CASE 1 ›

A 3-year-old boy was brought to our emergency department for evaluation of skin lesions that he’d had for 7 days. The boy would sometimes scratch the lesions, which began on his right flank as erythematous micropapules and later spread to his right lateral thigh and inner arm (FIGURE 1). His lymph nodes were not palpable.

The boy’s parents had been told to use a topical corticosteroid, but the rash did not improve. His family denied fever or other previous infectious or systemic symptoms, and said that he hadn’t come into contact with any irritants or allergenic substances.

CASE 2 ›

A 13-year-old girl came to our emergency department with a pruriginous rash on her right leg and abdomen that she’d had for 4 days (FIGURE 2). The millimetric papules had also spread to the right side of her trunk, her right arm and armpit, and her inner thigh. Before the rash, she’d had a fever, otalgia, and conjunctivitis. We noted redness of her left conjunctiva, eardrum, and pharynx. The girl’s lymph nodes were not palpable. Serologic examinations for Epstein-Barr virus, cytomegalovirus, rubella, parvovirus B19, and Mycoplasma were negative.

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

Both of these patients were given a diagnosis of asymmetric periflexural exanthem of childhood (APEC), based on the appearance and distribution of the rashes.

A rare condition that mostly affects young children

APEC is a rash of unknown cause, although epidemiologic and clinical findings support a viral etiology. Cases of this rash were first reported in 1992 by Bodemer et al, and a year later, Taïeb et al reported new cases, establishing the term “asymmetric periflexural exanthem.”^1,2 Several viruses have been related to APEC (including adenovirus, parvovirus B19, parainfluenza 2 and 3, and human herpesvirus 7), but none of these has been consistently associated with the rash.^3-5

Asymmetric periflexual exanthem of childhood is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.APEC tends to affect children between one and 5 years of age, but adult cases have been reported.^6,7 The condition occurs slightly more frequently among females and more often in winter and spring.^8,9 APEC is a rare condition; since 1992, there have only been about 300 cases reported in the literature.¹⁰

What you’ll see. The erythematous rash appears as an asymmetrical or unilateral papular, scarlatiniform, or eczematous exanthema. It initially affects the axilla or groin and may then progress to the extremities and trunk. Minor lesions infrequently present on the contralateral side. Most children who are affected by APEC are otherwise healthy and asymptomatic at presentation. The exanthem is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.^2,9 If the rash predominantly affects the lateral thoracic wall, it may be referred to as unilateral laterothoracic exanthem.¹¹ Regional lymphadenopathies can often be found, and there is no systemic involvement.

The differential diagnosis for this type of exanthem includes drug eruptions, pityriasis rosea, miliaria, scarlet fever, papular acrodermatitis of childhood, and other viral rashes. The asymmetric distribution of APEC helps to distinguish the condition. Other possible asymmetric skin lesions, such as contact dermatitis, tinea corporis, or lichen striatus, can be differentiated by the characteristics of the cutaneous lesions. Contact dermatitis lesions are more vesicular, pruritic, and related to the contact area. Tinea corporis lesions tend to be smaller, circular, well-limited, and often have pustules. Lichen striatus starts as small pink-, red-, or flesh-colored spots that join together to form a dull red and slightly scaly linear band over the course of one or 2 weeks.¹² Because APEC is self-limiting, a skin biopsy is usually not necessary.¹³

Lesions usually persist for one to 6 weeks and resolve with no sequelae. Only symptomatic treatment is required.⁹ Topical emollients, topical corticosteroids, or oral antihistamines can be used, if necessary.

Our patients. Both patients were treated with oral antihistamines and the rashes completely resolved within 2 to 3 weeks.

CORRESPONDENCE
Celia Horcajada-Reales, MD, Hospital Gregorio Marañón, Calle del Dr. Esquerdo, 46, 28007 Madrid, Spain; [email protected].

CASE 1 ›

A 3-year-old boy was brought to our emergency department for evaluation of skin lesions that he’d had for 7 days. The boy would sometimes scratch the lesions, which began on his right flank as erythematous micropapules and later spread to his right lateral thigh and inner arm (FIGURE 1). His lymph nodes were not palpable.

The boy’s parents had been told to use a topical corticosteroid, but the rash did not improve. His family denied fever or other previous infectious or systemic symptoms, and said that he hadn’t come into contact with any irritants or allergenic substances.

CASE 2 ›

A 13-year-old girl came to our emergency department with a pruriginous rash on her right leg and abdomen that she’d had for 4 days (FIGURE 2). The millimetric papules had also spread to the right side of her trunk, her right arm and armpit, and her inner thigh. Before the rash, she’d had a fever, otalgia, and conjunctivitis. We noted redness of her left conjunctiva, eardrum, and pharynx. The girl’s lymph nodes were not palpable. Serologic examinations for Epstein-Barr virus, cytomegalovirus, rubella, parvovirus B19, and Mycoplasma were negative.

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

Both of these patients were given a diagnosis of asymmetric periflexural exanthem of childhood (APEC), based on the appearance and distribution of the rashes.

A rare condition that mostly affects young children

APEC is a rash of unknown cause, although epidemiologic and clinical findings support a viral etiology. Cases of this rash were first reported in 1992 by Bodemer et al, and a year later, Taïeb et al reported new cases, establishing the term “asymmetric periflexural exanthem.”^1,2 Several viruses have been related to APEC (including adenovirus, parvovirus B19, parainfluenza 2 and 3, and human herpesvirus 7), but none of these has been consistently associated with the rash.^3-5

Asymmetric periflexual exanthem of childhood is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.APEC tends to affect children between one and 5 years of age, but adult cases have been reported.^6,7 The condition occurs slightly more frequently among females and more often in winter and spring.^8,9 APEC is a rare condition; since 1992, there have only been about 300 cases reported in the literature.¹⁰

What you’ll see. The erythematous rash appears as an asymmetrical or unilateral papular, scarlatiniform, or eczematous exanthema. It initially affects the axilla or groin and may then progress to the extremities and trunk. Minor lesions infrequently present on the contralateral side. Most children who are affected by APEC are otherwise healthy and asymptomatic at presentation. The exanthem is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.^2,9 If the rash predominantly affects the lateral thoracic wall, it may be referred to as unilateral laterothoracic exanthem.¹¹ Regional lymphadenopathies can often be found, and there is no systemic involvement.

The differential diagnosis for this type of exanthem includes drug eruptions, pityriasis rosea, miliaria, scarlet fever, papular acrodermatitis of childhood, and other viral rashes. The asymmetric distribution of APEC helps to distinguish the condition. Other possible asymmetric skin lesions, such as contact dermatitis, tinea corporis, or lichen striatus, can be differentiated by the characteristics of the cutaneous lesions. Contact dermatitis lesions are more vesicular, pruritic, and related to the contact area. Tinea corporis lesions tend to be smaller, circular, well-limited, and often have pustules. Lichen striatus starts as small pink-, red-, or flesh-colored spots that join together to form a dull red and slightly scaly linear band over the course of one or 2 weeks.¹² Because APEC is self-limiting, a skin biopsy is usually not necessary.¹³

Lesions usually persist for one to 6 weeks and resolve with no sequelae. Only symptomatic treatment is required.⁹ Topical emollients, topical corticosteroids, or oral antihistamines can be used, if necessary.

Our patients. Both patients were treated with oral antihistamines and the rashes completely resolved within 2 to 3 weeks.

CORRESPONDENCE
Celia Horcajada-Reales, MD, Hospital Gregorio Marañón, Calle del Dr. Esquerdo, 46, 28007 Madrid, Spain; [email protected].

CASE 1 ›

A 3-year-old boy was brought to our emergency department for evaluation of skin lesions that he’d had for 7 days. The boy would sometimes scratch the lesions, which began on his right flank as erythematous micropapules and later spread to his right lateral thigh and inner arm (FIGURE 1). His lymph nodes were not palpable.

The boy’s parents had been told to use a topical corticosteroid, but the rash did not improve. His family denied fever or other previous infectious or systemic symptoms, and said that he hadn’t come into contact with any irritants or allergenic substances.

CASE 2 ›

A 13-year-old girl came to our emergency department with a pruriginous rash on her right leg and abdomen that she’d had for 4 days (FIGURE 2). The millimetric papules had also spread to the right side of her trunk, her right arm and armpit, and her inner thigh. Before the rash, she’d had a fever, otalgia, and conjunctivitis. We noted redness of her left conjunctiva, eardrum, and pharynx. The girl’s lymph nodes were not palpable. Serologic examinations for Epstein-Barr virus, cytomegalovirus, rubella, parvovirus B19, and Mycoplasma were negative.

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

Both of these patients were given a diagnosis of asymmetric periflexural exanthem of childhood (APEC), based on the appearance and distribution of the rashes.

A rare condition that mostly affects young children

APEC is a rash of unknown cause, although epidemiologic and clinical findings support a viral etiology. Cases of this rash were first reported in 1992 by Bodemer et al, and a year later, Taïeb et al reported new cases, establishing the term “asymmetric periflexural exanthem.”^1,2 Several viruses have been related to APEC (including adenovirus, parvovirus B19, parainfluenza 2 and 3, and human herpesvirus 7), but none of these has been consistently associated with the rash.^3-5

Asymmetric periflexual exanthem of childhood is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.APEC tends to affect children between one and 5 years of age, but adult cases have been reported.^6,7 The condition occurs slightly more frequently among females and more often in winter and spring.^8,9 APEC is a rare condition; since 1992, there have only been about 300 cases reported in the literature.¹⁰

What you’ll see. The erythematous rash appears as an asymmetrical or unilateral papular, scarlatiniform, or eczematous exanthema. It initially affects the axilla or groin and may then progress to the extremities and trunk. Minor lesions infrequently present on the contralateral side. Most children who are affected by APEC are otherwise healthy and asymptomatic at presentation. The exanthem is occasionally pruritic and can be preceded by short respiratory or gastrointestinal prodromes or a low-grade fever.^2,9 If the rash predominantly affects the lateral thoracic wall, it may be referred to as unilateral laterothoracic exanthem.¹¹ Regional lymphadenopathies can often be found, and there is no systemic involvement.

The differential diagnosis for this type of exanthem includes drug eruptions, pityriasis rosea, miliaria, scarlet fever, papular acrodermatitis of childhood, and other viral rashes. The asymmetric distribution of APEC helps to distinguish the condition. Other possible asymmetric skin lesions, such as contact dermatitis, tinea corporis, or lichen striatus, can be differentiated by the characteristics of the cutaneous lesions. Contact dermatitis lesions are more vesicular, pruritic, and related to the contact area. Tinea corporis lesions tend to be smaller, circular, well-limited, and often have pustules. Lichen striatus starts as small pink-, red-, or flesh-colored spots that join together to form a dull red and slightly scaly linear band over the course of one or 2 weeks.¹² Because APEC is self-limiting, a skin biopsy is usually not necessary.¹³

Lesions usually persist for one to 6 weeks and resolve with no sequelae. Only symptomatic treatment is required.⁹ Topical emollients, topical corticosteroids, or oral antihistamines can be used, if necessary.

Our patients. Both patients were treated with oral antihistamines and the rashes completely resolved within 2 to 3 weeks.

CORRESPONDENCE
Celia Horcajada-Reales, MD, Hospital Gregorio Marañón, Calle del Dr. Esquerdo, 46, 28007 Madrid, Spain; [email protected].

A 62-year-old man presented to the emergency department (ED) with a swollen, red, and painful right lower leg. He’d had bilateral lower leg swelling for 2 months, but the left leg became increasingly painful and red over the past 3 days. The patient also had a 3-day history of a diffuse rash that began on his right upper arm and spread to his left arm, both palms, both legs, and his back. It was mildly pruritic, but not painful.

The patient indicated that he had recently sought care from his primary care physician for lower respiratory symptoms. He had just completed a 5-day course of azithromycin and prednisone (50 mg/d for 5 days) the day before his ED visit.

A lower extremity venous ultrasound revealed that the patient had a deep vein thrombosis (DVT). Computed tomography (CT) imaging of the chest with contrast revealed pulmonary emboli. He was treated with enoxaparin and warfarin. We diagnosed the rash based on the patient’s history and the appearance of the rash, which was comprised of blanching and erythematous macules with central clearing (FIGURE 1). (There were no blisters or mucosal involvement.)

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

Diagnosis: Erythema multiforme

The clinical exam was consistent with the diagnosis of erythema multiforme (EM). A diagnosis of EM can usually be made based on the clinical exam alone.¹ Typical targetoid lesions have a round shape and 3 concentric zones: A central dusky area of epidermal necrosis that may involve bullae, a paler pink or edematous zone, and a peripheral erythematous ring.² Atypical lesions, such as raised papules, may also be seen.²

The skin lesions of EM usually appear symmetrically on the distal extremities and spread in a centripetal manner.¹ Palms, soles, and mucosa can be involved.¹ EM with mucosal involvement is called “erythema multiforme major,” and EM without mucosal disease (as in our patient’s case) is called “erythema multiforme minor.”²

EM is an acute, immune-mediated eruption thought to be caused by a cell-mediated hypersensitivity to certain infections or drugs.² Ninety percent of cases are associated with an infection; herpes simplex virus (HSV) is the most common infectious agent.³  Mycoplasma pneumoniae is another culprit, especially in children. Medications are inciting factors about 10% of the time; nonsteroidal anti-inflammatory drugs, sulfonamides, antiepileptics, and antibiotics have been linked to EM eruptions.³

Herpes simplex virus is the most common infectious trigger for erythema multiforme.Interestingly, while azithromycin—the medication our patient had taken most recently—can cause EM, it has been mainly linked to cases of Stevens-Johnson syndrome (SJS).⁴ So, while we suspect that azithromycin was the trigger in our patient’s case, we can’t be sure. It’s also possible that Mycoplasma pneumoniae was the trigger for our patient’s EM. However, Mycoplasma pneumoniae is more common in adolescents.

Differential includes life-threatening conditions like SJS

The differential diagnosis for a non-vesicular palmar rash is discussed in the TABLE.^1,5-12 There is a wide spectrum of possible etiologies—from infectious and rheumatologic disorders to chronic liver disease. Histologic testing may be useful in differentiating EM from other diseases, but in most cases, it is not required to make a diagnosis.¹ Laboratory testing may reveal leukocytosis, an elevated erythrocyte sedimentation rate, and elevated liver function test results, but these are nonspecific.¹

It’s important to differentiate EM from life-threatening conditions like SJS and toxic epidermal necrolysis (TEN).⁵ EM is characterized by typical and atypical targetoid lesions with minimal mucosal involvement.^6,7 SJS is characterized by flat atypical targetoid lesions, confluent purpuric macules, severe mucosal erosions, and <10% epidermal detachment.^6,7 TEN is characterized by severe mucosal erosions and >30% epidermal detachment.^6,7

Lesions resolve on their own, but topical steroids can provide relief

It's important to differentiate erythema multiforme from Stevens-Johnson syndrome and toxic epidermal necrolysis.EM is a self-limiting disease; lesions resolve within about 2 weeks.³ Management begins by treating any suspected infection or discontinuing any suspected drugs.¹ In patients with co-existing or recurrent HSV infection, early treatment with an oral antiviral (such as acyclovir) may lessen the number and duration of lesions.^1,6 In addition, oral antihistamines and topical steroids may be used to provide symptomatic relief.^1,6 Use of oral corticosteroids can be considered in severe mucosal disease, although such use is considered controversial due to a lack of evidence.^1,6

Our patient remained hospitalized for 4 days. As noted earlier, his DVT and pulmonary embolism were treated with enoxaparin and the patient was sent home with a prescription for warfarin. Regarding the EM, his rash and itching improved significantly during the hospitalization (without any specific treatment) and was mostly resolved at a follow-up visit 6 days after discharge.

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, Colorado 80238; [email protected].

A 62-year-old man presented to the emergency department (ED) with a swollen, red, and painful right lower leg. He’d had bilateral lower leg swelling for 2 months, but the left leg became increasingly painful and red over the past 3 days. The patient also had a 3-day history of a diffuse rash that began on his right upper arm and spread to his left arm, both palms, both legs, and his back. It was mildly pruritic, but not painful.

The patient indicated that he had recently sought care from his primary care physician for lower respiratory symptoms. He had just completed a 5-day course of azithromycin and prednisone (50 mg/d for 5 days) the day before his ED visit.

A lower extremity venous ultrasound revealed that the patient had a deep vein thrombosis (DVT). Computed tomography (CT) imaging of the chest with contrast revealed pulmonary emboli. He was treated with enoxaparin and warfarin. We diagnosed the rash based on the patient’s history and the appearance of the rash, which was comprised of blanching and erythematous macules with central clearing (FIGURE 1). (There were no blisters or mucosal involvement.)

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

Diagnosis: Erythema multiforme

The clinical exam was consistent with the diagnosis of erythema multiforme (EM). A diagnosis of EM can usually be made based on the clinical exam alone.¹ Typical targetoid lesions have a round shape and 3 concentric zones: A central dusky area of epidermal necrosis that may involve bullae, a paler pink or edematous zone, and a peripheral erythematous ring.² Atypical lesions, such as raised papules, may also be seen.²

The skin lesions of EM usually appear symmetrically on the distal extremities and spread in a centripetal manner.¹ Palms, soles, and mucosa can be involved.¹ EM with mucosal involvement is called “erythema multiforme major,” and EM without mucosal disease (as in our patient’s case) is called “erythema multiforme minor.”²

EM is an acute, immune-mediated eruption thought to be caused by a cell-mediated hypersensitivity to certain infections or drugs.² Ninety percent of cases are associated with an infection; herpes simplex virus (HSV) is the most common infectious agent.³  Mycoplasma pneumoniae is another culprit, especially in children. Medications are inciting factors about 10% of the time; nonsteroidal anti-inflammatory drugs, sulfonamides, antiepileptics, and antibiotics have been linked to EM eruptions.³

Herpes simplex virus is the most common infectious trigger for erythema multiforme.Interestingly, while azithromycin—the medication our patient had taken most recently—can cause EM, it has been mainly linked to cases of Stevens-Johnson syndrome (SJS).⁴ So, while we suspect that azithromycin was the trigger in our patient’s case, we can’t be sure. It’s also possible that Mycoplasma pneumoniae was the trigger for our patient’s EM. However, Mycoplasma pneumoniae is more common in adolescents.

