patients, and commercial availability. It was approved by the US Food and Drug Administration in 2014 for cutaneous leishmaniasis due to L braziliensis, L panamensis, and Leishmania guyanensis; mucosal leishmaniasis due to L braziliensis; and visceral leishmaniasis due to Leishmania donovani in patients at least 12 years of age. For cutaneous leishmaniasis, the standard dosage of 50 mg twice daily (for patients weighing 30–44 kg) or 3 times daily (for patients weighing 45 kg or more) for 28 consecutive days has cure rates of 48% to 85% by 6 months after therapy ends. Cure is defined as epithelialization of lesions, no enlargement greater than 50% in lesions, no appearance of new lesions, and/or negative parasitology. The antileishmanial mechanism of action is unknown and likely involves interaction with lipids, inhibition of cytochrome c oxidase, and apoptosislike cell death. Miltefosine is contraindicated in pregnancy. The most common adverse reactions in patients include nausea (35.9%–41.7%), motion sickness (29.2%), headache (28.1%), and emesis (4.5%–27.5%). With the exception of headache, these adverse reactions can decrease with administration of food, fluids, and antiemetics. Potentially more serious but rarer adverse reactions include elevated serum creatinine (5%–25%) and transaminases (5%). Although our patients had mild hyperkalemia, it is not an established adverse reaction. However, renal injury has been reported.¹⁰

Conclusion

Cutaneous leishmaniasis is increasing in prevalence in the United States due to increased foreign travel. Providers should be familiar with the cutaneous presentation of leishmaniasis, even in areas of low prevalence, to limit the risk for mucocutaneous dissemination from infection with the subgenus Viannia. Prompt treatment is vital to ensuring the best prognosis, and first-line treatment with miltefosine should be strongly considered given its efficacy and tolerability.

THE CASE

A 28-year-old woman with an extensive psychiatric history—including generalized anxiety disorder, panic disorder, and recent postpartum depression—presented with a chief complaint of right leg weakness. She stated this weakness had begun 4 days earlier. It occurred episodically and was preceded by tingling and cramping sensations. Each episode lasted a couple of minutes and spontaneously resolved. Associated with it, she experienced slurred speech and altered mentation. There was no loss of consciousness and no pain. A panic attack usually followed, consisting of feelings of impending doom, rapid breathing, palpitations, and nausea.

She had 3 prior diagnostic evaluations for this same chief complaint, twice in an emergency department (ED) and once with her primary care physician. These evaluations included lab work and extensive head imaging, which demonstrated no acute intracranial pathology. At each previous presentation, the diagnosis was an exacerbation of her anxiety disorder, and she was treated with lorazepam.

At the current presentation, her vital signs were stable. Examination revealed a notably anxious patient. She repeatedly expressed concern that she might have a brain tumor or some other deadly disease, as she had a family history of brain cancer. Her physical exam was entirely normal, including normal strength, sensation, and reflexes in all extremities.

Further head imaging (computed tomography, CT angiography, and magnetic resonance imaging of the brain) failed to reveal an etiology of her symptoms. With no clear organic cause, her medical providers again suspected an anxiety or panic episode. She was given reassurance, and an outpatient neurology consult was arranged.

THE DIAGNOSIS

One week later, at her outpatient neurology appointment, an electroencephalogram (EEG) was performed. Following photic stimulation, the EEG showed multiple right- and left-hemisphere foci of cortical hyperexcitability including a subtle sharp component (see FIGURE). Immediately following the longest of these episodes, the patient expressed a sense of anxiety and an altered sensorium similar to her prior presentations.

The EEG findings, in addition to the postictal anxiety symptoms and clinical history, were all important components that led the treating neurologist to the diagnosis of localization-related (focal) epilepsy.¹ The patient was started on oxcarbazepine, a first-line anti-epileptic medication used in the treatment of focal epilepsy.² She is being followed by a neurologist regularly and after optimizing her anti-epileptic medication, is no longer having seizures.

DISCUSSION

The difficulty of this case stems from the atypical presentation of the patient’s seizures. The key step to the correct diagnosis was a neurological consultation and an ensuing EEG. However, the patient received a vast spectrum of care, including multiple work-ups, prior to a conclusive diagnosis—which highlights an important issue health care providers must address.

Continue to: The role of bias

The role of bias. From the patient’s initial visits to the ED to her hospital admission, there was a prominent affixation, known as the anchoring bias,³ by the clinicians providing her care: All were focused heavily on her psychiatric features. Conversely, the evaluation for patients with suspected psychiatric diagnoses should focus on successfully ruling out major organic etiology with a broad differential diagnosis. It is crucial for providers to take a step back and make a conscious attempt to avoid fixation on a particular diagnosis, especially when it is psychiatric in nature. This allows the provider to actively consider alternative explanations for a patient presentation and work through a more encompassing differential.

The distinguishing symptoms. There is a common association between comorbid mood disorders (eg, depression, anxiety) and epilepsy.⁴ Another clue is ictal anxiety or nervousness, which is commonly observed in patients with partial seizures (and occurred with our patient).

