Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

Clinical experience and observational studies made us aware that African American patients responded differently to some treatments than the white male patients in the clinical trials. This awareness led to some interesting biologic hypotheses and, over the past 13 years, has led to trials focused on the treatment of heart failure and hypertension in African Americans. But a full biologic understanding of the apparent racial differences in clinical response to specific therapies has for the most part remained elusive.

Contributing to this understanding gap was that we historically did not fully appreciate the differences according to race (and likely sex) in the clinical progression of diseases such as hypertension, heart failure, and, as discussed in this issue of the Journal by Dr. Joseph V. Nally, Jr., chronic kidney disease. African Americans with congestive heart failure seem to fare worse than their white counterparts with the same disease. Given the strong link between heart failure and chronic kidney disease and the crosstalk between the heart and kidneys, it is no surprise that African Americans with chronic kidney disease progress to end-stage renal disease at a higher rate than whites. Yet, as Dr. Nally points out, once on dialysis, African Americans live longer—an intriguing observation that came from analysis of large databases devoted to the study of patients with chronic kidney disease.

As a patient’s self-defined racial identity may not be biologically accurate, using molecular genetic techniques to delve more deeply into the characteristics of patients in these chronic kidney disease registries is starting to yield fascinating results—and even more questions. Links between APOL1 gene polymorphisms and the occurrence of renal disease and the survival of transplanted kidneys is assuredly just the start of a journey of genomic discovery and understanding.

Readers will note the short editor’s note at the start of Dr. Nally’s article, indicating that it was based on a Medicine Grand Rounds lecture at Cleveland Clinic, the 14th annual Lawrence “Chris” Crain Memorial Lecture. In 1997, Chris became the first African American chief resident in internal medicine at Cleveland Clinic, and I had the pleasure of interacting with him while he was in that role. Chris was a natural leader. He was soft-spoken, curious, and passionate about delivering and understanding the basics of high-quality clinical care.

After his residency, with Byron Hoogwerf as the internal medicine program director, Chris trained with Joe Nally as his program director in nephrology, and further developed his interest in renal and cardiovascular disease in African Americans. He moved to Atlanta, where he died far too prematurely in July 2003. That year, in conjunction with Chris’s mother, wife, extended family, and other faculty, Drs. Hoogwerf and Nally established the Lawrence “Chris” Crain Memorial Lectureship, devoted to Chris’s passion of furthering our understanding and our ability to deliver optimal care to African American patients with cardiovascular and renal disease.

I am pleased to share this lecture with you.

A woman in her 30s presented with an itchy skin-colored rash over her left scapular region that had first appeared 8 years earlier. It had started as itchy skin-colored papules that coalesced to a patch and later became hyperpigmented because of repeated scratching.

She had undergone total thyroidectomy for medullary thyroid carcinoma 1 year ago, and the rash had been diagnosed at that time as lichen planus. She was referred to us by her physician for histopathologic confirmation of the lesions. She denied any history of episodic headache or palpitation.

Her urine normetanephrine excretion was elevated at 1,425 μg/day (reference range 148–560), and her metanephrine excretion was also high at 2,024 μg/day (reference range 44–261).

At a 3-month follow-up visit, the woman’s skin lesions had improved with twice-a-day application of mometasone 0.1% cream; she was lost to follow-up after that visit.

MULTIPLE ENDOCRINE NEOPLASIA

Our patient’s scapular lesions and first-degree family history of MEN type 2A confirmed the diagnosis of the newly recognized variant, MEN type 2A-related cutaneous lichen amyloidosis, in which the characteristic pigmented scapular rash typically predates the first diagnosis of neoplasia.¹ The dermal amyloidosis is caused by deposition of keratinlike peptides rather than calcitoninlike peptides.²

A recent systematic review on MEN type 2A with cutaneous lichen amyloidosis showed a female preponderance and a high penetrance of cutaneous lichen amyloidosis, which was the second most frequent manifestation of the syndrome, preceded only by medullary thyroid carcinoma.¹

As in our patient’s case, scapular rash and a history of medullary thyroid carcinoma should prompt an investigation for MEN type 2A. These patients should be closely followed for underlying MEN type 2A-related neoplasms.

The mucosal neuromas and skin lipomas seen in MEN type 1 and MEN type 2B are absent in MEN type 2A.³ Cutaneous lichen amyloidosis is the only dermatologic marker for MEN type 2A. Owing to a similar genetic background, cutaneous lichen amyloidosis is also associated with familial medullary thyroid carcinoma, another rare variant of MEN type 2A.⁴

DIFFERENTIAL DIAGNOSIS

Notalgia paresthetica is a unilateral chronic neuropathic pruritus on the back, mostly located between the shoulders and corresponding to the second and the sixth thoracic nerves. It is mostly attributed to compression of spinal nerves by an abnormality of the thoracic spine.⁵ In our patient, this was ruled out by the radiologic evaluation.

Before MEN type 2A with cutaneous lichen amyloidosis was recognized as a variant of MEN type 2A, lesions suggestive of notalgia paresthetica were reported with MEN type 2A.³ The classic infrascapular location, history of painful neck muscle spasms, touch hyperesthesia of the lesions, and absence of amyloid deposits on histopathologic study help to differentiate notalgia paresthetica from cutaneous lichen amyloidosis. However, later phases of notalgia paresthetica may show amyloid deposits on histopathologic study, while detection of a scant amount of amyloid is difficult in the early stages of cutaneous lichen amyloidosis.

TAKE-HOME POINT

Cutaneous lichen amyloidosis is usually seen on the extensor surfaces of the extremities. It is considered benign, caused by filamentous degeneration of keratinocytes from repeated scratching. But cutaneous lichen amyloidosis at an early age in the scapular area of women warrants a detailed family history for endocrine neoplasia, blood pressure monitoring, thyroid palpation, and blood testing for serum calcium, calcitonin, and parathyroid hormone.

A woman in her 30s presented with an itchy skin-colored rash over her left scapular region that had first appeared 8 years earlier. It had started as itchy skin-colored papules that coalesced to a patch and later became hyperpigmented because of repeated scratching.

She had undergone total thyroidectomy for medullary thyroid carcinoma 1 year ago, and the rash had been diagnosed at that time as lichen planus. She was referred to us by her physician for histopathologic confirmation of the lesions. She denied any history of episodic headache or palpitation.

Her urine normetanephrine excretion was elevated at 1,425 μg/day (reference range 148–560), and her metanephrine excretion was also high at 2,024 μg/day (reference range 44–261).

At a 3-month follow-up visit, the woman’s skin lesions had improved with twice-a-day application of mometasone 0.1% cream; she was lost to follow-up after that visit.

MULTIPLE ENDOCRINE NEOPLASIA

Our patient’s scapular lesions and first-degree family history of MEN type 2A confirmed the diagnosis of the newly recognized variant, MEN type 2A-related cutaneous lichen amyloidosis, in which the characteristic pigmented scapular rash typically predates the first diagnosis of neoplasia.¹ The dermal amyloidosis is caused by deposition of keratinlike peptides rather than calcitoninlike peptides.²

A recent systematic review on MEN type 2A with cutaneous lichen amyloidosis showed a female preponderance and a high penetrance of cutaneous lichen amyloidosis, which was the second most frequent manifestation of the syndrome, preceded only by medullary thyroid carcinoma.¹

As in our patient’s case, scapular rash and a history of medullary thyroid carcinoma should prompt an investigation for MEN type 2A. These patients should be closely followed for underlying MEN type 2A-related neoplasms.

The mucosal neuromas and skin lipomas seen in MEN type 1 and MEN type 2B are absent in MEN type 2A.³ Cutaneous lichen amyloidosis is the only dermatologic marker for MEN type 2A. Owing to a similar genetic background, cutaneous lichen amyloidosis is also associated with familial medullary thyroid carcinoma, another rare variant of MEN type 2A.⁴

DIFFERENTIAL DIAGNOSIS

Notalgia paresthetica is a unilateral chronic neuropathic pruritus on the back, mostly located between the shoulders and corresponding to the second and the sixth thoracic nerves. It is mostly attributed to compression of spinal nerves by an abnormality of the thoracic spine.⁵ In our patient, this was ruled out by the radiologic evaluation.

Before MEN type 2A with cutaneous lichen amyloidosis was recognized as a variant of MEN type 2A, lesions suggestive of notalgia paresthetica were reported with MEN type 2A.³ The classic infrascapular location, history of painful neck muscle spasms, touch hyperesthesia of the lesions, and absence of amyloid deposits on histopathologic study help to differentiate notalgia paresthetica from cutaneous lichen amyloidosis. However, later phases of notalgia paresthetica may show amyloid deposits on histopathologic study, while detection of a scant amount of amyloid is difficult in the early stages of cutaneous lichen amyloidosis.

TAKE-HOME POINT

Cutaneous lichen amyloidosis is usually seen on the extensor surfaces of the extremities. It is considered benign, caused by filamentous degeneration of keratinocytes from repeated scratching. But cutaneous lichen amyloidosis at an early age in the scapular area of women warrants a detailed family history for endocrine neoplasia, blood pressure monitoring, thyroid palpation, and blood testing for serum calcium, calcitonin, and parathyroid hormone.

A woman in her 30s presented with an itchy skin-colored rash over her left scapular region that had first appeared 8 years earlier. It had started as itchy skin-colored papules that coalesced to a patch and later became hyperpigmented because of repeated scratching.

She had undergone total thyroidectomy for medullary thyroid carcinoma 1 year ago, and the rash had been diagnosed at that time as lichen planus. She was referred to us by her physician for histopathologic confirmation of the lesions. She denied any history of episodic headache or palpitation.

Her urine normetanephrine excretion was elevated at 1,425 μg/day (reference range 148–560), and her metanephrine excretion was also high at 2,024 μg/day (reference range 44–261).

At a 3-month follow-up visit, the woman’s skin lesions had improved with twice-a-day application of mometasone 0.1% cream; she was lost to follow-up after that visit.

MULTIPLE ENDOCRINE NEOPLASIA

Our patient’s scapular lesions and first-degree family history of MEN type 2A confirmed the diagnosis of the newly recognized variant, MEN type 2A-related cutaneous lichen amyloidosis, in which the characteristic pigmented scapular rash typically predates the first diagnosis of neoplasia.¹ The dermal amyloidosis is caused by deposition of keratinlike peptides rather than calcitoninlike peptides.²

A recent systematic review on MEN type 2A with cutaneous lichen amyloidosis showed a female preponderance and a high penetrance of cutaneous lichen amyloidosis, which was the second most frequent manifestation of the syndrome, preceded only by medullary thyroid carcinoma.¹

As in our patient’s case, scapular rash and a history of medullary thyroid carcinoma should prompt an investigation for MEN type 2A. These patients should be closely followed for underlying MEN type 2A-related neoplasms.

The mucosal neuromas and skin lipomas seen in MEN type 1 and MEN type 2B are absent in MEN type 2A.³ Cutaneous lichen amyloidosis is the only dermatologic marker for MEN type 2A. Owing to a similar genetic background, cutaneous lichen amyloidosis is also associated with familial medullary thyroid carcinoma, another rare variant of MEN type 2A.⁴

DIFFERENTIAL DIAGNOSIS

Notalgia paresthetica is a unilateral chronic neuropathic pruritus on the back, mostly located between the shoulders and corresponding to the second and the sixth thoracic nerves. It is mostly attributed to compression of spinal nerves by an abnormality of the thoracic spine.⁵ In our patient, this was ruled out by the radiologic evaluation.

Before MEN type 2A with cutaneous lichen amyloidosis was recognized as a variant of MEN type 2A, lesions suggestive of notalgia paresthetica were reported with MEN type 2A.³ The classic infrascapular location, history of painful neck muscle spasms, touch hyperesthesia of the lesions, and absence of amyloid deposits on histopathologic study help to differentiate notalgia paresthetica from cutaneous lichen amyloidosis. However, later phases of notalgia paresthetica may show amyloid deposits on histopathologic study, while detection of a scant amount of amyloid is difficult in the early stages of cutaneous lichen amyloidosis.

TAKE-HOME POINT

Cutaneous lichen amyloidosis is usually seen on the extensor surfaces of the extremities. It is considered benign, caused by filamentous degeneration of keratinocytes from repeated scratching. But cutaneous lichen amyloidosis at an early age in the scapular area of women warrants a detailed family history for endocrine neoplasia, blood pressure monitoring, thyroid palpation, and blood testing for serum calcium, calcitonin, and parathyroid hormone.

A 28-year-old man developed fever, night sweats, nausea, headache, reduced appetite, skin rash, and hemoptysis 2 weeks after returning to the United States from Mexico.

The patient had fistulizing Crohn disease and had been taking the tumor necrosis factor alpha (TNF-alpha) blocker adalimumab for the past 3 months. He had no risk factors for human immunodeficiency virus infection, and he had stopped smoking 1 year previously. Chest radiography and a tuberculin skin test before he started adalimumab therapy were negative. While in Mexico, he did not drink more than 1 alcoholic beverage a day.

He had presented recently to his local hospital with the same symptoms and had been prescribed ciprofloxacin, metronidazole, ceftriaxone, vancomycin, and ampicillin, which he was still taking but with no improvement of symptoms. Blood cultures drawn before the start of antibiotic therapy had been negative. Urinalysis, a screen for infectious mononucleosis, and lumbar puncture were also negative. Results of renal function testing were normal except for the anion gap, which was 20.8 mmol/L (reference range 10–20).

INITIAL EVALUATION

On presentation to this hospital, the patient was afebrile but continued to have temperature spikes up to 39.0°C (102.2°F). His heart rate was 90 per minute, blood pressure 104/61 mm Hg, respiratory rate 18 per minute, and oxygen saturation 95% on 2 L of oxygen via nasal cannula.

• White blood cell count 10.0 × 10⁹/L (reference range 4.0–10.0 × 10⁹/L)
• Lymphocyte count 6.1 × 10⁹/L (1.2–3.4)
• Hemoglobin level 13.6 g/dL (14.0–18.0)
• Platelet count 87 × 10^9/L (150–400),  reaching a nadir of 62 on hospital day 23
• Albumin 47 g/L (35–50)
• Total bilirubin 48 µmol/L (2–20)
• Alkaline phosphatase 137 U/L (40–135)
• Alanine aminotransferase 22 U/L (9–69)
• Aspartate aminotransferase 72 U/L (5–45).

He continued to have temperature spikes. His alkaline phosphatase level plateaued at 1,015 U/L on day 30, while his alanine aminotransferase and aspartate aminotransferase levels remained stable.

The patient’s ceftriaxone was continued, and the other antibiotics were replaced with doxycycline. Fluconazole was added when sputum culture grew Candida albicans. However, these drugs were later discontinued in view of worsening results on liver enzyme testing.

The evaluation continues

Sputum cultures were negative for acid-fast bacilli on 3 occasions.

Serologic testing was negative for:

• Hepatitis B surface antigen (but hepatitis B surface antibody was positive at > 1,000 IU/L)

• Hepatitis C virus antibody
• Cytomegalovirus immunoglobulin (Ig) G
• Toxoplasma gondii IgG
• Epstein-Barr virus viral capsid antigen IgM
• Rickettsia antibodies
• Antinuclear antibody
• Antineutrophil cytoplasmic antibody
• Antiglomerular basement membrane antibody.

Chest radiography showed blunting of both costophrenic angles and mild prominence of right perihilar interstitial markings and the right hilum.

Computed tomography of the chest, abdomen, and pelvis showed a subpleural density in the lower lobe of the right lung, small bilateral pleural effusions, right hilar lymphadenopathy, and splenomegaly with no specific hepatobiliary abnormality.

A white blood cell nuclear scan found no occult infection.

Abdominal ultrasonography showed a prominent liver and spleen. The liver parenchyma showed diffuse decreased echogenicity, suggestive of hepatitis.

Transesophageal echocardiography showed no vegetations or valvular abnormalities.

Bronchoscopy showed normal airways without evidence of pulmonary hemorrhage. No foci of infection were obtained. A focus of granuloma consisting of epithelioid histiocytes in tight clusters was seen on washings from the right lower lobe, but no malignant cells were seen.

Sections of pathologically enlarged right hilar and subcarinal lymph nodes obtained with transbronchial needle aspiration were sent for cytologic analysis and flow cytometry.

Cultures for tuberculous and fungal organisms were negative.

A clue. On further inquiry, the patient said he had gone swimming in the natural pool, or cenote, under a rock formation at Cenote Maya Park in Mexico.

1. Which of the following is not in the differential diagnosis?

• Disseminated tuberculosis
• Coccidioidomycosis
• Subacute infective endocarditis
• Disseminated histoplasmosis
• Blastomycosis

Although the patient has a systemic disease, subacute infective endocarditis is not likely because of a lack of predisposing factors such as a history of endocarditis, abnormal or artificial heart valve, or intravenous drug abuse. Moreover, negative blood cultures and the absence of vegetations on echocardiography make endocarditis very unlikely.

Given that the patient is immunosuppressed, opportunistic infection must be at the top of the differential diagnosis. Histoplasmosis, coccidioidomycosis, and blastomycosis are endemic in Mexico. Disseminated histoplasmosis is the most likely diagnosis; coccidioidomycosis and blastomycosis are less likely, based on the history, signs, and symptoms. Disseminated tuberculosis must be excluded before other diagnostic possibilities are considered.

TUBERCULOSIS IN PATIENTS ON TNF-ALPHA ANTAGONISTS

Tuberculosis has been reported in patients taking TNF-alpha antagonists.¹ The frequency of tuberculosis is much higher than that of other opportunistic infections, and over 50% of reported cases involve extrapulmonary tissues in patients treated with TNF-alpha antagonists.²

British Thoracic Society guidelines recommend screening for latent tuberculosis before starting treatment with a TNF-alpha antagonist; the screening should include a history of tuberculosis treatment, a clinical examination, chest radiography, and a tuberculin skin test.³ Patients found to have active tuberculosis should receive a minimum of 2 months of standard treatment before starting a TNF-alpha antagonist. Patients with evidence of past tuberculosis or a history of tuberculosis who received adequate treatment should be monitored regularly. Patients with prior tuberculosis not adequately treated should receive chemoprophylaxis before starting a TNF-alpha antagonist.

Fever, night sweats, and intrathoracic and intra-abdominal lymphadenopathy are common features of disseminated tuberculosis. Upper-lobe cavitary disease or miliary lesions may be seen on chest radiography, but atypical presentations with lower-lobe infiltrate are not uncommon in immunosuppressed patients.⁴

A negative tuberculin skin test and a normal chest radiograph 3 months ago, along with negative sputum and bronchial lavage fluid cultures and no history of tuberculosis contact, make tuberculosis unlikely in our patient.

COCCIDIOIDOMYCOSIS

Coccidioidomycosis (valley fever) is caused by the fungus Coccidioides immitis, which lives in the soil and is acquired by inhalation of airborne microscopic spores.

Fatigue, cough, fever, shortness of breath, headache, night sweats, muscle or joint pain, and a rash on the upper body or legs are common symptoms. It may cause a self-limiting flulike illness. From 5% to 10% of patients may develop serious long-term lung problems. In a small number of patients, the disease may progress beyond the lungs to involve the central nervous system, spinal cord, skin, bones, and joints.⁵

Serologic testing is highly useful for the diagnosis. Antigen testing has a sensitivity of 71% and a specificity of 98% for the diagnosis, but cross-reactivity occurs in 10% of patients with other types of mycosis. Respiratory secretions and tissue samples should undergo microscopic study and culture.

BLASTOMYCOSIS

Blastomycosis is caused by the fungus Blastomyces dermatitidis, which lives in soil and in association with decomposing organic matter such as wood and leaves. Inhalation of spores may cause a flulike illness or pneumonia. In serious cases, the disease can spread to skin and bone.

The diagnosis is established with fungal cultures of tissue samples or body fluids (bone marrow, liver tissue, skin, sputum, blood). Rapid diagnosis may be obtained by examination of the secretions under a microscope, where typical broad-based budding yeast can be seen in almost 90% of cases.⁶ Antigen may also be detected in urine and serum⁷; the sensitivity of antigen testing is 93% and the specificity is 98%. Serologic testing is not recommended for diagnosis of blastomycosis because of poor sensitivity and specificity.⁸

NARROWING THE DIFFERENTIAL

Both coccidioidomycosis and blastomycosis should be included in the differential diagnosis of a systemic disease with subacute onset and prominent lung involvement in a patient returning from travel to Mexico. The lack of involvement of the central nervous system, spinal cord, bones, or joints makes these infections less likely in our patient.

However, swimming in a cenote under a rock formation is an important clue to the diagnosis in our patient, as it puts him at risk of inhaling microconidia or hyphal elements of histoplasmosis. This, along with his immunocompromised status, fever, hemoptysis, night sweats, skin and lung features, and the generally subacute course of his illness, make disseminated histoplasmosis the most likely diagnosis.

Radiologic findings of pulmonary infiltrate with effusion and elevated lactate dehydrogenase, aminotransferases, and alkaline phosphatase increase the likelihood of disseminated histoplasmosis.

Histoplasma capsulatum is a dimorphic fungus that thrives in the soil and caves of regions with moderate climate, especially in soil containing large amounts of bird excreta or bat guano.⁹ Bats are natural hosts of this organism, and it is endemic in North and Central America, including parts of Mexico. Air currents can carry the microconidia for miles, thus exposing people without direct contact with contaminated sites.

The infection is usually acquired by inhalation of microconidia or small hyphal elements or by reactivation of previously quiescent foci of infection in an immunosuppressed patient. Most patients exposed to H capsulatum remain asymptomatic or develop mild symptoms, which are self-limiting. A small number develop acute pulmonary histoplasmosis or chronic cavitary histoplasmosis. Disseminated disease usually occurs only in an immunosuppressed host.

Acute pulmonary histoplasmosis presents with fever, malaise, headache, weakness, substernal chest pain, and dry cough and may be associated with erythema nodosum, erythema multiforme, and arthralgias. It may be mistaken for sarcoidosis since enlarged hilar and mediastinal lymph nodes are often seen on chest radiography.¹⁰

Progressive disseminated histoplasmosis is defined as a clinical illness that does not improve after at least 3 weeks of observation and is associated with physical or radiographic findings with or without laboratory evidence of extrapulmonary involvement.¹¹

Fever, malaise, anorexia, weight loss, night sweats, hepatosplenomegaly, and lymphadenopathy are features of progressive disseminated histoplasmosis.

Cutaneous manifestations of disseminated histoplasmosis occur in 10% to 25% of patients with acquired immunodeficiency syndrome and include papules, plaques with or without crust, pustules, nodules, lesions resembling molluscum contagiosum virus infection, acneiform eruptions, erythematous macules, and keratotic plaques.¹²

TESTING FOR HISTOPLASMOSIS

2. What investigation is least likely to help confirm the diagnosis of disseminated histoplasmosis?

• Polymerase chain reaction (PCR) testing of serum, cerebrospinal fluid, and bronchoalveolar lavage specimens
• Urinary Histoplasma antigen testing
• Serologic testing
• Blood and bronchoalveolar lavage cultures

Urinary Histoplasma antigen has a sensitivity of 90% for the diagnosis of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.¹⁸ It is less useful for pulmonary forms of histoplasmosis: the sensitivity is 75% and may even be less in milder or chronic forms of pneumonia.¹⁹ False-positive reactions may occur in patients with other fungal infections such as coccidioidomycosis, blastomycosis, paracoccidioidomycosis and penicilliosis.²⁰ Urine antigen levels can also be used to monitor therapy, since levels decrease during therapy and increase in 90% of those who have a relapse.²¹

Our patient’s urinary Histoplasma antigen level was greater than 23.0 ng/mL (positive is > 0.50).

Serologic testing. Immunodiffusion immunoglobulin G (IgG) testing for Histoplasma and Blastomyces was negative, as was an enzyme immunoassay for Coccidioides IgG and IgM. However, antibody tests are less useful in immunosuppressed patients,²² and thus a negative result does not rule out histoplasmosis. A fourfold rise in complement fixation antibody titer is diagnostic of acute histoplasmosis. A single complement fixation titer of 1:32 is suggestive but not diagnostic of histoplasmosis. Cross-reactions may occur with other fungal infections like blastomycosis. The immunodiffusion assay has a greater specificity but slightly less sensitivity than the complement fixation assay.¹⁹

Culture of H capsulatum is the definitive test to establish a diagnosis of histoplasmosis. Culture can be performed on samples taken from blood, bone marrow, sputum, and bronchoalveolar lavage fluid, or from lung, liver, or lymph node tissue. Cultures are positive in 74% to 82% of cases of progressive disseminated histoplasmosis.¹³ However, treatment should not await culture results since the fungus may take several weeks to grow.

Back to our patient

Although Histoplasma serologic studies and cultures were negative, the diagnosis of disseminated histoplasmosis was made on the basis of the patient’s immunosuppressed status, travel history, clinical features, and positivity for urine Histoplasma antigen. Though urine histoplama antigen may be falsely positive in other fungal infections such as coccidioidomycosis, paracoccidioidomycosis, and blastomycosis, clinical features and the absence of central nervous system, joint, and bone involvement suggested disseminated histoplasmosis.

3. What is the appropriate treatment for this patient?

• Amphotericin B followed by oral itraconozole
• Oral fluconazole
• Oral itraconazole

Liposomal amphotericin B or amphotericin B deoxycholate is recommended as initial therapy for moderately severe to severe and progressive disseminated histoplasmosis. It should be continued for 1 to 2 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days, then 200 mg 2 times daily for at least 12 months).

Monitoring itraconazole therapy through random serum levels is strongly recommended, and a random concentration of at least 1.0 mg/mL is recommended.²³

Urine antigen levels should be measured before treatment is started, at 2 weeks, at 1 month, then every 3 months during therapy, continuing for 12 months after treatment is stopped.¹¹

Lifelong suppressive therapy with itraconazole 200 mg daily may be required in immunosuppressed patients and patients who have a relapse despite appropriate therapy.¹¹

While oral itraconazole is used as a sole agent for the treatment of mild to moderate acute pulmonary histoplasmosis and chronic cavitary pulmonary histoplasmosis, oral treatment alone with either fluconazole or itraconazole is not recommended for the treatment of progressive disseminated histoplasmosis.¹¹

COMPLICATIONS OF HISTOPLASMOSIS

4. Which of the following is not a possible complication of histoplasmosis?

• Chronic cavitary pulmonary histoplasmosis
• Fibrosing mediastinitis
• Hypoadrenalism
• Hypothyroidism

Chronic cavitary pulmonary histoplasmosis usually develops in patients with underlying emphysema. Fatigue, night sweats, fever, anorexia, and weight loss are features of chronic cavitary pulmonary histoplasmosis. Progression of necrosis may lead to “marching cavity,” in which necrosis increases the size of the cavity and may consume an entire lobe.¹⁰

Fibrosing mediastinitis is an uncommon but often lethal complication of disseminated histoplasmosis. Increasing dyspnea, cough, hemoptysis, and signs of superior vena cava syndrome and right heart failure may develop. However, fibrosing mediastinitis is thought to be due to an exuberant immune response to past Histoplasma infection and would not be expected in an immunocompromised patient.¹⁷

Hypoadrenalism. Extensive destruction of the adrenal glands may lead to hypoadrenalism, manifesting as orthostatic hypotension, hyperkalemia, hyponatremia, and evidence of markedly enlarged adrenal glands with central necrosis on computed tomography.²⁴

Hypothyroidism. Acute or disseminated histoplasmosis has not been reported to cause thyroid dysfunction.