Differential includes life-threatening conditions like SJS

The differential diagnosis for a non-vesicular palmar rash is discussed in the TABLE.^1,5-12 There is a wide spectrum of possible etiologies—from infectious and rheumatologic disorders to chronic liver disease. Histologic testing may be useful in differentiating EM from other diseases, but in most cases, it is not required to make a diagnosis.¹ Laboratory testing may reveal leukocytosis, an elevated erythrocyte sedimentation rate, and elevated liver function test results, but these are nonspecific.¹

It’s important to differentiate EM from life-threatening conditions like SJS and toxic epidermal necrolysis (TEN).⁵ EM is characterized by typical and atypical targetoid lesions with minimal mucosal involvement.^6,7 SJS is characterized by flat atypical targetoid lesions, confluent purpuric macules, severe mucosal erosions, and <10% epidermal detachment.^6,7 TEN is characterized by severe mucosal erosions and >30% epidermal detachment.^6,7

Lesions resolve on their own, but topical steroids can provide relief

It's important to differentiate erythema multiforme from Stevens-Johnson syndrome and toxic epidermal necrolysis.EM is a self-limiting disease; lesions resolve within about 2 weeks.³ Management begins by treating any suspected infection or discontinuing any suspected drugs.¹ In patients with co-existing or recurrent HSV infection, early treatment with an oral antiviral (such as acyclovir) may lessen the number and duration of lesions.^1,6 In addition, oral antihistamines and topical steroids may be used to provide symptomatic relief.^1,6 Use of oral corticosteroids can be considered in severe mucosal disease, although such use is considered controversial due to a lack of evidence.^1,6

Our patient remained hospitalized for 4 days. As noted earlier, his DVT and pulmonary embolism were treated with enoxaparin and the patient was sent home with a prescription for warfarin. Regarding the EM, his rash and itching improved significantly during the hospitalization (without any specific treatment) and was mostly resolved at a follow-up visit 6 days after discharge.

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, Colorado 80238; [email protected].

A 62-year-old man presented to the emergency department (ED) with a swollen, red, and painful right lower leg. He’d had bilateral lower leg swelling for 2 months, but the left leg became increasingly painful and red over the past 3 days. The patient also had a 3-day history of a diffuse rash that began on his right upper arm and spread to his left arm, both palms, both legs, and his back. It was mildly pruritic, but not painful.

The patient indicated that he had recently sought care from his primary care physician for lower respiratory symptoms. He had just completed a 5-day course of azithromycin and prednisone (50 mg/d for 5 days) the day before his ED visit.

A lower extremity venous ultrasound revealed that the patient had a deep vein thrombosis (DVT). Computed tomography (CT) imaging of the chest with contrast revealed pulmonary emboli. He was treated with enoxaparin and warfarin. We diagnosed the rash based on the patient’s history and the appearance of the rash, which was comprised of blanching and erythematous macules with central clearing (FIGURE 1). (There were no blisters or mucosal involvement.)

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

Diagnosis: Erythema multiforme

The clinical exam was consistent with the diagnosis of erythema multiforme (EM). A diagnosis of EM can usually be made based on the clinical exam alone.¹ Typical targetoid lesions have a round shape and 3 concentric zones: A central dusky area of epidermal necrosis that may involve bullae, a paler pink or edematous zone, and a peripheral erythematous ring.² Atypical lesions, such as raised papules, may also be seen.²

The skin lesions of EM usually appear symmetrically on the distal extremities and spread in a centripetal manner.¹ Palms, soles, and mucosa can be involved.¹ EM with mucosal involvement is called “erythema multiforme major,” and EM without mucosal disease (as in our patient’s case) is called “erythema multiforme minor.”²

EM is an acute, immune-mediated eruption thought to be caused by a cell-mediated hypersensitivity to certain infections or drugs.² Ninety percent of cases are associated with an infection; herpes simplex virus (HSV) is the most common infectious agent.³  Mycoplasma pneumoniae is another culprit, especially in children. Medications are inciting factors about 10% of the time; nonsteroidal anti-inflammatory drugs, sulfonamides, antiepileptics, and antibiotics have been linked to EM eruptions.³

Herpes simplex virus is the most common infectious trigger for erythema multiforme.Interestingly, while azithromycin—the medication our patient had taken most recently—can cause EM, it has been mainly linked to cases of Stevens-Johnson syndrome (SJS).⁴ So, while we suspect that azithromycin was the trigger in our patient’s case, we can’t be sure. It’s also possible that Mycoplasma pneumoniae was the trigger for our patient’s EM. However, Mycoplasma pneumoniae is more common in adolescents.

Differential includes life-threatening conditions like SJS

The differential diagnosis for a non-vesicular palmar rash is discussed in the TABLE.^1,5-12 There is a wide spectrum of possible etiologies—from infectious and rheumatologic disorders to chronic liver disease. Histologic testing may be useful in differentiating EM from other diseases, but in most cases, it is not required to make a diagnosis.¹ Laboratory testing may reveal leukocytosis, an elevated erythrocyte sedimentation rate, and elevated liver function test results, but these are nonspecific.¹

It’s important to differentiate EM from life-threatening conditions like SJS and toxic epidermal necrolysis (TEN).⁵ EM is characterized by typical and atypical targetoid lesions with minimal mucosal involvement.^6,7 SJS is characterized by flat atypical targetoid lesions, confluent purpuric macules, severe mucosal erosions, and <10% epidermal detachment.^6,7 TEN is characterized by severe mucosal erosions and >30% epidermal detachment.^6,7

Lesions resolve on their own, but topical steroids can provide relief

It's important to differentiate erythema multiforme from Stevens-Johnson syndrome and toxic epidermal necrolysis.EM is a self-limiting disease; lesions resolve within about 2 weeks.³ Management begins by treating any suspected infection or discontinuing any suspected drugs.¹ In patients with co-existing or recurrent HSV infection, early treatment with an oral antiviral (such as acyclovir) may lessen the number and duration of lesions.^1,6 In addition, oral antihistamines and topical steroids may be used to provide symptomatic relief.^1,6 Use of oral corticosteroids can be considered in severe mucosal disease, although such use is considered controversial due to a lack of evidence.^1,6

Our patient remained hospitalized for 4 days. As noted earlier, his DVT and pulmonary embolism were treated with enoxaparin and the patient was sent home with a prescription for warfarin. Regarding the EM, his rash and itching improved significantly during the hospitalization (without any specific treatment) and was mostly resolved at a follow-up visit 6 days after discharge.

CORRESPONDENCE
Morteza Khodaee, MD, MPH, AFW Clinic, 3055 Roslyn Street, Denver, Colorado 80238; [email protected].

The study¹ that served as the basis for the PURL entitled, “Ramipril for claudication?” (J Fam Pract. 2013;62:579-580), has been retracted from the Journal of the American Medical Association.² Therefore we, on behalf of all of the authors of the PURL, are retracting the PURL, as well.

According to JAMA’s retraction statement, the first author of the article admitted to data fabrication following an internal investigation.² The source article does not provide subgroup analysis to determine how much of an effect the fabricated data may have had on the final reported outcome. However, a separately reported (and also retracted) sub-analysis of this study indicates that 165/212 (77.8%) patients were enrolled from the site of the first author.³

The question remains: Does ramipril work for symptoms of claudication?

The question remains: Does ramipril work for symptoms of claudication? A completely separate group of researchers conducted a similar, but smaller, randomized clinical trial of ramipril in patients with intermittent claudication.⁴ In this study, 33 patients were randomized to ramipril or placebo for a 24-week trial. The ramipril group (n=14) improved maximum treadmill walking distance by an adjusted mean of 131 meters (m) (95% confidence interval [CI], 62-199; P=.001), improved treadmill intermittent claudication distance by 122 m (95% CI, 56-188; P=.001), and improved patient-reported walking distance by 159 m (95% CI, 66-313; P=.043).

The 2004 Heart Outcomes Prevention Evaluation (HOPE) study indicates that ramipril maintains a mortality benefit for patients with intermittent claudication.⁵ A subgroup of this study included 1725 patients with baseline peripheral artery disease who were randomized to ramipril at 10 mg, which yielded a relative risk (RR) of 0.75 (95% CI, 0.61-0.92) for the primary outcome (cardiovascular mortality, myocardial infarction, stroke). This alone validates the use of ramipril in patients with intermittent claudication. But with the retraction of the large randomized controlled trial, we are not sure how much it may improve walk distances. Further studies might better clarify if ramipril provides symptomatic benefit by reducing claudication symptoms, in addition to the known cardiovascular mortality benefit.

Luke Stephens, MD, MSPH
Park Ridge, IL

James J. Stevermer, MD, MSPH
Columbia, MO

The study¹ that served as the basis for the PURL entitled, “Ramipril for claudication?” (J Fam Pract. 2013;62:579-580), has been retracted from the Journal of the American Medical Association.² Therefore we, on behalf of all of the authors of the PURL, are retracting the PURL, as well.

According to JAMA’s retraction statement, the first author of the article admitted to data fabrication following an internal investigation.² The source article does not provide subgroup analysis to determine how much of an effect the fabricated data may have had on the final reported outcome. However, a separately reported (and also retracted) sub-analysis of this study indicates that 165/212 (77.8%) patients were enrolled from the site of the first author.³

The question remains: Does ramipril work for symptoms of claudication?

The question remains: Does ramipril work for symptoms of claudication? A completely separate group of researchers conducted a similar, but smaller, randomized clinical trial of ramipril in patients with intermittent claudication.⁴ In this study, 33 patients were randomized to ramipril or placebo for a 24-week trial. The ramipril group (n=14) improved maximum treadmill walking distance by an adjusted mean of 131 meters (m) (95% confidence interval [CI], 62-199; P=.001), improved treadmill intermittent claudication distance by 122 m (95% CI, 56-188; P=.001), and improved patient-reported walking distance by 159 m (95% CI, 66-313; P=.043).

The 2004 Heart Outcomes Prevention Evaluation (HOPE) study indicates that ramipril maintains a mortality benefit for patients with intermittent claudication.⁵ A subgroup of this study included 1725 patients with baseline peripheral artery disease who were randomized to ramipril at 10 mg, which yielded a relative risk (RR) of 0.75 (95% CI, 0.61-0.92) for the primary outcome (cardiovascular mortality, myocardial infarction, stroke). This alone validates the use of ramipril in patients with intermittent claudication. But with the retraction of the large randomized controlled trial, we are not sure how much it may improve walk distances. Further studies might better clarify if ramipril provides symptomatic benefit by reducing claudication symptoms, in addition to the known cardiovascular mortality benefit.

Luke Stephens, MD, MSPH
Park Ridge, IL

James J. Stevermer, MD, MSPH
Columbia, MO

The study¹ that served as the basis for the PURL entitled, “Ramipril for claudication?” (J Fam Pract. 2013;62:579-580), has been retracted from the Journal of the American Medical Association.² Therefore we, on behalf of all of the authors of the PURL, are retracting the PURL, as well.

According to JAMA’s retraction statement, the first author of the article admitted to data fabrication following an internal investigation.² The source article does not provide subgroup analysis to determine how much of an effect the fabricated data may have had on the final reported outcome. However, a separately reported (and also retracted) sub-analysis of this study indicates that 165/212 (77.8%) patients were enrolled from the site of the first author.³

The question remains: Does ramipril work for symptoms of claudication?

The question remains: Does ramipril work for symptoms of claudication? A completely separate group of researchers conducted a similar, but smaller, randomized clinical trial of ramipril in patients with intermittent claudication.⁴ In this study, 33 patients were randomized to ramipril or placebo for a 24-week trial. The ramipril group (n=14) improved maximum treadmill walking distance by an adjusted mean of 131 meters (m) (95% confidence interval [CI], 62-199; P=.001), improved treadmill intermittent claudication distance by 122 m (95% CI, 56-188; P=.001), and improved patient-reported walking distance by 159 m (95% CI, 66-313; P=.043).

The 2004 Heart Outcomes Prevention Evaluation (HOPE) study indicates that ramipril maintains a mortality benefit for patients with intermittent claudication.⁵ A subgroup of this study included 1725 patients with baseline peripheral artery disease who were randomized to ramipril at 10 mg, which yielded a relative risk (RR) of 0.75 (95% CI, 0.61-0.92) for the primary outcome (cardiovascular mortality, myocardial infarction, stroke). This alone validates the use of ramipril in patients with intermittent claudication. But with the retraction of the large randomized controlled trial, we are not sure how much it may improve walk distances. Further studies might better clarify if ramipril provides symptomatic benefit by reducing claudication symptoms, in addition to the known cardiovascular mortality benefit.

Luke Stephens, MD, MSPH
Park Ridge, IL

James J. Stevermer, MD, MSPH
Columbia, MO

The article, “Bone disease in patients with kidney disease: A tricky interplay” (J Fam Pract. 2016;65:606-612), incorrectly stated: “Elevations of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) lead to hyperphosphatemia and hypocalcemia because of decreased urinary excretion of phosphorus.” In fact, FGF23 normally acts to lower blood phosphate levels. Furthermore, an elevated phosphorus level causes an increase in serum calcium levels and not hypocalcemia. This sentence, and the 2 that followed it, should have read:

“Elevations of FGF23 lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism, driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This increased level of bone breakdown escalates fracture risk.”

This information has been corrected in the online version of the article.

The article, “Bone disease in patients with kidney disease: A tricky interplay” (J Fam Pract. 2016;65:606-612), incorrectly stated: “Elevations of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) lead to hyperphosphatemia and hypocalcemia because of decreased urinary excretion of phosphorus.” In fact, FGF23 normally acts to lower blood phosphate levels. Furthermore, an elevated phosphorus level causes an increase in serum calcium levels and not hypocalcemia. This sentence, and the 2 that followed it, should have read:

“Elevations of FGF23 lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism, driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This increased level of bone breakdown escalates fracture risk.”

This information has been corrected in the online version of the article.

The article, “Bone disease in patients with kidney disease: A tricky interplay” (J Fam Pract. 2016;65:606-612), incorrectly stated: “Elevations of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) lead to hyperphosphatemia and hypocalcemia because of decreased urinary excretion of phosphorus.” In fact, FGF23 normally acts to lower blood phosphate levels. Furthermore, an elevated phosphorus level causes an increase in serum calcium levels and not hypocalcemia. This sentence, and the 2 that followed it, should have read:

“Elevations of FGF23 lower blood phosphate levels by inhibiting phosphate reabsorption in the kidneys, thus increasing urinary excretion of phosphorus. Secondary hyperparathyroidism, driven by hypocalcemia, responds to normalize serum calcium levels by increasing the number and size of osteoclasts actively breaking down bone matrix. This increased level of bone breakdown escalates fracture risk.”

This information has been corrected in the online version of the article.

CE/CME No: CR-1611

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand the prevalence and risks of Chagas disease in the United States.
• Explain the pathophysiology of Chagas disease, including the vector and transmission routes of the disease.
• Describe the clinical presentation of both the acute and chronic forms of the disease and learn when to suspect an infection.
• Outline a plan for diagnosis and treatment of Chagas disease.
• Educate women with Chagas disease about the risk of transmission for future offspring.

FACULTY

Jessica McDonald works in the Emergency Medicine Department at Dekalb Medical Center, Atlanta. Jill Mattingly is Academic Coordinator and Clinical Assistant Professor in the Physician Assistant Program at Mercer University, Atlanta.
The authors have no financial relationships to disclose.

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of November 2016.

Article begins on next page >>

Chagas disease, a parasitic infection, is increasingly being detected in the United States, most likely due to immigration from endemic countries in South and Central America. Approximately 300,000 persons in the US have chronic Chagas disease, and up to 30% of them will develop clinically evident cardiovascular and/or gastrointestinal disease. Here’s practical guidance to help you recognize the features of symptomatic Chagas disease and follow up with appropriate evaluation and management.