These ictal episodes can be difficult to identify within the context of an isolated psychiatric diagnosis.⁵ The distinction can be clarified by the presence of associated somatic symptoms, which in this case included unilateral cramping, paresthesia, and weakness. These symptoms should clue in a practitioner to the possibility of underlying neurologic pathology, which should prompt the ordering of either an EEG or, at minimum, a neurological consultation.

THE TAKEAWAY

This case report shows how anchoring bias can lead to a delay in diagnosis and treatment. Avoidance of this type of bias requires heightened cognitive awareness by medical providers. A more system-based approach is to have structured diagnostic assessments,⁶ such as conducting a thorough neurological exam for patients with somatic symptoms and exacerbating comorbid psychiatric conditions.

It may also help to review cases like this with colleagues from diverse disciplinary backgrounds, highlighting thought processes and sharing uncertainty.³ These processes may shed light on confounding diagnoses that might be playing a role in a patient’s presentation and ultimately aid in the decision-making process.

CORRESPONDENCE
Paimon Ameli, DO, Naval Medical Center San Diego, 34800 Bob Wilson Drive, San Diego, CA 92134; [email protected]

THE CASE

A 28-year-old woman with an extensive psychiatric history—including generalized anxiety disorder, panic disorder, and recent postpartum depression—presented with a chief complaint of right leg weakness. She stated this weakness had begun 4 days earlier. It occurred episodically and was preceded by tingling and cramping sensations. Each episode lasted a couple of minutes and spontaneously resolved. Associated with it, she experienced slurred speech and altered mentation. There was no loss of consciousness and no pain. A panic attack usually followed, consisting of feelings of impending doom, rapid breathing, palpitations, and nausea.

She had 3 prior diagnostic evaluations for this same chief complaint, twice in an emergency department (ED) and once with her primary care physician. These evaluations included lab work and extensive head imaging, which demonstrated no acute intracranial pathology. At each previous presentation, the diagnosis was an exacerbation of her anxiety disorder, and she was treated with lorazepam.

At the current presentation, her vital signs were stable. Examination revealed a notably anxious patient. She repeatedly expressed concern that she might have a brain tumor or some other deadly disease, as she had a family history of brain cancer. Her physical exam was entirely normal, including normal strength, sensation, and reflexes in all extremities.

Further head imaging (computed tomography, CT angiography, and magnetic resonance imaging of the brain) failed to reveal an etiology of her symptoms. With no clear organic cause, her medical providers again suspected an anxiety or panic episode. She was given reassurance, and an outpatient neurology consult was arranged.

THE DIAGNOSIS

One week later, at her outpatient neurology appointment, an electroencephalogram (EEG) was performed. Following photic stimulation, the EEG showed multiple right- and left-hemisphere foci of cortical hyperexcitability including a subtle sharp component (see FIGURE). Immediately following the longest of these episodes, the patient expressed a sense of anxiety and an altered sensorium similar to her prior presentations.

The EEG findings, in addition to the postictal anxiety symptoms and clinical history, were all important components that led the treating neurologist to the diagnosis of localization-related (focal) epilepsy.¹ The patient was started on oxcarbazepine, a first-line anti-epileptic medication used in the treatment of focal epilepsy.² She is being followed by a neurologist regularly and after optimizing her anti-epileptic medication, is no longer having seizures.

DISCUSSION

The difficulty of this case stems from the atypical presentation of the patient’s seizures. The key step to the correct diagnosis was a neurological consultation and an ensuing EEG. However, the patient received a vast spectrum of care, including multiple work-ups, prior to a conclusive diagnosis—which highlights an important issue health care providers must address.

Continue to: The role of bias

The role of bias. From the patient’s initial visits to the ED to her hospital admission, there was a prominent affixation, known as the anchoring bias,³ by the clinicians providing her care: All were focused heavily on her psychiatric features. Conversely, the evaluation for patients with suspected psychiatric diagnoses should focus on successfully ruling out major organic etiology with a broad differential diagnosis. It is crucial for providers to take a step back and make a conscious attempt to avoid fixation on a particular diagnosis, especially when it is psychiatric in nature. This allows the provider to actively consider alternative explanations for a patient presentation and work through a more encompassing differential.

The distinguishing symptoms. There is a common association between comorbid mood disorders (eg, depression, anxiety) and epilepsy.⁴ Another clue is ictal anxiety or nervousness, which is commonly observed in patients with partial seizures (and occurred with our patient).

These ictal episodes can be difficult to identify within the context of an isolated psychiatric diagnosis.⁵ The distinction can be clarified by the presence of associated somatic symptoms, which in this case included unilateral cramping, paresthesia, and weakness. These symptoms should clue in a practitioner to the possibility of underlying neurologic pathology, which should prompt the ordering of either an EEG or, at minimum, a neurological consultation.