CASE CONCLUSION

Our patient was treated with itraconazole 200 mg twice daily for 24 months. Although the literature supports lifelong itraconazole therapy in immunosuppressed patients, our patient was reluctant to do so. He agreed to close monitoring. If symptoms recur, itraconazole will be reinstituted and continued lifelong.

A 28-year-old man developed fever, night sweats, nausea, headache, reduced appetite, skin rash, and hemoptysis 2 weeks after returning to the United States from Mexico.

The patient had fistulizing Crohn disease and had been taking the tumor necrosis factor alpha (TNF-alpha) blocker adalimumab for the past 3 months. He had no risk factors for human immunodeficiency virus infection, and he had stopped smoking 1 year previously. Chest radiography and a tuberculin skin test before he started adalimumab therapy were negative. While in Mexico, he did not drink more than 1 alcoholic beverage a day.

He had presented recently to his local hospital with the same symptoms and had been prescribed ciprofloxacin, metronidazole, ceftriaxone, vancomycin, and ampicillin, which he was still taking but with no improvement of symptoms. Blood cultures drawn before the start of antibiotic therapy had been negative. Urinalysis, a screen for infectious mononucleosis, and lumbar puncture were also negative. Results of renal function testing were normal except for the anion gap, which was 20.8 mmol/L (reference range 10–20).

INITIAL EVALUATION

On presentation to this hospital, the patient was afebrile but continued to have temperature spikes up to 39.0°C (102.2°F). His heart rate was 90 per minute, blood pressure 104/61 mm Hg, respiratory rate 18 per minute, and oxygen saturation 95% on 2 L of oxygen via nasal cannula.

• White blood cell count 10.0 × 10⁹/L (reference range 4.0–10.0 × 10⁹/L)
• Lymphocyte count 6.1 × 10⁹/L (1.2–3.4)
• Hemoglobin level 13.6 g/dL (14.0–18.0)
• Platelet count 87 × 10^9/L (150–400),  reaching a nadir of 62 on hospital day 23
• Albumin 47 g/L (35–50)
• Total bilirubin 48 µmol/L (2–20)
• Alkaline phosphatase 137 U/L (40–135)
• Alanine aminotransferase 22 U/L (9–69)
• Aspartate aminotransferase 72 U/L (5–45).

He continued to have temperature spikes. His alkaline phosphatase level plateaued at 1,015 U/L on day 30, while his alanine aminotransferase and aspartate aminotransferase levels remained stable.

The patient’s ceftriaxone was continued, and the other antibiotics were replaced with doxycycline. Fluconazole was added when sputum culture grew Candida albicans. However, these drugs were later discontinued in view of worsening results on liver enzyme testing.

The evaluation continues

Sputum cultures were negative for acid-fast bacilli on 3 occasions.

Serologic testing was negative for:

• Hepatitis B surface antigen (but hepatitis B surface antibody was positive at > 1,000 IU/L)

• Hepatitis C virus antibody
• Cytomegalovirus immunoglobulin (Ig) G
• Toxoplasma gondii IgG
• Epstein-Barr virus viral capsid antigen IgM
• Rickettsia antibodies
• Antinuclear antibody
• Antineutrophil cytoplasmic antibody
• Antiglomerular basement membrane antibody.

Chest radiography showed blunting of both costophrenic angles and mild prominence of right perihilar interstitial markings and the right hilum.

Computed tomography of the chest, abdomen, and pelvis showed a subpleural density in the lower lobe of the right lung, small bilateral pleural effusions, right hilar lymphadenopathy, and splenomegaly with no specific hepatobiliary abnormality.

A white blood cell nuclear scan found no occult infection.

Abdominal ultrasonography showed a prominent liver and spleen. The liver parenchyma showed diffuse decreased echogenicity, suggestive of hepatitis.

Transesophageal echocardiography showed no vegetations or valvular abnormalities.

Bronchoscopy showed normal airways without evidence of pulmonary hemorrhage. No foci of infection were obtained. A focus of granuloma consisting of epithelioid histiocytes in tight clusters was seen on washings from the right lower lobe, but no malignant cells were seen.

Sections of pathologically enlarged right hilar and subcarinal lymph nodes obtained with transbronchial needle aspiration were sent for cytologic analysis and flow cytometry.

Cultures for tuberculous and fungal organisms were negative.

A clue. On further inquiry, the patient said he had gone swimming in the natural pool, or cenote, under a rock formation at Cenote Maya Park in Mexico.

1. Which of the following is not in the differential diagnosis?

• Disseminated tuberculosis
• Coccidioidomycosis
• Subacute infective endocarditis
• Disseminated histoplasmosis
• Blastomycosis

Although the patient has a systemic disease, subacute infective endocarditis is not likely because of a lack of predisposing factors such as a history of endocarditis, abnormal or artificial heart valve, or intravenous drug abuse. Moreover, negative blood cultures and the absence of vegetations on echocardiography make endocarditis very unlikely.

Given that the patient is immunosuppressed, opportunistic infection must be at the top of the differential diagnosis. Histoplasmosis, coccidioidomycosis, and blastomycosis are endemic in Mexico. Disseminated histoplasmosis is the most likely diagnosis; coccidioidomycosis and blastomycosis are less likely, based on the history, signs, and symptoms. Disseminated tuberculosis must be excluded before other diagnostic possibilities are considered.

TUBERCULOSIS IN PATIENTS ON TNF-ALPHA ANTAGONISTS

Tuberculosis has been reported in patients taking TNF-alpha antagonists.¹ The frequency of tuberculosis is much higher than that of other opportunistic infections, and over 50% of reported cases involve extrapulmonary tissues in patients treated with TNF-alpha antagonists.²

British Thoracic Society guidelines recommend screening for latent tuberculosis before starting treatment with a TNF-alpha antagonist; the screening should include a history of tuberculosis treatment, a clinical examination, chest radiography, and a tuberculin skin test.³ Patients found to have active tuberculosis should receive a minimum of 2 months of standard treatment before starting a TNF-alpha antagonist. Patients with evidence of past tuberculosis or a history of tuberculosis who received adequate treatment should be monitored regularly. Patients with prior tuberculosis not adequately treated should receive chemoprophylaxis before starting a TNF-alpha antagonist.

Fever, night sweats, and intrathoracic and intra-abdominal lymphadenopathy are common features of disseminated tuberculosis. Upper-lobe cavitary disease or miliary lesions may be seen on chest radiography, but atypical presentations with lower-lobe infiltrate are not uncommon in immunosuppressed patients.⁴

A negative tuberculin skin test and a normal chest radiograph 3 months ago, along with negative sputum and bronchial lavage fluid cultures and no history of tuberculosis contact, make tuberculosis unlikely in our patient.

COCCIDIOIDOMYCOSIS

Coccidioidomycosis (valley fever) is caused by the fungus Coccidioides immitis, which lives in the soil and is acquired by inhalation of airborne microscopic spores.

Fatigue, cough, fever, shortness of breath, headache, night sweats, muscle or joint pain, and a rash on the upper body or legs are common symptoms. It may cause a self-limiting flulike illness. From 5% to 10% of patients may develop serious long-term lung problems. In a small number of patients, the disease may progress beyond the lungs to involve the central nervous system, spinal cord, skin, bones, and joints.⁵

Serologic testing is highly useful for the diagnosis. Antigen testing has a sensitivity of 71% and a specificity of 98% for the diagnosis, but cross-reactivity occurs in 10% of patients with other types of mycosis. Respiratory secretions and tissue samples should undergo microscopic study and culture.

BLASTOMYCOSIS

Blastomycosis is caused by the fungus Blastomyces dermatitidis, which lives in soil and in association with decomposing organic matter such as wood and leaves. Inhalation of spores may cause a flulike illness or pneumonia. In serious cases, the disease can spread to skin and bone.

The diagnosis is established with fungal cultures of tissue samples or body fluids (bone marrow, liver tissue, skin, sputum, blood). Rapid diagnosis may be obtained by examination of the secretions under a microscope, where typical broad-based budding yeast can be seen in almost 90% of cases.⁶ Antigen may also be detected in urine and serum⁷; the sensitivity of antigen testing is 93% and the specificity is 98%. Serologic testing is not recommended for diagnosis of blastomycosis because of poor sensitivity and specificity.⁸

NARROWING THE DIFFERENTIAL

Both coccidioidomycosis and blastomycosis should be included in the differential diagnosis of a systemic disease with subacute onset and prominent lung involvement in a patient returning from travel to Mexico. The lack of involvement of the central nervous system, spinal cord, bones, or joints makes these infections less likely in our patient.

However, swimming in a cenote under a rock formation is an important clue to the diagnosis in our patient, as it puts him at risk of inhaling microconidia or hyphal elements of histoplasmosis. This, along with his immunocompromised status, fever, hemoptysis, night sweats, skin and lung features, and the generally subacute course of his illness, make disseminated histoplasmosis the most likely diagnosis.

Radiologic findings of pulmonary infiltrate with effusion and elevated lactate dehydrogenase, aminotransferases, and alkaline phosphatase increase the likelihood of disseminated histoplasmosis.

Histoplasma capsulatum is a dimorphic fungus that thrives in the soil and caves of regions with moderate climate, especially in soil containing large amounts of bird excreta or bat guano.⁹ Bats are natural hosts of this organism, and it is endemic in North and Central America, including parts of Mexico. Air currents can carry the microconidia for miles, thus exposing people without direct contact with contaminated sites.

The infection is usually acquired by inhalation of microconidia or small hyphal elements or by reactivation of previously quiescent foci of infection in an immunosuppressed patient. Most patients exposed to H capsulatum remain asymptomatic or develop mild symptoms, which are self-limiting. A small number develop acute pulmonary histoplasmosis or chronic cavitary histoplasmosis. Disseminated disease usually occurs only in an immunosuppressed host.

Acute pulmonary histoplasmosis presents with fever, malaise, headache, weakness, substernal chest pain, and dry cough and may be associated with erythema nodosum, erythema multiforme, and arthralgias. It may be mistaken for sarcoidosis since enlarged hilar and mediastinal lymph nodes are often seen on chest radiography.¹⁰

Progressive disseminated histoplasmosis is defined as a clinical illness that does not improve after at least 3 weeks of observation and is associated with physical or radiographic findings with or without laboratory evidence of extrapulmonary involvement.¹¹

Fever, malaise, anorexia, weight loss, night sweats, hepatosplenomegaly, and lymphadenopathy are features of progressive disseminated histoplasmosis.

Cutaneous manifestations of disseminated histoplasmosis occur in 10% to 25% of patients with acquired immunodeficiency syndrome and include papules, plaques with or without crust, pustules, nodules, lesions resembling molluscum contagiosum virus infection, acneiform eruptions, erythematous macules, and keratotic plaques.¹²

TESTING FOR HISTOPLASMOSIS

2. What investigation is least likely to help confirm the diagnosis of disseminated histoplasmosis?

• Polymerase chain reaction (PCR) testing of serum, cerebrospinal fluid, and bronchoalveolar lavage specimens
• Urinary Histoplasma antigen testing
• Serologic testing
• Blood and bronchoalveolar lavage cultures

Urinary Histoplasma antigen has a sensitivity of 90% for the diagnosis of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.¹⁸ It is less useful for pulmonary forms of histoplasmosis: the sensitivity is 75% and may even be less in milder or chronic forms of pneumonia.¹⁹ False-positive reactions may occur in patients with other fungal infections such as coccidioidomycosis, blastomycosis, paracoccidioidomycosis and penicilliosis.²⁰ Urine antigen levels can also be used to monitor therapy, since levels decrease during therapy and increase in 90% of those who have a relapse.²¹

Our patient’s urinary Histoplasma antigen level was greater than 23.0 ng/mL (positive is > 0.50).

Serologic testing. Immunodiffusion immunoglobulin G (IgG) testing for Histoplasma and Blastomyces was negative, as was an enzyme immunoassay for Coccidioides IgG and IgM. However, antibody tests are less useful in immunosuppressed patients,²² and thus a negative result does not rule out histoplasmosis. A fourfold rise in complement fixation antibody titer is diagnostic of acute histoplasmosis. A single complement fixation titer of 1:32 is suggestive but not diagnostic of histoplasmosis. Cross-reactions may occur with other fungal infections like blastomycosis. The immunodiffusion assay has a greater specificity but slightly less sensitivity than the complement fixation assay.¹⁹

Culture of H capsulatum is the definitive test to establish a diagnosis of histoplasmosis. Culture can be performed on samples taken from blood, bone marrow, sputum, and bronchoalveolar lavage fluid, or from lung, liver, or lymph node tissue. Cultures are positive in 74% to 82% of cases of progressive disseminated histoplasmosis.¹³ However, treatment should not await culture results since the fungus may take several weeks to grow.

Back to our patient

Although Histoplasma serologic studies and cultures were negative, the diagnosis of disseminated histoplasmosis was made on the basis of the patient’s immunosuppressed status, travel history, clinical features, and positivity for urine Histoplasma antigen. Though urine histoplama antigen may be falsely positive in other fungal infections such as coccidioidomycosis, paracoccidioidomycosis, and blastomycosis, clinical features and the absence of central nervous system, joint, and bone involvement suggested disseminated histoplasmosis.

3. What is the appropriate treatment for this patient?

• Amphotericin B followed by oral itraconozole
• Oral fluconazole
• Oral itraconazole

Liposomal amphotericin B or amphotericin B deoxycholate is recommended as initial therapy for moderately severe to severe and progressive disseminated histoplasmosis. It should be continued for 1 to 2 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days, then 200 mg 2 times daily for at least 12 months).

Monitoring itraconazole therapy through random serum levels is strongly recommended, and a random concentration of at least 1.0 mg/mL is recommended.²³

Urine antigen levels should be measured before treatment is started, at 2 weeks, at 1 month, then every 3 months during therapy, continuing for 12 months after treatment is stopped.¹¹

Lifelong suppressive therapy with itraconazole 200 mg daily may be required in immunosuppressed patients and patients who have a relapse despite appropriate therapy.¹¹

While oral itraconazole is used as a sole agent for the treatment of mild to moderate acute pulmonary histoplasmosis and chronic cavitary pulmonary histoplasmosis, oral treatment alone with either fluconazole or itraconazole is not recommended for the treatment of progressive disseminated histoplasmosis.¹¹

COMPLICATIONS OF HISTOPLASMOSIS

4. Which of the following is not a possible complication of histoplasmosis?

• Chronic cavitary pulmonary histoplasmosis
• Fibrosing mediastinitis
• Hypoadrenalism
• Hypothyroidism

Chronic cavitary pulmonary histoplasmosis usually develops in patients with underlying emphysema. Fatigue, night sweats, fever, anorexia, and weight loss are features of chronic cavitary pulmonary histoplasmosis. Progression of necrosis may lead to “marching cavity,” in which necrosis increases the size of the cavity and may consume an entire lobe.¹⁰

Fibrosing mediastinitis is an uncommon but often lethal complication of disseminated histoplasmosis. Increasing dyspnea, cough, hemoptysis, and signs of superior vena cava syndrome and right heart failure may develop. However, fibrosing mediastinitis is thought to be due to an exuberant immune response to past Histoplasma infection and would not be expected in an immunocompromised patient.¹⁷

Hypoadrenalism. Extensive destruction of the adrenal glands may lead to hypoadrenalism, manifesting as orthostatic hypotension, hyperkalemia, hyponatremia, and evidence of markedly enlarged adrenal glands with central necrosis on computed tomography.²⁴

Hypothyroidism. Acute or disseminated histoplasmosis has not been reported to cause thyroid dysfunction.

CASE CONCLUSION

Our patient was treated with itraconazole 200 mg twice daily for 24 months. Although the literature supports lifelong itraconazole therapy in immunosuppressed patients, our patient was reluctant to do so. He agreed to close monitoring. If symptoms recur, itraconazole will be reinstituted and continued lifelong.

A 28-year-old man developed fever, night sweats, nausea, headache, reduced appetite, skin rash, and hemoptysis 2 weeks after returning to the United States from Mexico.

The patient had fistulizing Crohn disease and had been taking the tumor necrosis factor alpha (TNF-alpha) blocker adalimumab for the past 3 months. He had no risk factors for human immunodeficiency virus infection, and he had stopped smoking 1 year previously. Chest radiography and a tuberculin skin test before he started adalimumab therapy were negative. While in Mexico, he did not drink more than 1 alcoholic beverage a day.

He had presented recently to his local hospital with the same symptoms and had been prescribed ciprofloxacin, metronidazole, ceftriaxone, vancomycin, and ampicillin, which he was still taking but with no improvement of symptoms. Blood cultures drawn before the start of antibiotic therapy had been negative. Urinalysis, a screen for infectious mononucleosis, and lumbar puncture were also negative. Results of renal function testing were normal except for the anion gap, which was 20.8 mmol/L (reference range 10–20).

INITIAL EVALUATION

On presentation to this hospital, the patient was afebrile but continued to have temperature spikes up to 39.0°C (102.2°F). His heart rate was 90 per minute, blood pressure 104/61 mm Hg, respiratory rate 18 per minute, and oxygen saturation 95% on 2 L of oxygen via nasal cannula.

• White blood cell count 10.0 × 10⁹/L (reference range 4.0–10.0 × 10⁹/L)
• Lymphocyte count 6.1 × 10⁹/L (1.2–3.4)
• Hemoglobin level 13.6 g/dL (14.0–18.0)
• Platelet count 87 × 10^9/L (150–400),  reaching a nadir of 62 on hospital day 23
• Albumin 47 g/L (35–50)
• Total bilirubin 48 µmol/L (2–20)
• Alkaline phosphatase 137 U/L (40–135)
• Alanine aminotransferase 22 U/L (9–69)
• Aspartate aminotransferase 72 U/L (5–45).

He continued to have temperature spikes. His alkaline phosphatase level plateaued at 1,015 U/L on day 30, while his alanine aminotransferase and aspartate aminotransferase levels remained stable.

The patient’s ceftriaxone was continued, and the other antibiotics were replaced with doxycycline. Fluconazole was added when sputum culture grew Candida albicans. However, these drugs were later discontinued in view of worsening results on liver enzyme testing.

The evaluation continues

Sputum cultures were negative for acid-fast bacilli on 3 occasions.

Serologic testing was negative for:

• Hepatitis B surface antigen (but hepatitis B surface antibody was positive at > 1,000 IU/L)

• Hepatitis C virus antibody
• Cytomegalovirus immunoglobulin (Ig) G
• Toxoplasma gondii IgG
• Epstein-Barr virus viral capsid antigen IgM
• Rickettsia antibodies
• Antinuclear antibody
• Antineutrophil cytoplasmic antibody
• Antiglomerular basement membrane antibody.

Chest radiography showed blunting of both costophrenic angles and mild prominence of right perihilar interstitial markings and the right hilum.

Computed tomography of the chest, abdomen, and pelvis showed a subpleural density in the lower lobe of the right lung, small bilateral pleural effusions, right hilar lymphadenopathy, and splenomegaly with no specific hepatobiliary abnormality.

A white blood cell nuclear scan found no occult infection.

Abdominal ultrasonography showed a prominent liver and spleen. The liver parenchyma showed diffuse decreased echogenicity, suggestive of hepatitis.

Transesophageal echocardiography showed no vegetations or valvular abnormalities.

Bronchoscopy showed normal airways without evidence of pulmonary hemorrhage. No foci of infection were obtained. A focus of granuloma consisting of epithelioid histiocytes in tight clusters was seen on washings from the right lower lobe, but no malignant cells were seen.

Sections of pathologically enlarged right hilar and subcarinal lymph nodes obtained with transbronchial needle aspiration were sent for cytologic analysis and flow cytometry.

Cultures for tuberculous and fungal organisms were negative.

A clue. On further inquiry, the patient said he had gone swimming in the natural pool, or cenote, under a rock formation at Cenote Maya Park in Mexico.

1. Which of the following is not in the differential diagnosis?

• Disseminated tuberculosis
• Coccidioidomycosis
• Subacute infective endocarditis
• Disseminated histoplasmosis
• Blastomycosis

Although the patient has a systemic disease, subacute infective endocarditis is not likely because of a lack of predisposing factors such as a history of endocarditis, abnormal or artificial heart valve, or intravenous drug abuse. Moreover, negative blood cultures and the absence of vegetations on echocardiography make endocarditis very unlikely.

Given that the patient is immunosuppressed, opportunistic infection must be at the top of the differential diagnosis. Histoplasmosis, coccidioidomycosis, and blastomycosis are endemic in Mexico. Disseminated histoplasmosis is the most likely diagnosis; coccidioidomycosis and blastomycosis are less likely, based on the history, signs, and symptoms. Disseminated tuberculosis must be excluded before other diagnostic possibilities are considered.

TUBERCULOSIS IN PATIENTS ON TNF-ALPHA ANTAGONISTS

Tuberculosis has been reported in patients taking TNF-alpha antagonists.¹ The frequency of tuberculosis is much higher than that of other opportunistic infections, and over 50% of reported cases involve extrapulmonary tissues in patients treated with TNF-alpha antagonists.²

British Thoracic Society guidelines recommend screening for latent tuberculosis before starting treatment with a TNF-alpha antagonist; the screening should include a history of tuberculosis treatment, a clinical examination, chest radiography, and a tuberculin skin test.³ Patients found to have active tuberculosis should receive a minimum of 2 months of standard treatment before starting a TNF-alpha antagonist. Patients with evidence of past tuberculosis or a history of tuberculosis who received adequate treatment should be monitored regularly. Patients with prior tuberculosis not adequately treated should receive chemoprophylaxis before starting a TNF-alpha antagonist.

Fever, night sweats, and intrathoracic and intra-abdominal lymphadenopathy are common features of disseminated tuberculosis. Upper-lobe cavitary disease or miliary lesions may be seen on chest radiography, but atypical presentations with lower-lobe infiltrate are not uncommon in immunosuppressed patients.⁴

A negative tuberculin skin test and a normal chest radiograph 3 months ago, along with negative sputum and bronchial lavage fluid cultures and no history of tuberculosis contact, make tuberculosis unlikely in our patient.

COCCIDIOIDOMYCOSIS

Coccidioidomycosis (valley fever) is caused by the fungus Coccidioides immitis, which lives in the soil and is acquired by inhalation of airborne microscopic spores.

Fatigue, cough, fever, shortness of breath, headache, night sweats, muscle or joint pain, and a rash on the upper body or legs are common symptoms. It may cause a self-limiting flulike illness. From 5% to 10% of patients may develop serious long-term lung problems. In a small number of patients, the disease may progress beyond the lungs to involve the central nervous system, spinal cord, skin, bones, and joints.⁵

Serologic testing is highly useful for the diagnosis. Antigen testing has a sensitivity of 71% and a specificity of 98% for the diagnosis, but cross-reactivity occurs in 10% of patients with other types of mycosis. Respiratory secretions and tissue samples should undergo microscopic study and culture.

BLASTOMYCOSIS

Blastomycosis is caused by the fungus Blastomyces dermatitidis, which lives in soil and in association with decomposing organic matter such as wood and leaves. Inhalation of spores may cause a flulike illness or pneumonia. In serious cases, the disease can spread to skin and bone.

The diagnosis is established with fungal cultures of tissue samples or body fluids (bone marrow, liver tissue, skin, sputum, blood). Rapid diagnosis may be obtained by examination of the secretions under a microscope, where typical broad-based budding yeast can be seen in almost 90% of cases.⁶ Antigen may also be detected in urine and serum⁷; the sensitivity of antigen testing is 93% and the specificity is 98%. Serologic testing is not recommended for diagnosis of blastomycosis because of poor sensitivity and specificity.⁸

NARROWING THE DIFFERENTIAL

Both coccidioidomycosis and blastomycosis should be included in the differential diagnosis of a systemic disease with subacute onset and prominent lung involvement in a patient returning from travel to Mexico. The lack of involvement of the central nervous system, spinal cord, bones, or joints makes these infections less likely in our patient.

However, swimming in a cenote under a rock formation is an important clue to the diagnosis in our patient, as it puts him at risk of inhaling microconidia or hyphal elements of histoplasmosis. This, along with his immunocompromised status, fever, hemoptysis, night sweats, skin and lung features, and the generally subacute course of his illness, make disseminated histoplasmosis the most likely diagnosis.

Radiologic findings of pulmonary infiltrate with effusion and elevated lactate dehydrogenase, aminotransferases, and alkaline phosphatase increase the likelihood of disseminated histoplasmosis.

Histoplasma capsulatum is a dimorphic fungus that thrives in the soil and caves of regions with moderate climate, especially in soil containing large amounts of bird excreta or bat guano.⁹ Bats are natural hosts of this organism, and it is endemic in North and Central America, including parts of Mexico. Air currents can carry the microconidia for miles, thus exposing people without direct contact with contaminated sites.

The infection is usually acquired by inhalation of microconidia or small hyphal elements or by reactivation of previously quiescent foci of infection in an immunosuppressed patient. Most patients exposed to H capsulatum remain asymptomatic or develop mild symptoms, which are self-limiting. A small number develop acute pulmonary histoplasmosis or chronic cavitary histoplasmosis. Disseminated disease usually occurs only in an immunosuppressed host.

Acute pulmonary histoplasmosis presents with fever, malaise, headache, weakness, substernal chest pain, and dry cough and may be associated with erythema nodosum, erythema multiforme, and arthralgias. It may be mistaken for sarcoidosis since enlarged hilar and mediastinal lymph nodes are often seen on chest radiography.¹⁰

Progressive disseminated histoplasmosis is defined as a clinical illness that does not improve after at least 3 weeks of observation and is associated with physical or radiographic findings with or without laboratory evidence of extrapulmonary involvement.¹¹

Fever, malaise, anorexia, weight loss, night sweats, hepatosplenomegaly, and lymphadenopathy are features of progressive disseminated histoplasmosis.