Chagas disease, also known as American trypanosomiasis, is caused by the protozoan parasite Trypanosoma cruzi.¹ It is most commonly spread by triatomine bugs infected with T cruzi and is endemic in many parts of Mexico and Central and South America.² Chagas disease was first described in 1909 by Brazilian physician Carlos Chagas.³ Since its discovery, it has often been considered a disease affecting only the poor living in endemic areas of Latin America. However, 6 million to 7 million people are infected with T cruzi worldwide, and estimates suggest that Mexico and the US rank third and seventh, respectively, in the number of persons with T cruzi infection in the Western Hemisphere.^1,4

An estimated 300,000 persons in the US have Chagas disease; most of them are not aware that they are infected.^5,6 The increasing presence of the disease in the US, which traditionally has been considered a nonendemic area, is due to immigration from endemic areas, with subsequent infections occurring through mechanisms that do not require contact with the triatomine vector (eg, congenital transmission).¹ Between 1981 and 2005, more than 7 million people from T cruzi-endemic countries in Latin America moved to the US and became legal residents.³

Early detection and treatment of Chagas disease is important because up to 30% of patients with chronic infection will develop a heart disorder, which can range in severity from conduction system abnormalities to dilated cardiomyopathy.⁴ In some areas of southern Mexico, Chagas disease is the most common cause of dilated cardiomyopathy.¹ Equally concerning is the fact that untreated mothers with Chagas disease can transmit T cruzi to their infants.^1,3 An estimated 315 babies are born with congenital Chagas disease each year in the US, an incidence equivalent to that of phenylketonuria.⁷ It is estimated that congenital transmission is responsible for up to one-quarter of new infections worldwide.¹ Unfortunately, obstetricians are not well informed about the risk factors for congenital Chagas disease, and very limited screening of at-risk women is performed. In a 2008 survey exploring health care providers’ knowledge of and understanding about Chagas disease, obstetricians and gynecologists had the greatest knowledge deficits about the disease, although considerable deficits were also seen among other specialties.¹

KISSING BUG DISEASE: ETIOLOGY/PATHOPHYSIOLOGY

Exposure to the protozoan parasite T cruzi, the cause of Chagas disease, typically occurs following the bite of a triatomine bug. Also known as “kissing bugs” because they usually bite exposed areas of the skin such as the face, triatomine bugs feed on human blood, typically at night, and act as a vector for the parasite.⁸ The parasite lives in the feces and urine of the triatomine bugs and is excreted near the bite during or shortly after a blood meal. The bitten person will then unknowingly smear the infected feces into the bite wound, eyes, mouth, or any opening in the skin, which gives the parasites systemic access.⁴ Once in the host’s bloodstream, the parasite replicates in host cells, a process that ends in cell lysis and hematogenous spread. At this point, the parasites can be seen on peripheral blood smear. Noninfected triatomine insects become infected and continue the cycle when they feed on an infected human host (see Figure 1).³ Persons of lower socioeconomic status living in endemic areas in Latin America are at a higher risk for contracting Chagas disease because “kissing bugs” commonly live in wall or roof cracks of poorly built homes. Populations living in poverty are also at risk due to minimal access to health care and prenatal care.⁴ Transmission of T cruzi not involving triatomine vectors occurs congenitally or through blood transfusions, consumption of contaminated food, and organ donations.⁴

Acute phase

Infection with the T cruzi parasite is followed by an asymptomatic incubation period of one to two weeks, which is then followed by an acute phase that can last eight to 12 weeks.⁵ The acute phase is characterized by a large amount of parasites in the bloodstream (see Table 1). The patient is often asymptomatic but can have nonspecific symptoms such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain.⁴ Because symptoms during the acute phase are typically mild, many patients do not seek medical attention until they transition into the chronic phase.⁴ Infants are more likely to experience severe symptoms, including myocarditis or meningoencephalitis, and thus are more likely to present during the acute phase.⁹

If the patient acquired the infection through an organ transplant, the acute phase symptoms can be delayed, on average, up to 112 days.5 These patients will have more noticeable symptoms, including hepatosplenomegaly, myocarditis, and congestive heart failure. Due to the known risk for transmission through organ transplants, donors are often screened for Chagas disease. Unfortunately, this screening is selective and often inconsistent.⁵ Therefore, the presence of the previously mentioned symptoms in a person who recently received an organ transplant should raise suspicion of Chagas disease.⁵

Chronic phase

Patients not treated during the acute phase will pass into the chronic phase of Chagas disease.⁵ This may occur due to reactivation of T cruzi infection via immunosuppression.⁹ At this time, the previously asymptomatic patient will have typical signs and symptoms of chronic disease, along with nodules, panniculitis, and myocarditis.^4,9,10 During the chronic phase, parasites are undetectable by microscopy, but the patient can still spread the disease to the vector as well as to others congenitally and through organ donation and blood transfusions.^5,9

Patients with chronic T cruzi infection who remain without signs or symptoms of infection are considered to have the indeterminate form of chronic disease. Many patients will remain in the indeterminate form throughout their lives, but between 20% and 30% will progress to the determinate form of chronic disease over years to decades.³ The determinate form is characterized by clinically evident disease and is classically divided into cardiac Chagas disease and digestive Chagas disease.⁵ Symptoms of the chronic phase depend on the genotype of T cruzi that caused the infection. The AG genotype has a higher incidence of digestive disease.¹¹

Cardiac Chagas disease is believed to occur due to parasite invasion and persistence in cardiac tissue, leading to immune-mediated myocardial injury.⁵ Chagas cardiomyopathy is characterized by chronic myocarditis affecting all cardiac chambers and disturbances in the electrical conduction system; patients also often develop apical aneurysms. Longstanding cardiac Chagas disease can lead to more serious complications, such as episodes of ventricular tachycardia, heart block, thromboembolic phenomena, severe bradycardia, dilated cardiomyopathy, and congestive heart failure. Patients may complain of presyncope, syncope, and episodes of palpitations. They are also at high risk for sudden cardiac death.⁵ Patients with cardiomyopathy or cardiac insufficiency secondary to Chagas disease have a worse prognosis than those with idiopathic cardiomyopathy or decompensated heart failure due to other etiologies.¹²

Less common than cardiac Chagas disease, digestive Chagas disease occurs mostly in Argentina, Bolivia, Chile, Paraguay, Uruguay, and parts of Peru and Brazil; it is rarely seen in northern South America, Central America, or Mexico.⁵ The parasite causes gastrointestinal symptoms by damaging intramural neurons, resulting in denervation of hollow viscera. Since it affects the esophagus and colon, patients may present with dysphagia, odynophagia, cough, reflux, weight loss, constipation, and abdominal pain.⁵

The physical examination of a patient with suspected Chagas disease can be crucial to the diagnosis. As noted, there are often few specific symptoms or physical exam findings during the acute phase. However, in some patients, swelling and inflammation may be evident at the site of inoculation, often on the face or extremities. This finding is called a chagoma. The Romaña sign, characterized by painless unilateral swelling of the upper and lower eyelid, can also be seen if the infection occurred through the conjunctiva.⁵ A nonpruritic morbilliform rash, called schizotrypanides, may be a presenting symptom in patients with acute disease.¹³ Children younger than 2 years of age are at increased risk for a severe acute infection, with signs and symptoms of pericardial effusion, myocarditis, and meningoencephalitis. Children can also develop generalized edema and lymphadenopathy. Those children who develop severe manifestations during acute infection have an increased risk for mortality.⁵

Chronic chagasic cardiomyopathy may present with signs of left-sided heart failure (pulmonary edema, dyspnea at rest or exertion), biventricular heart failure (hepatomegaly, peripheral edema, jugular venous distention), or thromboembolic events to the brain, lower extremities, and lungs.¹³ Chronic chagasic megaesophagus may lead to weight loss, esophageal dysmotility, pneumonitis due to aspiration of food trapped in the esophagus and stomach, salivary gland enlargement, and erosive esophagitis, which increases the risk for esophageal cancer. Chronic chagasic megacolon can present as an intestinal obstruction, volvulus, abdominal distention, or fecaloma.¹³

Clinicians should be alert to the possibility of congenital T cruzi infection in children born to women who emigrated from an endemic area or who visited an area with a high prevalence of Chagas disease. Most newborns with T cruzi infection are asymptomatic, but in some cases a thorough neonatal exam can lead to the diagnosis. Manifestations of symptomatic congenital infection include hepatosplenomegaly, low birth weight, premature birth, and low Apgar scores.⁵ Lab tests may reveal thrombocytopenia and anemia. Neonates with severe disease may also have respiratory distress, meningoencephalitis, and gastrointestinal problems.⁵

LABORATORY WORK-UP

Laboratory work-up for Chagas disease depends on the provider’s awareness of the disease and its symptoms. All patients should undergo routine blood work, including complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), and liver function tests to rule out other etiologies that manifest with similar symptoms. If the patient presents during the acute phase, microscopy of blood smears with Giemsa stain should be done to visualize the parasites. In the patient who presents during the chronic phase with cardiac symptoms, measurement of B-type natriuretic peptide, troponin, C-reactive protein, and the erythrocyte sedimentation rate can be used to rule out other differential diagnoses. Electrocardiogram (ECG) may show a right bundle-branch block or left anterior fascicular block.⁵ Echocardiogram may show left ventricular wall motion abnormalities and/or cardiomyopathy with congestive heart failure.^5,10 A work-up for di­gestive Chagas disease may include a barium swallow, kidney-ureter-bladder x-ray, or MRI/CT of the abdomen.¹⁴

Accurate diagnosis of Chagas disease requires a thorough history and physical exam, as well as a high index of suspicion. Recent travel to an endemic area of Chagas disease in combination with the typical signs and symptoms—such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain—should prompt the provider to perform more specific tests.⁴ Inquiry about past medical history, blood transfusions, and surgeries is also imperative to make the correct diagnosis.⁵

The approach to diagnosis of Chagas disease depends on whether the patient presents during the acute or chronic phase. During the acute phase, the count of the trypomastigote, the mature extracellular form of the parasite T cruzi, is at its highest, making this the best time to obtain an accurate diagnosis if an infection is suspected.³ Microscopy of fresh preparations of anticoagulated blood or buffy coat may show motile parasites.¹⁰ Other options include visualization of parasites in a blood smear with Giemsa stain or hemoculture. Hemoculture is a sensitive test but takes several weeks to show growth of the parasites. Therefore, polymerase chain reaction (PCR) assay is the preferred diagnostic test due to its high sensitivity and quick turnaround time.⁵

Because no diagnostic gold standard exists for chronic disease, confidently diagnosing Chagas in the United States can be difficult.⁵ Past the acute phase (about three months after infection), microscopy and PCR cannot be used due to low parasi­temia. If an infection with T cruzi is suspected but nine to 14 weeks have passed since exposure, serology is the method of choice for diagnosis. The enzyme-linked immunosorbent assay (ELISA) and immunofluorescent-antibody assay (IFA) are most often used to identify immunoglobulin (Ig) G antibodies to the parasite.

The difficulty of diagnosing Chagas disease in the chronic phase lies in the fact that neither ELISA or IFA alone is sensitive or specific enough to confirm the diagnosis.⁵ In order to make a serologic diagnosis of infection, positive results are needed from two serologic tests based on two different antigens or by using two different techniques (eg, ELISA or IFA). If the two tests are discordant, a third test must be done to determine the patient’s infection status. The radioimmunoprecipitation assay (RIPA) and trypomastigote excreted-secreted antigen immunoblot (TESA-blot) have been traditionally used as confirmatory tests, but even they do not have high sensitivity and specificity. A case of indeterminate Chagas disease is confirmed with positive serologic testing in a patient without symptoms and with normal ECG, chest x-ray, and imaging of the colon and esophagus.¹⁵

The preferred protocol for diagnosis of congenital Chagas disease first requires positive serologic testing confirming the infection in the mother (see Figure 2).¹⁶ Once that is determined, microscopic and PCR-based examinations of cord blood and peripheral blood specimens are carried out during the first one to two months of the infant’s life.¹⁰ PCR is the preferred test for early congenital Chagas disease, recipients of organ transplants, and after accidental exposure since results can determine if the patient is infected earlier than trypomastigotes (developmental stage of trypanosomes) can be seen on a peripheral blood smear.⁵

If there is a suspicion of Chagas disease, the patient should be referred to an infectious disease specialist for diagnosis and treatment. Nifurtimox and benz­nidazole are the only drugs that have been shown to improve the course of Chagas disease.⁵ However, neither drug is approved by the FDA, and both can only be obtained from the CDC, which makes treatment a challenge.⁹ In addition, up to 30% of patients terminate treatment due to the many adverse effects of these drugs.¹⁷

The dosage regimen for nifurtimox is 8-10 mg/kg/d divided into three doses for 90 days.¹⁰ Anorexia, weight loss, nausea, vomiting, and abdominal pain occur in up to 70% of patients.⁵ Irritability, insomnia, disorientation, and tremors can also occur. Neurotoxicity leading to peripheral neuropathy is dose dependent and requires treatment termination.⁵

Benznidazole is better tolerated and is active against the trypomastigotes as well as the amastigotes or intracellular form of the parasite.¹⁰ The dosage regimen for benznidazole is 5-7 mg/kg/d divided into two doses for 60 days.¹⁰ Dermatologic reactions such as rash, photosensitivity, and exfoliative dermatitis are the most common adverse effects. Peripheral neuropathy and bone marrow suppression are dose dependent and require therapy cessation.⁵

The CDC recommends treatment for all cases of acute disease (including congenital disease) regardless of age, and for chronic disease in patients up to age 50 who have not progressed to cardiomyopathy. In patients older than 50, treatment should be determined after weighing the potential risks and benefits (see Table 2).¹⁸

The success of treatment is determined in part by the phase of the disease. Cure rates in patients treated with either nifurtimox or benznidazole during the acute phase range from 65% to 80%.¹⁷ Chronic disease shows less of a response to traditional antiparasitic drug regimens, but higher rates of success are seen in younger patients.⁵ According to current estimates, successful treatment of chronic disease is limited to 15% to 30% patients.¹⁷ Treatment of congenital Chagas disease should begin as soon as the diagnosis is confirmed, and cure rates are greater than 90% if patients are treated within the first year of life.¹⁰ Treating congenital Chagas disease is important because the infection can be passed to future generations even if the disease never manifests with symptoms.¹⁹ However, if an expecting mother has known Chagas disease, antiparasitic medications are not recommended during the pregnancy because of a lack of fetal safety data for the two antiparasitic agents.²⁰ Instead, it is recommended that women of childbearing age be treated before pregnancy, as rates of congenital infection are 25 times lower in women who are treated than in those who are not.²¹

PRE- AND POSTEXPOSURE PATIENT EDUCATION

Patient education mainly focuses on how to prevent Chagas disease and prognosis once diagnosed. During travel to endemic areas, the use of insecticides and residing in well-built households are the most important prevention measures. No vaccine is available, and primary chemoprophylaxis of persons visiting endemic areas is not recommended due to the low risk for infection and concerns about adverse effects.¹³

The survival rate of those who remain in the indeterminate phase is the same as that of the general population. However, findings that most strongly predict mortality include ventricular tachycardia, cardiomegaly, congestive heart failure (NYHA class III/IV), left ventricular systolic dysfunction, and male sex.¹⁰ Patients diagnosed with Chagas disease should be strongly encouraged not to donate blood or organs.¹⁰ Some organ and blood donation organizations selectively or universally screen donated specimens; however, this screening is not required by law.⁵ Family members of those diagnosed with the disease should also be tested, especially if the patient is a woman who has children or who plans to become pregnant.¹⁰

In patients confirmed to have Chagas disease but without symptoms and a normal ECG, further initial evaluation is not required.¹⁰ An annual history, physical exam, and ECG should be done. Those who have symptoms or ECG changes should have a complete cardiac work-up, including a 24-hour ambulatory ECG, exercise stress test, and echocardiogram to determine functional capacity. A barium swallow, barium enema, esophageal manometry, and endoscopy may be indicated in patients with gastrointestinal symptoms of Chagas disease but otherwise are not recommended. Patients taking antiparasitic drugs should have a CBC and CMP at the start of treatment and then bimonthly until the end of treatment to monitor for rare bone marrow suppression. Nifurtimox and benznidazole are also known to be mutagenic and increase the risk for lymphoma in animal studies, but this risk has not been documented in humans.¹⁰

CONCLUSION

Chagas disease is considered one of the neglected tropical diseases due to its high prevalence, chronic course, debilitating symptoms, and association with poverty.⁷ It is evident that incidence and prevalence of Chagas disease in the US are increasing due to recent immigration and mother-to-child transmission. Therefore, family practice clinicians must be able to recognize the red flags that suggest a T cruzi infection.^5,9 Enhanced awareness of Chagas disease among health care providers will lead to better symptom control and cure rates for affected patients and may also prevent congenital infections. These efforts could serve to remove Chagas disease from the list of neglected tropical diseases.

CE/CME No: CR-1611

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand the prevalence and risks of Chagas disease in the United States.
• Explain the pathophysiology of Chagas disease, including the vector and transmission routes of the disease.
• Describe the clinical presentation of both the acute and chronic forms of the disease and learn when to suspect an infection.
• Outline a plan for diagnosis and treatment of Chagas disease.
• Educate women with Chagas disease about the risk of transmission for future offspring.

FACULTY

Jessica McDonald works in the Emergency Medicine Department at Dekalb Medical Center, Atlanta. Jill Mattingly is Academic Coordinator and Clinical Assistant Professor in the Physician Assistant Program at Mercer University, Atlanta.
The authors have no financial relationships to disclose.

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of November 2016.

Article begins on next page >>

Chagas disease, a parasitic infection, is increasingly being detected in the United States, most likely due to immigration from endemic countries in South and Central America. Approximately 300,000 persons in the US have chronic Chagas disease, and up to 30% of them will develop clinically evident cardiovascular and/or gastrointestinal disease. Here’s practical guidance to help you recognize the features of symptomatic Chagas disease and follow up with appropriate evaluation and management.