THE TAKEAWAY

This case report shows how anchoring bias can lead to a delay in diagnosis and treatment. Avoidance of this type of bias requires heightened cognitive awareness by medical providers. A more system-based approach is to have structured diagnostic assessments,⁶ such as conducting a thorough neurological exam for patients with somatic symptoms and exacerbating comorbid psychiatric conditions.

It may also help to review cases like this with colleagues from diverse disciplinary backgrounds, highlighting thought processes and sharing uncertainty.³ These processes may shed light on confounding diagnoses that might be playing a role in a patient’s presentation and ultimately aid in the decision-making process.

CORRESPONDENCE
Paimon Ameli, DO, Naval Medical Center San Diego, 34800 Bob Wilson Drive, San Diego, CA 92134; [email protected]

THE CASE

A 28-year-old woman with an extensive psychiatric history—including generalized anxiety disorder, panic disorder, and recent postpartum depression—presented with a chief complaint of right leg weakness. She stated this weakness had begun 4 days earlier. It occurred episodically and was preceded by tingling and cramping sensations. Each episode lasted a couple of minutes and spontaneously resolved. Associated with it, she experienced slurred speech and altered mentation. There was no loss of consciousness and no pain. A panic attack usually followed, consisting of feelings of impending doom, rapid breathing, palpitations, and nausea.

She had 3 prior diagnostic evaluations for this same chief complaint, twice in an emergency department (ED) and once with her primary care physician. These evaluations included lab work and extensive head imaging, which demonstrated no acute intracranial pathology. At each previous presentation, the diagnosis was an exacerbation of her anxiety disorder, and she was treated with lorazepam.

At the current presentation, her vital signs were stable. Examination revealed a notably anxious patient. She repeatedly expressed concern that she might have a brain tumor or some other deadly disease, as she had a family history of brain cancer. Her physical exam was entirely normal, including normal strength, sensation, and reflexes in all extremities.

Further head imaging (computed tomography, CT angiography, and magnetic resonance imaging of the brain) failed to reveal an etiology of her symptoms. With no clear organic cause, her medical providers again suspected an anxiety or panic episode. She was given reassurance, and an outpatient neurology consult was arranged.

THE DIAGNOSIS

One week later, at her outpatient neurology appointment, an electroencephalogram (EEG) was performed. Following photic stimulation, the EEG showed multiple right- and left-hemisphere foci of cortical hyperexcitability including a subtle sharp component (see FIGURE). Immediately following the longest of these episodes, the patient expressed a sense of anxiety and an altered sensorium similar to her prior presentations.

The EEG findings, in addition to the postictal anxiety symptoms and clinical history, were all important components that led the treating neurologist to the diagnosis of localization-related (focal) epilepsy.¹ The patient was started on oxcarbazepine, a first-line anti-epileptic medication used in the treatment of focal epilepsy.² She is being followed by a neurologist regularly and after optimizing her anti-epileptic medication, is no longer having seizures.

DISCUSSION

The difficulty of this case stems from the atypical presentation of the patient’s seizures. The key step to the correct diagnosis was a neurological consultation and an ensuing EEG. However, the patient received a vast spectrum of care, including multiple work-ups, prior to a conclusive diagnosis—which highlights an important issue health care providers must address.

Continue to: The role of bias

The role of bias. From the patient’s initial visits to the ED to her hospital admission, there was a prominent affixation, known as the anchoring bias,³ by the clinicians providing her care: All were focused heavily on her psychiatric features. Conversely, the evaluation for patients with suspected psychiatric diagnoses should focus on successfully ruling out major organic etiology with a broad differential diagnosis. It is crucial for providers to take a step back and make a conscious attempt to avoid fixation on a particular diagnosis, especially when it is psychiatric in nature. This allows the provider to actively consider alternative explanations for a patient presentation and work through a more encompassing differential.

The distinguishing symptoms. There is a common association between comorbid mood disorders (eg, depression, anxiety) and epilepsy.⁴ Another clue is ictal anxiety or nervousness, which is commonly observed in patients with partial seizures (and occurred with our patient).

These ictal episodes can be difficult to identify within the context of an isolated psychiatric diagnosis.⁵ The distinction can be clarified by the presence of associated somatic symptoms, which in this case included unilateral cramping, paresthesia, and weakness. These symptoms should clue in a practitioner to the possibility of underlying neurologic pathology, which should prompt the ordering of either an EEG or, at minimum, a neurological consultation.

THE TAKEAWAY

This case report shows how anchoring bias can lead to a delay in diagnosis and treatment. Avoidance of this type of bias requires heightened cognitive awareness by medical providers. A more system-based approach is to have structured diagnostic assessments,⁶ such as conducting a thorough neurological exam for patients with somatic symptoms and exacerbating comorbid psychiatric conditions.

It may also help to review cases like this with colleagues from diverse disciplinary backgrounds, highlighting thought processes and sharing uncertainty.³ These processes may shed light on confounding diagnoses that might be playing a role in a patient’s presentation and ultimately aid in the decision-making process.

CORRESPONDENCE
Paimon Ameli, DO, Naval Medical Center San Diego, 34800 Bob Wilson Drive, San Diego, CA 92134; [email protected]