Cutaneous manifestations of disseminated histoplasmosis occur in 10% to 25% of patients with acquired immunodeficiency syndrome and include papules, plaques with or without crust, pustules, nodules, lesions resembling molluscum contagiosum virus infection, acneiform eruptions, erythematous macules, and keratotic plaques.¹²

TESTING FOR HISTOPLASMOSIS

2. What investigation is least likely to help confirm the diagnosis of disseminated histoplasmosis?

• Polymerase chain reaction (PCR) testing of serum, cerebrospinal fluid, and bronchoalveolar lavage specimens
• Urinary Histoplasma antigen testing
• Serologic testing
• Blood and bronchoalveolar lavage cultures

Urinary Histoplasma antigen has a sensitivity of 90% for the diagnosis of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.¹⁸ It is less useful for pulmonary forms of histoplasmosis: the sensitivity is 75% and may even be less in milder or chronic forms of pneumonia.¹⁹ False-positive reactions may occur in patients with other fungal infections such as coccidioidomycosis, blastomycosis, paracoccidioidomycosis and penicilliosis.²⁰ Urine antigen levels can also be used to monitor therapy, since levels decrease during therapy and increase in 90% of those who have a relapse.²¹

Our patient’s urinary Histoplasma antigen level was greater than 23.0 ng/mL (positive is > 0.50).

Serologic testing. Immunodiffusion immunoglobulin G (IgG) testing for Histoplasma and Blastomyces was negative, as was an enzyme immunoassay for Coccidioides IgG and IgM. However, antibody tests are less useful in immunosuppressed patients,²² and thus a negative result does not rule out histoplasmosis. A fourfold rise in complement fixation antibody titer is diagnostic of acute histoplasmosis. A single complement fixation titer of 1:32 is suggestive but not diagnostic of histoplasmosis. Cross-reactions may occur with other fungal infections like blastomycosis. The immunodiffusion assay has a greater specificity but slightly less sensitivity than the complement fixation assay.¹⁹

Culture of H capsulatum is the definitive test to establish a diagnosis of histoplasmosis. Culture can be performed on samples taken from blood, bone marrow, sputum, and bronchoalveolar lavage fluid, or from lung, liver, or lymph node tissue. Cultures are positive in 74% to 82% of cases of progressive disseminated histoplasmosis.¹³ However, treatment should not await culture results since the fungus may take several weeks to grow.

Back to our patient

Although Histoplasma serologic studies and cultures were negative, the diagnosis of disseminated histoplasmosis was made on the basis of the patient’s immunosuppressed status, travel history, clinical features, and positivity for urine Histoplasma antigen. Though urine histoplama antigen may be falsely positive in other fungal infections such as coccidioidomycosis, paracoccidioidomycosis, and blastomycosis, clinical features and the absence of central nervous system, joint, and bone involvement suggested disseminated histoplasmosis.

3. What is the appropriate treatment for this patient?

• Amphotericin B followed by oral itraconozole
• Oral fluconazole
• Oral itraconazole

Liposomal amphotericin B or amphotericin B deoxycholate is recommended as initial therapy for moderately severe to severe and progressive disseminated histoplasmosis. It should be continued for 1 to 2 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days, then 200 mg 2 times daily for at least 12 months).

Monitoring itraconazole therapy through random serum levels is strongly recommended, and a random concentration of at least 1.0 mg/mL is recommended.²³

Urine antigen levels should be measured before treatment is started, at 2 weeks, at 1 month, then every 3 months during therapy, continuing for 12 months after treatment is stopped.¹¹

Lifelong suppressive therapy with itraconazole 200 mg daily may be required in immunosuppressed patients and patients who have a relapse despite appropriate therapy.¹¹

While oral itraconazole is used as a sole agent for the treatment of mild to moderate acute pulmonary histoplasmosis and chronic cavitary pulmonary histoplasmosis, oral treatment alone with either fluconazole or itraconazole is not recommended for the treatment of progressive disseminated histoplasmosis.¹¹

COMPLICATIONS OF HISTOPLASMOSIS

4. Which of the following is not a possible complication of histoplasmosis?

• Chronic cavitary pulmonary histoplasmosis
• Fibrosing mediastinitis
• Hypoadrenalism
• Hypothyroidism

Chronic cavitary pulmonary histoplasmosis usually develops in patients with underlying emphysema. Fatigue, night sweats, fever, anorexia, and weight loss are features of chronic cavitary pulmonary histoplasmosis. Progression of necrosis may lead to “marching cavity,” in which necrosis increases the size of the cavity and may consume an entire lobe.¹⁰

Fibrosing mediastinitis is an uncommon but often lethal complication of disseminated histoplasmosis. Increasing dyspnea, cough, hemoptysis, and signs of superior vena cava syndrome and right heart failure may develop. However, fibrosing mediastinitis is thought to be due to an exuberant immune response to past Histoplasma infection and would not be expected in an immunocompromised patient.¹⁷

Hypoadrenalism. Extensive destruction of the adrenal glands may lead to hypoadrenalism, manifesting as orthostatic hypotension, hyperkalemia, hyponatremia, and evidence of markedly enlarged adrenal glands with central necrosis on computed tomography.²⁴

Hypothyroidism. Acute or disseminated histoplasmosis has not been reported to cause thyroid dysfunction.

CASE CONCLUSION

Our patient was treated with itraconazole 200 mg twice daily for 24 months. Although the literature supports lifelong itraconazole therapy in immunosuppressed patients, our patient was reluctant to do so. He agreed to close monitoring. If symptoms recur, itraconazole will be reinstituted and continued lifelong.

A 32-year-old woman presented to our emergency department with chest pain and painful ulcerations on her arms, abdomen, back, groin, axillae, and in her mouth. She first noticed the ulcers 7 days earlier.

She also reported bloody diarrhea, which had started 2 years earlier, with 10 or more bowel movements daily. She described her stools as semiformed and associated with urgency and painful abdominal cramps.

Medical history

Her medical history included obstructive sleep apnea and morbid obesity. She had first presented 2 years earlier to another hospital with diarrhea, abdominal pain, and rectal bleeding. At that time, results of esophagogastroduodenoscopy and colonoscopy were reported as normal. Later, she became pregnant, and her symptoms went away. She had a normal pregnancy and delivery.

About 1 year postpartum, her abdominal pain and bloody diarrhea recurred. Colonoscopy showed severe sigmoid inflammation with small, shallow ulcerations and friable mucosa interrupted by areas of normal mucosa. Histopathologic study of the colonic mucosa indicated mild to moderate chronic active colitis consisting of focal areas of cryptitis with occasional crypt abscess formation. She was diagnosed with Crohn colitis based on the endoscopic appearance, histopathology, and clinical presentation. The endoscope, however, could not be advanced beyond the sigmoid colon, which suggested stenosis. She was started on 5-aminosalicylic acid (5-ASA) but developed visual hallucinations, and the medication was stopped.

Her symptoms continued, and she developed worsening rectal bleeding and anemia that required hospitalization and blood transfusions. Another colonoscopy performed 1 month before this emergency department visit had shown multiple mucosal ulcerations, but again, the colonoscope could not be advanced beyond the sigmoid colon. She was started on oral corticosteroids, which provided only minimal clinical improvement.

Her current medications included atenolol (for sinus tachycardia), prednisone (initial dose 60 mg/day tapered to 20 mg/day at presentation), and ciprofloxacin.

Her family history was unknown because she had been adopted.

About 1 week before presentation, she had noticed ulcers developing on her arms, abdomen, back, groin, oral mucosa, and axillae. The ulcers were large and painful, with occasional spontaneous bleeding. She also reported pustules and ulcerations at sites of previous skin punctures, consistent with pathergy.

Findings on presentation

• Temperature 99.5°F (37.5°C)
• Heart rate 124 beats per minute
• Respiratory rate 22 breaths per minute
• Oxygen saturation 100% on room air
• Blood pressure 128/81 mm Hg
• Body mass index 67 kg/m² (morbidly obese).

She had multiple greyish-white patches and erosions over the soft palate, tongue, and upper and lower lip mucosa, erythematous pustules in the axillae bilaterally, and large erythematous, sharply demarcated ulcerations with a fibrinous base bilaterally covering her arms, thighs, groin, and abdomen.

Blood testing showed multiple abnormal results (Table 1). Urinalysis revealed a urine protein concentration of 100 mg/dL (reference range 0), more than 25 white blood cells per high-power field (reference range < 5),  6 to 10 red blood cells per high-power field (0–3), and more than 10 casts per low-power field (0), which suggested a urinary tract infection with hematuria.

Computed tomography (CT) of the abdomen and pelvis with intravenous and oral contrast showed diffuse fatty infiltration of the liver and wall thickening of the rectum and sigmoid colon.

She was admitted to the medical intensive care unit for potential septic shock. Intravenous vancomycin and ciprofloxacin were started (the latter owing to penicillin allergy).

1. What is the most likely diagnosis in our patient?

• Ulcerative colitis
• Crohn disease
• Behçet disease
• Intestinal tuberculosis
• Herpes simplex virus infection
• Cytomegalovirus infection

All of the above can cause diarrhea in combination with mucocutaneous lesions and other manifestations.

Ulcerative colitis and Crohn disease: Mucocutaneous findings

Extraintestinal manifestations of inflammatory bowel diseases (Crohn disease, ulcerative colitis, and Behçet disease) include arthritis, ocular involvement, mucocutaneous manifestations, and liver involvement in the form of primary sclerosing cholangitis. Less common extraintestinal manifestations include vascular, renal, pulmonary, cardiac, and neurologic involvement.

Mucocutaneous findings are observed in 5% to 10% of patients with ulcerative colitis and 20% to 75% of patients with Crohn disease.^1–3 The most common are erythema nodosum and pyoderma gangrenosum.⁴

Yüksel et al⁵ reported that of 352 patients with inflammatory bowel disease, 7.4% had erythema nodosum and 2.3% had pyoderma gangrenosum. Erythema nodosum was significantly more common in patients with Crohn disease than in those with ulcerative colitis, and its severity was linked with higher disease activity. Lesions frequently resolved when bowel disease subsided.

Lebwohl and Lebwohl⁶ reported that pyoderma gangrenosum occurred in up to 20% of patients with Crohn disease and up to 10% of those with ulcerative colitis. It is not known whether pyoderma gangrenosum correlates with intestinal disease severity.

Other mucocutaneous manifestations of inflammatory bowel disease include oral aphthous ulcers, acute febrile neutrophilic dermatosis (Sweet syndrome), and metastatic Crohn disease. Aphthous ulcers in the oral cavity, often observed in both Crohn disease and ulcerative colitis, cannot be differentiated on clinical examination from herpes simplex virus (HSV) type 1-induced or idiopathic mucous membrane ulcers. The most common ulcer locations are the lips and buccal mucosa. If biopsied (seldom required), noncaseating granulomas can be identified that are comparable with intestinal mucosal granulomas found in Crohn disease.⁷

Behçet disease has similar signs

Oral aphthous ulcers are also the most frequent symptom in Behçet disease, occurring in 97% to 100% of cases.⁸ They most commonly affect the tongue, lips, buccal mucosa, and gingiva.

Cutaneous manifestations include erythema nodosum-like lesions, which present as erythematous painful nodules over pretibial surfaces of the lower limbs but can also affect the arms and thighs; they can also present as papulopustular rosacea eruptions composed of papules, pustules, and noninflammatory comedones, most commonly on the chest, back, and shoulders.^8,9

Pathergy, ie, skin hyperresponse to minor trauma such as a bump or bruise, is a typical trait of Behçet disease. A positive pathergy test (ie, skin hyperreactivity to a needlestick or intracutaneous injection) has a specificity of 98.4% in patients with Behçet disease.¹⁰

Interestingly, there appears to be a regional difference in the susceptibility to pathergy. While a pathergy response in patients with Behçet disease is rare in the United States and the United Kingdom, it is very common in Japan, Turkey, and Israel.¹¹

Patient demographics also distinguish Beh­çet disease from Crohn disease. The prevalence of Behçet disease is highest along the Silk Road from the Mediterranean Basin to East Asia and lowest in North America and Northern Europe.¹² The mean age at onset is around the third and fourth decades. In males, the prevalence is highest in Mediterranean, Middle Eastern, and Asian countries. In females, the prevalence is highest in the United States, Northern Europe, and East Asia.¹⁰

Tuberculosis

Tubercular skin lesions can present in different forms.¹³ Lupus vulgaris, the most common, occurs after primary infection and presents as translucent brown nodules, mainly over the face and neck. So-called scrofuloderma is common at the site of a lymph node. It appears as a gradually enlarging subcutaneous nodule followed by skin breaks and ulcerations. Tuberculosis verrucosa cutis, also known as warty tuberculosis, is common in developing countries and presents as warty plaque over the hands, knees, and buttocks.¹⁴ Tuberculids are skin reactions to systemic tuberculosis infection.

Herpes simplex virus

Mucocutaneous manifestations of herpes simplex virus affect the oral cavity (gingivo­stomatitis, pharyngitis, and lip border lesions), the entire integumentary system, the eyes (HSV-1), and the genital region (HSV-2). The classic presentation is systemic symptoms (fever and malaise) associated with multiple vesicles on an erythematous base in a distinct region of skin. The virus can remain latent with reactivation occurring because of illness, immunosuppression, or stress. Pruritus and pain precede the appearance of these lesions.

Cytomegalovirus

Primary cytomegalovirus infection is subclinical in almost all cases unless the patient is immunocompromised, and it presents similarly to mononucleosis induced by Epstein-Barr virus. The skin manifestations are nonspecific and can include macular, maculopapular, morbilliform, and urticarial rashes, but usually not ulcerations.¹⁵

OUR PATIENT: BEHÇET DISEASE OR CROHN DISEASE?

In our patient, oral mucosal aphthous ulcers and the location of pustular skin lesions, in addition to pathergy, were highly suggestive of Behçet disease. However, Crohn disease with mucocutaneous manifestations remained in the differential diagnosis.

Because there is significant overlap between these diseases, it is important to know the key distinguishing features. Oral aphthous ulcers, pathergy, uveitis, skin and genital lesions, and neurologic involvement are much more common in Behçet disease than in Crohn disease.^16,17 Demographic information was not helpful in this case, given that the patient was adopted.

2. What should be the next step in the work-up?

• CT enterography
• Skin biopsy
• Colonoscopy with biopsy
• C-reactive protein, erythrocyte sedimentation rate, and fecal calprotecting testing

The endoscopic appearance and histopathology of the affected tissues are crucial for the diagnosis. Differentiating between Crohn disease and Behçet disease can be particularly challenging because of significant overlap between the intestinal and extraintestinal manifestations of the two diseases, especially the oral lesions and arthralgias. Thus, both colonoscopy with biopsy of the intestinal lesions and biopsy of a cutaneous ulceration should be pursued.

No single test or feature is pathognomonic for Behçet disease. Although many diagnostic criteria have been established, those of the International Study Group (Table 2) are the most widely used.¹⁸ Their sensitivity for Beh­çet disease has been found to be 92%, and their specificity  97%.¹⁹

Both CT enterography and inflammatory markers would depict inflammation, but since this is present in both Crohn disease and Beh­çet disease, these tests would not be helpful in this situation.

Endoscopic appearance of Crohn disease and Behçet disease

Intestinal Behçet disease, like Crohn disease, is an inflammatory bowel disease occurring throughout the gastrointestinal tract (small and large bowel). Both are chronic diseases with a waxing and waning course and have similar extraintestinal manifestations. Typical endoscopic lesions are deep, sharply demarcated (“punched-out”), round ulcers. The intestinal Behçet disease and Crohn disease ulcer phenotype and distribution can look the same, and in both entities, rectal sparing and “skip lesions” have been described.^20–22

Nevertheless, findings on endoscopy have been analyzed to try to differentiate between Crohn disease and Behçet disease.

In 2009, Lee et al²³ published a simple and accurate strategy for distinguishing the two diseases endoscopically. The authors reviewed 250 patients (115 with Behçet disease, 135 with Crohn disease) with ulcers on colonoscopy and identified 5 endoscopic findings indicative of intestinal Behçet disease:

• Round ulcers
• Focal single or focal multiple distribution of ulcers
• Fewer than 6 ulcers
• Absence of a “cobblestone” appearance
• Absence of aphthous lesions.

The two most accurate factors were absence of a cobblestone appearance (sensitivity 100%) and round ulcer shape (specificity 97.5 %). When more than one factor was present, specificity increased but sensitivity decreased.

From Lee SK, Kim BK, Kim TI, Kim WH. Differential diagnosis of intestinal Behçet’s disease and Crohn’s disease by colonoscopic findings. Endoscopy 2009; 41:9–16; copyright Georg Thieme Verlag KG.

Using a classification and regression tree analysis, the investigators created an algorithm that endoscopically differentiates between Crohn disease and Behçet disease (Figure 1) with an accuracy of 92 %.²³

Histopathologic analysis of both colonic and skin lesions can provide additional clues to the correct diagnosis. Vasculitis suggests Behçet disease, whereas granulomas suggest Crohn disease.

CASE CONTINUED: SKIN BIOPSY AND COLONOSCOPY

Punch biopsy of the skin was performed on the right anterior thigh. Histopathologic analysis revealed acanthotic epidermis, a discrete full-thickness necrotic ulcer with a neutrophilic base, granulation tissue, and vasculitic changes. There were no vasculitic changes or granulomas outside the ulcer base. Cytomegalovirus staining was negative. An interferon-gamma release assay for tuberculosis was negative. Eye examination results were normal.

Colonoscopy showed multiple deep, round, and confluent ulcers with a punched-out appearance and fissures with normal intervening mucosa in the entire examined colon (Figure 2). The terminal ileal mucosa was normal. Colonic biopsies were consistent with cryptitis and rare crypt abscesses. Vasculitis was not identified.

Although the histologic changes were nonspecific, at this point we considered Beh­çet disease to be more likely than Crohn disease, given the typical endoscopic appearance and skin changes.

3. Which is not considered a standard treatment for intestinal Behçet disease?

• Mesalamine (5-ASA)
• Corticosteroids
• Immunosuppressants
• Mycophenolate mofetil
• Surgery

Overall, data on the management of intestinal Behçet disease are limited. The data that do exist have shown that 5-ASA, corticosteroids, immunosuppressants, and surgery are options, but not mycophenolate mofetil.

Consensus recommendations from the Japanese IBD Research Group,²⁴ published in 2007, included 5-ASA, corticosteroids, immunosuppressants, enteral and total parenteral nutrition, and surgical resection. In 2014, the group published a second consensus statement, adding anti-tumor necrosis factor (TNF) agents as standard therapy for this disease.²²

Mycophenolate mofetil has not been shown to be effective in the treatment of mucocutaneous Behçet disease,²⁵ although it may be effective in the treatment of its neurologic manifestations.²⁶ Data regarding its efficacy in intestinal Behçet disease are sparse.

Differences in treatment for Crohn and Behçet disease

Although the treatment options are comparable for Behçet disease and Crohn disease, certain features differ.

Doses of 5-ASA and immunnosuppressive agents are typically higher in Crohn disease. For example, the optimal dose of 5-ASA is up to 3 g/day for Behçet disease but up to 4.8 g/day for Crohn disease.

Standard dosing for azathioprine is 50 to 100 mg/day for Behçet disease but 2 to 2.5 mg/kg/day (eg, 168 to 210 mg/day for a 185-lb patient) for Crohn disease.

In addition, evidence supporting the use of biologic agents such as anti-TNF agents or vedolizumab is more abundant in Crohn disease.

Finally, data on monitoring drug levels of immunomodulators or biologics are available only for patients with Crohn disease, not Behçet disease. Thus, an accurate diagnosis is important.

CASE CONTINUED: EMERGENCY LAPAROTOMY

Our patient continued to experience abdominal pain and bloody diarrhea despite receiving corticosteroids intravenously in high doses. We were also considering anti-TNF therapy.

At this point, CT of her abdomen and pelvis was repeated and showed free intraperitoneal air consistent with a perforation of the transverse colon.

She underwent emergency exploratory laparotomy. Intraoperative findings included pneumoperitoneum but no gross peritoneal contamination, extensive colitis with a contained splenic flexure perforation, and normal small-bowel features without evidence of enteritis. Subtotal colectomy, implantation of the rectal stump into the subcutaneous tissue, and end-ileostomy were performed.

After 23 days of recovery in the hospital, she was discharged on oral antibiotics and 4 weeks of steroid taper.

PROGNOSIS OF INTESTINAL BEHÇET DISEASE

4. What can the patient expect from her intestinal Behçet disease in the future?

• The disease is cured after resection of the diseased segments
• Behçet disease is a progressive lifelong disorder that can recur after surgery

Like Crohn disease, Behçet disease should be considered a lifelong progressive disorder, even after surgical resection of diseased segments.

It is unclear which patients will have a complicated disease course and need treatment with stronger immunosuppression. In patients with intestinal Behçet disease whose disease is in remission on thiopurine therapy, the 1-year relapse rate has been reported as 5.8%, and the 5-year relapse rate 51.7%.^27,28 After surgical resection, the 5-year recurrence rate was 47.2%, and 30.6% of patients needed repeat surgery.²⁹ Predictors of poor prognosis were younger age, higher erythrocyte sedimentation rate, higher C-reactive protein level, low albumin level at diagnosis, and a high disease-activity index for intestinal Behçet disease.³⁰

The Korean IBD Study Group has developed and validated a disease activity index for intestinal Behçet disease.²⁸ The index has a list of weighted scores for 8 symptoms, which provides for a more objective assessment of disease activity for determining the best treatment approach.

CASE CONTINUED

The patient has continued with her follow-up care and appointments in gastroenterology, rheumatology, and dermatology clinics. She still complains of intermittent abdominal pain, occasional bleeding at the rectal stump, intermittent skin lesions mainly in the form of pustular lesions, and intermittent joint pain. If symptoms persist, anti-TNF therapy is an option.

A 32-year-old woman presented to our emergency department with chest pain and painful ulcerations on her arms, abdomen, back, groin, axillae, and in her mouth. She first noticed the ulcers 7 days earlier.

She also reported bloody diarrhea, which had started 2 years earlier, with 10 or more bowel movements daily. She described her stools as semiformed and associated with urgency and painful abdominal cramps.

Medical history

Her medical history included obstructive sleep apnea and morbid obesity. She had first presented 2 years earlier to another hospital with diarrhea, abdominal pain, and rectal bleeding. At that time, results of esophagogastroduodenoscopy and colonoscopy were reported as normal. Later, she became pregnant, and her symptoms went away. She had a normal pregnancy and delivery.

About 1 year postpartum, her abdominal pain and bloody diarrhea recurred. Colonoscopy showed severe sigmoid inflammation with small, shallow ulcerations and friable mucosa interrupted by areas of normal mucosa. Histopathologic study of the colonic mucosa indicated mild to moderate chronic active colitis consisting of focal areas of cryptitis with occasional crypt abscess formation. She was diagnosed with Crohn colitis based on the endoscopic appearance, histopathology, and clinical presentation. The endoscope, however, could not be advanced beyond the sigmoid colon, which suggested stenosis. She was started on 5-aminosalicylic acid (5-ASA) but developed visual hallucinations, and the medication was stopped.

Her symptoms continued, and she developed worsening rectal bleeding and anemia that required hospitalization and blood transfusions. Another colonoscopy performed 1 month before this emergency department visit had shown multiple mucosal ulcerations, but again, the colonoscope could not be advanced beyond the sigmoid colon. She was started on oral corticosteroids, which provided only minimal clinical improvement.

Her current medications included atenolol (for sinus tachycardia), prednisone (initial dose 60 mg/day tapered to 20 mg/day at presentation), and ciprofloxacin.

Her family history was unknown because she had been adopted.

About 1 week before presentation, she had noticed ulcers developing on her arms, abdomen, back, groin, oral mucosa, and axillae. The ulcers were large and painful, with occasional spontaneous bleeding. She also reported pustules and ulcerations at sites of previous skin punctures, consistent with pathergy.

Findings on presentation

• Temperature 99.5°F (37.5°C)
• Heart rate 124 beats per minute
• Respiratory rate 22 breaths per minute
• Oxygen saturation 100% on room air
• Blood pressure 128/81 mm Hg
• Body mass index 67 kg/m² (morbidly obese).

She had multiple greyish-white patches and erosions over the soft palate, tongue, and upper and lower lip mucosa, erythematous pustules in the axillae bilaterally, and large erythematous, sharply demarcated ulcerations with a fibrinous base bilaterally covering her arms, thighs, groin, and abdomen.

Blood testing showed multiple abnormal results (Table 1). Urinalysis revealed a urine protein concentration of 100 mg/dL (reference range 0), more than 25 white blood cells per high-power field (reference range < 5),  6 to 10 red blood cells per high-power field (0–3), and more than 10 casts per low-power field (0), which suggested a urinary tract infection with hematuria.

Computed tomography (CT) of the abdomen and pelvis with intravenous and oral contrast showed diffuse fatty infiltration of the liver and wall thickening of the rectum and sigmoid colon.

She was admitted to the medical intensive care unit for potential septic shock. Intravenous vancomycin and ciprofloxacin were started (the latter owing to penicillin allergy).

1. What is the most likely diagnosis in our patient?

• Ulcerative colitis
• Crohn disease
• Behçet disease
• Intestinal tuberculosis
• Herpes simplex virus infection
• Cytomegalovirus infection

All of the above can cause diarrhea in combination with mucocutaneous lesions and other manifestations.

Ulcerative colitis and Crohn disease: Mucocutaneous findings

Extraintestinal manifestations of inflammatory bowel diseases (Crohn disease, ulcerative colitis, and Behçet disease) include arthritis, ocular involvement, mucocutaneous manifestations, and liver involvement in the form of primary sclerosing cholangitis. Less common extraintestinal manifestations include vascular, renal, pulmonary, cardiac, and neurologic involvement.

Mucocutaneous findings are observed in 5% to 10% of patients with ulcerative colitis and 20% to 75% of patients with Crohn disease.^1–3 The most common are erythema nodosum and pyoderma gangrenosum.⁴

Yüksel et al⁵ reported that of 352 patients with inflammatory bowel disease, 7.4% had erythema nodosum and 2.3% had pyoderma gangrenosum. Erythema nodosum was significantly more common in patients with Crohn disease than in those with ulcerative colitis, and its severity was linked with higher disease activity. Lesions frequently resolved when bowel disease subsided.