Chagas disease, also known as American trypanosomiasis, is caused by the protozoan parasite Trypanosoma cruzi.¹ It is most commonly spread by triatomine bugs infected with T cruzi and is endemic in many parts of Mexico and Central and South America.² Chagas disease was first described in 1909 by Brazilian physician Carlos Chagas.³ Since its discovery, it has often been considered a disease affecting only the poor living in endemic areas of Latin America. However, 6 million to 7 million people are infected with T cruzi worldwide, and estimates suggest that Mexico and the US rank third and seventh, respectively, in the number of persons with T cruzi infection in the Western Hemisphere.^1,4

An estimated 300,000 persons in the US have Chagas disease; most of them are not aware that they are infected.^5,6 The increasing presence of the disease in the US, which traditionally has been considered a nonendemic area, is due to immigration from endemic areas, with subsequent infections occurring through mechanisms that do not require contact with the triatomine vector (eg, congenital transmission).¹ Between 1981 and 2005, more than 7 million people from T cruzi-endemic countries in Latin America moved to the US and became legal residents.³

Early detection and treatment of Chagas disease is important because up to 30% of patients with chronic infection will develop a heart disorder, which can range in severity from conduction system abnormalities to dilated cardiomyopathy.⁴ In some areas of southern Mexico, Chagas disease is the most common cause of dilated cardiomyopathy.¹ Equally concerning is the fact that untreated mothers with Chagas disease can transmit T cruzi to their infants.^1,3 An estimated 315 babies are born with congenital Chagas disease each year in the US, an incidence equivalent to that of phenylketonuria.⁷ It is estimated that congenital transmission is responsible for up to one-quarter of new infections worldwide.¹ Unfortunately, obstetricians are not well informed about the risk factors for congenital Chagas disease, and very limited screening of at-risk women is performed. In a 2008 survey exploring health care providers’ knowledge of and understanding about Chagas disease, obstetricians and gynecologists had the greatest knowledge deficits about the disease, although considerable deficits were also seen among other specialties.¹

KISSING BUG DISEASE: ETIOLOGY/PATHOPHYSIOLOGY

Exposure to the protozoan parasite T cruzi, the cause of Chagas disease, typically occurs following the bite of a triatomine bug. Also known as “kissing bugs” because they usually bite exposed areas of the skin such as the face, triatomine bugs feed on human blood, typically at night, and act as a vector for the parasite.⁸ The parasite lives in the feces and urine of the triatomine bugs and is excreted near the bite during or shortly after a blood meal. The bitten person will then unknowingly smear the infected feces into the bite wound, eyes, mouth, or any opening in the skin, which gives the parasites systemic access.⁴ Once in the host’s bloodstream, the parasite replicates in host cells, a process that ends in cell lysis and hematogenous spread. At this point, the parasites can be seen on peripheral blood smear. Noninfected triatomine insects become infected and continue the cycle when they feed on an infected human host (see Figure 1).³ Persons of lower socioeconomic status living in endemic areas in Latin America are at a higher risk for contracting Chagas disease because “kissing bugs” commonly live in wall or roof cracks of poorly built homes. Populations living in poverty are also at risk due to minimal access to health care and prenatal care.⁴ Transmission of T cruzi not involving triatomine vectors occurs congenitally or through blood transfusions, consumption of contaminated food, and organ donations.⁴

Acute phase

Infection with the T cruzi parasite is followed by an asymptomatic incubation period of one to two weeks, which is then followed by an acute phase that can last eight to 12 weeks.⁵ The acute phase is characterized by a large amount of parasites in the bloodstream (see Table 1). The patient is often asymptomatic but can have nonspecific symptoms such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain.⁴ Because symptoms during the acute phase are typically mild, many patients do not seek medical attention until they transition into the chronic phase.⁴ Infants are more likely to experience severe symptoms, including myocarditis or meningoencephalitis, and thus are more likely to present during the acute phase.⁹

If the patient acquired the infection through an organ transplant, the acute phase symptoms can be delayed, on average, up to 112 days.5 These patients will have more noticeable symptoms, including hepatosplenomegaly, myocarditis, and congestive heart failure. Due to the known risk for transmission through organ transplants, donors are often screened for Chagas disease. Unfortunately, this screening is selective and often inconsistent.⁵ Therefore, the presence of the previously mentioned symptoms in a person who recently received an organ transplant should raise suspicion of Chagas disease.⁵

Chronic phase

Patients not treated during the acute phase will pass into the chronic phase of Chagas disease.⁵ This may occur due to reactivation of T cruzi infection via immunosuppression.⁹ At this time, the previously asymptomatic patient will have typical signs and symptoms of chronic disease, along with nodules, panniculitis, and myocarditis.^4,9,10 During the chronic phase, parasites are undetectable by microscopy, but the patient can still spread the disease to the vector as well as to others congenitally and through organ donation and blood transfusions.^5,9

Patients with chronic T cruzi infection who remain without signs or symptoms of infection are considered to have the indeterminate form of chronic disease. Many patients will remain in the indeterminate form throughout their lives, but between 20% and 30% will progress to the determinate form of chronic disease over years to decades.³ The determinate form is characterized by clinically evident disease and is classically divided into cardiac Chagas disease and digestive Chagas disease.⁵ Symptoms of the chronic phase depend on the genotype of T cruzi that caused the infection. The AG genotype has a higher incidence of digestive disease.¹¹

Cardiac Chagas disease is believed to occur due to parasite invasion and persistence in cardiac tissue, leading to immune-mediated myocardial injury.⁵ Chagas cardiomyopathy is characterized by chronic myocarditis affecting all cardiac chambers and disturbances in the electrical conduction system; patients also often develop apical aneurysms. Longstanding cardiac Chagas disease can lead to more serious complications, such as episodes of ventricular tachycardia, heart block, thromboembolic phenomena, severe bradycardia, dilated cardiomyopathy, and congestive heart failure. Patients may complain of presyncope, syncope, and episodes of palpitations. They are also at high risk for sudden cardiac death.⁵ Patients with cardiomyopathy or cardiac insufficiency secondary to Chagas disease have a worse prognosis than those with idiopathic cardiomyopathy or decompensated heart failure due to other etiologies.¹²

Less common than cardiac Chagas disease, digestive Chagas disease occurs mostly in Argentina, Bolivia, Chile, Paraguay, Uruguay, and parts of Peru and Brazil; it is rarely seen in northern South America, Central America, or Mexico.⁵ The parasite causes gastrointestinal symptoms by damaging intramural neurons, resulting in denervation of hollow viscera. Since it affects the esophagus and colon, patients may present with dysphagia, odynophagia, cough, reflux, weight loss, constipation, and abdominal pain.⁵

The physical examination of a patient with suspected Chagas disease can be crucial to the diagnosis. As noted, there are often few specific symptoms or physical exam findings during the acute phase. However, in some patients, swelling and inflammation may be evident at the site of inoculation, often on the face or extremities. This finding is called a chagoma. The Romaña sign, characterized by painless unilateral swelling of the upper and lower eyelid, can also be seen if the infection occurred through the conjunctiva.⁵ A nonpruritic morbilliform rash, called schizotrypanides, may be a presenting symptom in patients with acute disease.¹³ Children younger than 2 years of age are at increased risk for a severe acute infection, with signs and symptoms of pericardial effusion, myocarditis, and meningoencephalitis. Children can also develop generalized edema and lymphadenopathy. Those children who develop severe manifestations during acute infection have an increased risk for mortality.⁵

Chronic chagasic cardiomyopathy may present with signs of left-sided heart failure (pulmonary edema, dyspnea at rest or exertion), biventricular heart failure (hepatomegaly, peripheral edema, jugular venous distention), or thromboembolic events to the brain, lower extremities, and lungs.¹³ Chronic chagasic megaesophagus may lead to weight loss, esophageal dysmotility, pneumonitis due to aspiration of food trapped in the esophagus and stomach, salivary gland enlargement, and erosive esophagitis, which increases the risk for esophageal cancer. Chronic chagasic megacolon can present as an intestinal obstruction, volvulus, abdominal distention, or fecaloma.¹³

Clinicians should be alert to the possibility of congenital T cruzi infection in children born to women who emigrated from an endemic area or who visited an area with a high prevalence of Chagas disease. Most newborns with T cruzi infection are asymptomatic, but in some cases a thorough neonatal exam can lead to the diagnosis. Manifestations of symptomatic congenital infection include hepatosplenomegaly, low birth weight, premature birth, and low Apgar scores.⁵ Lab tests may reveal thrombocytopenia and anemia. Neonates with severe disease may also have respiratory distress, meningoencephalitis, and gastrointestinal problems.⁵

LABORATORY WORK-UP

Laboratory work-up for Chagas disease depends on the provider’s awareness of the disease and its symptoms. All patients should undergo routine blood work, including complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), and liver function tests to rule out other etiologies that manifest with similar symptoms. If the patient presents during the acute phase, microscopy of blood smears with Giemsa stain should be done to visualize the parasites. In the patient who presents during the chronic phase with cardiac symptoms, measurement of B-type natriuretic peptide, troponin, C-reactive protein, and the erythrocyte sedimentation rate can be used to rule out other differential diagnoses. Electrocardiogram (ECG) may show a right bundle-branch block or left anterior fascicular block.⁵ Echocardiogram may show left ventricular wall motion abnormalities and/or cardiomyopathy with congestive heart failure.^5,10 A work-up for di­gestive Chagas disease may include a barium swallow, kidney-ureter-bladder x-ray, or MRI/CT of the abdomen.¹⁴

Accurate diagnosis of Chagas disease requires a thorough history and physical exam, as well as a high index of suspicion. Recent travel to an endemic area of Chagas disease in combination with the typical signs and symptoms—such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain—should prompt the provider to perform more specific tests.⁴ Inquiry about past medical history, blood transfusions, and surgeries is also imperative to make the correct diagnosis.⁵

The approach to diagnosis of Chagas disease depends on whether the patient presents during the acute or chronic phase. During the acute phase, the count of the trypomastigote, the mature extracellular form of the parasite T cruzi, is at its highest, making this the best time to obtain an accurate diagnosis if an infection is suspected.³ Microscopy of fresh preparations of anticoagulated blood or buffy coat may show motile parasites.¹⁰ Other options include visualization of parasites in a blood smear with Giemsa stain or hemoculture. Hemoculture is a sensitive test but takes several weeks to show growth of the parasites. Therefore, polymerase chain reaction (PCR) assay is the preferred diagnostic test due to its high sensitivity and quick turnaround time.⁵

Because no diagnostic gold standard exists for chronic disease, confidently diagnosing Chagas in the United States can be difficult.⁵ Past the acute phase (about three months after infection), microscopy and PCR cannot be used due to low parasi­temia. If an infection with T cruzi is suspected but nine to 14 weeks have passed since exposure, serology is the method of choice for diagnosis. The enzyme-linked immunosorbent assay (ELISA) and immunofluorescent-antibody assay (IFA) are most often used to identify immunoglobulin (Ig) G antibodies to the parasite.

The difficulty of diagnosing Chagas disease in the chronic phase lies in the fact that neither ELISA or IFA alone is sensitive or specific enough to confirm the diagnosis.⁵ In order to make a serologic diagnosis of infection, positive results are needed from two serologic tests based on two different antigens or by using two different techniques (eg, ELISA or IFA). If the two tests are discordant, a third test must be done to determine the patient’s infection status. The radioimmunoprecipitation assay (RIPA) and trypomastigote excreted-secreted antigen immunoblot (TESA-blot) have been traditionally used as confirmatory tests, but even they do not have high sensitivity and specificity. A case of indeterminate Chagas disease is confirmed with positive serologic testing in a patient without symptoms and with normal ECG, chest x-ray, and imaging of the colon and esophagus.¹⁵

The preferred protocol for diagnosis of congenital Chagas disease first requires positive serologic testing confirming the infection in the mother (see Figure 2).¹⁶ Once that is determined, microscopic and PCR-based examinations of cord blood and peripheral blood specimens are carried out during the first one to two months of the infant’s life.¹⁰ PCR is the preferred test for early congenital Chagas disease, recipients of organ transplants, and after accidental exposure since results can determine if the patient is infected earlier than trypomastigotes (developmental stage of trypanosomes) can be seen on a peripheral blood smear.⁵

If there is a suspicion of Chagas disease, the patient should be referred to an infectious disease specialist for diagnosis and treatment. Nifurtimox and benz­nidazole are the only drugs that have been shown to improve the course of Chagas disease.⁵ However, neither drug is approved by the FDA, and both can only be obtained from the CDC, which makes treatment a challenge.⁹ In addition, up to 30% of patients terminate treatment due to the many adverse effects of these drugs.¹⁷

The dosage regimen for nifurtimox is 8-10 mg/kg/d divided into three doses for 90 days.¹⁰ Anorexia, weight loss, nausea, vomiting, and abdominal pain occur in up to 70% of patients.⁵ Irritability, insomnia, disorientation, and tremors can also occur. Neurotoxicity leading to peripheral neuropathy is dose dependent and requires treatment termination.⁵

Benznidazole is better tolerated and is active against the trypomastigotes as well as the amastigotes or intracellular form of the parasite.¹⁰ The dosage regimen for benznidazole is 5-7 mg/kg/d divided into two doses for 60 days.¹⁰ Dermatologic reactions such as rash, photosensitivity, and exfoliative dermatitis are the most common adverse effects. Peripheral neuropathy and bone marrow suppression are dose dependent and require therapy cessation.⁵

The CDC recommends treatment for all cases of acute disease (including congenital disease) regardless of age, and for chronic disease in patients up to age 50 who have not progressed to cardiomyopathy. In patients older than 50, treatment should be determined after weighing the potential risks and benefits (see Table 2).¹⁸

The success of treatment is determined in part by the phase of the disease. Cure rates in patients treated with either nifurtimox or benznidazole during the acute phase range from 65% to 80%.¹⁷ Chronic disease shows less of a response to traditional antiparasitic drug regimens, but higher rates of success are seen in younger patients.⁵ According to current estimates, successful treatment of chronic disease is limited to 15% to 30% patients.¹⁷ Treatment of congenital Chagas disease should begin as soon as the diagnosis is confirmed, and cure rates are greater than 90% if patients are treated within the first year of life.¹⁰ Treating congenital Chagas disease is important because the infection can be passed to future generations even if the disease never manifests with symptoms.¹⁹ However, if an expecting mother has known Chagas disease, antiparasitic medications are not recommended during the pregnancy because of a lack of fetal safety data for the two antiparasitic agents.²⁰ Instead, it is recommended that women of childbearing age be treated before pregnancy, as rates of congenital infection are 25 times lower in women who are treated than in those who are not.²¹

PRE- AND POSTEXPOSURE PATIENT EDUCATION

Patient education mainly focuses on how to prevent Chagas disease and prognosis once diagnosed. During travel to endemic areas, the use of insecticides and residing in well-built households are the most important prevention measures. No vaccine is available, and primary chemoprophylaxis of persons visiting endemic areas is not recommended due to the low risk for infection and concerns about adverse effects.¹³

The survival rate of those who remain in the indeterminate phase is the same as that of the general population. However, findings that most strongly predict mortality include ventricular tachycardia, cardiomegaly, congestive heart failure (NYHA class III/IV), left ventricular systolic dysfunction, and male sex.¹⁰ Patients diagnosed with Chagas disease should be strongly encouraged not to donate blood or organs.¹⁰ Some organ and blood donation organizations selectively or universally screen donated specimens; however, this screening is not required by law.⁵ Family members of those diagnosed with the disease should also be tested, especially if the patient is a woman who has children or who plans to become pregnant.¹⁰

In patients confirmed to have Chagas disease but without symptoms and a normal ECG, further initial evaluation is not required.¹⁰ An annual history, physical exam, and ECG should be done. Those who have symptoms or ECG changes should have a complete cardiac work-up, including a 24-hour ambulatory ECG, exercise stress test, and echocardiogram to determine functional capacity. A barium swallow, barium enema, esophageal manometry, and endoscopy may be indicated in patients with gastrointestinal symptoms of Chagas disease but otherwise are not recommended. Patients taking antiparasitic drugs should have a CBC and CMP at the start of treatment and then bimonthly until the end of treatment to monitor for rare bone marrow suppression. Nifurtimox and benznidazole are also known to be mutagenic and increase the risk for lymphoma in animal studies, but this risk has not been documented in humans.¹⁰

CONCLUSION

Chagas disease is considered one of the neglected tropical diseases due to its high prevalence, chronic course, debilitating symptoms, and association with poverty.⁷ It is evident that incidence and prevalence of Chagas disease in the US are increasing due to recent immigration and mother-to-child transmission. Therefore, family practice clinicians must be able to recognize the red flags that suggest a T cruzi infection.^5,9 Enhanced awareness of Chagas disease among health care providers will lead to better symptom control and cure rates for affected patients and may also prevent congenital infections. These efforts could serve to remove Chagas disease from the list of neglected tropical diseases.

CE/CME No: CR-1611

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand the prevalence and risks of Chagas disease in the United States.
• Explain the pathophysiology of Chagas disease, including the vector and transmission routes of the disease.
• Describe the clinical presentation of both the acute and chronic forms of the disease and learn when to suspect an infection.
• Outline a plan for diagnosis and treatment of Chagas disease.
• Educate women with Chagas disease about the risk of transmission for future offspring.

FACULTY

Jessica McDonald works in the Emergency Medicine Department at Dekalb Medical Center, Atlanta. Jill Mattingly is Academic Coordinator and Clinical Assistant Professor in the Physician Assistant Program at Mercer University, Atlanta.
The authors have no financial relationships to disclose.

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of November 2016.

Article begins on next page >>

Chagas disease, a parasitic infection, is increasingly being detected in the United States, most likely due to immigration from endemic countries in South and Central America. Approximately 300,000 persons in the US have chronic Chagas disease, and up to 30% of them will develop clinically evident cardiovascular and/or gastrointestinal disease. Here’s practical guidance to help you recognize the features of symptomatic Chagas disease and follow up with appropriate evaluation and management.

Chagas disease, also known as American trypanosomiasis, is caused by the protozoan parasite Trypanosoma cruzi.¹ It is most commonly spread by triatomine bugs infected with T cruzi and is endemic in many parts of Mexico and Central and South America.² Chagas disease was first described in 1909 by Brazilian physician Carlos Chagas.³ Since its discovery, it has often been considered a disease affecting only the poor living in endemic areas of Latin America. However, 6 million to 7 million people are infected with T cruzi worldwide, and estimates suggest that Mexico and the US rank third and seventh, respectively, in the number of persons with T cruzi infection in the Western Hemisphere.^1,4

An estimated 300,000 persons in the US have Chagas disease; most of them are not aware that they are infected.^5,6 The increasing presence of the disease in the US, which traditionally has been considered a nonendemic area, is due to immigration from endemic areas, with subsequent infections occurring through mechanisms that do not require contact with the triatomine vector (eg, congenital transmission).¹ Between 1981 and 2005, more than 7 million people from T cruzi-endemic countries in Latin America moved to the US and became legal residents.³

Early detection and treatment of Chagas disease is important because up to 30% of patients with chronic infection will develop a heart disorder, which can range in severity from conduction system abnormalities to dilated cardiomyopathy.⁴ In some areas of southern Mexico, Chagas disease is the most common cause of dilated cardiomyopathy.¹ Equally concerning is the fact that untreated mothers with Chagas disease can transmit T cruzi to their infants.^1,3 An estimated 315 babies are born with congenital Chagas disease each year in the US, an incidence equivalent to that of phenylketonuria.⁷ It is estimated that congenital transmission is responsible for up to one-quarter of new infections worldwide.¹ Unfortunately, obstetricians are not well informed about the risk factors for congenital Chagas disease, and very limited screening of at-risk women is performed. In a 2008 survey exploring health care providers’ knowledge of and understanding about Chagas disease, obstetricians and gynecologists had the greatest knowledge deficits about the disease, although considerable deficits were also seen among other specialties.¹

KISSING BUG DISEASE: ETIOLOGY/PATHOPHYSIOLOGY

Exposure to the protozoan parasite T cruzi, the cause of Chagas disease, typically occurs following the bite of a triatomine bug. Also known as “kissing bugs” because they usually bite exposed areas of the skin such as the face, triatomine bugs feed on human blood, typically at night, and act as a vector for the parasite.⁸ The parasite lives in the feces and urine of the triatomine bugs and is excreted near the bite during or shortly after a blood meal. The bitten person will then unknowingly smear the infected feces into the bite wound, eyes, mouth, or any opening in the skin, which gives the parasites systemic access.⁴ Once in the host’s bloodstream, the parasite replicates in host cells, a process that ends in cell lysis and hematogenous spread. At this point, the parasites can be seen on peripheral blood smear. Noninfected triatomine insects become infected and continue the cycle when they feed on an infected human host (see Figure 1).³ Persons of lower socioeconomic status living in endemic areas in Latin America are at a higher risk for contracting Chagas disease because “kissing bugs” commonly live in wall or roof cracks of poorly built homes. Populations living in poverty are also at risk due to minimal access to health care and prenatal care.⁴ Transmission of T cruzi not involving triatomine vectors occurs congenitally or through blood transfusions, consumption of contaminated food, and organ donations.⁴

Acute phase

Infection with the T cruzi parasite is followed by an asymptomatic incubation period of one to two weeks, which is then followed by an acute phase that can last eight to 12 weeks.⁵ The acute phase is characterized by a large amount of parasites in the bloodstream (see Table 1). The patient is often asymptomatic but can have nonspecific symptoms such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain.⁴ Because symptoms during the acute phase are typically mild, many patients do not seek medical attention until they transition into the chronic phase.⁴ Infants are more likely to experience severe symptoms, including myocarditis or meningoencephalitis, and thus are more likely to present during the acute phase.⁹

If the patient acquired the infection through an organ transplant, the acute phase symptoms can be delayed, on average, up to 112 days.5 These patients will have more noticeable symptoms, including hepatosplenomegaly, myocarditis, and congestive heart failure. Due to the known risk for transmission through organ transplants, donors are often screened for Chagas disease. Unfortunately, this screening is selective and often inconsistent.⁵ Therefore, the presence of the previously mentioned symptoms in a person who recently received an organ transplant should raise suspicion of Chagas disease.⁵

Chronic phase

Patients not treated during the acute phase will pass into the chronic phase of Chagas disease.⁵ This may occur due to reactivation of T cruzi infection via immunosuppression.⁹ At this time, the previously asymptomatic patient will have typical signs and symptoms of chronic disease, along with nodules, panniculitis, and myocarditis.^4,9,10 During the chronic phase, parasites are undetectable by microscopy, but the patient can still spread the disease to the vector as well as to others congenitally and through organ donation and blood transfusions.^5,9

Patients with chronic T cruzi infection who remain without signs or symptoms of infection are considered to have the indeterminate form of chronic disease. Many patients will remain in the indeterminate form throughout their lives, but between 20% and 30% will progress to the determinate form of chronic disease over years to decades.³ The determinate form is characterized by clinically evident disease and is classically divided into cardiac Chagas disease and digestive Chagas disease.⁵ Symptoms of the chronic phase depend on the genotype of T cruzi that caused the infection. The AG genotype has a higher incidence of digestive disease.¹¹

Cardiac Chagas disease is believed to occur due to parasite invasion and persistence in cardiac tissue, leading to immune-mediated myocardial injury.⁵ Chagas cardiomyopathy is characterized by chronic myocarditis affecting all cardiac chambers and disturbances in the electrical conduction system; patients also often develop apical aneurysms. Longstanding cardiac Chagas disease can lead to more serious complications, such as episodes of ventricular tachycardia, heart block, thromboembolic phenomena, severe bradycardia, dilated cardiomyopathy, and congestive heart failure. Patients may complain of presyncope, syncope, and episodes of palpitations. They are also at high risk for sudden cardiac death.⁵ Patients with cardiomyopathy or cardiac insufficiency secondary to Chagas disease have a worse prognosis than those with idiopathic cardiomyopathy or decompensated heart failure due to other etiologies.¹²

Less common than cardiac Chagas disease, digestive Chagas disease occurs mostly in Argentina, Bolivia, Chile, Paraguay, Uruguay, and parts of Peru and Brazil; it is rarely seen in northern South America, Central America, or Mexico.⁵ The parasite causes gastrointestinal symptoms by damaging intramural neurons, resulting in denervation of hollow viscera. Since it affects the esophagus and colon, patients may present with dysphagia, odynophagia, cough, reflux, weight loss, constipation, and abdominal pain.⁵

The physical examination of a patient with suspected Chagas disease can be crucial to the diagnosis. As noted, there are often few specific symptoms or physical exam findings during the acute phase. However, in some patients, swelling and inflammation may be evident at the site of inoculation, often on the face or extremities. This finding is called a chagoma. The Romaña sign, characterized by painless unilateral swelling of the upper and lower eyelid, can also be seen if the infection occurred through the conjunctiva.⁵ A nonpruritic morbilliform rash, called schizotrypanides, may be a presenting symptom in patients with acute disease.¹³ Children younger than 2 years of age are at increased risk for a severe acute infection, with signs and symptoms of pericardial effusion, myocarditis, and meningoencephalitis. Children can also develop generalized edema and lymphadenopathy. Those children who develop severe manifestations during acute infection have an increased risk for mortality.⁵

Chronic chagasic cardiomyopathy may present with signs of left-sided heart failure (pulmonary edema, dyspnea at rest or exertion), biventricular heart failure (hepatomegaly, peripheral edema, jugular venous distention), or thromboembolic events to the brain, lower extremities, and lungs.¹³ Chronic chagasic megaesophagus may lead to weight loss, esophageal dysmotility, pneumonitis due to aspiration of food trapped in the esophagus and stomach, salivary gland enlargement, and erosive esophagitis, which increases the risk for esophageal cancer. Chronic chagasic megacolon can present as an intestinal obstruction, volvulus, abdominal distention, or fecaloma.¹³

Clinicians should be alert to the possibility of congenital T cruzi infection in children born to women who emigrated from an endemic area or who visited an area with a high prevalence of Chagas disease. Most newborns with T cruzi infection are asymptomatic, but in some cases a thorough neonatal exam can lead to the diagnosis. Manifestations of symptomatic congenital infection include hepatosplenomegaly, low birth weight, premature birth, and low Apgar scores.⁵ Lab tests may reveal thrombocytopenia and anemia. Neonates with severe disease may also have respiratory distress, meningoencephalitis, and gastrointestinal problems.⁵

LABORATORY WORK-UP

Laboratory work-up for Chagas disease depends on the provider’s awareness of the disease and its symptoms. All patients should undergo routine blood work, including complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), and liver function tests to rule out other etiologies that manifest with similar symptoms. If the patient presents during the acute phase, microscopy of blood smears with Giemsa stain should be done to visualize the parasites. In the patient who presents during the chronic phase with cardiac symptoms, measurement of B-type natriuretic peptide, troponin, C-reactive protein, and the erythrocyte sedimentation rate can be used to rule out other differential diagnoses. Electrocardiogram (ECG) may show a right bundle-branch block or left anterior fascicular block.⁵ Echocardiogram may show left ventricular wall motion abnormalities and/or cardiomyopathy with congestive heart failure.^5,10 A work-up for di­gestive Chagas disease may include a barium swallow, kidney-ureter-bladder x-ray, or MRI/CT of the abdomen.¹⁴

Accurate diagnosis of Chagas disease requires a thorough history and physical exam, as well as a high index of suspicion. Recent travel to an endemic area of Chagas disease in combination with the typical signs and symptoms—such as fever, headache, lymphadenopathy, shortness of breath, myalgia, swelling, and abdominal or chest pain—should prompt the provider to perform more specific tests.⁴ Inquiry about past medical history, blood transfusions, and surgeries is also imperative to make the correct diagnosis.⁵

The approach to diagnosis of Chagas disease depends on whether the patient presents during the acute or chronic phase. During the acute phase, the count of the trypomastigote, the mature extracellular form of the parasite T cruzi, is at its highest, making this the best time to obtain an accurate diagnosis if an infection is suspected.³ Microscopy of fresh preparations of anticoagulated blood or buffy coat may show motile parasites.¹⁰ Other options include visualization of parasites in a blood smear with Giemsa stain or hemoculture. Hemoculture is a sensitive test but takes several weeks to show growth of the parasites. Therefore, polymerase chain reaction (PCR) assay is the preferred diagnostic test due to its high sensitivity and quick turnaround time.⁵

Because no diagnostic gold standard exists for chronic disease, confidently diagnosing Chagas in the United States can be difficult.⁵ Past the acute phase (about three months after infection), microscopy and PCR cannot be used due to low parasi­temia. If an infection with T cruzi is suspected but nine to 14 weeks have passed since exposure, serology is the method of choice for diagnosis. The enzyme-linked immunosorbent assay (ELISA) and immunofluorescent-antibody assay (IFA) are most often used to identify immunoglobulin (Ig) G antibodies to the parasite.

The difficulty of diagnosing Chagas disease in the chronic phase lies in the fact that neither ELISA or IFA alone is sensitive or specific enough to confirm the diagnosis.⁵ In order to make a serologic diagnosis of infection, positive results are needed from two serologic tests based on two different antigens or by using two different techniques (eg, ELISA or IFA). If the two tests are discordant, a third test must be done to determine the patient’s infection status. The radioimmunoprecipitation assay (RIPA) and trypomastigote excreted-secreted antigen immunoblot (TESA-blot) have been traditionally used as confirmatory tests, but even they do not have high sensitivity and specificity. A case of indeterminate Chagas disease is confirmed with positive serologic testing in a patient without symptoms and with normal ECG, chest x-ray, and imaging of the colon and esophagus.¹⁵

The preferred protocol for diagnosis of congenital Chagas disease first requires positive serologic testing confirming the infection in the mother (see Figure 2).¹⁶ Once that is determined, microscopic and PCR-based examinations of cord blood and peripheral blood specimens are carried out during the first one to two months of the infant’s life.¹⁰ PCR is the preferred test for early congenital Chagas disease, recipients of organ transplants, and after accidental exposure since results can determine if the patient is infected earlier than trypomastigotes (developmental stage of trypanosomes) can be seen on a peripheral blood smear.⁵

If there is a suspicion of Chagas disease, the patient should be referred to an infectious disease specialist for diagnosis and treatment. Nifurtimox and benz­nidazole are the only drugs that have been shown to improve the course of Chagas disease.⁵ However, neither drug is approved by the FDA, and both can only be obtained from the CDC, which makes treatment a challenge.⁹ In addition, up to 30% of patients terminate treatment due to the many adverse effects of these drugs.¹⁷

The dosage regimen for nifurtimox is 8-10 mg/kg/d divided into three doses for 90 days.¹⁰ Anorexia, weight loss, nausea, vomiting, and abdominal pain occur in up to 70% of patients.⁵ Irritability, insomnia, disorientation, and tremors can also occur. Neurotoxicity leading to peripheral neuropathy is dose dependent and requires treatment termination.⁵

Benznidazole is better tolerated and is active against the trypomastigotes as well as the amastigotes or intracellular form of the parasite.¹⁰ The dosage regimen for benznidazole is 5-7 mg/kg/d divided into two doses for 60 days.¹⁰ Dermatologic reactions such as rash, photosensitivity, and exfoliative dermatitis are the most common adverse effects. Peripheral neuropathy and bone marrow suppression are dose dependent and require therapy cessation.⁵

The CDC recommends treatment for all cases of acute disease (including congenital disease) regardless of age, and for chronic disease in patients up to age 50 who have not progressed to cardiomyopathy. In patients older than 50, treatment should be determined after weighing the potential risks and benefits (see Table 2).¹⁸

The success of treatment is determined in part by the phase of the disease. Cure rates in patients treated with either nifurtimox or benznidazole during the acute phase range from 65% to 80%.¹⁷ Chronic disease shows less of a response to traditional antiparasitic drug regimens, but higher rates of success are seen in younger patients.⁵ According to current estimates, successful treatment of chronic disease is limited to 15% to 30% patients.¹⁷ Treatment of congenital Chagas disease should begin as soon as the diagnosis is confirmed, and cure rates are greater than 90% if patients are treated within the first year of life.¹⁰ Treating congenital Chagas disease is important because the infection can be passed to future generations even if the disease never manifests with symptoms.¹⁹ However, if an expecting mother has known Chagas disease, antiparasitic medications are not recommended during the pregnancy because of a lack of fetal safety data for the two antiparasitic agents.²⁰ Instead, it is recommended that women of childbearing age be treated before pregnancy, as rates of congenital infection are 25 times lower in women who are treated than in those who are not.²¹

PRE- AND POSTEXPOSURE PATIENT EDUCATION

Patient education mainly focuses on how to prevent Chagas disease and prognosis once diagnosed. During travel to endemic areas, the use of insecticides and residing in well-built households are the most important prevention measures. No vaccine is available, and primary chemoprophylaxis of persons visiting endemic areas is not recommended due to the low risk for infection and concerns about adverse effects.¹³

The survival rate of those who remain in the indeterminate phase is the same as that of the general population. However, findings that most strongly predict mortality include ventricular tachycardia, cardiomegaly, congestive heart failure (NYHA class III/IV), left ventricular systolic dysfunction, and male sex.¹⁰ Patients diagnosed with Chagas disease should be strongly encouraged not to donate blood or organs.¹⁰ Some organ and blood donation organizations selectively or universally screen donated specimens; however, this screening is not required by law.⁵ Family members of those diagnosed with the disease should also be tested, especially if the patient is a woman who has children or who plans to become pregnant.¹⁰

In patients confirmed to have Chagas disease but without symptoms and a normal ECG, further initial evaluation is not required.¹⁰ An annual history, physical exam, and ECG should be done. Those who have symptoms or ECG changes should have a complete cardiac work-up, including a 24-hour ambulatory ECG, exercise stress test, and echocardiogram to determine functional capacity. A barium swallow, barium enema, esophageal manometry, and endoscopy may be indicated in patients with gastrointestinal symptoms of Chagas disease but otherwise are not recommended. Patients taking antiparasitic drugs should have a CBC and CMP at the start of treatment and then bimonthly until the end of treatment to monitor for rare bone marrow suppression. Nifurtimox and benznidazole are also known to be mutagenic and increase the risk for lymphoma in animal studies, but this risk has not been documented in humans.¹⁰

CONCLUSION

Chagas disease is considered one of the neglected tropical diseases due to its high prevalence, chronic course, debilitating symptoms, and association with poverty.⁷ It is evident that incidence and prevalence of Chagas disease in the US are increasing due to recent immigration and mother-to-child transmission. Therefore, family practice clinicians must be able to recognize the red flags that suggest a T cruzi infection.^5,9 Enhanced awareness of Chagas disease among health care providers will lead to better symptom control and cure rates for affected patients and may also prevent congenital infections. These efforts could serve to remove Chagas disease from the list of neglected tropical diseases.

EVIDENCE SUMMARY

The TABLE^1-4 shows the major results of the meta-analyses for the various medical therapy trials.

Two systematic reviews with meta-analyses evaluated treatment with INS for CRS with nasal polyps (40 RCTs; 3624 patients, mean age 48 years, 64% male) and without polyps (10 RCTs; 590 patients, mean age 39 years, 51% male).^1,2 Trials reported sinonasal symptom outcomes differently and couldn’t be combined. In addition to reducing rate of polyp occurrence, for both CRS with and without polyps, key findings were:

• Global symptom scores were better for INS than placebo.
• Proportion of patients responding was greater for INS than with placebo.

There was no significant difference between adverse event rates with INS and placebo.

A systematic review and meta-analysis (8 RCTs, 389 patients) compared different SI regimens for CRS.³ The standardized mean difference was used to combine trials using various symptom outcomes. Key findings included the following:

• SI was better than no treatment.
• SI adjunctive therapy (with an antihistamine) improved disease-specific quality-of-life scores.
• SI was less effective than INS therapy for symptom improvement.

Hypertonic and isotonic saline yielded similar symptom scores. No adverse effects were reported.

One meta-analysis evaluated patient-reported outcomes with 12 weeks of macrolide therapy compared to placebo using the results of the SinoNasal Outcome Test (SNOT). The SNOT is a quality-of-life questionnaire that lists symptoms and the social-emotional consequences of CRS; a negative change in the SNOT score, on a 0 to 5 scale, indicates improvement. Overall the SNOT score improved 8% with macrolide therapy—statistically significant, but of uncertain clinical importance.⁴

Surgery improves nasal obstruction, pain, and postnasal discharge

A systematic review of 21 studies (prospective RCTs, prospective controlled clinical trials, cohort studies, case series, and retrospective record reviews) with a total of 2070 patients analyzed the effectiveness of endoscopic sinus surgery alone for improving CRS symptoms.⁵ Mean duration of post-operative follow-up was 14 months. Meta-analysis was performed separately for each symptom and the standard mean difference of the symptom severity score before and after surgery was reported as the effect size (ES) for the outcome measure (an ES of 0.2 is considered small; 0.6, moderate; 1.2, large; and 2, very large).

All symptoms improved compared to their preoperative severity scores. Nasal obstruction improved the most (ES=1.73; 95% CI, 1.45-2.02). Large symptom improvement was also observed for facial pain (ES=1.13; 95% CI, 0.96-1.31) and postnasal discharge (ES=1.19; 95% CI, 0.96-1.43).