Lebwohl and Lebwohl⁶ reported that pyoderma gangrenosum occurred in up to 20% of patients with Crohn disease and up to 10% of those with ulcerative colitis. It is not known whether pyoderma gangrenosum correlates with intestinal disease severity.

Other mucocutaneous manifestations of inflammatory bowel disease include oral aphthous ulcers, acute febrile neutrophilic dermatosis (Sweet syndrome), and metastatic Crohn disease. Aphthous ulcers in the oral cavity, often observed in both Crohn disease and ulcerative colitis, cannot be differentiated on clinical examination from herpes simplex virus (HSV) type 1-induced or idiopathic mucous membrane ulcers. The most common ulcer locations are the lips and buccal mucosa. If biopsied (seldom required), noncaseating granulomas can be identified that are comparable with intestinal mucosal granulomas found in Crohn disease.⁷

Behçet disease has similar signs

Oral aphthous ulcers are also the most frequent symptom in Behçet disease, occurring in 97% to 100% of cases.⁸ They most commonly affect the tongue, lips, buccal mucosa, and gingiva.

Cutaneous manifestations include erythema nodosum-like lesions, which present as erythematous painful nodules over pretibial surfaces of the lower limbs but can also affect the arms and thighs; they can also present as papulopustular rosacea eruptions composed of papules, pustules, and noninflammatory comedones, most commonly on the chest, back, and shoulders.^8,9

Pathergy, ie, skin hyperresponse to minor trauma such as a bump or bruise, is a typical trait of Behçet disease. A positive pathergy test (ie, skin hyperreactivity to a needlestick or intracutaneous injection) has a specificity of 98.4% in patients with Behçet disease.¹⁰

Interestingly, there appears to be a regional difference in the susceptibility to pathergy. While a pathergy response in patients with Behçet disease is rare in the United States and the United Kingdom, it is very common in Japan, Turkey, and Israel.¹¹

Patient demographics also distinguish Beh­çet disease from Crohn disease. The prevalence of Behçet disease is highest along the Silk Road from the Mediterranean Basin to East Asia and lowest in North America and Northern Europe.¹² The mean age at onset is around the third and fourth decades. In males, the prevalence is highest in Mediterranean, Middle Eastern, and Asian countries. In females, the prevalence is highest in the United States, Northern Europe, and East Asia.¹⁰

Tuberculosis

Tubercular skin lesions can present in different forms.¹³ Lupus vulgaris, the most common, occurs after primary infection and presents as translucent brown nodules, mainly over the face and neck. So-called scrofuloderma is common at the site of a lymph node. It appears as a gradually enlarging subcutaneous nodule followed by skin breaks and ulcerations. Tuberculosis verrucosa cutis, also known as warty tuberculosis, is common in developing countries and presents as warty plaque over the hands, knees, and buttocks.¹⁴ Tuberculids are skin reactions to systemic tuberculosis infection.

Herpes simplex virus

Mucocutaneous manifestations of herpes simplex virus affect the oral cavity (gingivo­stomatitis, pharyngitis, and lip border lesions), the entire integumentary system, the eyes (HSV-1), and the genital region (HSV-2). The classic presentation is systemic symptoms (fever and malaise) associated with multiple vesicles on an erythematous base in a distinct region of skin. The virus can remain latent with reactivation occurring because of illness, immunosuppression, or stress. Pruritus and pain precede the appearance of these lesions.

Cytomegalovirus

Primary cytomegalovirus infection is subclinical in almost all cases unless the patient is immunocompromised, and it presents similarly to mononucleosis induced by Epstein-Barr virus. The skin manifestations are nonspecific and can include macular, maculopapular, morbilliform, and urticarial rashes, but usually not ulcerations.¹⁵

OUR PATIENT: BEHÇET DISEASE OR CROHN DISEASE?

In our patient, oral mucosal aphthous ulcers and the location of pustular skin lesions, in addition to pathergy, were highly suggestive of Behçet disease. However, Crohn disease with mucocutaneous manifestations remained in the differential diagnosis.

Because there is significant overlap between these diseases, it is important to know the key distinguishing features. Oral aphthous ulcers, pathergy, uveitis, skin and genital lesions, and neurologic involvement are much more common in Behçet disease than in Crohn disease.^16,17 Demographic information was not helpful in this case, given that the patient was adopted.

2. What should be the next step in the work-up?

• CT enterography
• Skin biopsy
• Colonoscopy with biopsy
• C-reactive protein, erythrocyte sedimentation rate, and fecal calprotecting testing

The endoscopic appearance and histopathology of the affected tissues are crucial for the diagnosis. Differentiating between Crohn disease and Behçet disease can be particularly challenging because of significant overlap between the intestinal and extraintestinal manifestations of the two diseases, especially the oral lesions and arthralgias. Thus, both colonoscopy with biopsy of the intestinal lesions and biopsy of a cutaneous ulceration should be pursued.

No single test or feature is pathognomonic for Behçet disease. Although many diagnostic criteria have been established, those of the International Study Group (Table 2) are the most widely used.¹⁸ Their sensitivity for Beh­çet disease has been found to be 92%, and their specificity  97%.¹⁹

Both CT enterography and inflammatory markers would depict inflammation, but since this is present in both Crohn disease and Beh­çet disease, these tests would not be helpful in this situation.

Endoscopic appearance of Crohn disease and Behçet disease

Intestinal Behçet disease, like Crohn disease, is an inflammatory bowel disease occurring throughout the gastrointestinal tract (small and large bowel). Both are chronic diseases with a waxing and waning course and have similar extraintestinal manifestations. Typical endoscopic lesions are deep, sharply demarcated (“punched-out”), round ulcers. The intestinal Behçet disease and Crohn disease ulcer phenotype and distribution can look the same, and in both entities, rectal sparing and “skip lesions” have been described.^20–22

Nevertheless, findings on endoscopy have been analyzed to try to differentiate between Crohn disease and Behçet disease.

In 2009, Lee et al²³ published a simple and accurate strategy for distinguishing the two diseases endoscopically. The authors reviewed 250 patients (115 with Behçet disease, 135 with Crohn disease) with ulcers on colonoscopy and identified 5 endoscopic findings indicative of intestinal Behçet disease:

• Round ulcers
• Focal single or focal multiple distribution of ulcers
• Fewer than 6 ulcers
• Absence of a “cobblestone” appearance
• Absence of aphthous lesions.

The two most accurate factors were absence of a cobblestone appearance (sensitivity 100%) and round ulcer shape (specificity 97.5 %). When more than one factor was present, specificity increased but sensitivity decreased.

From Lee SK, Kim BK, Kim TI, Kim WH. Differential diagnosis of intestinal Behçet’s disease and Crohn’s disease by colonoscopic findings. Endoscopy 2009; 41:9–16; copyright Georg Thieme Verlag KG.

Using a classification and regression tree analysis, the investigators created an algorithm that endoscopically differentiates between Crohn disease and Behçet disease (Figure 1) with an accuracy of 92 %.²³

Histopathologic analysis of both colonic and skin lesions can provide additional clues to the correct diagnosis. Vasculitis suggests Behçet disease, whereas granulomas suggest Crohn disease.

CASE CONTINUED: SKIN BIOPSY AND COLONOSCOPY

Punch biopsy of the skin was performed on the right anterior thigh. Histopathologic analysis revealed acanthotic epidermis, a discrete full-thickness necrotic ulcer with a neutrophilic base, granulation tissue, and vasculitic changes. There were no vasculitic changes or granulomas outside the ulcer base. Cytomegalovirus staining was negative. An interferon-gamma release assay for tuberculosis was negative. Eye examination results were normal.

Colonoscopy showed multiple deep, round, and confluent ulcers with a punched-out appearance and fissures with normal intervening mucosa in the entire examined colon (Figure 2). The terminal ileal mucosa was normal. Colonic biopsies were consistent with cryptitis and rare crypt abscesses. Vasculitis was not identified.

Although the histologic changes were nonspecific, at this point we considered Beh­çet disease to be more likely than Crohn disease, given the typical endoscopic appearance and skin changes.

3. Which is not considered a standard treatment for intestinal Behçet disease?

• Mesalamine (5-ASA)
• Corticosteroids
• Immunosuppressants
• Mycophenolate mofetil
• Surgery

Overall, data on the management of intestinal Behçet disease are limited. The data that do exist have shown that 5-ASA, corticosteroids, immunosuppressants, and surgery are options, but not mycophenolate mofetil.

Consensus recommendations from the Japanese IBD Research Group,²⁴ published in 2007, included 5-ASA, corticosteroids, immunosuppressants, enteral and total parenteral nutrition, and surgical resection. In 2014, the group published a second consensus statement, adding anti-tumor necrosis factor (TNF) agents as standard therapy for this disease.²²

Mycophenolate mofetil has not been shown to be effective in the treatment of mucocutaneous Behçet disease,²⁵ although it may be effective in the treatment of its neurologic manifestations.²⁶ Data regarding its efficacy in intestinal Behçet disease are sparse.

Differences in treatment for Crohn and Behçet disease

Although the treatment options are comparable for Behçet disease and Crohn disease, certain features differ.

Doses of 5-ASA and immunnosuppressive agents are typically higher in Crohn disease. For example, the optimal dose of 5-ASA is up to 3 g/day for Behçet disease but up to 4.8 g/day for Crohn disease.

Standard dosing for azathioprine is 50 to 100 mg/day for Behçet disease but 2 to 2.5 mg/kg/day (eg, 168 to 210 mg/day for a 185-lb patient) for Crohn disease.

In addition, evidence supporting the use of biologic agents such as anti-TNF agents or vedolizumab is more abundant in Crohn disease.

Finally, data on monitoring drug levels of immunomodulators or biologics are available only for patients with Crohn disease, not Behçet disease. Thus, an accurate diagnosis is important.

CASE CONTINUED: EMERGENCY LAPAROTOMY

Our patient continued to experience abdominal pain and bloody diarrhea despite receiving corticosteroids intravenously in high doses. We were also considering anti-TNF therapy.

At this point, CT of her abdomen and pelvis was repeated and showed free intraperitoneal air consistent with a perforation of the transverse colon.

She underwent emergency exploratory laparotomy. Intraoperative findings included pneumoperitoneum but no gross peritoneal contamination, extensive colitis with a contained splenic flexure perforation, and normal small-bowel features without evidence of enteritis. Subtotal colectomy, implantation of the rectal stump into the subcutaneous tissue, and end-ileostomy were performed.

After 23 days of recovery in the hospital, she was discharged on oral antibiotics and 4 weeks of steroid taper.

PROGNOSIS OF INTESTINAL BEHÇET DISEASE

4. What can the patient expect from her intestinal Behçet disease in the future?

• The disease is cured after resection of the diseased segments
• Behçet disease is a progressive lifelong disorder that can recur after surgery

Like Crohn disease, Behçet disease should be considered a lifelong progressive disorder, even after surgical resection of diseased segments.

It is unclear which patients will have a complicated disease course and need treatment with stronger immunosuppression. In patients with intestinal Behçet disease whose disease is in remission on thiopurine therapy, the 1-year relapse rate has been reported as 5.8%, and the 5-year relapse rate 51.7%.^27,28 After surgical resection, the 5-year recurrence rate was 47.2%, and 30.6% of patients needed repeat surgery.²⁹ Predictors of poor prognosis were younger age, higher erythrocyte sedimentation rate, higher C-reactive protein level, low albumin level at diagnosis, and a high disease-activity index for intestinal Behçet disease.³⁰

The Korean IBD Study Group has developed and validated a disease activity index for intestinal Behçet disease.²⁸ The index has a list of weighted scores for 8 symptoms, which provides for a more objective assessment of disease activity for determining the best treatment approach.

CASE CONTINUED

The patient has continued with her follow-up care and appointments in gastroenterology, rheumatology, and dermatology clinics. She still complains of intermittent abdominal pain, occasional bleeding at the rectal stump, intermittent skin lesions mainly in the form of pustular lesions, and intermittent joint pain. If symptoms persist, anti-TNF therapy is an option.

A 32-year-old woman presented to our emergency department with chest pain and painful ulcerations on her arms, abdomen, back, groin, axillae, and in her mouth. She first noticed the ulcers 7 days earlier.

She also reported bloody diarrhea, which had started 2 years earlier, with 10 or more bowel movements daily. She described her stools as semiformed and associated with urgency and painful abdominal cramps.

Medical history

Her medical history included obstructive sleep apnea and morbid obesity. She had first presented 2 years earlier to another hospital with diarrhea, abdominal pain, and rectal bleeding. At that time, results of esophagogastroduodenoscopy and colonoscopy were reported as normal. Later, she became pregnant, and her symptoms went away. She had a normal pregnancy and delivery.

About 1 year postpartum, her abdominal pain and bloody diarrhea recurred. Colonoscopy showed severe sigmoid inflammation with small, shallow ulcerations and friable mucosa interrupted by areas of normal mucosa. Histopathologic study of the colonic mucosa indicated mild to moderate chronic active colitis consisting of focal areas of cryptitis with occasional crypt abscess formation. She was diagnosed with Crohn colitis based on the endoscopic appearance, histopathology, and clinical presentation. The endoscope, however, could not be advanced beyond the sigmoid colon, which suggested stenosis. She was started on 5-aminosalicylic acid (5-ASA) but developed visual hallucinations, and the medication was stopped.

Her symptoms continued, and she developed worsening rectal bleeding and anemia that required hospitalization and blood transfusions. Another colonoscopy performed 1 month before this emergency department visit had shown multiple mucosal ulcerations, but again, the colonoscope could not be advanced beyond the sigmoid colon. She was started on oral corticosteroids, which provided only minimal clinical improvement.

Her current medications included atenolol (for sinus tachycardia), prednisone (initial dose 60 mg/day tapered to 20 mg/day at presentation), and ciprofloxacin.

Her family history was unknown because she had been adopted.

About 1 week before presentation, she had noticed ulcers developing on her arms, abdomen, back, groin, oral mucosa, and axillae. The ulcers were large and painful, with occasional spontaneous bleeding. She also reported pustules and ulcerations at sites of previous skin punctures, consistent with pathergy.

Findings on presentation

• Temperature 99.5°F (37.5°C)
• Heart rate 124 beats per minute
• Respiratory rate 22 breaths per minute
• Oxygen saturation 100% on room air
• Blood pressure 128/81 mm Hg
• Body mass index 67 kg/m² (morbidly obese).

She had multiple greyish-white patches and erosions over the soft palate, tongue, and upper and lower lip mucosa, erythematous pustules in the axillae bilaterally, and large erythematous, sharply demarcated ulcerations with a fibrinous base bilaterally covering her arms, thighs, groin, and abdomen.

Blood testing showed multiple abnormal results (Table 1). Urinalysis revealed a urine protein concentration of 100 mg/dL (reference range 0), more than 25 white blood cells per high-power field (reference range < 5),  6 to 10 red blood cells per high-power field (0–3), and more than 10 casts per low-power field (0), which suggested a urinary tract infection with hematuria.

Computed tomography (CT) of the abdomen and pelvis with intravenous and oral contrast showed diffuse fatty infiltration of the liver and wall thickening of the rectum and sigmoid colon.

She was admitted to the medical intensive care unit for potential septic shock. Intravenous vancomycin and ciprofloxacin were started (the latter owing to penicillin allergy).

1. What is the most likely diagnosis in our patient?

• Ulcerative colitis
• Crohn disease
• Behçet disease
• Intestinal tuberculosis
• Herpes simplex virus infection
• Cytomegalovirus infection

All of the above can cause diarrhea in combination with mucocutaneous lesions and other manifestations.

Ulcerative colitis and Crohn disease: Mucocutaneous findings

Extraintestinal manifestations of inflammatory bowel diseases (Crohn disease, ulcerative colitis, and Behçet disease) include arthritis, ocular involvement, mucocutaneous manifestations, and liver involvement in the form of primary sclerosing cholangitis. Less common extraintestinal manifestations include vascular, renal, pulmonary, cardiac, and neurologic involvement.

Mucocutaneous findings are observed in 5% to 10% of patients with ulcerative colitis and 20% to 75% of patients with Crohn disease.^1–3 The most common are erythema nodosum and pyoderma gangrenosum.⁴

Yüksel et al⁵ reported that of 352 patients with inflammatory bowel disease, 7.4% had erythema nodosum and 2.3% had pyoderma gangrenosum. Erythema nodosum was significantly more common in patients with Crohn disease than in those with ulcerative colitis, and its severity was linked with higher disease activity. Lesions frequently resolved when bowel disease subsided.

Lebwohl and Lebwohl⁶ reported that pyoderma gangrenosum occurred in up to 20% of patients with Crohn disease and up to 10% of those with ulcerative colitis. It is not known whether pyoderma gangrenosum correlates with intestinal disease severity.

Other mucocutaneous manifestations of inflammatory bowel disease include oral aphthous ulcers, acute febrile neutrophilic dermatosis (Sweet syndrome), and metastatic Crohn disease. Aphthous ulcers in the oral cavity, often observed in both Crohn disease and ulcerative colitis, cannot be differentiated on clinical examination from herpes simplex virus (HSV) type 1-induced or idiopathic mucous membrane ulcers. The most common ulcer locations are the lips and buccal mucosa. If biopsied (seldom required), noncaseating granulomas can be identified that are comparable with intestinal mucosal granulomas found in Crohn disease.⁷

Behçet disease has similar signs

Oral aphthous ulcers are also the most frequent symptom in Behçet disease, occurring in 97% to 100% of cases.⁸ They most commonly affect the tongue, lips, buccal mucosa, and gingiva.

Cutaneous manifestations include erythema nodosum-like lesions, which present as erythematous painful nodules over pretibial surfaces of the lower limbs but can also affect the arms and thighs; they can also present as papulopustular rosacea eruptions composed of papules, pustules, and noninflammatory comedones, most commonly on the chest, back, and shoulders.^8,9

Pathergy, ie, skin hyperresponse to minor trauma such as a bump or bruise, is a typical trait of Behçet disease. A positive pathergy test (ie, skin hyperreactivity to a needlestick or intracutaneous injection) has a specificity of 98.4% in patients with Behçet disease.¹⁰

Interestingly, there appears to be a regional difference in the susceptibility to pathergy. While a pathergy response in patients with Behçet disease is rare in the United States and the United Kingdom, it is very common in Japan, Turkey, and Israel.¹¹

Patient demographics also distinguish Beh­çet disease from Crohn disease. The prevalence of Behçet disease is highest along the Silk Road from the Mediterranean Basin to East Asia and lowest in North America and Northern Europe.¹² The mean age at onset is around the third and fourth decades. In males, the prevalence is highest in Mediterranean, Middle Eastern, and Asian countries. In females, the prevalence is highest in the United States, Northern Europe, and East Asia.¹⁰

Tuberculosis

Tubercular skin lesions can present in different forms.¹³ Lupus vulgaris, the most common, occurs after primary infection and presents as translucent brown nodules, mainly over the face and neck. So-called scrofuloderma is common at the site of a lymph node. It appears as a gradually enlarging subcutaneous nodule followed by skin breaks and ulcerations. Tuberculosis verrucosa cutis, also known as warty tuberculosis, is common in developing countries and presents as warty plaque over the hands, knees, and buttocks.¹⁴ Tuberculids are skin reactions to systemic tuberculosis infection.

Herpes simplex virus

Mucocutaneous manifestations of herpes simplex virus affect the oral cavity (gingivo­stomatitis, pharyngitis, and lip border lesions), the entire integumentary system, the eyes (HSV-1), and the genital region (HSV-2). The classic presentation is systemic symptoms (fever and malaise) associated with multiple vesicles on an erythematous base in a distinct region of skin. The virus can remain latent with reactivation occurring because of illness, immunosuppression, or stress. Pruritus and pain precede the appearance of these lesions.

Cytomegalovirus

Primary cytomegalovirus infection is subclinical in almost all cases unless the patient is immunocompromised, and it presents similarly to mononucleosis induced by Epstein-Barr virus. The skin manifestations are nonspecific and can include macular, maculopapular, morbilliform, and urticarial rashes, but usually not ulcerations.¹⁵

OUR PATIENT: BEHÇET DISEASE OR CROHN DISEASE?

In our patient, oral mucosal aphthous ulcers and the location of pustular skin lesions, in addition to pathergy, were highly suggestive of Behçet disease. However, Crohn disease with mucocutaneous manifestations remained in the differential diagnosis.

Because there is significant overlap between these diseases, it is important to know the key distinguishing features. Oral aphthous ulcers, pathergy, uveitis, skin and genital lesions, and neurologic involvement are much more common in Behçet disease than in Crohn disease.^16,17 Demographic information was not helpful in this case, given that the patient was adopted.

2. What should be the next step in the work-up?

• CT enterography
• Skin biopsy
• Colonoscopy with biopsy
• C-reactive protein, erythrocyte sedimentation rate, and fecal calprotecting testing

The endoscopic appearance and histopathology of the affected tissues are crucial for the diagnosis. Differentiating between Crohn disease and Behçet disease can be particularly challenging because of significant overlap between the intestinal and extraintestinal manifestations of the two diseases, especially the oral lesions and arthralgias. Thus, both colonoscopy with biopsy of the intestinal lesions and biopsy of a cutaneous ulceration should be pursued.

No single test or feature is pathognomonic for Behçet disease. Although many diagnostic criteria have been established, those of the International Study Group (Table 2) are the most widely used.¹⁸ Their sensitivity for Beh­çet disease has been found to be 92%, and their specificity  97%.¹⁹

Both CT enterography and inflammatory markers would depict inflammation, but since this is present in both Crohn disease and Beh­çet disease, these tests would not be helpful in this situation.

Endoscopic appearance of Crohn disease and Behçet disease

Intestinal Behçet disease, like Crohn disease, is an inflammatory bowel disease occurring throughout the gastrointestinal tract (small and large bowel). Both are chronic diseases with a waxing and waning course and have similar extraintestinal manifestations. Typical endoscopic lesions are deep, sharply demarcated (“punched-out”), round ulcers. The intestinal Behçet disease and Crohn disease ulcer phenotype and distribution can look the same, and in both entities, rectal sparing and “skip lesions” have been described.^20–22

Nevertheless, findings on endoscopy have been analyzed to try to differentiate between Crohn disease and Behçet disease.

In 2009, Lee et al²³ published a simple and accurate strategy for distinguishing the two diseases endoscopically. The authors reviewed 250 patients (115 with Behçet disease, 135 with Crohn disease) with ulcers on colonoscopy and identified 5 endoscopic findings indicative of intestinal Behçet disease:

• Round ulcers
• Focal single or focal multiple distribution of ulcers
• Fewer than 6 ulcers
• Absence of a “cobblestone” appearance
• Absence of aphthous lesions.

The two most accurate factors were absence of a cobblestone appearance (sensitivity 100%) and round ulcer shape (specificity 97.5 %). When more than one factor was present, specificity increased but sensitivity decreased.

From Lee SK, Kim BK, Kim TI, Kim WH. Differential diagnosis of intestinal Behçet’s disease and Crohn’s disease by colonoscopic findings. Endoscopy 2009; 41:9–16; copyright Georg Thieme Verlag KG.

Using a classification and regression tree analysis, the investigators created an algorithm that endoscopically differentiates between Crohn disease and Behçet disease (Figure 1) with an accuracy of 92 %.²³

Histopathologic analysis of both colonic and skin lesions can provide additional clues to the correct diagnosis. Vasculitis suggests Behçet disease, whereas granulomas suggest Crohn disease.

CASE CONTINUED: SKIN BIOPSY AND COLONOSCOPY

Punch biopsy of the skin was performed on the right anterior thigh. Histopathologic analysis revealed acanthotic epidermis, a discrete full-thickness necrotic ulcer with a neutrophilic base, granulation tissue, and vasculitic changes. There were no vasculitic changes or granulomas outside the ulcer base. Cytomegalovirus staining was negative. An interferon-gamma release assay for tuberculosis was negative. Eye examination results were normal.

Colonoscopy showed multiple deep, round, and confluent ulcers with a punched-out appearance and fissures with normal intervening mucosa in the entire examined colon (Figure 2). The terminal ileal mucosa was normal. Colonic biopsies were consistent with cryptitis and rare crypt abscesses. Vasculitis was not identified.

Although the histologic changes were nonspecific, at this point we considered Beh­çet disease to be more likely than Crohn disease, given the typical endoscopic appearance and skin changes.

3. Which is not considered a standard treatment for intestinal Behçet disease?

• Mesalamine (5-ASA)
• Corticosteroids
• Immunosuppressants
• Mycophenolate mofetil
• Surgery

Overall, data on the management of intestinal Behçet disease are limited. The data that do exist have shown that 5-ASA, corticosteroids, immunosuppressants, and surgery are options, but not mycophenolate mofetil.

Consensus recommendations from the Japanese IBD Research Group,²⁴ published in 2007, included 5-ASA, corticosteroids, immunosuppressants, enteral and total parenteral nutrition, and surgical resection. In 2014, the group published a second consensus statement, adding anti-tumor necrosis factor (TNF) agents as standard therapy for this disease.²²

Mycophenolate mofetil has not been shown to be effective in the treatment of mucocutaneous Behçet disease,²⁵ although it may be effective in the treatment of its neurologic manifestations.²⁶ Data regarding its efficacy in intestinal Behçet disease are sparse.

Differences in treatment for Crohn and Behçet disease

Although the treatment options are comparable for Behçet disease and Crohn disease, certain features differ.

Doses of 5-ASA and immunnosuppressive agents are typically higher in Crohn disease. For example, the optimal dose of 5-ASA is up to 3 g/day for Behçet disease but up to 4.8 g/day for Crohn disease.

Standard dosing for azathioprine is 50 to 100 mg/day for Behçet disease but 2 to 2.5 mg/kg/day (eg, 168 to 210 mg/day for a 185-lb patient) for Crohn disease.

In addition, evidence supporting the use of biologic agents such as anti-TNF agents or vedolizumab is more abundant in Crohn disease.

Finally, data on monitoring drug levels of immunomodulators or biologics are available only for patients with Crohn disease, not Behçet disease. Thus, an accurate diagnosis is important.

CASE CONTINUED: EMERGENCY LAPAROTOMY

Our patient continued to experience abdominal pain and bloody diarrhea despite receiving corticosteroids intravenously in high doses. We were also considering anti-TNF therapy.

At this point, CT of her abdomen and pelvis was repeated and showed free intraperitoneal air consistent with a perforation of the transverse colon.

She underwent emergency exploratory laparotomy. Intraoperative findings included pneumoperitoneum but no gross peritoneal contamination, extensive colitis with a contained splenic flexure perforation, and normal small-bowel features without evidence of enteritis. Subtotal colectomy, implantation of the rectal stump into the subcutaneous tissue, and end-ileostomy were performed.