Surgery and medical therapy may provide comparable symptom relief

A recent Cochrane review of 4 low-quality RCTs including 378 patients compared surgical with medical interventions for CRS with nasal polyps. Study heterogeneity and selective outcome reporting prevented meta-analysis.

The 3 comparison groups were endoscopic sinus surgery vs systemic steroids + INS; polypectomy vs systemic steroid + INS; and endoscopic surgery + INS vs antibiotic + “high-dose” INS. Overall, neither surgery nor medical therapy was superior in terms of patient-reported symptom scores or quality-of-life measures.⁶

EVIDENCE SUMMARY

The TABLE^1-4 shows the major results of the meta-analyses for the various medical therapy trials.

Two systematic reviews with meta-analyses evaluated treatment with INS for CRS with nasal polyps (40 RCTs; 3624 patients, mean age 48 years, 64% male) and without polyps (10 RCTs; 590 patients, mean age 39 years, 51% male).^1,2 Trials reported sinonasal symptom outcomes differently and couldn’t be combined. In addition to reducing rate of polyp occurrence, for both CRS with and without polyps, key findings were:

• Global symptom scores were better for INS than placebo.
• Proportion of patients responding was greater for INS than with placebo.

There was no significant difference between adverse event rates with INS and placebo.

A systematic review and meta-analysis (8 RCTs, 389 patients) compared different SI regimens for CRS.³ The standardized mean difference was used to combine trials using various symptom outcomes. Key findings included the following:

• SI was better than no treatment.
• SI adjunctive therapy (with an antihistamine) improved disease-specific quality-of-life scores.
• SI was less effective than INS therapy for symptom improvement.

Hypertonic and isotonic saline yielded similar symptom scores. No adverse effects were reported.

One meta-analysis evaluated patient-reported outcomes with 12 weeks of macrolide therapy compared to placebo using the results of the SinoNasal Outcome Test (SNOT). The SNOT is a quality-of-life questionnaire that lists symptoms and the social-emotional consequences of CRS; a negative change in the SNOT score, on a 0 to 5 scale, indicates improvement. Overall the SNOT score improved 8% with macrolide therapy—statistically significant, but of uncertain clinical importance.⁴

Surgery improves nasal obstruction, pain, and postnasal discharge

A systematic review of 21 studies (prospective RCTs, prospective controlled clinical trials, cohort studies, case series, and retrospective record reviews) with a total of 2070 patients analyzed the effectiveness of endoscopic sinus surgery alone for improving CRS symptoms.⁵ Mean duration of post-operative follow-up was 14 months. Meta-analysis was performed separately for each symptom and the standard mean difference of the symptom severity score before and after surgery was reported as the effect size (ES) for the outcome measure (an ES of 0.2 is considered small; 0.6, moderate; 1.2, large; and 2, very large).

All symptoms improved compared to their preoperative severity scores. Nasal obstruction improved the most (ES=1.73; 95% CI, 1.45-2.02). Large symptom improvement was also observed for facial pain (ES=1.13; 95% CI, 0.96-1.31) and postnasal discharge (ES=1.19; 95% CI, 0.96-1.43).

Surgery and medical therapy may provide comparable symptom relief

A recent Cochrane review of 4 low-quality RCTs including 378 patients compared surgical with medical interventions for CRS with nasal polyps. Study heterogeneity and selective outcome reporting prevented meta-analysis.

The 3 comparison groups were endoscopic sinus surgery vs systemic steroids + INS; polypectomy vs systemic steroid + INS; and endoscopic surgery + INS vs antibiotic + “high-dose” INS. Overall, neither surgery nor medical therapy was superior in terms of patient-reported symptom scores or quality-of-life measures.⁶

EVIDENCE SUMMARY

The TABLE^1-4 shows the major results of the meta-analyses for the various medical therapy trials.

Two systematic reviews with meta-analyses evaluated treatment with INS for CRS with nasal polyps (40 RCTs; 3624 patients, mean age 48 years, 64% male) and without polyps (10 RCTs; 590 patients, mean age 39 years, 51% male).^1,2 Trials reported sinonasal symptom outcomes differently and couldn’t be combined. In addition to reducing rate of polyp occurrence, for both CRS with and without polyps, key findings were:

• Global symptom scores were better for INS than placebo.
• Proportion of patients responding was greater for INS than with placebo.

There was no significant difference between adverse event rates with INS and placebo.

A systematic review and meta-analysis (8 RCTs, 389 patients) compared different SI regimens for CRS.³ The standardized mean difference was used to combine trials using various symptom outcomes. Key findings included the following:

• SI was better than no treatment.
• SI adjunctive therapy (with an antihistamine) improved disease-specific quality-of-life scores.
• SI was less effective than INS therapy for symptom improvement.

Hypertonic and isotonic saline yielded similar symptom scores. No adverse effects were reported.

One meta-analysis evaluated patient-reported outcomes with 12 weeks of macrolide therapy compared to placebo using the results of the SinoNasal Outcome Test (SNOT). The SNOT is a quality-of-life questionnaire that lists symptoms and the social-emotional consequences of CRS; a negative change in the SNOT score, on a 0 to 5 scale, indicates improvement. Overall the SNOT score improved 8% with macrolide therapy—statistically significant, but of uncertain clinical importance.⁴

Surgery improves nasal obstruction, pain, and postnasal discharge

A systematic review of 21 studies (prospective RCTs, prospective controlled clinical trials, cohort studies, case series, and retrospective record reviews) with a total of 2070 patients analyzed the effectiveness of endoscopic sinus surgery alone for improving CRS symptoms.⁵ Mean duration of post-operative follow-up was 14 months. Meta-analysis was performed separately for each symptom and the standard mean difference of the symptom severity score before and after surgery was reported as the effect size (ES) for the outcome measure (an ES of 0.2 is considered small; 0.6, moderate; 1.2, large; and 2, very large).

All symptoms improved compared to their preoperative severity scores. Nasal obstruction improved the most (ES=1.73; 95% CI, 1.45-2.02). Large symptom improvement was also observed for facial pain (ES=1.13; 95% CI, 0.96-1.31) and postnasal discharge (ES=1.19; 95% CI, 0.96-1.43).

Surgery and medical therapy may provide comparable symptom relief

A recent Cochrane review of 4 low-quality RCTs including 378 patients compared surgical with medical interventions for CRS with nasal polyps. Study heterogeneity and selective outcome reporting prevented meta-analysis.

The 3 comparison groups were endoscopic sinus surgery vs systemic steroids + INS; polypectomy vs systemic steroid + INS; and endoscopic surgery + INS vs antibiotic + “high-dose” INS. Overall, neither surgery nor medical therapy was superior in terms of patient-reported symptom scores or quality-of-life measures.⁶

EVIDENCE SUMMARY

In 2015, the American College of Rheumatology (ACR) redefined the clinical criteria for diagnosis of gout based on a 3-step system¹ that can be found at: http://goutclassificationcalculator.auckland.ac.nz. The ACR rule was derived from a cross-sectional study of 983 patients in 25 rheumatology centers in 16 countries who presented with a swollen joint.² Of the 983 patients, 509 had gout; the prevalence was 52%. Data from 653 of these patients were used to develop the rule and then validated in the remaining 330 patients.

Compared with the gold standard of monosodium urate crystals in synovial fluid, the ACR rule has a sensitivity of 92% and a specificity of 89%. The rule, designed for the research setting, involves using synovial fluid analysis, ultrasound imaging, and radiography, which makes it less useful in a primary care setting.

The Netherlands rule for primary care

A prospective diagnostic study in 328 family medicine patients (74% male; mean age 57) with monoarthritis tested the ability of multiple clinical variables to diagnose gout using monosodium urate crystals in synovial fluid as the gold standard.³ The prevalence of gout in this population was 57%.

The best diagnostic rule (Netherlands rule) comprised the following predefined variables: male sex, previous patient-reported arthritis attack, onset within one day, joint redness, first metatarsophalangeal joint (MTP1) involvement, hypertension or cardiovascular disease (angina pectoris, myocardial infarction, heart failure, cerebrovascular accident, transient ischemic attack, or peripheral vascular disease), and serum uric acid level above 5.88 mg/dL. The rule gives one point for each item. A score >8 had a positive likelihood ratio for diagnosing gout of 3.48 (TABLE¹) and a higher positive predictive value (PPV) than family physicians’ clinical impressions (83% vs 64%).

The prevalence of gout in patients with scores of <4, 4 to 8, and >8 were 2.8%, 27%, and 80%, respectively. For scores of 4 to 8, the probability of gout is indeterminate, and synovial fluid analysis is recommended.

The Netherlands rule, validated in a secondary care practice of 390 patients with monoarthritis, found that a score >8 had a PPV of 87% and a score <4 had a negative predictive value of 95%.⁴ The probability of gout based on this rule can be calculated at http://www.umcn.nl/goutcalc.

Clinical prediction rules effectively diagnose gout without joint fluid analysis.In the study used to develop the Netherlands rule, no patients with a high probability of gout had septic arthritis. The ability of the rule to differentiate between gout and septic arthritis was tested retrospectively in 33 patients with acute gout (podagra excluded) diagnosed by the presence of monosodium urate joint crystals and 27 patients with septic arthritis diagnosed by positive bacterial culture.⁵ Patients with gout had significantly higher scores than patients with septic arthritis (7.8 ± 1.59 vs 3.4 ± 2.3; P<.001).

A study of 82 Veterans Administration patients compared the American Rheumatology Association (ARA), New York, and Rome prediction rules with regard to their ability to diagnose gout with synovial urate crystals.⁶ The ARA criteria for gout diagnosis require either tophi or monosodium urate crystals in synovial fluid, or 6 out of a list of 12 other criteria.⁷

The New York prediction rule requires that patients meet 2 or more of the following criteria: at least 2 attacks of painful joint swelling with complete resolution within 2 weeks, podagra, tophi, and rapid response to colchicine treatment, defined as a major reduction in the objective signs of inflammation within 48 hours.

The Rome prediction rule requires meeting 2 of 3 criteria: serum uric acid >7 mg/dL in men and >6 mg/dL in women, presence of tophi, and history of attacks of painful joint swelling with abrupt onset and resolution within 2 weeks.

The New York prediction rule had the highest positive likelihood ratio of 4.4 compared with the ARA (1.8) and Rome (4.3) rules.⁶ The utility of the New York and Rome rules, although they have fewer criteria than ARA, is limited by the fact that they include a previous episode of joint swelling and tophi. These criteria increase their specificity but make them less useful in diagnosing a first episode of gout, when tophi are unlikely to have developed.

Prediction rules are more sensitive in established gout

The new ACR prediction rule was compared with the ARA, Rome, and New York clinical prediction rules using urate crystals as the gold standard in early (less than 2 years) and established disease (longer than 2 years).⁸ All clinical prediction rules were more sensitive in established disease than early disease (95.3% vs 84.1%; P<.001) and more specific in early disease than established disease (79.9% vs 52.5%; P<.001).

EVIDENCE SUMMARY

In 2015, the American College of Rheumatology (ACR) redefined the clinical criteria for diagnosis of gout based on a 3-step system¹ that can be found at: http://goutclassificationcalculator.auckland.ac.nz. The ACR rule was derived from a cross-sectional study of 983 patients in 25 rheumatology centers in 16 countries who presented with a swollen joint.² Of the 983 patients, 509 had gout; the prevalence was 52%. Data from 653 of these patients were used to develop the rule and then validated in the remaining 330 patients.

Compared with the gold standard of monosodium urate crystals in synovial fluid, the ACR rule has a sensitivity of 92% and a specificity of 89%. The rule, designed for the research setting, involves using synovial fluid analysis, ultrasound imaging, and radiography, which makes it less useful in a primary care setting.

The Netherlands rule for primary care

A prospective diagnostic study in 328 family medicine patients (74% male; mean age 57) with monoarthritis tested the ability of multiple clinical variables to diagnose gout using monosodium urate crystals in synovial fluid as the gold standard.³ The prevalence of gout in this population was 57%.

The best diagnostic rule (Netherlands rule) comprised the following predefined variables: male sex, previous patient-reported arthritis attack, onset within one day, joint redness, first metatarsophalangeal joint (MTP1) involvement, hypertension or cardiovascular disease (angina pectoris, myocardial infarction, heart failure, cerebrovascular accident, transient ischemic attack, or peripheral vascular disease), and serum uric acid level above 5.88 mg/dL. The rule gives one point for each item. A score >8 had a positive likelihood ratio for diagnosing gout of 3.48 (TABLE¹) and a higher positive predictive value (PPV) than family physicians’ clinical impressions (83% vs 64%).

The prevalence of gout in patients with scores of <4, 4 to 8, and >8 were 2.8%, 27%, and 80%, respectively. For scores of 4 to 8, the probability of gout is indeterminate, and synovial fluid analysis is recommended.

The Netherlands rule, validated in a secondary care practice of 390 patients with monoarthritis, found that a score >8 had a PPV of 87% and a score <4 had a negative predictive value of 95%.⁴ The probability of gout based on this rule can be calculated at http://www.umcn.nl/goutcalc.

Clinical prediction rules effectively diagnose gout without joint fluid analysis.In the study used to develop the Netherlands rule, no patients with a high probability of gout had septic arthritis. The ability of the rule to differentiate between gout and septic arthritis was tested retrospectively in 33 patients with acute gout (podagra excluded) diagnosed by the presence of monosodium urate joint crystals and 27 patients with septic arthritis diagnosed by positive bacterial culture.⁵ Patients with gout had significantly higher scores than patients with septic arthritis (7.8 ± 1.59 vs 3.4 ± 2.3; P<.001).

A study of 82 Veterans Administration patients compared the American Rheumatology Association (ARA), New York, and Rome prediction rules with regard to their ability to diagnose gout with synovial urate crystals.⁶ The ARA criteria for gout diagnosis require either tophi or monosodium urate crystals in synovial fluid, or 6 out of a list of 12 other criteria.⁷

The New York prediction rule requires that patients meet 2 or more of the following criteria: at least 2 attacks of painful joint swelling with complete resolution within 2 weeks, podagra, tophi, and rapid response to colchicine treatment, defined as a major reduction in the objective signs of inflammation within 48 hours.

The Rome prediction rule requires meeting 2 of 3 criteria: serum uric acid >7 mg/dL in men and >6 mg/dL in women, presence of tophi, and history of attacks of painful joint swelling with abrupt onset and resolution within 2 weeks.

The New York prediction rule had the highest positive likelihood ratio of 4.4 compared with the ARA (1.8) and Rome (4.3) rules.⁶ The utility of the New York and Rome rules, although they have fewer criteria than ARA, is limited by the fact that they include a previous episode of joint swelling and tophi. These criteria increase their specificity but make them less useful in diagnosing a first episode of gout, when tophi are unlikely to have developed.

Prediction rules are more sensitive in established gout

The new ACR prediction rule was compared with the ARA, Rome, and New York clinical prediction rules using urate crystals as the gold standard in early (less than 2 years) and established disease (longer than 2 years).⁸ All clinical prediction rules were more sensitive in established disease than early disease (95.3% vs 84.1%; P<.001) and more specific in early disease than established disease (79.9% vs 52.5%; P<.001).

EVIDENCE SUMMARY

In 2015, the American College of Rheumatology (ACR) redefined the clinical criteria for diagnosis of gout based on a 3-step system¹ that can be found at: http://goutclassificationcalculator.auckland.ac.nz. The ACR rule was derived from a cross-sectional study of 983 patients in 25 rheumatology centers in 16 countries who presented with a swollen joint.² Of the 983 patients, 509 had gout; the prevalence was 52%. Data from 653 of these patients were used to develop the rule and then validated in the remaining 330 patients.

Compared with the gold standard of monosodium urate crystals in synovial fluid, the ACR rule has a sensitivity of 92% and a specificity of 89%. The rule, designed for the research setting, involves using synovial fluid analysis, ultrasound imaging, and radiography, which makes it less useful in a primary care setting.

The Netherlands rule for primary care

A prospective diagnostic study in 328 family medicine patients (74% male; mean age 57) with monoarthritis tested the ability of multiple clinical variables to diagnose gout using monosodium urate crystals in synovial fluid as the gold standard.³ The prevalence of gout in this population was 57%.

The best diagnostic rule (Netherlands rule) comprised the following predefined variables: male sex, previous patient-reported arthritis attack, onset within one day, joint redness, first metatarsophalangeal joint (MTP1) involvement, hypertension or cardiovascular disease (angina pectoris, myocardial infarction, heart failure, cerebrovascular accident, transient ischemic attack, or peripheral vascular disease), and serum uric acid level above 5.88 mg/dL. The rule gives one point for each item. A score >8 had a positive likelihood ratio for diagnosing gout of 3.48 (TABLE¹) and a higher positive predictive value (PPV) than family physicians’ clinical impressions (83% vs 64%).

The prevalence of gout in patients with scores of <4, 4 to 8, and >8 were 2.8%, 27%, and 80%, respectively. For scores of 4 to 8, the probability of gout is indeterminate, and synovial fluid analysis is recommended.

The Netherlands rule, validated in a secondary care practice of 390 patients with monoarthritis, found that a score >8 had a PPV of 87% and a score <4 had a negative predictive value of 95%.⁴ The probability of gout based on this rule can be calculated at http://www.umcn.nl/goutcalc.

Clinical prediction rules effectively diagnose gout without joint fluid analysis.In the study used to develop the Netherlands rule, no patients with a high probability of gout had septic arthritis. The ability of the rule to differentiate between gout and septic arthritis was tested retrospectively in 33 patients with acute gout (podagra excluded) diagnosed by the presence of monosodium urate joint crystals and 27 patients with septic arthritis diagnosed by positive bacterial culture.⁵ Patients with gout had significantly higher scores than patients with septic arthritis (7.8 ± 1.59 vs 3.4 ± 2.3; P<.001).

A study of 82 Veterans Administration patients compared the American Rheumatology Association (ARA), New York, and Rome prediction rules with regard to their ability to diagnose gout with synovial urate crystals.⁶ The ARA criteria for gout diagnosis require either tophi or monosodium urate crystals in synovial fluid, or 6 out of a list of 12 other criteria.⁷

The New York prediction rule requires that patients meet 2 or more of the following criteria: at least 2 attacks of painful joint swelling with complete resolution within 2 weeks, podagra, tophi, and rapid response to colchicine treatment, defined as a major reduction in the objective signs of inflammation within 48 hours.

The Rome prediction rule requires meeting 2 of 3 criteria: serum uric acid >7 mg/dL in men and >6 mg/dL in women, presence of tophi, and history of attacks of painful joint swelling with abrupt onset and resolution within 2 weeks.

The New York prediction rule had the highest positive likelihood ratio of 4.4 compared with the ARA (1.8) and Rome (4.3) rules.⁶ The utility of the New York and Rome rules, although they have fewer criteria than ARA, is limited by the fact that they include a previous episode of joint swelling and tophi. These criteria increase their specificity but make them less useful in diagnosing a first episode of gout, when tophi are unlikely to have developed.

Prediction rules are more sensitive in established gout

The new ACR prediction rule was compared with the ARA, Rome, and New York clinical prediction rules using urate crystals as the gold standard in early (less than 2 years) and established disease (longer than 2 years).⁸ All clinical prediction rules were more sensitive in established disease than early disease (95.3% vs 84.1%; P<.001) and more specific in early disease than established disease (79.9% vs 52.5%; P<.001).

EVIDENCE SUMMARY

A post-hoc analysis of a prospective RCT (the Diabetes Prevention Program) comprising 3081 patients with impaired glucose metabolism who received metformin, a lifestyle modification program, or no intervention (placebo) found that metformin reduced the risk of developing diabetes only for patients in the highest risk quartile over 2.8 years. Lifestyle modification reduced diabetes risk in all patients.¹

Investigators stratified patients who met National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome into risk quartiles for progression to diabetes using a model they developed based on 7 parameters: fasting plasma glucose, hemoglobin A1c, history of high blood glucose, waist:hip ratio, waist circumference, triglycerides, and height (TABLE¹). The model reasonably fit outcomes—the percentage of patients in each quartile who developed diabetes—with an area under the receiver operator characteristic curve of 0.73 (a measure of diagnostic accuracy where 1 is a perfect predictor and 0.5 is random).

Lifestyle modification reduced risk in all quartiles with progressively greater effect as risk increased (lowest risk quartile: ARR=4.9%, 3-year NNT=20.4; highest risk quartile: ARR=28.3%; 3-year NNT=3.5).

There were 2 key weaknesses of the risk model: It wasn’t validated in a separate population and the true incidence of diabetes among patients taking placebo was higher than predicted. The investigators compared their risk prediction model results with the Framingham Risk Score (FRS) for diabetes and found that they correlated well, although the FRS results were consistently about 6% (absolute) higher when corrected for duration. (The FRS calculator is available online at www.framinghamheartstudy.org/risk-functions/diabetes/.)

Lifestyle change reduces diabetes risk more than metformin

The original Diabetes Prevention Program found that intensive lifestyle intervention and metformin reduced the number of diabetes cases over 2.8 years among 3234 patients at risk for developing diabetes.²

Compared with no intervention, fewer patients developed diabetes with either metformin or lifestyle improvement, although lifestyle change had the larger effect (no intervention: 11 cases per 100 person-years; metformin: 7.8 cases; 95% confidence interval [CI], 6.8-8.8; ARR=3.2% per year vs no intervention; lifestyle improvements: 4.8 cases; 95% CI, 4.1-5.7; ARR=6.2% per year vs no intervention).

A 10-year follow-up study to the Diabetes Prevention Program found that, compared with no intervention, both metformin and lifestyle interventions continued to be associated with a lower incidence of diabetes (no intervention: 7.8 cases per 100 person-years; 95% CI, 4.8-6.5; metformin: 6.4 cases; 95% CI, 4.2-5.7; ARR=1.4% per year; lifestyle interventions: 5.3 cases; 95% CI, 5.1-6.8; ARR=2.5% per year).³

Researchers originally randomized 3234 patients with body mass index ≥24 kg/m², fasting blood sugar 95 to 125 mg/dL, and 2-hour post 75-gm glucose value of 149 to 199 mg/dL to 3 groups: intensive lifestyle modification (weight loss goal of 7%, 150 minutes a week of exercise), metformin (850 mg twice daily), and no inter­vention. After the 2.8-year follow-up period, 2766 patients continued for another 5.7 years of follow-up. Investigators offered group lifestyle counseling to all patients and continued metformin at the same dose in the second group.

Earlier study shows an effect for metformin, but with a caveat

An earlier RCT found that metformin reduced the risk of developing diabetes in patients with metabolic syndrome.⁴ Investigators randomized 70 patients to metformin (250 mg 3 times daily) or placebo for a year. Fewer patients developed diabetes with metformin (3% vs 16.2%, P=.011; NNT=7.6) and more had a normal glucose tolerance test result (84.9% vs 51.4%, P=.011; NNT=3). However, by current American Diabetes Association criteria, half of the subjects had early diabetes at baseline.

Metformin lowers fasting blood sugar, but may not reverse metabolic syndrome

A post-hoc analysis of another RCT found that metformin reduced fasting plasma glucose (FPG) levels in patients with upper-body obesity and metabolic syndrome (by 1999 World Health Organization criteria but not NCEP ATP III criteria).⁵

Investigators randomized 457 patients to metformin 850 mg once daily or placebo and followed them for a year. FPG levels decreased with metformin but increased with placebo (reduction FPG 5.9 mg/dL vs increase FPG 12.3 mg/dL; P<.04). The investigators didn’t report whether any patients developed diabetes.

However, another RCT (155 patients) that compared metformin 850 mg twice daily with placebo in subjects with metabolic syndrome but without diabetes found greater normalization of FPG (5% vs 0%; P=.005), but no reversal of metabolic syndrome or change in Framingham 10-year risk score after 12 weeks.⁶

EVIDENCE SUMMARY

A post-hoc analysis of a prospective RCT (the Diabetes Prevention Program) comprising 3081 patients with impaired glucose metabolism who received metformin, a lifestyle modification program, or no intervention (placebo) found that metformin reduced the risk of developing diabetes only for patients in the highest risk quartile over 2.8 years. Lifestyle modification reduced diabetes risk in all patients.¹

Investigators stratified patients who met National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome into risk quartiles for progression to diabetes using a model they developed based on 7 parameters: fasting plasma glucose, hemoglobin A1c, history of high blood glucose, waist:hip ratio, waist circumference, triglycerides, and height (TABLE¹). The model reasonably fit outcomes—the percentage of patients in each quartile who developed diabetes—with an area under the receiver operator characteristic curve of 0.73 (a measure of diagnostic accuracy where 1 is a perfect predictor and 0.5 is random).

Lifestyle modification reduced risk in all quartiles with progressively greater effect as risk increased (lowest risk quartile: ARR=4.9%, 3-year NNT=20.4; highest risk quartile: ARR=28.3%; 3-year NNT=3.5).

There were 2 key weaknesses of the risk model: It wasn’t validated in a separate population and the true incidence of diabetes among patients taking placebo was higher than predicted. The investigators compared their risk prediction model results with the Framingham Risk Score (FRS) for diabetes and found that they correlated well, although the FRS results were consistently about 6% (absolute) higher when corrected for duration. (The FRS calculator is available online at www.framinghamheartstudy.org/risk-functions/diabetes/.)

Lifestyle change reduces diabetes risk more than metformin

The original Diabetes Prevention Program found that intensive lifestyle intervention and metformin reduced the number of diabetes cases over 2.8 years among 3234 patients at risk for developing diabetes.²

Compared with no intervention, fewer patients developed diabetes with either metformin or lifestyle improvement, although lifestyle change had the larger effect (no intervention: 11 cases per 100 person-years; metformin: 7.8 cases; 95% confidence interval [CI], 6.8-8.8; ARR=3.2% per year vs no intervention; lifestyle improvements: 4.8 cases; 95% CI, 4.1-5.7; ARR=6.2% per year vs no intervention).

A 10-year follow-up study to the Diabetes Prevention Program found that, compared with no intervention, both metformin and lifestyle interventions continued to be associated with a lower incidence of diabetes (no intervention: 7.8 cases per 100 person-years; 95% CI, 4.8-6.5; metformin: 6.4 cases; 95% CI, 4.2-5.7; ARR=1.4% per year; lifestyle interventions: 5.3 cases; 95% CI, 5.1-6.8; ARR=2.5% per year).³

Researchers originally randomized 3234 patients with body mass index ≥24 kg/m², fasting blood sugar 95 to 125 mg/dL, and 2-hour post 75-gm glucose value of 149 to 199 mg/dL to 3 groups: intensive lifestyle modification (weight loss goal of 7%, 150 minutes a week of exercise), metformin (850 mg twice daily), and no inter­vention. After the 2.8-year follow-up period, 2766 patients continued for another 5.7 years of follow-up. Investigators offered group lifestyle counseling to all patients and continued metformin at the same dose in the second group.

Earlier study shows an effect for metformin, but with a caveat

An earlier RCT found that metformin reduced the risk of developing diabetes in patients with metabolic syndrome.⁴ Investigators randomized 70 patients to metformin (250 mg 3 times daily) or placebo for a year. Fewer patients developed diabetes with metformin (3% vs 16.2%, P=.011; NNT=7.6) and more had a normal glucose tolerance test result (84.9% vs 51.4%, P=.011; NNT=3). However, by current American Diabetes Association criteria, half of the subjects had early diabetes at baseline.

Metformin lowers fasting blood sugar, but may not reverse metabolic syndrome

A post-hoc analysis of another RCT found that metformin reduced fasting plasma glucose (FPG) levels in patients with upper-body obesity and metabolic syndrome (by 1999 World Health Organization criteria but not NCEP ATP III criteria).⁵

Investigators randomized 457 patients to metformin 850 mg once daily or placebo and followed them for a year. FPG levels decreased with metformin but increased with placebo (reduction FPG 5.9 mg/dL vs increase FPG 12.3 mg/dL; P<.04). The investigators didn’t report whether any patients developed diabetes.

However, another RCT (155 patients) that compared metformin 850 mg twice daily with placebo in subjects with metabolic syndrome but without diabetes found greater normalization of FPG (5% vs 0%; P=.005), but no reversal of metabolic syndrome or change in Framingham 10-year risk score after 12 weeks.⁶

EVIDENCE SUMMARY

A post-hoc analysis of a prospective RCT (the Diabetes Prevention Program) comprising 3081 patients with impaired glucose metabolism who received metformin, a lifestyle modification program, or no intervention (placebo) found that metformin reduced the risk of developing diabetes only for patients in the highest risk quartile over 2.8 years. Lifestyle modification reduced diabetes risk in all patients.¹

Investigators stratified patients who met National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome into risk quartiles for progression to diabetes using a model they developed based on 7 parameters: fasting plasma glucose, hemoglobin A1c, history of high blood glucose, waist:hip ratio, waist circumference, triglycerides, and height (TABLE¹). The model reasonably fit outcomes—the percentage of patients in each quartile who developed diabetes—with an area under the receiver operator characteristic curve of 0.73 (a measure of diagnostic accuracy where 1 is a perfect predictor and 0.5 is random).

Lifestyle modification reduced risk in all quartiles with progressively greater effect as risk increased (lowest risk quartile: ARR=4.9%, 3-year NNT=20.4; highest risk quartile: ARR=28.3%; 3-year NNT=3.5).

There were 2 key weaknesses of the risk model: It wasn’t validated in a separate population and the true incidence of diabetes among patients taking placebo was higher than predicted. The investigators compared their risk prediction model results with the Framingham Risk Score (FRS) for diabetes and found that they correlated well, although the FRS results were consistently about 6% (absolute) higher when corrected for duration. (The FRS calculator is available online at www.framinghamheartstudy.org/risk-functions/diabetes/.)

Lifestyle change reduces diabetes risk more than metformin

The original Diabetes Prevention Program found that intensive lifestyle intervention and metformin reduced the number of diabetes cases over 2.8 years among 3234 patients at risk for developing diabetes.²

Compared with no intervention, fewer patients developed diabetes with either metformin or lifestyle improvement, although lifestyle change had the larger effect (no intervention: 11 cases per 100 person-years; metformin: 7.8 cases; 95% confidence interval [CI], 6.8-8.8; ARR=3.2% per year vs no intervention; lifestyle improvements: 4.8 cases; 95% CI, 4.1-5.7; ARR=6.2% per year vs no intervention).

A 10-year follow-up study to the Diabetes Prevention Program found that, compared with no intervention, both metformin and lifestyle interventions continued to be associated with a lower incidence of diabetes (no intervention: 7.8 cases per 100 person-years; 95% CI, 4.8-6.5; metformin: 6.4 cases; 95% CI, 4.2-5.7; ARR=1.4% per year; lifestyle interventions: 5.3 cases; 95% CI, 5.1-6.8; ARR=2.5% per year).³

Researchers originally randomized 3234 patients with body mass index ≥24 kg/m², fasting blood sugar 95 to 125 mg/dL, and 2-hour post 75-gm glucose value of 149 to 199 mg/dL to 3 groups: intensive lifestyle modification (weight loss goal of 7%, 150 minutes a week of exercise), metformin (850 mg twice daily), and no inter­vention. After the 2.8-year follow-up period, 2766 patients continued for another 5.7 years of follow-up. Investigators offered group lifestyle counseling to all patients and continued metformin at the same dose in the second group.

Earlier study shows an effect for metformin, but with a caveat

An earlier RCT found that metformin reduced the risk of developing diabetes in patients with metabolic syndrome.⁴ Investigators randomized 70 patients to metformin (250 mg 3 times daily) or placebo for a year. Fewer patients developed diabetes with metformin (3% vs 16.2%, P=.011; NNT=7.6) and more had a normal glucose tolerance test result (84.9% vs 51.4%, P=.011; NNT=3). However, by current American Diabetes Association criteria, half of the subjects had early diabetes at baseline.

Metformin lowers fasting blood sugar, but may not reverse metabolic syndrome

A post-hoc analysis of another RCT found that metformin reduced fasting plasma glucose (FPG) levels in patients with upper-body obesity and metabolic syndrome (by 1999 World Health Organization criteria but not NCEP ATP III criteria).⁵

Investigators randomized 457 patients to metformin 850 mg once daily or placebo and followed them for a year. FPG levels decreased with metformin but increased with placebo (reduction FPG 5.9 mg/dL vs increase FPG 12.3 mg/dL; P<.04). The investigators didn’t report whether any patients developed diabetes.

However, another RCT (155 patients) that compared metformin 850 mg twice daily with placebo in subjects with metabolic syndrome but without diabetes found greater normalization of FPG (5% vs 0%; P=.005), but no reversal of metabolic syndrome or change in Framingham 10-year risk score after 12 weeks.⁶

Since Florida has seen several new cases of local mosquito-borne infection, controlling and preventing Zika infection has great urgency. Zika virus involves an arthropod-borne infection transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Other modes of transmission include the maternal-fetal route, any sexual contact, blood transfusions, organ or tissue transplantation, and laboratory exposure.¹

The first case of Zika infection in the United States and its territories occurred through international travel. According to the Centers for Disease Control and Prevention, as of October 12, 2016, there were 3807 travel-associated cases of Zika infection in the United States and 84 instances in its territories.² As for local transmission, there were 128 people evidencing a Zika infection in the United States and 25,871 in US territories.² Regions between Texas and Florida are at high risk because Aedes mosquitoes primarily inhabit the gulf coast.³ Many cases have occurred despite repellent use and eradication efforts, possibly due to resistance acquired by these mosquitoes.¹

Control measures include using insect repellents, aerial spraying of insecticides, eliminating mosquito breeding sites, covering water tanks, and using mosquito nets or door and window screens. Infection during pregnancy is the greatest concern because of congenital anomalies (including microcephaly) that negatively affect brain development.⁴

Before a possible conception or any sexual contact, women exposed to Zika—with or without symptoms—must wait at least 8 weeks; men with or without symptoms should abstain for 6 months.⁴ Individuals should avoid traveling to areas with Zika infestation, wear long-sleeved clothing treated with permethrin, and minimize outside exposure, especially in evening hours.⁴

The World Health Organization is utilizing genetically modified mosquitoes to diminish Aedes populations; trials conducted in affected areas of Brazil revealed that the number of Aedes mosquitoes was reduced by 90%.⁵ This method of mosquito control is currently being studied in the United States.⁶ Vaccinations to prevent Zika infection are also under investigation.

Physicians should educate patients regarding the clinical manifestations and complications of Zika virus infection; people need to know that the Zika virus can be sexually transmitted. Doctors should also counsel patients to curtail travel to areas that have Zika infestations, or to at least wear protective clothing while in such areas to minimize mosquito bite risk. Educating travelers about appropriate postponement of sexual contact after any exposure to the Zika virus is also essential.⁴

Hema Madhuri Mekala, MD
Priyanga Jayakumar, MD
Rajashekar Reddy Yeruva, MD
Steven Lippmann, MD
Louisville, KY

Since Florida has seen several new cases of local mosquito-borne infection, controlling and preventing Zika infection has great urgency. Zika virus involves an arthropod-borne infection transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Other modes of transmission include the maternal-fetal route, any sexual contact, blood transfusions, organ or tissue transplantation, and laboratory exposure.¹

The first case of Zika infection in the United States and its territories occurred through international travel. According to the Centers for Disease Control and Prevention, as of October 12, 2016, there were 3807 travel-associated cases of Zika infection in the United States and 84 instances in its territories.² As for local transmission, there were 128 people evidencing a Zika infection in the United States and 25,871 in US territories.² Regions between Texas and Florida are at high risk because Aedes mosquitoes primarily inhabit the gulf coast.³ Many cases have occurred despite repellent use and eradication efforts, possibly due to resistance acquired by these mosquitoes.¹

Control measures include using insect repellents, aerial spraying of insecticides, eliminating mosquito breeding sites, covering water tanks, and using mosquito nets or door and window screens. Infection during pregnancy is the greatest concern because of congenital anomalies (including microcephaly) that negatively affect brain development.⁴

Before a possible conception or any sexual contact, women exposed to Zika—with or without symptoms—must wait at least 8 weeks; men with or without symptoms should abstain for 6 months.⁴ Individuals should avoid traveling to areas with Zika infestation, wear long-sleeved clothing treated with permethrin, and minimize outside exposure, especially in evening hours.⁴

The World Health Organization is utilizing genetically modified mosquitoes to diminish Aedes populations; trials conducted in affected areas of Brazil revealed that the number of Aedes mosquitoes was reduced by 90%.⁵ This method of mosquito control is currently being studied in the United States.⁶ Vaccinations to prevent Zika infection are also under investigation.