After 23 days of recovery in the hospital, she was discharged on oral antibiotics and 4 weeks of steroid taper.

PROGNOSIS OF INTESTINAL BEHÇET DISEASE

4. What can the patient expect from her intestinal Behçet disease in the future?

• The disease is cured after resection of the diseased segments
• Behçet disease is a progressive lifelong disorder that can recur after surgery

Like Crohn disease, Behçet disease should be considered a lifelong progressive disorder, even after surgical resection of diseased segments.

It is unclear which patients will have a complicated disease course and need treatment with stronger immunosuppression. In patients with intestinal Behçet disease whose disease is in remission on thiopurine therapy, the 1-year relapse rate has been reported as 5.8%, and the 5-year relapse rate 51.7%.^27,28 After surgical resection, the 5-year recurrence rate was 47.2%, and 30.6% of patients needed repeat surgery.²⁹ Predictors of poor prognosis were younger age, higher erythrocyte sedimentation rate, higher C-reactive protein level, low albumin level at diagnosis, and a high disease-activity index for intestinal Behçet disease.³⁰

The Korean IBD Study Group has developed and validated a disease activity index for intestinal Behçet disease.²⁸ The index has a list of weighted scores for 8 symptoms, which provides for a more objective assessment of disease activity for determining the best treatment approach.

CASE CONTINUED

The patient has continued with her follow-up care and appointments in gastroenterology, rheumatology, and dermatology clinics. She still complains of intermittent abdominal pain, occasional bleeding at the rectal stump, intermittent skin lesions mainly in the form of pustular lesions, and intermittent joint pain. If symptoms persist, anti-TNF therapy is an option.

A  52-year-old woman with diabetes mellitus presented with a 1-month history of pain in the right lower abdomen and right back. Although she had a fever when the pain started and her pain was aggravated by walking, her pain and fever had gotten better after taking antibiotics prescribed earlier.

The patient was admitted to the hospital for percutaneous drainage, which produced 26 mL of pus on the first day and 320 mL on the next day; culture was positive for Escherichia coli. Urine culture was also positive for E coli; blood culture was not. We concluded that these results were secondary to pyeloneph­ritis.

We started intravenous piperacillin-tazobactam 2.25 g every 8 hours for empiric therapy. We changed this to oral ampicillin-cloxacillin 2 g/day after E coli was cultured and pyelonephritis was suspected. The patient was discharged after a 2-week hospital stay, with no significant complications.

ILIOPSOAS ABSCESS: DIAGNOSTIC CLUES

Iliopsoas abscess can occur at any age.^1–3 Pain is the most common symptom, occurring in more than 90% of patients.¹ Fever with temperatures over 38°C is less common at first, found in less than half of patients.^1,2

Only 13% of patients with iliopsoas abscess may have a palpable mass on physical examination.¹ The psoas sign—a worsening of lower abdominal pain on the affected side with passive extension of the thigh while supine—has a sensitivity of only 24% for iliopsoas abscess; it can also indicate inflammation to the iliopsoas muscle in other conditions such as retrocecal appendicitis.³

Hip flexion deformity can be a helpful diagnostic feature, as 96% of patients with iliopsoas abscess hold the hip in flexion to relieve pain.⁴ But pain on hip flexion can also occur in conditions such as septic arthritis.⁴

Inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein may be elevated in all patients with iliopsoas abscess, so if those markers are not elevated, we may have to consider other conditions such as cancer.¹ Computed tomography is nearly 100% sensitive for iliopsoas abscess and is the gold standard for diagnosis.³

TREATMENT

Inadequate treatment of iliopsoas abscess raises the risk of relapse and death.³ Drainage and appropriate antibiotic therapy have been shown to be effective.^1,3

Iliopsoas abscess can also be secondary to a number of conditions, eg, Crohn disease, appendicitis, intra-abdominal infection, and cancer,⁵ and the primary condition needs to be addressed. In addition, culture of a secondary abscess is more likely to grow mixed organisms.⁵

The average size of the abscess is 6 cm. Percutaneous drainage is required if the mass is larger than 3.5 cm.¹

TAKE-HOME MESSAGES

Iliopsoas abscess is difficult to diagnose because patients have few specific complaints. Checking for hip flexion deformity and inflammatory markers may help rule out the disease. When iliopsoas abscess is suspected, computed tomography is necessary to confirm the diagnosis. Drainage and appropriate antibiotics are effective treatment.

A  52-year-old woman with diabetes mellitus presented with a 1-month history of pain in the right lower abdomen and right back. Although she had a fever when the pain started and her pain was aggravated by walking, her pain and fever had gotten better after taking antibiotics prescribed earlier.

The patient was admitted to the hospital for percutaneous drainage, which produced 26 mL of pus on the first day and 320 mL on the next day; culture was positive for Escherichia coli. Urine culture was also positive for E coli; blood culture was not. We concluded that these results were secondary to pyeloneph­ritis.

We started intravenous piperacillin-tazobactam 2.25 g every 8 hours for empiric therapy. We changed this to oral ampicillin-cloxacillin 2 g/day after E coli was cultured and pyelonephritis was suspected. The patient was discharged after a 2-week hospital stay, with no significant complications.

ILIOPSOAS ABSCESS: DIAGNOSTIC CLUES

Iliopsoas abscess can occur at any age.^1–3 Pain is the most common symptom, occurring in more than 90% of patients.¹ Fever with temperatures over 38°C is less common at first, found in less than half of patients.^1,2

Only 13% of patients with iliopsoas abscess may have a palpable mass on physical examination.¹ The psoas sign—a worsening of lower abdominal pain on the affected side with passive extension of the thigh while supine—has a sensitivity of only 24% for iliopsoas abscess; it can also indicate inflammation to the iliopsoas muscle in other conditions such as retrocecal appendicitis.³

Hip flexion deformity can be a helpful diagnostic feature, as 96% of patients with iliopsoas abscess hold the hip in flexion to relieve pain.⁴ But pain on hip flexion can also occur in conditions such as septic arthritis.⁴

Inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein may be elevated in all patients with iliopsoas abscess, so if those markers are not elevated, we may have to consider other conditions such as cancer.¹ Computed tomography is nearly 100% sensitive for iliopsoas abscess and is the gold standard for diagnosis.³

TREATMENT

Inadequate treatment of iliopsoas abscess raises the risk of relapse and death.³ Drainage and appropriate antibiotic therapy have been shown to be effective.^1,3

Iliopsoas abscess can also be secondary to a number of conditions, eg, Crohn disease, appendicitis, intra-abdominal infection, and cancer,⁵ and the primary condition needs to be addressed. In addition, culture of a secondary abscess is more likely to grow mixed organisms.⁵

The average size of the abscess is 6 cm. Percutaneous drainage is required if the mass is larger than 3.5 cm.¹

TAKE-HOME MESSAGES

Iliopsoas abscess is difficult to diagnose because patients have few specific complaints. Checking for hip flexion deformity and inflammatory markers may help rule out the disease. When iliopsoas abscess is suspected, computed tomography is necessary to confirm the diagnosis. Drainage and appropriate antibiotics are effective treatment.

A  52-year-old woman with diabetes mellitus presented with a 1-month history of pain in the right lower abdomen and right back. Although she had a fever when the pain started and her pain was aggravated by walking, her pain and fever had gotten better after taking antibiotics prescribed earlier.

The patient was admitted to the hospital for percutaneous drainage, which produced 26 mL of pus on the first day and 320 mL on the next day; culture was positive for Escherichia coli. Urine culture was also positive for E coli; blood culture was not. We concluded that these results were secondary to pyeloneph­ritis.

We started intravenous piperacillin-tazobactam 2.25 g every 8 hours for empiric therapy. We changed this to oral ampicillin-cloxacillin 2 g/day after E coli was cultured and pyelonephritis was suspected. The patient was discharged after a 2-week hospital stay, with no significant complications.

ILIOPSOAS ABSCESS: DIAGNOSTIC CLUES

Iliopsoas abscess can occur at any age.^1–3 Pain is the most common symptom, occurring in more than 90% of patients.¹ Fever with temperatures over 38°C is less common at first, found in less than half of patients.^1,2

Only 13% of patients with iliopsoas abscess may have a palpable mass on physical examination.¹ The psoas sign—a worsening of lower abdominal pain on the affected side with passive extension of the thigh while supine—has a sensitivity of only 24% for iliopsoas abscess; it can also indicate inflammation to the iliopsoas muscle in other conditions such as retrocecal appendicitis.³

Hip flexion deformity can be a helpful diagnostic feature, as 96% of patients with iliopsoas abscess hold the hip in flexion to relieve pain.⁴ But pain on hip flexion can also occur in conditions such as septic arthritis.⁴

Inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein may be elevated in all patients with iliopsoas abscess, so if those markers are not elevated, we may have to consider other conditions such as cancer.¹ Computed tomography is nearly 100% sensitive for iliopsoas abscess and is the gold standard for diagnosis.³

TREATMENT

Inadequate treatment of iliopsoas abscess raises the risk of relapse and death.³ Drainage and appropriate antibiotic therapy have been shown to be effective.^1,3

Iliopsoas abscess can also be secondary to a number of conditions, eg, Crohn disease, appendicitis, intra-abdominal infection, and cancer,⁵ and the primary condition needs to be addressed. In addition, culture of a secondary abscess is more likely to grow mixed organisms.⁵

The average size of the abscess is 6 cm. Percutaneous drainage is required if the mass is larger than 3.5 cm.¹

TAKE-HOME MESSAGES

Iliopsoas abscess is difficult to diagnose because patients have few specific complaints. Checking for hip flexion deformity and inflammatory markers may help rule out the disease. When iliopsoas abscess is suspected, computed tomography is necessary to confirm the diagnosis. Drainage and appropriate antibiotics are effective treatment.

Pharmacotherapy and behavioral therapy are currently used with success in treating attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. Ongoing changes in healthcare require physicians to improve the quality of care, reduce costs of treatment, and manage their patients’ health, not just their illnesses. Behavioral and pharmacologic studies provide us with an opportunity to maximize treatment of ADHD and adapt it to the needs of individuals.

This article identifies common problems in treating ADHD, discusses limits of care in pharmacotherapy and behavioral intervention, and offers practical recommendations for treating ADHD in the changing world of healthcare.

A CHANGING MEDICAL CLIMATE

The Affordable Care Act of 2010 sought to transform medical care in the United States from procedures to performance, from acute episodes of illness to integrated care across the lifespan, and from inefficient care to efficient and affordable care with measurable outcomes. At the time of this writing, nobody knows whether the Affordable Care Act will survive, but these are still good goals. Because ADHD is the most common behavioral disorder of childhood, value-based care is essential.¹

ADHD ON THE RISE—WHY?

The prevalence of ADHD increased 42% from 2003 to 2011,² with increases in nearly all demographic groups in the United States regardless of race, sex, and socioeconomic status. More than 1 in 10 school-age children (11%) in the United States now meet the criteria for the diagnosis of ADHD; among adolescents, 1 in 5 high school boys and 1 in 11 high school girls meet the criteria.² 

Rates vary among states, from a low of 4.2% for children ages 4 to 17 in Nevada to a high of 14.6% in Arkansas.³ Worldwide estimates of ADHD prevalence range from 2.2% to 17.8%,⁴ with the most recent meta-analysis for North America and Europe indicating a 7.2% worldwide prevalence in people age 18  and younger.⁵

Such data have sparked criticism, with some saying that ADHD is overdiagnosed, others saying it is underdiagnosed, and most agreeing that it is misdiagnosed.

Changing definitions of ADHD may have had a small effect on the increase in prevalence,⁶ but the change is more likely a result of heightened awareness and recognition of symptoms. Even so, guidelines for diagnosing ADHD are still not rigorously applied, contributing to misdiagnosis. For example, in a study of 50 pediatric practices, only half of clinicians said they followed diagnostic guidelines to determine symptom criteria from at least 2 sources and across 2 settings, yet nearly all (93%) reported immediately prescribing medications for treatment.⁷

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,⁸ requires evidence of a persistent pattern of inattention or hyperactivity/impulsivity, or both, with a severity that interferes with developmental functioning in 2 or more settings; was present before age 12; and cannot be accounted for by another behavioral health disorder such as depression, anxiety, or trauma. The diagnosis should document the presence of at least 6 of 9 symptoms of inattention (or 5 symptoms for teens age 17 or older), or at least 6 of 9 symptoms of hyperactive/impulsive behavior (5 symptoms for teens age 17 and older). Symptoms are best documented when reported by at least 2 observers.

COSTS OF ADHD

ADHD is expensive to society. National yearly healthcare costs have ranged from $143 billion to $266 billion,⁹ with over half this amount assumed directly by families.¹⁰ Even in previous decades when prevalence rates hovered around 5%, the cost of workday loss in the United States was high for adult patients and for parents of young children with ADHD needing to take time off from work for doctors’ visits.¹¹ Projections across 10 countries indicated that adults with ADHD lost more workdays than did workers without ADHD.¹²

There is also a trend toward visits that are more expensive. Between 2000 and 2010, the number of visits for ADHD to psychiatrists rose from 24% to 36%, while the number of less-costly visits to pediatricians decreased from 54% to 47%.¹³

Thus, over the past 15 years, symptoms of ADHD have become more readily recognized, prevalence rates in the population have increased significantly, and associated costs have increased dramatically, with costs extending beyond individual impairment to a loss of productivity at the workplace. And treatment, typically with drugs, has been used without sufficient application of current diagnostic criteria. What impact does this have on the practicing physician?

DRUG TREATMENT: GOLD STANDARD OR NATIONAL DISASTER?

Stimulants are considered the standard of medical care for the symptoms of ADHD, according to the 2011 practice guidelines of the American Academy of Pediatrics.¹⁴ They are efficacious and cost-effective when optimal dosing is achieved, since the patient usually manages treatment independently, requiring minimal physician input in the months and years after successful titration.

For these reasons, the use of stimulants to treat ADHD has increased dramatically in the last decade. According to the National Survey of Children’s Health, as a result of an increase in parent-reported ADHD, more US children were receiving medical treatment for the disorder in 2011 than in any previous year reported, and the prevalence of pharmacotherapy in children ages 14 to 17 increased 28% over the 4 years from 2007 to 2011.²

Dr. Keith Conners, an early advocate for recognition of ADHD, has called the staggering increase in the rates of diagnosis and drug treatment a “national disaster of dangerous proportions.”¹⁵ Nevertheless, many children and families have benefited in a cost-effective manner.

Physicians typically rely on 4 strategies to titrate stimulants,¹⁶ presented below in order of increasing complexity.

Prescribe-and-wait

Often, physicians write a prescription and direct the parent to call back or visit the office to relay the child’s response after a specified period, typically 1 week to 1 month.

This method is convenient in a busy practice and is informative to the physician in a general way. The drawback to this method is that it seldom results in optimal treatment. If the parent does not call back, the physician may assume the treatment was successful without being certain.

Dose-to-improvement

In this approach, the physician monitors titration more closely and increases the dose until a positive response is achieved, after which the dose is maintained. This method reduces symptoms but does not ensure optimal treatment, as there still may be room for improvement.

Forced-dose titration

This method is often used in clinical trials. The dose is ramped up until side effects occur and is then reduced until the side effects go away.

This method often results in optimal dosing, as a forced dose yields a greater reduction in symptoms. But it requires close monitoring by the physician, with multiple reports from parents and teachers after each dose increase to determine whether benefit at the higher dose outweighs the side effects and whether side effects can be managed.

Blinded placebo trial

Also often used in research, this method typically requires a research pharmacy to prepare capsules of stimulant medicine in low, moderate, high, and placebo doses.¹⁷ All doses are blinded and given over 4 weeks in a forced-dose titration—a placebo capsule with 3 active medication doses in escalating order, which is typical of outpatient pediatric practice. Placebo capsules are randomly assigned to 1 of the 4 weeks, and behavior is monitored over the 7 days of administration by teachers and parents.

This strategy has benefits similar to those of forced-dose titration, and it further delineates medicine response—both side effects and behavior change—by adding a no-medicine placebo condition. It is a systematic, monitored “experiment” for parents who are wary or distrustful of ADHD pharmacotherapy, and it has notable benefits.¹⁸ It is also useful for teenagers who are reluctant to use medicine to treat symptoms. It arrives at optimal treatment in a timely manner, usually about 4 to 5 weeks.

On the other hand, this approach requires diligence from families, teachers, and caregivers during the initiation phase, and it requires consistent engagement of the physician team.

Some pediatricians designate a caregiver to monitor titration with the parent; with each new weekly dose, the caregiver reports the child’s progress to the physician.

ENSURING ADHERENCE

Essential to effective stimulant treatment for ADHD is not whether the medicine works (it does),¹⁹ but whether the patient continues to use it.

In treatment studies and pharmacy database analyses, rates of inconsistent use or discontinuation of medication (both considered nonadherence) were 13.2% to 64% within the first year,²⁰ and more than 95% of teenagers discontinue pharmacotherapy before age 21.²¹

Clinician engagement at the onset of stimulant titration is instrumental to treatment adherence.^22,23 When pharmacotherapy is loosely monitored during initiation, adherence is highly inconsistent. Some physicians wait as long as 72 days after first prescribing a medication to contact the patient or family,⁷ and most children with ADHD who discontinue their medications do so within the first year.²⁴

FACTORS THAT INHIBIT ADHERENCE

What factors inhibit adherence to successful pharmacotherapy for ADHD?

Treatment nonadherence is often associated with a parent’s perception that the medication is not working.²⁵ Physicians can often overcome this perception by speaking with the parent, conveying that at the start of treatment titrating to the optimal dose takes time, and that it does not mean “something is wrong.” But without physician contact, parents do not have the occasion to discuss side effects and benefits and tend not to voice fears such as whether the medicine will affect the child’s physical development or result in drug abuse later in life.²⁶

At the beginning of treatment, a child may become too focused, alarming the parent. This overfocused effect is often misunderstood and does not always persist. In addition, when a child better manages his or her own behavior, the contrast to previous behavior may look like something is wrong, when instead the child’s behavior is actually normalizing. Medicine-induced anxiety—in the child or, by association, in the parent—may be misunderstood, and subsequently the parent just stops the child’s treatment rather than seek physician guidance.

Nonadherence is also more prevalent with immediate-release than with extended-release formulations.^27,28

Problems can be summarized as follows⁷:

• Systematic physician observation of response to stimulant titration is often missing at the onset of treatment
• “Best dose” is inconsistently achieved
• Patient adherence to treatment is inconsistently monitored.

The long-term consequences of nonadherence to therapy for ADHD have not been sufficiently examined,²⁰ but some groups, especially adolescents, show problematic outcomes when treatment is not applied. For example, in one longitudinal study, substance use disorder was significantly higher in youths with ADHD who were never treated with medicine than in “neurotypical” youths and those with ADHD who were treated pharmacologically.²⁹

Although opinions vary as to the advantages of drug therapy vs behavioral intervention in ADHD, there is evidence that a combined approach is best.^30–33 Pharmacotherapy works inside the skin to reduce symptoms of inattention and overactivity, and behavioral therapy works outside the skin to teach new skills.

Based on outcomes data from the Center for Pediatric Behavioral Health, Cleveland Clinic Children’s.

A report from the US Centers for Disease Control and Prevention in 2016 stated that behavioral therapy should be the first treatment for young children with ADHD (ages 2 to 5), but noted that only 40% to 50% of young children with ADHD receive psychological services.³⁶ At the same time, the use of pharmacotherapy has increased tremendously.

Beginning treatment with behavioral therapy rather than medicine has been found to be more cost-effective over time. For children ages 4 to 5, behavioral therapy is recommended as the first line by the clinical practice guidelines of the American Academy of Pediatrics.¹⁴ Beginning treatment with behavioral intervention has been shown to produce better outcomes overall than beginning with medication and indicates that lower doses may be used compared with pharmacotherapy that is not preceded by behavioral therapy.³⁷ Findings also indicate that starting with behavioral therapy increases the cost-effectiveness of treatment for children with ADHD.³⁸

Behavioral intervention has modest advantages over medicine for non-ADHD symptoms,⁴² as the practice satisfies the adage “pills don’t teach skills.”²⁶ One advantage is that caregivers take an active role in managing child compliance, social interactions, and classroom deportment, as opposed to the relatively passive role of prescribing medicine only. Parents and teachers form collaborative partnerships to increase consistency and extend the reach of change. In the National Institute of Mental Health multimodal treatment study, the only children whose behavior normalized were those who used medicine and whose caregivers gave up negative, harsh, inconsistent, and ineffective discipline⁴³; that is, parents changed their own behavior.

Parent training is important, as parents must often manage their children’s behavior on their own the best they can, with little coaching and assistance. Primary care physicians may often refer parents to established local programs for training, and ongoing coaching can ensure that skills acquired in such training programs continue to be systematically applied.
Pharmacotherapy is focused almost solely on reducing symptoms, but reducing symptoms does not necessarily lead to improved functioning. A multimodal approach helps individuals adapt to demanding settings, achieve personal goals, and contribute to social relationships. Outcomes depend on teaching what to do as well as reducing what not to do. Behavioral therapy⁴⁴ shaped by peers, caregivers, teachers, and other factors can be effectively remediate the difficulties of children with ADHD.

The disadvantages of behavioral therapy are that it is not readily available, adds initial cost to treatment, and requires parents to invest more time at the beginning of intervention. But behavioral therapy reduces costs over time, enhances ADHD pharmacotherapy, often reduces the need for higher dosing, reduces visits to the doctor’s office, maintains behavior improvement and symptom reduction in the long term, and significantly increases quality of care.⁴²

A RECOMMENDED ADHD CARE PATH

How do we increase quality of care, reduce costs, and improve value of care for patients with ADHD? The treatment of ADHD as a chronic condition is collaborative. Several practices may be combined in a quality care path.

Follow up more frequently at the start of drug treatment

Physicians may give more frequent attention to the process of pharmacotherapy at the start of treatment. Pharmacotherapy is typically introduced by the prescribe-and-wait method, which often produces less than optimal dosing, limited treatment adherence, and inconsistent outcomes.^45,46 Though the cost of giving a prescription is low, the cost for unsustained treatment is high, and this undermines the usefulness of medical therapy. The simple solution is systematic titration through frequent contact between the prescribing physician and the parents in the first few weeks of pharmacotherapy. Subsequent ongoing monitoring of adherence in the first year is likely to reduce costs over time.⁴⁷

Achieve optimal dosing

Pharmacotherapy should be applied with a plan in mind to produce evidence that optimal dosing has been achieved, ie, improvement is consistently observed in school and home.⁴⁸

If side effects occur, parents and physician must determine whether they outweigh the benefits. If the benefits outweigh the side effects, then the physician and parents should maintain treatment and manage side effects accordingly. If the side effects outweigh the benefits, the titration process should continue with different dosing or delivery until optimal dosing is achieved or until the physician determines that pharmacotherapy is no longer appropriate.

Though different procedures to measure optimal dosing are available, medication effectiveness can be determined in 7-day-per-dose exposure during a period when the child’s schedule is consistent. A consistent schedule is important, as medicine effects are difficult to determine during loosely defined schedules such as during school vacations or holidays. Involving multiple observers is important as well. Teachers, for example, are rarely consulted during titration⁴⁹ though they are excellent observers and are with the child daily when medication is most effective.

Given the evidence that behavioral intervention enhances drug therapy,⁵⁰ behavioral therapy should be integrated with drug therapy to create an inclusive context for change. Behavioral therapy is delivered in a variety of ways including individual and group parent training, home management consultation, daily school report cards, behavioral coaching, classroom behavior management, and peer interventions. Behavioral intervention enhances stimulant effectiveness⁵¹ to improve compliance, on-task behavior, academic performance, social relationships and family functioning.⁵²

Behavioral therapy is now generally included in health insurance coverage. In addition, many clinics now offer shared medical appointments that combine close monitoring of drug therapy with behavioral coaching to small groups of parents in order to manage symptoms of ADHD at a minimal cost.

Measure outcomes

Measuring outcomes of ADHD treatment over time improves care. The primary care physician may use electronic medical record data management to track a patient’s progress related to ADHD features. The Clinical Global Improvement scale is a 7-point assessment that is easily done by parents and the physician at well visits and is ubiquitous in ADHD clinical trials.⁵³ Change over time indicates when to suggest changes in treatment.

Finally, clinicians can demonstrate that appropriate, comprehensive care does not simply relieve ADHD symptoms, but also promotes quality of life. Healthcare providers can guide parents to improve existing abilities in children rather than leave parents with the notion that something is wrong with their child.

For example, research suggests that some patients with ADHD show enhanced creativity^54,55; cognitive profiles with abilities in logical thinking, reasoning, and common sense⁵⁶; and the capacity for intense focus in areas of interest.⁵⁷ Some authors have even speculated that historical figures such as Thomas Edison and Albert Einstein would have been diagnosed with ADHD by today’s standards.⁵⁸

MEETING THE DEMANDS OF AFFORDABLE CARE

Many children and youth diagnosed with ADHD still receive no or insufficient pharmacotherapy and behavioral therapy. More than one-third of children reported by their parents as not receiving treatment were also reported to have moderate or severe ADHD.^59,60

At the same time, though more children today are being prescribed pharmacotherapy when ADHD is diagnosed, physician involvement is often limited during titration,⁷ and treatment usually consists of reducing symptoms without increasing adaptive behaviors with behavioral therapy.⁴⁵ In addition, even though ADHD symptoms initially improve with pharmacotherapy, improvement is not sustained because of poor adherence.

The healthcare costs of ADHD are high because impairment extends beyond the patient to disrupt family life and even the workplace, as parents take time off to manage children. Because of uncertain costs of quality treatment, the best-practice treatment option for ADHD—ie, combined behavioral therapy and medicine—is increasingly accessible but still not as widely accessible as medication treatment. The value of care improves slowly while the number of patients continues to increase. However, caregivers have the opportunity to add value to the treatment of ADHD.

When we improve medication management, improve adherence to treatment, combine behavioral therapy and pharmacotherapy, consistently measure outcomes, and recognize positive traits of ADHD in our patients, we may turn the demands of affordable care into a breakthrough for many who live with the condition.

Acknowledgment: The authors wish to thank Ralph D’Alessio, BA, for his services in reference review and for his conscientious participation in the Cleveland Clinic Medication Monitoring Clinic, ADHD Center for Evaluation and Treatment.