Physicians should educate patients regarding the clinical manifestations and complications of Zika virus infection; people need to know that the Zika virus can be sexually transmitted. Doctors should also counsel patients to curtail travel to areas that have Zika infestations, or to at least wear protective clothing while in such areas to minimize mosquito bite risk. Educating travelers about appropriate postponement of sexual contact after any exposure to the Zika virus is also essential.⁴

Hema Madhuri Mekala, MD
Priyanga Jayakumar, MD
Rajashekar Reddy Yeruva, MD
Steven Lippmann, MD
Louisville, KY

Since Florida has seen several new cases of local mosquito-borne infection, controlling and preventing Zika infection has great urgency. Zika virus involves an arthropod-borne infection transmitted by Aedes aegypti and Aedes albopictus mosquitoes. Other modes of transmission include the maternal-fetal route, any sexual contact, blood transfusions, organ or tissue transplantation, and laboratory exposure.¹

The first case of Zika infection in the United States and its territories occurred through international travel. According to the Centers for Disease Control and Prevention, as of October 12, 2016, there were 3807 travel-associated cases of Zika infection in the United States and 84 instances in its territories.² As for local transmission, there were 128 people evidencing a Zika infection in the United States and 25,871 in US territories.² Regions between Texas and Florida are at high risk because Aedes mosquitoes primarily inhabit the gulf coast.³ Many cases have occurred despite repellent use and eradication efforts, possibly due to resistance acquired by these mosquitoes.¹

Control measures include using insect repellents, aerial spraying of insecticides, eliminating mosquito breeding sites, covering water tanks, and using mosquito nets or door and window screens. Infection during pregnancy is the greatest concern because of congenital anomalies (including microcephaly) that negatively affect brain development.⁴

Before a possible conception or any sexual contact, women exposed to Zika—with or without symptoms—must wait at least 8 weeks; men with or without symptoms should abstain for 6 months.⁴ Individuals should avoid traveling to areas with Zika infestation, wear long-sleeved clothing treated with permethrin, and minimize outside exposure, especially in evening hours.⁴

The World Health Organization is utilizing genetically modified mosquitoes to diminish Aedes populations; trials conducted in affected areas of Brazil revealed that the number of Aedes mosquitoes was reduced by 90%.⁵ This method of mosquito control is currently being studied in the United States.⁶ Vaccinations to prevent Zika infection are also under investigation.

Physicians should educate patients regarding the clinical manifestations and complications of Zika virus infection; people need to know that the Zika virus can be sexually transmitted. Doctors should also counsel patients to curtail travel to areas that have Zika infestations, or to at least wear protective clothing while in such areas to minimize mosquito bite risk. Educating travelers about appropriate postponement of sexual contact after any exposure to the Zika virus is also essential.⁴

Hema Madhuri Mekala, MD
Priyanga Jayakumar, MD
Rajashekar Reddy Yeruva, MD
Steven Lippmann, MD
Louisville, KY

THE CASE

A 47-year-old African American woman was admitted to the hospital with pulmonary edema revealed on a computed tomography (CT) scan. She had a history of systemic lupus erythematosus (SLE), hypertension, and end-stage renal disease (ESRD). The patient had been hospitalized one month earlier for lupus nephritis with a hypertensive emergency that led to a seizure. During this earlier hospitalization, she was given a diagnosis of posterior reversible encephalopathy syndrome.

Two weeks into her more recent hospitalization, the patient developed a fever that was accompanied by cough and fatigue. By the third week, there was no identified cause of the fever, and the patient met the criteria for fever of unknown origin (FUO).

Her medications included cyclophosphamide, prednisone, nebivolol, clonidine, phenytoin, and epoetin alfa. The patient was also receiving dialysis every other day. Chest x-ray findings suggested pneumonia, and the patient was treated with vancomycin and piperacillin/tazobactam. However, her fever persisted after completing the antibiotics. Central line sepsis was high in the differential, as the patient was on dialysis, but blood and catheter tip cultures were negative. Chest and abdominal CT scans showed no new disease process. Urine and sputum cultures were collected and were negative for infection. Drug-induced fever was then suspected, but was ruled out when the fever persisted after the removal of potential offending agents (phenytoin, nebivolol, and cyclophosphamide).

THE DIAGNOSIS

We then followed the American Academy of Family Physicians’ diagnostic protocol for FUO.¹

Initial labs included a complete blood count (CBC), 2 blood cultures, a urine culture, erythrocyte sedimentation rate (ESR), a purified protein derivative skin test, chest and abdominal CT scans, and double-stranded DNA (dsDNA) levels (since this patient had known SLE). The patient’s hemoglobin level and mean corpuscular volume were consistent with normocytic anemia, which was attributed to the ESRD. The ESR was mildly elevated at 46 mm/hr, but dsDNA was not, ruling out a lupus flare. Thrombocytopenia (platelet count, 82 K/mcL) and lymphocytopenia (absolute lymphocyte count, 0.2 K/mcL) were assumed to be secondary to cyclophosphamide use.

Because the initial labs were non-diagnostic, we proceeded with a sputum stain and culture, human immunodeficiency virus testing, a hepatitis panel, and a peripheral blood smear.¹ All were negative except for the peripheral blood smear, which showed hemophagocytic cells. This was the first finding that brought hemophagocytic lymphohistiocytosis (HLH) into the differential.

We then performed a bone marrow biopsy (FIGURE), which also revealed hemophagocytic cells, so we ordered HLH-specific labs (more on those in a bit). Liver enzymes were elevated to 3 times their normal value. Triglycerides (414 mg/dL), ferritin (>15,000 ng/mL), and interleukin-2 (IL-2) receptor levels (>20,000 pg/m) were also elevated.

The patient was tested for herpes simplex virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV), since these viruses are associated with HLH. She had 3.1 million copies/mL of CMV, leading to the diagnosis of secondary HLH. This diagnosis might not have been made if not for a persistent fever investigation.

HLH is a life-threatening syndrome of excessive immune activation that results in tissue damage.² There are primary and secondary forms, but they share the same mechanism of impaired regulation of cytotoxic granules and cytokines. Primary HLH results from a congenital gene mutation,³ while secondary HLH is triggered by an autoimmune or inflammatory disease or an infection.⁴ EBV is the most common viral etiology, followed closely by CMV.⁵

The diagnosis may be established genetically (based on mutations of the genes loci PRF1, UNC13D, or STX11) or by fulfillment of 5 out of 8 criteria: fever; splenomegaly; cytopenia; hypertriglyceridemia; hypofibrinogenemia; hemophagocytosis in the bone marrow, spleen, or lymph nodes; low or absent natural killer cell activity; and an elevated ferritin level (>500 ng/mL). Elevated soluble CD25 and IL-2 receptor markers are HLH-specific markers.³ This patient had fever, cytopenia, hypertriglyceridemia, hemophagocytosis, and elevated ferritin with elevated IL-2, meeting the criteria for secondary HLH.

First treat the underlying condition, then the HLH

Treatment for HLH includes treating the underlying condition (such as EBV or CMV) with antiretroviral medications, and using immunosuppressive agents such as chemotherapy drugs and steroids for the HLH.

Our patient was treated with valganciclovir 900 mg/d for 2 weeks for the CMV and an etoposide/prednisone taper for 3 months for HLH chemotherapy and suppression. Within one month, her CMV viral load decreased to <300 copies/mL and her fever resolved. Ferritin, triglycerides, and liver enzyme levels returned to normal within 3 months.

THE TAKEAWAY

FUO can be frustrating for both the physician and the patient. Not only is the differential large, but testing is extensive. It is important to get a thorough history and to consider medications as the cause. Testing should be patient-specific and systematic. Persistent investigation is critical to saving the patient’s life.

THE CASE

A 47-year-old African American woman was admitted to the hospital with pulmonary edema revealed on a computed tomography (CT) scan. She had a history of systemic lupus erythematosus (SLE), hypertension, and end-stage renal disease (ESRD). The patient had been hospitalized one month earlier for lupus nephritis with a hypertensive emergency that led to a seizure. During this earlier hospitalization, she was given a diagnosis of posterior reversible encephalopathy syndrome.

Two weeks into her more recent hospitalization, the patient developed a fever that was accompanied by cough and fatigue. By the third week, there was no identified cause of the fever, and the patient met the criteria for fever of unknown origin (FUO).

Her medications included cyclophosphamide, prednisone, nebivolol, clonidine, phenytoin, and epoetin alfa. The patient was also receiving dialysis every other day. Chest x-ray findings suggested pneumonia, and the patient was treated with vancomycin and piperacillin/tazobactam. However, her fever persisted after completing the antibiotics. Central line sepsis was high in the differential, as the patient was on dialysis, but blood and catheter tip cultures were negative. Chest and abdominal CT scans showed no new disease process. Urine and sputum cultures were collected and were negative for infection. Drug-induced fever was then suspected, but was ruled out when the fever persisted after the removal of potential offending agents (phenytoin, nebivolol, and cyclophosphamide).

THE DIAGNOSIS

We then followed the American Academy of Family Physicians’ diagnostic protocol for FUO.¹

Initial labs included a complete blood count (CBC), 2 blood cultures, a urine culture, erythrocyte sedimentation rate (ESR), a purified protein derivative skin test, chest and abdominal CT scans, and double-stranded DNA (dsDNA) levels (since this patient had known SLE). The patient’s hemoglobin level and mean corpuscular volume were consistent with normocytic anemia, which was attributed to the ESRD. The ESR was mildly elevated at 46 mm/hr, but dsDNA was not, ruling out a lupus flare. Thrombocytopenia (platelet count, 82 K/mcL) and lymphocytopenia (absolute lymphocyte count, 0.2 K/mcL) were assumed to be secondary to cyclophosphamide use.

Because the initial labs were non-diagnostic, we proceeded with a sputum stain and culture, human immunodeficiency virus testing, a hepatitis panel, and a peripheral blood smear.¹ All were negative except for the peripheral blood smear, which showed hemophagocytic cells. This was the first finding that brought hemophagocytic lymphohistiocytosis (HLH) into the differential.

We then performed a bone marrow biopsy (FIGURE), which also revealed hemophagocytic cells, so we ordered HLH-specific labs (more on those in a bit). Liver enzymes were elevated to 3 times their normal value. Triglycerides (414 mg/dL), ferritin (>15,000 ng/mL), and interleukin-2 (IL-2) receptor levels (>20,000 pg/m) were also elevated.

The patient was tested for herpes simplex virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV), since these viruses are associated with HLH. She had 3.1 million copies/mL of CMV, leading to the diagnosis of secondary HLH. This diagnosis might not have been made if not for a persistent fever investigation.

HLH is a life-threatening syndrome of excessive immune activation that results in tissue damage.² There are primary and secondary forms, but they share the same mechanism of impaired regulation of cytotoxic granules and cytokines. Primary HLH results from a congenital gene mutation,³ while secondary HLH is triggered by an autoimmune or inflammatory disease or an infection.⁴ EBV is the most common viral etiology, followed closely by CMV.⁵

The diagnosis may be established genetically (based on mutations of the genes loci PRF1, UNC13D, or STX11) or by fulfillment of 5 out of 8 criteria: fever; splenomegaly; cytopenia; hypertriglyceridemia; hypofibrinogenemia; hemophagocytosis in the bone marrow, spleen, or lymph nodes; low or absent natural killer cell activity; and an elevated ferritin level (>500 ng/mL). Elevated soluble CD25 and IL-2 receptor markers are HLH-specific markers.³ This patient had fever, cytopenia, hypertriglyceridemia, hemophagocytosis, and elevated ferritin with elevated IL-2, meeting the criteria for secondary HLH.

First treat the underlying condition, then the HLH

Treatment for HLH includes treating the underlying condition (such as EBV or CMV) with antiretroviral medications, and using immunosuppressive agents such as chemotherapy drugs and steroids for the HLH.

Our patient was treated with valganciclovir 900 mg/d for 2 weeks for the CMV and an etoposide/prednisone taper for 3 months for HLH chemotherapy and suppression. Within one month, her CMV viral load decreased to <300 copies/mL and her fever resolved. Ferritin, triglycerides, and liver enzyme levels returned to normal within 3 months.

THE TAKEAWAY

FUO can be frustrating for both the physician and the patient. Not only is the differential large, but testing is extensive. It is important to get a thorough history and to consider medications as the cause. Testing should be patient-specific and systematic. Persistent investigation is critical to saving the patient’s life.

THE CASE

A 47-year-old African American woman was admitted to the hospital with pulmonary edema revealed on a computed tomography (CT) scan. She had a history of systemic lupus erythematosus (SLE), hypertension, and end-stage renal disease (ESRD). The patient had been hospitalized one month earlier for lupus nephritis with a hypertensive emergency that led to a seizure. During this earlier hospitalization, she was given a diagnosis of posterior reversible encephalopathy syndrome.

Two weeks into her more recent hospitalization, the patient developed a fever that was accompanied by cough and fatigue. By the third week, there was no identified cause of the fever, and the patient met the criteria for fever of unknown origin (FUO).

Her medications included cyclophosphamide, prednisone, nebivolol, clonidine, phenytoin, and epoetin alfa. The patient was also receiving dialysis every other day. Chest x-ray findings suggested pneumonia, and the patient was treated with vancomycin and piperacillin/tazobactam. However, her fever persisted after completing the antibiotics. Central line sepsis was high in the differential, as the patient was on dialysis, but blood and catheter tip cultures were negative. Chest and abdominal CT scans showed no new disease process. Urine and sputum cultures were collected and were negative for infection. Drug-induced fever was then suspected, but was ruled out when the fever persisted after the removal of potential offending agents (phenytoin, nebivolol, and cyclophosphamide).

THE DIAGNOSIS

We then followed the American Academy of Family Physicians’ diagnostic protocol for FUO.¹

Initial labs included a complete blood count (CBC), 2 blood cultures, a urine culture, erythrocyte sedimentation rate (ESR), a purified protein derivative skin test, chest and abdominal CT scans, and double-stranded DNA (dsDNA) levels (since this patient had known SLE). The patient’s hemoglobin level and mean corpuscular volume were consistent with normocytic anemia, which was attributed to the ESRD. The ESR was mildly elevated at 46 mm/hr, but dsDNA was not, ruling out a lupus flare. Thrombocytopenia (platelet count, 82 K/mcL) and lymphocytopenia (absolute lymphocyte count, 0.2 K/mcL) were assumed to be secondary to cyclophosphamide use.

Because the initial labs were non-diagnostic, we proceeded with a sputum stain and culture, human immunodeficiency virus testing, a hepatitis panel, and a peripheral blood smear.¹ All were negative except for the peripheral blood smear, which showed hemophagocytic cells. This was the first finding that brought hemophagocytic lymphohistiocytosis (HLH) into the differential.

We then performed a bone marrow biopsy (FIGURE), which also revealed hemophagocytic cells, so we ordered HLH-specific labs (more on those in a bit). Liver enzymes were elevated to 3 times their normal value. Triglycerides (414 mg/dL), ferritin (>15,000 ng/mL), and interleukin-2 (IL-2) receptor levels (>20,000 pg/m) were also elevated.

The patient was tested for herpes simplex virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV), since these viruses are associated with HLH. She had 3.1 million copies/mL of CMV, leading to the diagnosis of secondary HLH. This diagnosis might not have been made if not for a persistent fever investigation.

HLH is a life-threatening syndrome of excessive immune activation that results in tissue damage.² There are primary and secondary forms, but they share the same mechanism of impaired regulation of cytotoxic granules and cytokines. Primary HLH results from a congenital gene mutation,³ while secondary HLH is triggered by an autoimmune or inflammatory disease or an infection.⁴ EBV is the most common viral etiology, followed closely by CMV.⁵

The diagnosis may be established genetically (based on mutations of the genes loci PRF1, UNC13D, or STX11) or by fulfillment of 5 out of 8 criteria: fever; splenomegaly; cytopenia; hypertriglyceridemia; hypofibrinogenemia; hemophagocytosis in the bone marrow, spleen, or lymph nodes; low or absent natural killer cell activity; and an elevated ferritin level (>500 ng/mL). Elevated soluble CD25 and IL-2 receptor markers are HLH-specific markers.³ This patient had fever, cytopenia, hypertriglyceridemia, hemophagocytosis, and elevated ferritin with elevated IL-2, meeting the criteria for secondary HLH.

First treat the underlying condition, then the HLH

Treatment for HLH includes treating the underlying condition (such as EBV or CMV) with antiretroviral medications, and using immunosuppressive agents such as chemotherapy drugs and steroids for the HLH.

Our patient was treated with valganciclovir 900 mg/d for 2 weeks for the CMV and an etoposide/prednisone taper for 3 months for HLH chemotherapy and suppression. Within one month, her CMV viral load decreased to <300 copies/mL and her fever resolved. Ferritin, triglycerides, and liver enzyme levels returned to normal within 3 months.

THE TAKEAWAY

FUO can be frustrating for both the physician and the patient. Not only is the differential large, but testing is extensive. It is important to get a thorough history and to consider medications as the cause. Testing should be patient-specific and systematic. Persistent investigation is critical to saving the patient’s life.