Pharmacotherapy and behavioral therapy are currently used with success in treating attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. Ongoing changes in healthcare require physicians to improve the quality of care, reduce costs of treatment, and manage their patients’ health, not just their illnesses. Behavioral and pharmacologic studies provide us with an opportunity to maximize treatment of ADHD and adapt it to the needs of individuals.

This article identifies common problems in treating ADHD, discusses limits of care in pharmacotherapy and behavioral intervention, and offers practical recommendations for treating ADHD in the changing world of healthcare.

A CHANGING MEDICAL CLIMATE

The Affordable Care Act of 2010 sought to transform medical care in the United States from procedures to performance, from acute episodes of illness to integrated care across the lifespan, and from inefficient care to efficient and affordable care with measurable outcomes. At the time of this writing, nobody knows whether the Affordable Care Act will survive, but these are still good goals. Because ADHD is the most common behavioral disorder of childhood, value-based care is essential.¹

ADHD ON THE RISE—WHY?

The prevalence of ADHD increased 42% from 2003 to 2011,² with increases in nearly all demographic groups in the United States regardless of race, sex, and socioeconomic status. More than 1 in 10 school-age children (11%) in the United States now meet the criteria for the diagnosis of ADHD; among adolescents, 1 in 5 high school boys and 1 in 11 high school girls meet the criteria.² 

Rates vary among states, from a low of 4.2% for children ages 4 to 17 in Nevada to a high of 14.6% in Arkansas.³ Worldwide estimates of ADHD prevalence range from 2.2% to 17.8%,⁴ with the most recent meta-analysis for North America and Europe indicating a 7.2% worldwide prevalence in people age 18  and younger.⁵

Such data have sparked criticism, with some saying that ADHD is overdiagnosed, others saying it is underdiagnosed, and most agreeing that it is misdiagnosed.

Changing definitions of ADHD may have had a small effect on the increase in prevalence,⁶ but the change is more likely a result of heightened awareness and recognition of symptoms. Even so, guidelines for diagnosing ADHD are still not rigorously applied, contributing to misdiagnosis. For example, in a study of 50 pediatric practices, only half of clinicians said they followed diagnostic guidelines to determine symptom criteria from at least 2 sources and across 2 settings, yet nearly all (93%) reported immediately prescribing medications for treatment.⁷

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,⁸ requires evidence of a persistent pattern of inattention or hyperactivity/impulsivity, or both, with a severity that interferes with developmental functioning in 2 or more settings; was present before age 12; and cannot be accounted for by another behavioral health disorder such as depression, anxiety, or trauma. The diagnosis should document the presence of at least 6 of 9 symptoms of inattention (or 5 symptoms for teens age 17 or older), or at least 6 of 9 symptoms of hyperactive/impulsive behavior (5 symptoms for teens age 17 and older). Symptoms are best documented when reported by at least 2 observers.

COSTS OF ADHD

ADHD is expensive to society. National yearly healthcare costs have ranged from $143 billion to $266 billion,⁹ with over half this amount assumed directly by families.¹⁰ Even in previous decades when prevalence rates hovered around 5%, the cost of workday loss in the United States was high for adult patients and for parents of young children with ADHD needing to take time off from work for doctors’ visits.¹¹ Projections across 10 countries indicated that adults with ADHD lost more workdays than did workers without ADHD.¹²

There is also a trend toward visits that are more expensive. Between 2000 and 2010, the number of visits for ADHD to psychiatrists rose from 24% to 36%, while the number of less-costly visits to pediatricians decreased from 54% to 47%.¹³

Thus, over the past 15 years, symptoms of ADHD have become more readily recognized, prevalence rates in the population have increased significantly, and associated costs have increased dramatically, with costs extending beyond individual impairment to a loss of productivity at the workplace. And treatment, typically with drugs, has been used without sufficient application of current diagnostic criteria. What impact does this have on the practicing physician?

DRUG TREATMENT: GOLD STANDARD OR NATIONAL DISASTER?

Stimulants are considered the standard of medical care for the symptoms of ADHD, according to the 2011 practice guidelines of the American Academy of Pediatrics.¹⁴ They are efficacious and cost-effective when optimal dosing is achieved, since the patient usually manages treatment independently, requiring minimal physician input in the months and years after successful titration.

For these reasons, the use of stimulants to treat ADHD has increased dramatically in the last decade. According to the National Survey of Children’s Health, as a result of an increase in parent-reported ADHD, more US children were receiving medical treatment for the disorder in 2011 than in any previous year reported, and the prevalence of pharmacotherapy in children ages 14 to 17 increased 28% over the 4 years from 2007 to 2011.²

Dr. Keith Conners, an early advocate for recognition of ADHD, has called the staggering increase in the rates of diagnosis and drug treatment a “national disaster of dangerous proportions.”¹⁵ Nevertheless, many children and families have benefited in a cost-effective manner.

Physicians typically rely on 4 strategies to titrate stimulants,¹⁶ presented below in order of increasing complexity.

Prescribe-and-wait

Often, physicians write a prescription and direct the parent to call back or visit the office to relay the child’s response after a specified period, typically 1 week to 1 month.

This method is convenient in a busy practice and is informative to the physician in a general way. The drawback to this method is that it seldom results in optimal treatment. If the parent does not call back, the physician may assume the treatment was successful without being certain.

Dose-to-improvement

In this approach, the physician monitors titration more closely and increases the dose until a positive response is achieved, after which the dose is maintained. This method reduces symptoms but does not ensure optimal treatment, as there still may be room for improvement.

Forced-dose titration

This method is often used in clinical trials. The dose is ramped up until side effects occur and is then reduced until the side effects go away.

This method often results in optimal dosing, as a forced dose yields a greater reduction in symptoms. But it requires close monitoring by the physician, with multiple reports from parents and teachers after each dose increase to determine whether benefit at the higher dose outweighs the side effects and whether side effects can be managed.

Blinded placebo trial

Also often used in research, this method typically requires a research pharmacy to prepare capsules of stimulant medicine in low, moderate, high, and placebo doses.¹⁷ All doses are blinded and given over 4 weeks in a forced-dose titration—a placebo capsule with 3 active medication doses in escalating order, which is typical of outpatient pediatric practice. Placebo capsules are randomly assigned to 1 of the 4 weeks, and behavior is monitored over the 7 days of administration by teachers and parents.

This strategy has benefits similar to those of forced-dose titration, and it further delineates medicine response—both side effects and behavior change—by adding a no-medicine placebo condition. It is a systematic, monitored “experiment” for parents who are wary or distrustful of ADHD pharmacotherapy, and it has notable benefits.¹⁸ It is also useful for teenagers who are reluctant to use medicine to treat symptoms. It arrives at optimal treatment in a timely manner, usually about 4 to 5 weeks.

On the other hand, this approach requires diligence from families, teachers, and caregivers during the initiation phase, and it requires consistent engagement of the physician team.

Some pediatricians designate a caregiver to monitor titration with the parent; with each new weekly dose, the caregiver reports the child’s progress to the physician.

ENSURING ADHERENCE

Essential to effective stimulant treatment for ADHD is not whether the medicine works (it does),¹⁹ but whether the patient continues to use it.

In treatment studies and pharmacy database analyses, rates of inconsistent use or discontinuation of medication (both considered nonadherence) were 13.2% to 64% within the first year,²⁰ and more than 95% of teenagers discontinue pharmacotherapy before age 21.²¹

Clinician engagement at the onset of stimulant titration is instrumental to treatment adherence.^22,23 When pharmacotherapy is loosely monitored during initiation, adherence is highly inconsistent. Some physicians wait as long as 72 days after first prescribing a medication to contact the patient or family,⁷ and most children with ADHD who discontinue their medications do so within the first year.²⁴

FACTORS THAT INHIBIT ADHERENCE

What factors inhibit adherence to successful pharmacotherapy for ADHD?

Treatment nonadherence is often associated with a parent’s perception that the medication is not working.²⁵ Physicians can often overcome this perception by speaking with the parent, conveying that at the start of treatment titrating to the optimal dose takes time, and that it does not mean “something is wrong.” But without physician contact, parents do not have the occasion to discuss side effects and benefits and tend not to voice fears such as whether the medicine will affect the child’s physical development or result in drug abuse later in life.²⁶

At the beginning of treatment, a child may become too focused, alarming the parent. This overfocused effect is often misunderstood and does not always persist. In addition, when a child better manages his or her own behavior, the contrast to previous behavior may look like something is wrong, when instead the child’s behavior is actually normalizing. Medicine-induced anxiety—in the child or, by association, in the parent—may be misunderstood, and subsequently the parent just stops the child’s treatment rather than seek physician guidance.

Nonadherence is also more prevalent with immediate-release than with extended-release formulations.^27,28

Problems can be summarized as follows⁷:

• Systematic physician observation of response to stimulant titration is often missing at the onset of treatment
• “Best dose” is inconsistently achieved
• Patient adherence to treatment is inconsistently monitored.

The long-term consequences of nonadherence to therapy for ADHD have not been sufficiently examined,²⁰ but some groups, especially adolescents, show problematic outcomes when treatment is not applied. For example, in one longitudinal study, substance use disorder was significantly higher in youths with ADHD who were never treated with medicine than in “neurotypical” youths and those with ADHD who were treated pharmacologically.²⁹

Although opinions vary as to the advantages of drug therapy vs behavioral intervention in ADHD, there is evidence that a combined approach is best.^30–33 Pharmacotherapy works inside the skin to reduce symptoms of inattention and overactivity, and behavioral therapy works outside the skin to teach new skills.

Based on outcomes data from the Center for Pediatric Behavioral Health, Cleveland Clinic Children’s.

A report from the US Centers for Disease Control and Prevention in 2016 stated that behavioral therapy should be the first treatment for young children with ADHD (ages 2 to 5), but noted that only 40% to 50% of young children with ADHD receive psychological services.³⁶ At the same time, the use of pharmacotherapy has increased tremendously.

Beginning treatment with behavioral therapy rather than medicine has been found to be more cost-effective over time. For children ages 4 to 5, behavioral therapy is recommended as the first line by the clinical practice guidelines of the American Academy of Pediatrics.¹⁴ Beginning treatment with behavioral intervention has been shown to produce better outcomes overall than beginning with medication and indicates that lower doses may be used compared with pharmacotherapy that is not preceded by behavioral therapy.³⁷ Findings also indicate that starting with behavioral therapy increases the cost-effectiveness of treatment for children with ADHD.³⁸

Behavioral intervention has modest advantages over medicine for non-ADHD symptoms,⁴² as the practice satisfies the adage “pills don’t teach skills.”²⁶ One advantage is that caregivers take an active role in managing child compliance, social interactions, and classroom deportment, as opposed to the relatively passive role of prescribing medicine only. Parents and teachers form collaborative partnerships to increase consistency and extend the reach of change. In the National Institute of Mental Health multimodal treatment study, the only children whose behavior normalized were those who used medicine and whose caregivers gave up negative, harsh, inconsistent, and ineffective discipline⁴³; that is, parents changed their own behavior.

Parent training is important, as parents must often manage their children’s behavior on their own the best they can, with little coaching and assistance. Primary care physicians may often refer parents to established local programs for training, and ongoing coaching can ensure that skills acquired in such training programs continue to be systematically applied.
Pharmacotherapy is focused almost solely on reducing symptoms, but reducing symptoms does not necessarily lead to improved functioning. A multimodal approach helps individuals adapt to demanding settings, achieve personal goals, and contribute to social relationships. Outcomes depend on teaching what to do as well as reducing what not to do. Behavioral therapy⁴⁴ shaped by peers, caregivers, teachers, and other factors can be effectively remediate the difficulties of children with ADHD.

The disadvantages of behavioral therapy are that it is not readily available, adds initial cost to treatment, and requires parents to invest more time at the beginning of intervention. But behavioral therapy reduces costs over time, enhances ADHD pharmacotherapy, often reduces the need for higher dosing, reduces visits to the doctor’s office, maintains behavior improvement and symptom reduction in the long term, and significantly increases quality of care.⁴²

A RECOMMENDED ADHD CARE PATH

How do we increase quality of care, reduce costs, and improve value of care for patients with ADHD? The treatment of ADHD as a chronic condition is collaborative. Several practices may be combined in a quality care path.

Follow up more frequently at the start of drug treatment

Physicians may give more frequent attention to the process of pharmacotherapy at the start of treatment. Pharmacotherapy is typically introduced by the prescribe-and-wait method, which often produces less than optimal dosing, limited treatment adherence, and inconsistent outcomes.^45,46 Though the cost of giving a prescription is low, the cost for unsustained treatment is high, and this undermines the usefulness of medical therapy. The simple solution is systematic titration through frequent contact between the prescribing physician and the parents in the first few weeks of pharmacotherapy. Subsequent ongoing monitoring of adherence in the first year is likely to reduce costs over time.⁴⁷

Achieve optimal dosing

Pharmacotherapy should be applied with a plan in mind to produce evidence that optimal dosing has been achieved, ie, improvement is consistently observed in school and home.⁴⁸

If side effects occur, parents and physician must determine whether they outweigh the benefits. If the benefits outweigh the side effects, then the physician and parents should maintain treatment and manage side effects accordingly. If the side effects outweigh the benefits, the titration process should continue with different dosing or delivery until optimal dosing is achieved or until the physician determines that pharmacotherapy is no longer appropriate.

Though different procedures to measure optimal dosing are available, medication effectiveness can be determined in 7-day-per-dose exposure during a period when the child’s schedule is consistent. A consistent schedule is important, as medicine effects are difficult to determine during loosely defined schedules such as during school vacations or holidays. Involving multiple observers is important as well. Teachers, for example, are rarely consulted during titration⁴⁹ though they are excellent observers and are with the child daily when medication is most effective.

Given the evidence that behavioral intervention enhances drug therapy,⁵⁰ behavioral therapy should be integrated with drug therapy to create an inclusive context for change. Behavioral therapy is delivered in a variety of ways including individual and group parent training, home management consultation, daily school report cards, behavioral coaching, classroom behavior management, and peer interventions. Behavioral intervention enhances stimulant effectiveness⁵¹ to improve compliance, on-task behavior, academic performance, social relationships and family functioning.⁵²

Behavioral therapy is now generally included in health insurance coverage. In addition, many clinics now offer shared medical appointments that combine close monitoring of drug therapy with behavioral coaching to small groups of parents in order to manage symptoms of ADHD at a minimal cost.

Measure outcomes

Measuring outcomes of ADHD treatment over time improves care. The primary care physician may use electronic medical record data management to track a patient’s progress related to ADHD features. The Clinical Global Improvement scale is a 7-point assessment that is easily done by parents and the physician at well visits and is ubiquitous in ADHD clinical trials.⁵³ Change over time indicates when to suggest changes in treatment.

Finally, clinicians can demonstrate that appropriate, comprehensive care does not simply relieve ADHD symptoms, but also promotes quality of life. Healthcare providers can guide parents to improve existing abilities in children rather than leave parents with the notion that something is wrong with their child.

For example, research suggests that some patients with ADHD show enhanced creativity^54,55; cognitive profiles with abilities in logical thinking, reasoning, and common sense⁵⁶; and the capacity for intense focus in areas of interest.⁵⁷ Some authors have even speculated that historical figures such as Thomas Edison and Albert Einstein would have been diagnosed with ADHD by today’s standards.⁵⁸

MEETING THE DEMANDS OF AFFORDABLE CARE

Many children and youth diagnosed with ADHD still receive no or insufficient pharmacotherapy and behavioral therapy. More than one-third of children reported by their parents as not receiving treatment were also reported to have moderate or severe ADHD.^59,60

At the same time, though more children today are being prescribed pharmacotherapy when ADHD is diagnosed, physician involvement is often limited during titration,⁷ and treatment usually consists of reducing symptoms without increasing adaptive behaviors with behavioral therapy.⁴⁵ In addition, even though ADHD symptoms initially improve with pharmacotherapy, improvement is not sustained because of poor adherence.

The healthcare costs of ADHD are high because impairment extends beyond the patient to disrupt family life and even the workplace, as parents take time off to manage children. Because of uncertain costs of quality treatment, the best-practice treatment option for ADHD—ie, combined behavioral therapy and medicine—is increasingly accessible but still not as widely accessible as medication treatment. The value of care improves slowly while the number of patients continues to increase. However, caregivers have the opportunity to add value to the treatment of ADHD.

When we improve medication management, improve adherence to treatment, combine behavioral therapy and pharmacotherapy, consistently measure outcomes, and recognize positive traits of ADHD in our patients, we may turn the demands of affordable care into a breakthrough for many who live with the condition.

Acknowledgment: The authors wish to thank Ralph D’Alessio, BA, for his services in reference review and for his conscientious participation in the Cleveland Clinic Medication Monitoring Clinic, ADHD Center for Evaluation and Treatment.

Pharmacotherapy and behavioral therapy are currently used with success in treating attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. Ongoing changes in healthcare require physicians to improve the quality of care, reduce costs of treatment, and manage their patients’ health, not just their illnesses. Behavioral and pharmacologic studies provide us with an opportunity to maximize treatment of ADHD and adapt it to the needs of individuals.

This article identifies common problems in treating ADHD, discusses limits of care in pharmacotherapy and behavioral intervention, and offers practical recommendations for treating ADHD in the changing world of healthcare.

A CHANGING MEDICAL CLIMATE

The Affordable Care Act of 2010 sought to transform medical care in the United States from procedures to performance, from acute episodes of illness to integrated care across the lifespan, and from inefficient care to efficient and affordable care with measurable outcomes. At the time of this writing, nobody knows whether the Affordable Care Act will survive, but these are still good goals. Because ADHD is the most common behavioral disorder of childhood, value-based care is essential.¹

ADHD ON THE RISE—WHY?

The prevalence of ADHD increased 42% from 2003 to 2011,² with increases in nearly all demographic groups in the United States regardless of race, sex, and socioeconomic status. More than 1 in 10 school-age children (11%) in the United States now meet the criteria for the diagnosis of ADHD; among adolescents, 1 in 5 high school boys and 1 in 11 high school girls meet the criteria.² 

Rates vary among states, from a low of 4.2% for children ages 4 to 17 in Nevada to a high of 14.6% in Arkansas.³ Worldwide estimates of ADHD prevalence range from 2.2% to 17.8%,⁴ with the most recent meta-analysis for North America and Europe indicating a 7.2% worldwide prevalence in people age 18  and younger.⁵

Such data have sparked criticism, with some saying that ADHD is overdiagnosed, others saying it is underdiagnosed, and most agreeing that it is misdiagnosed.

Changing definitions of ADHD may have had a small effect on the increase in prevalence,⁶ but the change is more likely a result of heightened awareness and recognition of symptoms. Even so, guidelines for diagnosing ADHD are still not rigorously applied, contributing to misdiagnosis. For example, in a study of 50 pediatric practices, only half of clinicians said they followed diagnostic guidelines to determine symptom criteria from at least 2 sources and across 2 settings, yet nearly all (93%) reported immediately prescribing medications for treatment.⁷

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,⁸ requires evidence of a persistent pattern of inattention or hyperactivity/impulsivity, or both, with a severity that interferes with developmental functioning in 2 or more settings; was present before age 12; and cannot be accounted for by another behavioral health disorder such as depression, anxiety, or trauma. The diagnosis should document the presence of at least 6 of 9 symptoms of inattention (or 5 symptoms for teens age 17 or older), or at least 6 of 9 symptoms of hyperactive/impulsive behavior (5 symptoms for teens age 17 and older). Symptoms are best documented when reported by at least 2 observers.

COSTS OF ADHD

ADHD is expensive to society. National yearly healthcare costs have ranged from $143 billion to $266 billion,⁹ with over half this amount assumed directly by families.¹⁰ Even in previous decades when prevalence rates hovered around 5%, the cost of workday loss in the United States was high for adult patients and for parents of young children with ADHD needing to take time off from work for doctors’ visits.¹¹ Projections across 10 countries indicated that adults with ADHD lost more workdays than did workers without ADHD.¹²

There is also a trend toward visits that are more expensive. Between 2000 and 2010, the number of visits for ADHD to psychiatrists rose from 24% to 36%, while the number of less-costly visits to pediatricians decreased from 54% to 47%.¹³

Thus, over the past 15 years, symptoms of ADHD have become more readily recognized, prevalence rates in the population have increased significantly, and associated costs have increased dramatically, with costs extending beyond individual impairment to a loss of productivity at the workplace. And treatment, typically with drugs, has been used without sufficient application of current diagnostic criteria. What impact does this have on the practicing physician?

DRUG TREATMENT: GOLD STANDARD OR NATIONAL DISASTER?

Stimulants are considered the standard of medical care for the symptoms of ADHD, according to the 2011 practice guidelines of the American Academy of Pediatrics.¹⁴ They are efficacious and cost-effective when optimal dosing is achieved, since the patient usually manages treatment independently, requiring minimal physician input in the months and years after successful titration.

For these reasons, the use of stimulants to treat ADHD has increased dramatically in the last decade. According to the National Survey of Children’s Health, as a result of an increase in parent-reported ADHD, more US children were receiving medical treatment for the disorder in 2011 than in any previous year reported, and the prevalence of pharmacotherapy in children ages 14 to 17 increased 28% over the 4 years from 2007 to 2011.²

Dr. Keith Conners, an early advocate for recognition of ADHD, has called the staggering increase in the rates of diagnosis and drug treatment a “national disaster of dangerous proportions.”¹⁵ Nevertheless, many children and families have benefited in a cost-effective manner.

Physicians typically rely on 4 strategies to titrate stimulants,¹⁶ presented below in order of increasing complexity.

Prescribe-and-wait

Often, physicians write a prescription and direct the parent to call back or visit the office to relay the child’s response after a specified period, typically 1 week to 1 month.

This method is convenient in a busy practice and is informative to the physician in a general way. The drawback to this method is that it seldom results in optimal treatment. If the parent does not call back, the physician may assume the treatment was successful without being certain.

Dose-to-improvement

In this approach, the physician monitors titration more closely and increases the dose until a positive response is achieved, after which the dose is maintained. This method reduces symptoms but does not ensure optimal treatment, as there still may be room for improvement.

Forced-dose titration

This method is often used in clinical trials. The dose is ramped up until side effects occur and is then reduced until the side effects go away.

This method often results in optimal dosing, as a forced dose yields a greater reduction in symptoms. But it requires close monitoring by the physician, with multiple reports from parents and teachers after each dose increase to determine whether benefit at the higher dose outweighs the side effects and whether side effects can be managed.

Blinded placebo trial

Also often used in research, this method typically requires a research pharmacy to prepare capsules of stimulant medicine in low, moderate, high, and placebo doses.¹⁷ All doses are blinded and given over 4 weeks in a forced-dose titration—a placebo capsule with 3 active medication doses in escalating order, which is typical of outpatient pediatric practice. Placebo capsules are randomly assigned to 1 of the 4 weeks, and behavior is monitored over the 7 days of administration by teachers and parents.

This strategy has benefits similar to those of forced-dose titration, and it further delineates medicine response—both side effects and behavior change—by adding a no-medicine placebo condition. It is a systematic, monitored “experiment” for parents who are wary or distrustful of ADHD pharmacotherapy, and it has notable benefits.¹⁸ It is also useful for teenagers who are reluctant to use medicine to treat symptoms. It arrives at optimal treatment in a timely manner, usually about 4 to 5 weeks.

On the other hand, this approach requires diligence from families, teachers, and caregivers during the initiation phase, and it requires consistent engagement of the physician team.

Some pediatricians designate a caregiver to monitor titration with the parent; with each new weekly dose, the caregiver reports the child’s progress to the physician.

ENSURING ADHERENCE

Essential to effective stimulant treatment for ADHD is not whether the medicine works (it does),¹⁹ but whether the patient continues to use it.

In treatment studies and pharmacy database analyses, rates of inconsistent use or discontinuation of medication (both considered nonadherence) were 13.2% to 64% within the first year,²⁰ and more than 95% of teenagers discontinue pharmacotherapy before age 21.²¹

Clinician engagement at the onset of stimulant titration is instrumental to treatment adherence.^22,23 When pharmacotherapy is loosely monitored during initiation, adherence is highly inconsistent. Some physicians wait as long as 72 days after first prescribing a medication to contact the patient or family,⁷ and most children with ADHD who discontinue their medications do so within the first year.²⁴

FACTORS THAT INHIBIT ADHERENCE

What factors inhibit adherence to successful pharmacotherapy for ADHD?

Treatment nonadherence is often associated with a parent’s perception that the medication is not working.²⁵ Physicians can often overcome this perception by speaking with the parent, conveying that at the start of treatment titrating to the optimal dose takes time, and that it does not mean “something is wrong.” But without physician contact, parents do not have the occasion to discuss side effects and benefits and tend not to voice fears such as whether the medicine will affect the child’s physical development or result in drug abuse later in life.²⁶

At the beginning of treatment, a child may become too focused, alarming the parent. This overfocused effect is often misunderstood and does not always persist. In addition, when a child better manages his or her own behavior, the contrast to previous behavior may look like something is wrong, when instead the child’s behavior is actually normalizing. Medicine-induced anxiety—in the child or, by association, in the parent—may be misunderstood, and subsequently the parent just stops the child’s treatment rather than seek physician guidance.

Nonadherence is also more prevalent with immediate-release than with extended-release formulations.^27,28

Problems can be summarized as follows⁷:

• Systematic physician observation of response to stimulant titration is often missing at the onset of treatment
• “Best dose” is inconsistently achieved
• Patient adherence to treatment is inconsistently monitored.

The long-term consequences of nonadherence to therapy for ADHD have not been sufficiently examined,²⁰ but some groups, especially adolescents, show problematic outcomes when treatment is not applied. For example, in one longitudinal study, substance use disorder was significantly higher in youths with ADHD who were never treated with medicine than in “neurotypical” youths and those with ADHD who were treated pharmacologically.²⁹

Although opinions vary as to the advantages of drug therapy vs behavioral intervention in ADHD, there is evidence that a combined approach is best.^30–33 Pharmacotherapy works inside the skin to reduce symptoms of inattention and overactivity, and behavioral therapy works outside the skin to teach new skills.

Based on outcomes data from the Center for Pediatric Behavioral Health, Cleveland Clinic Children’s.

A report from the US Centers for Disease Control and Prevention in 2016 stated that behavioral therapy should be the first treatment for young children with ADHD (ages 2 to 5), but noted that only 40% to 50% of young children with ADHD receive psychological services.³⁶ At the same time, the use of pharmacotherapy has increased tremendously.

Beginning treatment with behavioral therapy rather than medicine has been found to be more cost-effective over time. For children ages 4 to 5, behavioral therapy is recommended as the first line by the clinical practice guidelines of the American Academy of Pediatrics.¹⁴ Beginning treatment with behavioral intervention has been shown to produce better outcomes overall than beginning with medication and indicates that lower doses may be used compared with pharmacotherapy that is not preceded by behavioral therapy.³⁷ Findings also indicate that starting with behavioral therapy increases the cost-effectiveness of treatment for children with ADHD.³⁸

Behavioral intervention has modest advantages over medicine for non-ADHD symptoms,⁴² as the practice satisfies the adage “pills don’t teach skills.”²⁶ One advantage is that caregivers take an active role in managing child compliance, social interactions, and classroom deportment, as opposed to the relatively passive role of prescribing medicine only. Parents and teachers form collaborative partnerships to increase consistency and extend the reach of change. In the National Institute of Mental Health multimodal treatment study, the only children whose behavior normalized were those who used medicine and whose caregivers gave up negative, harsh, inconsistent, and ineffective discipline⁴³; that is, parents changed their own behavior.

Parent training is important, as parents must often manage their children’s behavior on their own the best they can, with little coaching and assistance. Primary care physicians may often refer parents to established local programs for training, and ongoing coaching can ensure that skills acquired in such training programs continue to be systematically applied.
Pharmacotherapy is focused almost solely on reducing symptoms, but reducing symptoms does not necessarily lead to improved functioning. A multimodal approach helps individuals adapt to demanding settings, achieve personal goals, and contribute to social relationships. Outcomes depend on teaching what to do as well as reducing what not to do. Behavioral therapy⁴⁴ shaped by peers, caregivers, teachers, and other factors can be effectively remediate the difficulties of children with ADHD.

The disadvantages of behavioral therapy are that it is not readily available, adds initial cost to treatment, and requires parents to invest more time at the beginning of intervention. But behavioral therapy reduces costs over time, enhances ADHD pharmacotherapy, often reduces the need for higher dosing, reduces visits to the doctor’s office, maintains behavior improvement and symptom reduction in the long term, and significantly increases quality of care.⁴²

A RECOMMENDED ADHD CARE PATH

How do we increase quality of care, reduce costs, and improve value of care for patients with ADHD? The treatment of ADHD as a chronic condition is collaborative. Several practices may be combined in a quality care path.

Follow up more frequently at the start of drug treatment

Physicians may give more frequent attention to the process of pharmacotherapy at the start of treatment. Pharmacotherapy is typically introduced by the prescribe-and-wait method, which often produces less than optimal dosing, limited treatment adherence, and inconsistent outcomes.^45,46 Though the cost of giving a prescription is low, the cost for unsustained treatment is high, and this undermines the usefulness of medical therapy. The simple solution is systematic titration through frequent contact between the prescribing physician and the parents in the first few weeks of pharmacotherapy. Subsequent ongoing monitoring of adherence in the first year is likely to reduce costs over time.⁴⁷

Achieve optimal dosing

Pharmacotherapy should be applied with a plan in mind to produce evidence that optimal dosing has been achieved, ie, improvement is consistently observed in school and home.⁴⁸

If side effects occur, parents and physician must determine whether they outweigh the benefits. If the benefits outweigh the side effects, then the physician and parents should maintain treatment and manage side effects accordingly. If the side effects outweigh the benefits, the titration process should continue with different dosing or delivery until optimal dosing is achieved or until the physician determines that pharmacotherapy is no longer appropriate.

Though different procedures to measure optimal dosing are available, medication effectiveness can be determined in 7-day-per-dose exposure during a period when the child’s schedule is consistent. A consistent schedule is important, as medicine effects are difficult to determine during loosely defined schedules such as during school vacations or holidays. Involving multiple observers is important as well. Teachers, for example, are rarely consulted during titration⁴⁹ though they are excellent observers and are with the child daily when medication is most effective.

Given the evidence that behavioral intervention enhances drug therapy,⁵⁰ behavioral therapy should be integrated with drug therapy to create an inclusive context for change. Behavioral therapy is delivered in a variety of ways including individual and group parent training, home management consultation, daily school report cards, behavioral coaching, classroom behavior management, and peer interventions. Behavioral intervention enhances stimulant effectiveness⁵¹ to improve compliance, on-task behavior, academic performance, social relationships and family functioning.⁵²

Behavioral therapy is now generally included in health insurance coverage. In addition, many clinics now offer shared medical appointments that combine close monitoring of drug therapy with behavioral coaching to small groups of parents in order to manage symptoms of ADHD at a minimal cost.

Measure outcomes

Measuring outcomes of ADHD treatment over time improves care. The primary care physician may use electronic medical record data management to track a patient’s progress related to ADHD features. The Clinical Global Improvement scale is a 7-point assessment that is easily done by parents and the physician at well visits and is ubiquitous in ADHD clinical trials.⁵³ Change over time indicates when to suggest changes in treatment.

Finally, clinicians can demonstrate that appropriate, comprehensive care does not simply relieve ADHD symptoms, but also promotes quality of life. Healthcare providers can guide parents to improve existing abilities in children rather than leave parents with the notion that something is wrong with their child.

For example, research suggests that some patients with ADHD show enhanced creativity^54,55; cognitive profiles with abilities in logical thinking, reasoning, and common sense⁵⁶; and the capacity for intense focus in areas of interest.⁵⁷ Some authors have even speculated that historical figures such as Thomas Edison and Albert Einstein would have been diagnosed with ADHD by today’s standards.⁵⁸

MEETING THE DEMANDS OF AFFORDABLE CARE

Many children and youth diagnosed with ADHD still receive no or insufficient pharmacotherapy and behavioral therapy. More than one-third of children reported by their parents as not receiving treatment were also reported to have moderate or severe ADHD.^59,60

At the same time, though more children today are being prescribed pharmacotherapy when ADHD is diagnosed, physician involvement is often limited during titration,⁷ and treatment usually consists of reducing symptoms without increasing adaptive behaviors with behavioral therapy.⁴⁵ In addition, even though ADHD symptoms initially improve with pharmacotherapy, improvement is not sustained because of poor adherence.

The healthcare costs of ADHD are high because impairment extends beyond the patient to disrupt family life and even the workplace, as parents take time off to manage children. Because of uncertain costs of quality treatment, the best-practice treatment option for ADHD—ie, combined behavioral therapy and medicine—is increasingly accessible but still not as widely accessible as medication treatment. The value of care improves slowly while the number of patients continues to increase. However, caregivers have the opportunity to add value to the treatment of ADHD.

When we improve medication management, improve adherence to treatment, combine behavioral therapy and pharmacotherapy, consistently measure outcomes, and recognize positive traits of ADHD in our patients, we may turn the demands of affordable care into a breakthrough for many who live with the condition.

Acknowledgment: The authors wish to thank Ralph D’Alessio, BA, for his services in reference review and for his conscientious participation in the Cleveland Clinic Medication Monitoring Clinic, ADHD Center for Evaluation and Treatment.

Editor’s note: This Medical Grand Rounds was presented as the 14th Annual Lawrence “Chris” Crain Memorial Lecture, a series that has been dedicated to discussing kidney disease, hypertension, and health care disparities in the African American community. In 1997, Dr. Crain became the first African American chief medical resident at Cleveland Clinic, and was a nephrology fellow in 1998–1999. Dr. Nally was his teacher and mentor.

African Americans have a greater burden of chronic kidney disease than whites. They are more than 3 times as likely as whites to develop end-stage renal disease, even after adjusting for age, disease stage, smoking, medications, and comorbidities. Why this is so has been the focus of much speculation and research.

This article reviews recent advances in the understanding of the progression of chronic kidney disease, with particular scrutiny of the disease in African Americans. Breakthroughs in genetics that help explain the greater disease burden in African Americans are also discussed, as well as implications for organ transplant screening.

ADVANCING UNDERSTANDING OF CHRONIC KIDNEY DISEASE

In the 1990s, dialysis rolls grew by 8% to 10% annually. Unfortunately, many patients first met with a nephrologist on the eve of their first dialysis treatment; there was not yet an adequate way to recognize the disease earlier and slow its progression. And disease definitions were not yet standardized, which led to inadequate metrics and hampered the ability to move disease management forward.

Standardizing definitions

The situation improved in 2002, when the National Kidney Foundation published clinical practice guidelines for chronic kidney disease that included disease definitions and staging.¹ Chronic kidney disease was defined as a structural or functional abnormality of the kidney lasting at least 3 months, as manifested by either of the following:

• Kidney damage, with or without decreased glomerular filtration rate (GFR), as defined by pathologic abnormalities or markers of kidney damage in the blood, urine, or on imaging tests

• 

  GFR less than 60 mL/min/1.73 m², with or without kidney damage.

A subsequent major advance was the recognition that not only GFR but also albuminuria was important for staging of chronic kidney disease (Figure 1).²

Developing large databases

Surveillance and monitoring of chronic kidney disease have generated large databases that enable researchers to detect trends in disease progression.

US Renal Data System. The US Renal Data System has collected and reported on data for more than 20 years from the National Health and Nutrition Examination Survey and the Centers for Medicare and Medicaid Services about chronic and end-stage kidney disease in the United States.

Cleveland Clinic database. Cleveland Clinic has developed a validated chronic kidney disease registry based on its electronic health record.³ The data include demographics (age, sex, ethnic group), comorbidities, medications, and complete laboratory data.⁴

Alberta Kidney Disease Network. This Canadian research consortium links large laboratory and demographic databases to facilitate defining patient populations, such as those with kidney disease and other comorbidities.

Kaiser Permanente Renal Registry. Kaiser Permanente of Northern California insures more than one-third of adults in the San Francisco Bay Area. The renal registry includes all adults whose kidney function is known. Data on age, sex, and racial or ethnic group are available from the health-plan databases.

DEATHS FROM KIDNEY DISEASE

The mortality rate in patients with end-stage renal disease who are on dialysis has steadily fallen over the past 20 years, from an annual rate of about 25% in 1996 to 17% in 2014, suggesting that care improved during that time. Patients with transplants have a much lower mortality rate: less than 5% annually.⁵ But these data also highlight the persistent risk faced by patients with chronic kidney disease; even those with transplants have death rates comparable to those of patients with cancer, diabetes, or heart failure.

Death rates correlate with GFR

After the publication of definitions and staging by the National Kidney Foundation in 2002, Go et al⁶ studied more than 1 million patients with chronic kidney disease from the Kaiser Permanente Renal Registry and found that the rates of cardiovascular events and death from any cause increased with decreasing estimated GFR. These findings were confirmed in a later meta-analysis, which also found that an elevated urinary albumin-to-creatinine ratio (> 1.1 mg/mmol) is an independent predictor of all-cause mortality and cardiovascular mortality.⁷

Keith et al⁸ followed nearly 28,000 patients with chronic kidney disease (with an estimated GFR of less than 90 mL/min/1.73 m²) over 5 years. Patients with stage 3 disease (moderate disease, GFR = 30–59 mL/min/1.73 m²) were 20 times more likely to die than to progress to end-stage renal disease (24.3% vs 1.2%). Even those with stage 4 disease (severe disease, GFR = 15–29 mL/min/1.73 m²) were more than twice as likely to die as to progress to dialysis (45.7% vs 19.9%).

Similar observations were made by Thompson et al¹⁰ based on the Alberta Kidney Disease Network database. They tracked cardiovascular causes of death and found that regardless of estimated GFR, cardiovascular deaths were most often attributed to ischemic heart disease (about 55%). Other trends were also apparent: as the GFR fell, the incidence of stroke decreased, and heart failure and valvular heart disease increased.

AFRICAN AMERICANS WITH KIDNEY DISEASE: A DISTINCT GROUP

African Americans constitute about 12% of the US population but account for:

• 31% of end-stage renal disease
• 34% of the kidney transplant waiting list
• 28% of kidney transplants in 2015 (12% of living donor transplants, 35% of deceased donor transplants).

In addition, African Americans with chronic kidney disease tend to be:

• Younger and have more advanced kidney disease than whites¹¹
• Much more likely than whites to have diabetes, and somewhat more likely to have hypertension

• 

  Adapted from Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Nally JV Jr. Cause-specific deaths in non-dialysis-dependent CKD. J Am Soc Nephrol 2015; 26:2512–2520.

  More likely than whites to die of cardiovascular disease (37.4% vs 34.2%) (Figure 2).⁹

Overall, the prevalence of chronic kidney disease is slightly higher in African Americans than in whites. Interestingly, African Americans are slightly less likely than whites to have low estimated GFR values (6.2% vs 7.6% incidence of < 60 mL/min/1.73 m²) but are about 50% more likely to have proteinuria (12.3% vs 8.4% incidence of urine albumin-to-creatinine ratio ≥ 30 mg/g).

More likely to be on dialysis, but less likely to die

Although African Americans have only a slightly higher prevalence of chronic kidney disease (about 15% increased prevalence) than whites,¹² they are 3 times more likely to be on dialysis.

Nevertheless, for unknown reasons, African American adults on dialysis have about a 26% lower all-cause mortality rate than whites.⁵ One proposed explanation for this survival advantage has been that the mortality rate in African Americans with chronic kidney disease before entering dialysis is higher than in whites, leading to a “healthier population” on dialysis.¹³ However, this theory is based on a small study from more than a decade ago and has not been borne out by subsequent investigation.

African Americans with chronic kidney disease: Death rates not increased

African Americans over age 65 with chronic kidney disease have all-cause mortality rates similar to those of whites: about 11% annually. Breaking it down by disease severity, death rates in stage 3 disease are about 10% and jump to more than 15% in higher stages in both African Americans and whites.⁵

However, African Americans with chronic kidney disease have more heart disease and much more end-stage renal disease than whites.

Disease advances faster despite care

The incidence of end-stage renal disease is consistently more than 3 times higher in African Americans than in whites in the United States.^5,14

Multiple investigations have tried to determine why African Americans are disproportionately affected by progression of chronic kidney disease to end-stage renal disease. We recently examined this question in our Cleveland Clinic registry data. Even after adjusting for 17 variables (including demographics, comorbidities, insurance, medications, smoking, and chronic kidney disease stage), African Americans with chronic kidney disease were found to have an increased risk of progressing to end-stage renal disease compared with whites (subhazard ratio 1.38, 95% confidence interval 1.19–1.60).

We examined care measures from the Cleveland Clinic database. In terms of the number of laboratory tests ordered, clinic visits, and nephrology referrals, African Americans had at least as much care as whites, if not more. Similarly, African Americans’ access to renoprotective medicines (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, statins, beta-blockers) was the same as or more than for whites.

Although the frequently attributed reasons surrounding compliance and socioeconomic issues are worthy of examination, they do not appear to completely explain the differences in incidence and outcomes. This dichotomy of a marginally increased prevalence of chronic kidney disease in African Americans with mortality rates similar to those of whites, yet with a 3 times higher incidence of end-stage renal disease in African Americans, suggests a faster progression of the disease in African Americans, which may be genetically based.

In 2010, two variant alleles of the APOL1 gene on chromosome 22 were found to be associated with nondiabetic kidney disease.¹⁵ Three nephropathies are associated with being homozygous for these alleles:

• Focal segmental glomerulosclerosis, the leading cause of nephrotic syndrome in African Americans
• Hypertension-associated kidney disease with scarring of glomeruli in vessels, the primary cause of end-stage renal disease in African Americans
• Human immunodeficiency virus (HIV)- associated nephropathy, usually a focal segmental glomerulosclerosis type of lesion.

The first two conditions are about 3 to 5 times more prevalent in African Americans than in whites, and HIV-associated nephropathy is about 20 to 30 times more common. 

African sleeping sickness and chronic kidney disease

Retrospective analysis of biologic samples from trials of kidney disease in African Americans has revealed interesting results.

From Parsa A, Kao WH, Xie D, et al; AASK Study Investigators; CRIC Study Investigators. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013; 369:2183–2196. Reprinted with permission from Massachusetts Medical Society.

The Chronic Renal Insufficiency Cohort (CRIC) observation study¹⁸ enrolled patients with an estimated GFR of 20 to 70 mL/min/1.73 m², with a preference for African Americans and patients with diabetes. Nearly 3,000 participants had adequate samples for DNA testing. They found that African Americans with the double variant allele had worse outcomes, whether or not they had diabetes, compared with whites and African Americans without the homozygous gene variant.

Mechanism not well understood

The mechanism of renal injury is not well understood. Apolipoprotein L1, the protein coded for by APOL1, is a component of high-density lipoprotein. It is found in a different distribution pattern in people with normal kidneys vs those with nondiabetic kidney disease, especially in the arteries, arterioles, and podocytes.^19,20 It can be detected in blood plasma, but levels do not correlate with kidney disease.²¹ Not all patients with the high-risk variant develop chronic kidney disease; a “second hit” such as infection with HIV may be required.

Investigators have recently developed knockout mouse models of APOL1-associated kidney diseases that are helping to elucidate mechanisms.^22,23

EFFECT OF GENOTYPE ON KIDNEY TRANSPLANTS IN AFRICAN AMERICANS

African Americans receive about 30% of kidney transplants in the United States and represent about 15% to 20% of all donors.

Lee et al²⁴ reviewed 119 African American recipients of kidney transplants, about half of whom were homozygous for an APOL1 variant. After 5 years, no differences were found in allograft survival between recipients with 0, 1, or 2 risk alleles.

However, looking at the issue from the other side, Reeves-Daniel et al²⁵ studied the fate of more than 100 kidneys that were transplanted from African American donors, 16% of whom had the high-risk, homozygous genotype. In this case, graft failure was much likelier to occur with the high-risk donor kidneys (hazard ratio 3.84, P = .008). Similar outcomes were shown in a study of 2 centers²⁶ involving 675 transplants from deceased donors, 15% of which involved the high-risk genotype. The hazard ratio for graft failure was found to be 2.26 (P = .001) with high-risk donor kidneys.

These studies, which examined data from about 5 years after transplant, found that kidney failure does not tend to occur immediately in all cases, but gradually over time. Most high-risk kidneys were not lost within the 5 years of the studies.

The fact that the high-risk kidneys do not all fail immediately also suggests that a second hit is required for failure. Culprits postulated include a bacterial or viral infection (eg, BK virus, cytomegalovirus), ischemia or reperfusion injury, drug toxicity, and immune-mediated allograft injury (ie, rejection). 

Genetic testing for APOL1 risk variants is on the horizon for kidney transplant. But at this point, providing guidance for patients can be tricky. Two case studies^27,28 and epidemiologic data suggest that donors homozygous for an APOL1 variant and those with a family history of end-stage kidney disease are at increased risk of chronic kidney disease. Even so, most recipients even of these high-risk organs have good outcomes. If an African American patient needs a kidney and his or her sibling offers one, it is difficult to advise against it when the evidence is weak for immediate risk and when other options may not be readily available. Further investigation is clearly needed into whether APOL1 variants and other biomarkers can predict an organ’s success as a transplant.

The National Institutes of Health are currently funding prospective longitudinal studies with the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) to determine the impact of APOL1 genetic factors on transplant recipients as well as on living donors. Possible second hits will also be studied, as will other markers of renal dysfunction or disease in donors. Researchers are actively investigating these important questions.

KEEPING SCIENCE RELEVANT

In a recent commentary related to the murine knockout model of APOL1-associated kidney disease, O’Toole et al offered insightful observations regarding the potential clinical impact of these new genetic discoveries.²³

As we study the genetics of kidney disease in African American patients, we should keep in mind 3 critical questions of clinical importance:

Will findings identify better treatments for chronic kidney disease? The AASK trial found that knowing the genetics did not affect outcomes of routine therapy. However, basic science investigations are currently underway targeting APOL1 variants which might reduce the increased kidney disease risk among people of African descent.

Should patients be genotyped for APOL1 risk variants? For patients with chronic kidney disease, it does not seem useful at this time. But for renal transplant donors, the answer is probably yes.

How does this discovery help us to understand our patients better? The implications are enormous for combatting the assumptions that rapid chronic kidney disease progression reflects poor patient compliance or other socioeconomic factors. We now understand that genetics, at least in part, drives renal disease outcomes in African American patients.

Editor’s note: This Medical Grand Rounds was presented as the 14th Annual Lawrence “Chris” Crain Memorial Lecture, a series that has been dedicated to discussing kidney disease, hypertension, and health care disparities in the African American community. In 1997, Dr. Crain became the first African American chief medical resident at Cleveland Clinic, and was a nephrology fellow in 1998–1999. Dr. Nally was his teacher and mentor.

African Americans have a greater burden of chronic kidney disease than whites. They are more than 3 times as likely as whites to develop end-stage renal disease, even after adjusting for age, disease stage, smoking, medications, and comorbidities. Why this is so has been the focus of much speculation and research.

This article reviews recent advances in the understanding of the progression of chronic kidney disease, with particular scrutiny of the disease in African Americans. Breakthroughs in genetics that help explain the greater disease burden in African Americans are also discussed, as well as implications for organ transplant screening.

ADVANCING UNDERSTANDING OF CHRONIC KIDNEY DISEASE

In the 1990s, dialysis rolls grew by 8% to 10% annually. Unfortunately, many patients first met with a nephrologist on the eve of their first dialysis treatment; there was not yet an adequate way to recognize the disease earlier and slow its progression. And disease definitions were not yet standardized, which led to inadequate metrics and hampered the ability to move disease management forward.

Standardizing definitions

The situation improved in 2002, when the National Kidney Foundation published clinical practice guidelines for chronic kidney disease that included disease definitions and staging.¹ Chronic kidney disease was defined as a structural or functional abnormality of the kidney lasting at least 3 months, as manifested by either of the following:

• Kidney damage, with or without decreased glomerular filtration rate (GFR), as defined by pathologic abnormalities or markers of kidney damage in the blood, urine, or on imaging tests

• 

  GFR less than 60 mL/min/1.73 m², with or without kidney damage.

A subsequent major advance was the recognition that not only GFR but also albuminuria was important for staging of chronic kidney disease (Figure 1).²

Developing large databases

Surveillance and monitoring of chronic kidney disease have generated large databases that enable researchers to detect trends in disease progression.

US Renal Data System. The US Renal Data System has collected and reported on data for more than 20 years from the National Health and Nutrition Examination Survey and the Centers for Medicare and Medicaid Services about chronic and end-stage kidney disease in the United States.

Cleveland Clinic database. Cleveland Clinic has developed a validated chronic kidney disease registry based on its electronic health record.³ The data include demographics (age, sex, ethnic group), comorbidities, medications, and complete laboratory data.⁴

Alberta Kidney Disease Network. This Canadian research consortium links large laboratory and demographic databases to facilitate defining patient populations, such as those with kidney disease and other comorbidities.

Kaiser Permanente Renal Registry. Kaiser Permanente of Northern California insures more than one-third of adults in the San Francisco Bay Area. The renal registry includes all adults whose kidney function is known. Data on age, sex, and racial or ethnic group are available from the health-plan databases.

DEATHS FROM KIDNEY DISEASE

The mortality rate in patients with end-stage renal disease who are on dialysis has steadily fallen over the past 20 years, from an annual rate of about 25% in 1996 to 17% in 2014, suggesting that care improved during that time. Patients with transplants have a much lower mortality rate: less than 5% annually.⁵ But these data also highlight the persistent risk faced by patients with chronic kidney disease; even those with transplants have death rates comparable to those of patients with cancer, diabetes, or heart failure.

Death rates correlate with GFR

After the publication of definitions and staging by the National Kidney Foundation in 2002, Go et al⁶ studied more than 1 million patients with chronic kidney disease from the Kaiser Permanente Renal Registry and found that the rates of cardiovascular events and death from any cause increased with decreasing estimated GFR. These findings were confirmed in a later meta-analysis, which also found that an elevated urinary albumin-to-creatinine ratio (> 1.1 mg/mmol) is an independent predictor of all-cause mortality and cardiovascular mortality.⁷

Keith et al⁸ followed nearly 28,000 patients with chronic kidney disease (with an estimated GFR of less than 90 mL/min/1.73 m²) over 5 years. Patients with stage 3 disease (moderate disease, GFR = 30–59 mL/min/1.73 m²) were 20 times more likely to die than to progress to end-stage renal disease (24.3% vs 1.2%). Even those with stage 4 disease (severe disease, GFR = 15–29 mL/min/1.73 m²) were more than twice as likely to die as to progress to dialysis (45.7% vs 19.9%).

Similar observations were made by Thompson et al¹⁰ based on the Alberta Kidney Disease Network database. They tracked cardiovascular causes of death and found that regardless of estimated GFR, cardiovascular deaths were most often attributed to ischemic heart disease (about 55%). Other trends were also apparent: as the GFR fell, the incidence of stroke decreased, and heart failure and valvular heart disease increased.

AFRICAN AMERICANS WITH KIDNEY DISEASE: A DISTINCT GROUP

African Americans constitute about 12% of the US population but account for:

• 31% of end-stage renal disease
• 34% of the kidney transplant waiting list
• 28% of kidney transplants in 2015 (12% of living donor transplants, 35% of deceased donor transplants).

In addition, African Americans with chronic kidney disease tend to be:

• Younger and have more advanced kidney disease than whites¹¹
• Much more likely than whites to have diabetes, and somewhat more likely to have hypertension

• 

  Adapted from Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Nally JV Jr. Cause-specific deaths in non-dialysis-dependent CKD. J Am Soc Nephrol 2015; 26:2512–2520.

  More likely than whites to die of cardiovascular disease (37.4% vs 34.2%) (Figure 2).⁹

Overall, the prevalence of chronic kidney disease is slightly higher in African Americans than in whites. Interestingly, African Americans are slightly less likely than whites to have low estimated GFR values (6.2% vs 7.6% incidence of < 60 mL/min/1.73 m²) but are about 50% more likely to have proteinuria (12.3% vs 8.4% incidence of urine albumin-to-creatinine ratio ≥ 30 mg/g).

More likely to be on dialysis, but less likely to die

Although African Americans have only a slightly higher prevalence of chronic kidney disease (about 15% increased prevalence) than whites,¹² they are 3 times more likely to be on dialysis.

Nevertheless, for unknown reasons, African American adults on dialysis have about a 26% lower all-cause mortality rate than whites.⁵ One proposed explanation for this survival advantage has been that the mortality rate in African Americans with chronic kidney disease before entering dialysis is higher than in whites, leading to a “healthier population” on dialysis.¹³ However, this theory is based on a small study from more than a decade ago and has not been borne out by subsequent investigation.

African Americans with chronic kidney disease: Death rates not increased

African Americans over age 65 with chronic kidney disease have all-cause mortality rates similar to those of whites: about 11% annually. Breaking it down by disease severity, death rates in stage 3 disease are about 10% and jump to more than 15% in higher stages in both African Americans and whites.⁵

However, African Americans with chronic kidney disease have more heart disease and much more end-stage renal disease than whites.

Disease advances faster despite care

The incidence of end-stage renal disease is consistently more than 3 times higher in African Americans than in whites in the United States.^5,14

Multiple investigations have tried to determine why African Americans are disproportionately affected by progression of chronic kidney disease to end-stage renal disease. We recently examined this question in our Cleveland Clinic registry data. Even after adjusting for 17 variables (including demographics, comorbidities, insurance, medications, smoking, and chronic kidney disease stage), African Americans with chronic kidney disease were found to have an increased risk of progressing to end-stage renal disease compared with whites (subhazard ratio 1.38, 95% confidence interval 1.19–1.60).

We examined care measures from the Cleveland Clinic database. In terms of the number of laboratory tests ordered, clinic visits, and nephrology referrals, African Americans had at least as much care as whites, if not more. Similarly, African Americans’ access to renoprotective medicines (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, statins, beta-blockers) was the same as or more than for whites.

Although the frequently attributed reasons surrounding compliance and socioeconomic issues are worthy of examination, they do not appear to completely explain the differences in incidence and outcomes. This dichotomy of a marginally increased prevalence of chronic kidney disease in African Americans with mortality rates similar to those of whites, yet with a 3 times higher incidence of end-stage renal disease in African Americans, suggests a faster progression of the disease in African Americans, which may be genetically based.

In 2010, two variant alleles of the APOL1 gene on chromosome 22 were found to be associated with nondiabetic kidney disease.¹⁵ Three nephropathies are associated with being homozygous for these alleles:

• Focal segmental glomerulosclerosis, the leading cause of nephrotic syndrome in African Americans
• Hypertension-associated kidney disease with scarring of glomeruli in vessels, the primary cause of end-stage renal disease in African Americans
• Human immunodeficiency virus (HIV)- associated nephropathy, usually a focal segmental glomerulosclerosis type of lesion.

The first two conditions are about 3 to 5 times more prevalent in African Americans than in whites, and HIV-associated nephropathy is about 20 to 30 times more common. 

African sleeping sickness and chronic kidney disease

Retrospective analysis of biologic samples from trials of kidney disease in African Americans has revealed interesting results.

From Parsa A, Kao WH, Xie D, et al; AASK Study Investigators; CRIC Study Investigators. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013; 369:2183–2196. Reprinted with permission from Massachusetts Medical Society.

The Chronic Renal Insufficiency Cohort (CRIC) observation study¹⁸ enrolled patients with an estimated GFR of 20 to 70 mL/min/1.73 m², with a preference for African Americans and patients with diabetes. Nearly 3,000 participants had adequate samples for DNA testing. They found that African Americans with the double variant allele had worse outcomes, whether or not they had diabetes, compared with whites and African Americans without the homozygous gene variant.

Mechanism not well understood

The mechanism of renal injury is not well understood. Apolipoprotein L1, the protein coded for by APOL1, is a component of high-density lipoprotein. It is found in a different distribution pattern in people with normal kidneys vs those with nondiabetic kidney disease, especially in the arteries, arterioles, and podocytes.^19,20 It can be detected in blood plasma, but levels do not correlate with kidney disease.²¹ Not all patients with the high-risk variant develop chronic kidney disease; a “second hit” such as infection with HIV may be required.

Investigators have recently developed knockout mouse models of APOL1-associated kidney diseases that are helping to elucidate mechanisms.^22,23

EFFECT OF GENOTYPE ON KIDNEY TRANSPLANTS IN AFRICAN AMERICANS

African Americans receive about 30% of kidney transplants in the United States and represent about 15% to 20% of all donors.

Lee et al²⁴ reviewed 119 African American recipients of kidney transplants, about half of whom were homozygous for an APOL1 variant. After 5 years, no differences were found in allograft survival between recipients with 0, 1, or 2 risk alleles.

However, looking at the issue from the other side, Reeves-Daniel et al²⁵ studied the fate of more than 100 kidneys that were transplanted from African American donors, 16% of whom had the high-risk, homozygous genotype. In this case, graft failure was much likelier to occur with the high-risk donor kidneys (hazard ratio 3.84, P = .008). Similar outcomes were shown in a study of 2 centers²⁶ involving 675 transplants from deceased donors, 15% of which involved the high-risk genotype. The hazard ratio for graft failure was found to be 2.26 (P = .001) with high-risk donor kidneys.

These studies, which examined data from about 5 years after transplant, found that kidney failure does not tend to occur immediately in all cases, but gradually over time. Most high-risk kidneys were not lost within the 5 years of the studies.

The fact that the high-risk kidneys do not all fail immediately also suggests that a second hit is required for failure. Culprits postulated include a bacterial or viral infection (eg, BK virus, cytomegalovirus), ischemia or reperfusion injury, drug toxicity, and immune-mediated allograft injury (ie, rejection). 

Genetic testing for APOL1 risk variants is on the horizon for kidney transplant. But at this point, providing guidance for patients can be tricky. Two case studies^27,28 and epidemiologic data suggest that donors homozygous for an APOL1 variant and those with a family history of end-stage kidney disease are at increased risk of chronic kidney disease. Even so, most recipients even of these high-risk organs have good outcomes. If an African American patient needs a kidney and his or her sibling offers one, it is difficult to advise against it when the evidence is weak for immediate risk and when other options may not be readily available. Further investigation is clearly needed into whether APOL1 variants and other biomarkers can predict an organ’s success as a transplant.

The National Institutes of Health are currently funding prospective longitudinal studies with the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) to determine the impact of APOL1 genetic factors on transplant recipients as well as on living donors. Possible second hits will also be studied, as will other markers of renal dysfunction or disease in donors. Researchers are actively investigating these important questions.

KEEPING SCIENCE RELEVANT

In a recent commentary related to the murine knockout model of APOL1-associated kidney disease, O’Toole et al offered insightful observations regarding the potential clinical impact of these new genetic discoveries.²³

As we study the genetics of kidney disease in African American patients, we should keep in mind 3 critical questions of clinical importance:

Will findings identify better treatments for chronic kidney disease? The AASK trial found that knowing the genetics did not affect outcomes of routine therapy. However, basic science investigations are currently underway targeting APOL1 variants which might reduce the increased kidney disease risk among people of African descent.

Should patients be genotyped for APOL1 risk variants? For patients with chronic kidney disease, it does not seem useful at this time. But for renal transplant donors, the answer is probably yes.

How does this discovery help us to understand our patients better? The implications are enormous for combatting the assumptions that rapid chronic kidney disease progression reflects poor patient compliance or other socioeconomic factors. We now understand that genetics, at least in part, drives renal disease outcomes in African American patients.

Editor’s note: This Medical Grand Rounds was presented as the 14th Annual Lawrence “Chris” Crain Memorial Lecture, a series that has been dedicated to discussing kidney disease, hypertension, and health care disparities in the African American community. In 1997, Dr. Crain became the first African American chief medical resident at Cleveland Clinic, and was a nephrology fellow in 1998–1999. Dr. Nally was his teacher and mentor.

African Americans have a greater burden of chronic kidney disease than whites. They are more than 3 times as likely as whites to develop end-stage renal disease, even after adjusting for age, disease stage, smoking, medications, and comorbidities. Why this is so has been the focus of much speculation and research.

This article reviews recent advances in the understanding of the progression of chronic kidney disease, with particular scrutiny of the disease in African Americans. Breakthroughs in genetics that help explain the greater disease burden in African Americans are also discussed, as well as implications for organ transplant screening.

ADVANCING UNDERSTANDING OF CHRONIC KIDNEY DISEASE

In the 1990s, dialysis rolls grew by 8% to 10% annually. Unfortunately, many patients first met with a nephrologist on the eve of their first dialysis treatment; there was not yet an adequate way to recognize the disease earlier and slow its progression. And disease definitions were not yet standardized, which led to inadequate metrics and hampered the ability to move disease management forward.

Standardizing definitions

The situation improved in 2002, when the National Kidney Foundation published clinical practice guidelines for chronic kidney disease that included disease definitions and staging.¹ Chronic kidney disease was defined as a structural or functional abnormality of the kidney lasting at least 3 months, as manifested by either of the following:

• Kidney damage, with or without decreased glomerular filtration rate (GFR), as defined by pathologic abnormalities or markers of kidney damage in the blood, urine, or on imaging tests

• 

  GFR less than 60 mL/min/1.73 m², with or without kidney damage.

A subsequent major advance was the recognition that not only GFR but also albuminuria was important for staging of chronic kidney disease (Figure 1).²

Developing large databases

Surveillance and monitoring of chronic kidney disease have generated large databases that enable researchers to detect trends in disease progression.

US Renal Data System. The US Renal Data System has collected and reported on data for more than 20 years from the National Health and Nutrition Examination Survey and the Centers for Medicare and Medicaid Services about chronic and end-stage kidney disease in the United States.

Cleveland Clinic database. Cleveland Clinic has developed a validated chronic kidney disease registry based on its electronic health record.³ The data include demographics (age, sex, ethnic group), comorbidities, medications, and complete laboratory data.⁴

Alberta Kidney Disease Network. This Canadian research consortium links large laboratory and demographic databases to facilitate defining patient populations, such as those with kidney disease and other comorbidities.

Kaiser Permanente Renal Registry. Kaiser Permanente of Northern California insures more than one-third of adults in the San Francisco Bay Area. The renal registry includes all adults whose kidney function is known. Data on age, sex, and racial or ethnic group are available from the health-plan databases.

DEATHS FROM KIDNEY DISEASE

The mortality rate in patients with end-stage renal disease who are on dialysis has steadily fallen over the past 20 years, from an annual rate of about 25% in 1996 to 17% in 2014, suggesting that care improved during that time. Patients with transplants have a much lower mortality rate: less than 5% annually.⁵ But these data also highlight the persistent risk faced by patients with chronic kidney disease; even those with transplants have death rates comparable to those of patients with cancer, diabetes, or heart failure.

Death rates correlate with GFR

After the publication of definitions and staging by the National Kidney Foundation in 2002, Go et al⁶ studied more than 1 million patients with chronic kidney disease from the Kaiser Permanente Renal Registry and found that the rates of cardiovascular events and death from any cause increased with decreasing estimated GFR. These findings were confirmed in a later meta-analysis, which also found that an elevated urinary albumin-to-creatinine ratio (> 1.1 mg/mmol) is an independent predictor of all-cause mortality and cardiovascular mortality.⁷

Keith et al⁸ followed nearly 28,000 patients with chronic kidney disease (with an estimated GFR of less than 90 mL/min/1.73 m²) over 5 years. Patients with stage 3 disease (moderate disease, GFR = 30–59 mL/min/1.73 m²) were 20 times more likely to die than to progress to end-stage renal disease (24.3% vs 1.2%). Even those with stage 4 disease (severe disease, GFR = 15–29 mL/min/1.73 m²) were more than twice as likely to die as to progress to dialysis (45.7% vs 19.9%).

Similar observations were made by Thompson et al¹⁰ based on the Alberta Kidney Disease Network database. They tracked cardiovascular causes of death and found that regardless of estimated GFR, cardiovascular deaths were most often attributed to ischemic heart disease (about 55%). Other trends were also apparent: as the GFR fell, the incidence of stroke decreased, and heart failure and valvular heart disease increased.

AFRICAN AMERICANS WITH KIDNEY DISEASE: A DISTINCT GROUP

African Americans constitute about 12% of the US population but account for:

• 31% of end-stage renal disease
• 34% of the kidney transplant waiting list
• 28% of kidney transplants in 2015 (12% of living donor transplants, 35% of deceased donor transplants).

In addition, African Americans with chronic kidney disease tend to be:

• Younger and have more advanced kidney disease than whites¹¹
• Much more likely than whites to have diabetes, and somewhat more likely to have hypertension

• 

  Adapted from Navaneethan SD, Schold JD, Arrigain S, Jolly SE, Nally JV Jr. Cause-specific deaths in non-dialysis-dependent CKD. J Am Soc Nephrol 2015; 26:2512–2520.

  More likely than whites to die of cardiovascular disease (37.4% vs 34.2%) (Figure 2).⁹

Overall, the prevalence of chronic kidney disease is slightly higher in African Americans than in whites. Interestingly, African Americans are slightly less likely than whites to have low estimated GFR values (6.2% vs 7.6% incidence of < 60 mL/min/1.73 m²) but are about 50% more likely to have proteinuria (12.3% vs 8.4% incidence of urine albumin-to-creatinine ratio ≥ 30 mg/g).

More likely to be on dialysis, but less likely to die

Although African Americans have only a slightly higher prevalence of chronic kidney disease (about 15% increased prevalence) than whites,¹² they are 3 times more likely to be on dialysis.

Nevertheless, for unknown reasons, African American adults on dialysis have about a 26% lower all-cause mortality rate than whites.⁵ One proposed explanation for this survival advantage has been that the mortality rate in African Americans with chronic kidney disease before entering dialysis is higher than in whites, leading to a “healthier population” on dialysis.¹³ However, this theory is based on a small study from more than a decade ago and has not been borne out by subsequent investigation.

African Americans with chronic kidney disease: Death rates not increased

African Americans over age 65 with chronic kidney disease have all-cause mortality rates similar to those of whites: about 11% annually. Breaking it down by disease severity, death rates in stage 3 disease are about 10% and jump to more than 15% in higher stages in both African Americans and whites.⁵

However, African Americans with chronic kidney disease have more heart disease and much more end-stage renal disease than whites.

Disease advances faster despite care

The incidence of end-stage renal disease is consistently more than 3 times higher in African Americans than in whites in the United States.^5,14

Multiple investigations have tried to determine why African Americans are disproportionately affected by progression of chronic kidney disease to end-stage renal disease. We recently examined this question in our Cleveland Clinic registry data. Even after adjusting for 17 variables (including demographics, comorbidities, insurance, medications, smoking, and chronic kidney disease stage), African Americans with chronic kidney disease were found to have an increased risk of progressing to end-stage renal disease compared with whites (subhazard ratio 1.38, 95% confidence interval 1.19–1.60).

We examined care measures from the Cleveland Clinic database. In terms of the number of laboratory tests ordered, clinic visits, and nephrology referrals, African Americans had at least as much care as whites, if not more. Similarly, African Americans’ access to renoprotective medicines (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, statins, beta-blockers) was the same as or more than for whites.

Although the frequently attributed reasons surrounding compliance and socioeconomic issues are worthy of examination, they do not appear to completely explain the differences in incidence and outcomes. This dichotomy of a marginally increased prevalence of chronic kidney disease in African Americans with mortality rates similar to those of whites, yet with a 3 times higher incidence of end-stage renal disease in African Americans, suggests a faster progression of the disease in African Americans, which may be genetically based.

In 2010, two variant alleles of the APOL1 gene on chromosome 22 were found to be associated with nondiabetic kidney disease.¹⁵ Three nephropathies are associated with being homozygous for these alleles:

• Focal segmental glomerulosclerosis, the leading cause of nephrotic syndrome in African Americans
• Hypertension-associated kidney disease with scarring of glomeruli in vessels, the primary cause of end-stage renal disease in African Americans
• Human immunodeficiency virus (HIV)- associated nephropathy, usually a focal segmental glomerulosclerosis type of lesion.

The first two conditions are about 3 to 5 times more prevalent in African Americans than in whites, and HIV-associated nephropathy is about 20 to 30 times more common. 

African sleeping sickness and chronic kidney disease

Retrospective analysis of biologic samples from trials of kidney disease in African Americans has revealed interesting results.

From Parsa A, Kao WH, Xie D, et al; AASK Study Investigators; CRIC Study Investigators. APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013; 369:2183–2196. Reprinted with permission from Massachusetts Medical Society.

The Chronic Renal Insufficiency Cohort (CRIC) observation study¹⁸ enrolled patients with an estimated GFR of 20 to 70 mL/min/1.73 m², with a preference for African Americans and patients with diabetes. Nearly 3,000 participants had adequate samples for DNA testing. They found that African Americans with the double variant allele had worse outcomes, whether or not they had diabetes, compared with whites and African Americans without the homozygous gene variant.

Mechanism not well understood

The mechanism of renal injury is not well understood. Apolipoprotein L1, the protein coded for by APOL1, is a component of high-density lipoprotein. It is found in a different distribution pattern in people with normal kidneys vs those with nondiabetic kidney disease, especially in the arteries, arterioles, and podocytes.^19,20 It can be detected in blood plasma, but levels do not correlate with kidney disease.²¹ Not all patients with the high-risk variant develop chronic kidney disease; a “second hit” such as infection with HIV may be required.

Investigators have recently developed knockout mouse models of APOL1-associated kidney diseases that are helping to elucidate mechanisms.^22,23

EFFECT OF GENOTYPE ON KIDNEY TRANSPLANTS IN AFRICAN AMERICANS

African Americans receive about 30% of kidney transplants in the United States and represent about 15% to 20% of all donors.

Lee et al²⁴ reviewed 119 African American recipients of kidney transplants, about half of whom were homozygous for an APOL1 variant. After 5 years, no differences were found in allograft survival between recipients with 0, 1, or 2 risk alleles.

However, looking at the issue from the other side, Reeves-Daniel et al²⁵ studied the fate of more than 100 kidneys that were transplanted from African American donors, 16% of whom had the high-risk, homozygous genotype. In this case, graft failure was much likelier to occur with the high-risk donor kidneys (hazard ratio 3.84, P = .008). Similar outcomes were shown in a study of 2 centers²⁶ involving 675 transplants from deceased donors, 15% of which involved the high-risk genotype. The hazard ratio for graft failure was found to be 2.26 (P = .001) with high-risk donor kidneys.

These studies, which examined data from about 5 years after transplant, found that kidney failure does not tend to occur immediately in all cases, but gradually over time. Most high-risk kidneys were not lost within the 5 years of the studies.

The fact that the high-risk kidneys do not all fail immediately also suggests that a second hit is required for failure. Culprits postulated include a bacterial or viral infection (eg, BK virus, cytomegalovirus), ischemia or reperfusion injury, drug toxicity, and immune-mediated allograft injury (ie, rejection). 

Genetic testing for APOL1 risk variants is on the horizon for kidney transplant. But at this point, providing guidance for patients can be tricky. Two case studies^27,28 and epidemiologic data suggest that donors homozygous for an APOL1 variant and those with a family history of end-stage kidney disease are at increased risk of chronic kidney disease. Even so, most recipients even of these high-risk organs have good outcomes. If an African American patient needs a kidney and his or her sibling offers one, it is difficult to advise against it when the evidence is weak for immediate risk and when other options may not be readily available. Further investigation is clearly needed into whether APOL1 variants and other biomarkers can predict an organ’s success as a transplant.

The National Institutes of Health are currently funding prospective longitudinal studies with the APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) to determine the impact of APOL1 genetic factors on transplant recipients as well as on living donors. Possible second hits will also be studied, as will other markers of renal dysfunction or disease in donors. Researchers are actively investigating these important questions.

KEEPING SCIENCE RELEVANT

In a recent commentary related to the murine knockout model of APOL1-associated kidney disease, O’Toole et al offered insightful observations regarding the potential clinical impact of these new genetic discoveries.²³

As we study the genetics of kidney disease in African American patients, we should keep in mind 3 critical questions of clinical importance:

Will findings identify better treatments for chronic kidney disease? The AASK trial found that knowing the genetics did not affect outcomes of routine therapy. However, basic science investigations are currently underway targeting APOL1 variants which might reduce the increased kidney disease risk among people of African descent.

Should patients be genotyped for APOL1 risk variants? For patients with chronic kidney disease, it does not seem useful at this time. But for renal transplant donors, the answer is probably yes.

How does this discovery help us to understand our patients better? The implications are enormous for combatting the assumptions that rapid chronic kidney disease progression reflects poor patient compliance or other socioeconomic factors. We now understand that genetics, at least in part, drives renal disease outcomes in African American patients.

Click here to access the November 2017 Digital Edition.

Table of Contents

• HIV-Positive Veteran With Progressive Visual Changes
• Duodenal Perforation After Endoscopic Procedure
• Providers’ Attitudes and Knowledge of Lesbian, Gay, Bisexual, and Transgender Health
• Shoulder Pain—Is It From the Shoulder, Neck, or Both?
• Responding to the Opiod Crisis: An IHS Pharmacist-Led Pain Management Clinic
• Introducing the VA Boston Medical Forum
• Psychological Consequences of Detainee Operations
• Bryant Homer Womack: Honoring Sacrifice

Click here to access the November 2017 Digital Edition.

Table of Contents

• HIV-Positive Veteran With Progressive Visual Changes
• Duodenal Perforation After Endoscopic Procedure
• Providers’ Attitudes and Knowledge of Lesbian, Gay, Bisexual, and Transgender Health
• Shoulder Pain—Is It From the Shoulder, Neck, or Both?
• Responding to the Opiod Crisis: An IHS Pharmacist-Led Pain Management Clinic
• Introducing the VA Boston Medical Forum
• Psychological Consequences of Detainee Operations
• Bryant Homer Womack: Honoring Sacrifice

Click here to access the November 2017 Digital Edition.

Table of Contents

• HIV-Positive Veteran With Progressive Visual Changes
• Duodenal Perforation After Endoscopic Procedure
• Providers’ Attitudes and Knowledge of Lesbian, Gay, Bisexual, and Transgender Health
• Shoulder Pain—Is It From the Shoulder, Neck, or Both?
• Responding to the Opiod Crisis: An IHS Pharmacist-Led Pain Management Clinic
• Introducing the VA Boston Medical Forum
• Psychological Consequences of Detainee Operations
• Bryant Homer Womack: Honoring Sacrifice

►Lakshmana Swamy, MD, chief medical resident, VA Boston Healthcare System (VABHS) and Boston Medical Center. Dr. Serrao, when you hear about vision changes in a patient with HIV, what differential diagnosis is generated? What epidemiologic or historical factors can help distinguish these entities?

►Richard Serrao, MD, Infectious Disease Service, VABHS and assistant professor of medicine, Boston University School of Medicine. The differential diagnoses for vision changes in a patient with HIV is based on the overall immunosuppression of the patient: the lower the patient’s CD4 count, the higher the number of etiologies.¹ The portions of the visual pathway as well as the pattern of vision loss are useful in narrowing the differential. For example, monocular visual disturbances with dermatomal vesicles within the ophthalmic division of the trigeminal nerve strongly implicates varicella zoster retinitis or keratitis; abducens nerve palsy could suggest granulomatous basilar meningitis from cryptococcosis. Likewise, ongoing fevers in an advanced AIDS patient with concomitant colitis, hepatitis, and pneumonitis is strongly suspicious for cytomegalovirus (CMV) retinitis with wide dissemination.

Geographic epidemiologic factors can suggest pathogens more prevalent to certain regions of the world, such as histoplasma chorioretinitis in a resident of the central and eastern U.S. or tuberculosis in a returning traveler. Likewise, a cat owner or one who consumes steak tartare increases the likelihood for toxoplasma retinochoroiditis, or syphilis in men who have sex with men (MSM) in the U.S. given that the majority of new cases occur in this patient population. Other clues one should consider include the presence of splinter hemorrhages in the extremities in an intravenous drug user, raising the possibility of embolic endophthalmitis from bacterial or fungal endocarditis. A variety of other diagnoses can certainly occur as a result of drug treatment (uveitis from rifampin, for example), immune reconstitution from HAART, infections with other HIV-associated pathogens, such as Pneumocystis jiroveci, and many non-HIV-related ocular diseases.

►Dr. Swamy. Dr. Butler, what concerns do you have when you hear about an HIV-infected patient with vision loss from the ophthalmology perspective?

►Nicholas Butler, MD, Ophthalmology Service, Uveitis and Ocular Immunology, VABHS and assistant professor of ophthalmology, Harvard Medical School. Of course, patients with HIV suffer from common causes of vision loss—cataract, glaucoma, diabetes, macular degeneration, for instance—just like those without HIV infection. If there is no significant immunodeficiency, then the patient’s HIV status would be less relevant, and these more common causes of vision loss should be pursued. My first task would be to determine the patient’s most recent CD4 T-cell count.

Assuming an HIV-positive individual is experiencing visual symptoms related to his/her underlying HIV infection (especially in the setting of CD4 counts < 200 cells/mm³), ocular opportunistic infections (OOI) come to mind first. Despite a reduction in incidence of 75% to 80% in the HAART-era, CMV retinitis remains the most common OOI in patients with AIDS and carries the greatest risk of ocular morbidity.² In fact, based on enrollment data for the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), the prevalence of CMV retinitis among patients with AIDS is more than 20-fold higher than all other ocular complications of AIDS (OOIs and ocular neoplastic disease), including Kaposi sarcoma, lymphoma, herpes zoster ophthalmicus, ocular syphilis, ocular toxoplasma, necrotizing herpetic retinitis, cryptococcal choroiditis, and pneumocystis choroiditis.³ Beyond ocular opportunistic infections, the most common retinal finding in HIV-positive people is HIV retinopathy, nonspecific microvascular findings in the retina affecting nearly 70% of those with advanced HIV disease. Fortunately, HIV retinopathy is generally asymptomatic.⁴

►Dr. Swamy. Thank you for those explanations. Based on Dr. Serrao’s differential, it is worth noting that this patient is MSM. He was evaluated in urgent care with the initial examination showing a temperature of 98.0° F, pulse 83 beats per minute, and blood pressure 110/70 mm Hg. The eye exam showed no injection with normal extraocular movements. Initial laboratory data were notable for a CD4 count of 730 cells/mm³ with fewer than 20 HIV viral copies/mL. Cytomegalovirus immunoglobulin G (IgG) was positive, and immunoglobulin M (IgM) was negative. A Lyme antibody was positive with negative IgM and IgG by Western blot. Additional tests can be seen in Tables 1 and 2. The patient has good immunologic and virologic control. How does this change your thinking about the case?

►Dr. Serrao. His CD4 count is well above 350, increasing the likelihood of a relatively uncomplicated course and treatment. Cytomegalovirus antibodies reflect prior infection. As CMV generally does not manifest with disease of any variety (including CMV retinitis) at this high CD4 count, one can presume he does not have CMV retinitis as a cause for his visual changes. CMV retinitis occurs mainly when substantial CD4 depletion has occurred (typically less than 50 cells/mm³). A positive Lyme antibody screen, not specific to Lyme, can be falsely positive in other treponema diseases (eg, Treponema pallidum, the etiologic organism of syphilis) as evidenced by negative confirmatory Western blot IgG and IgM. Antineutrophil cystoplasmic antibodies, lysozyme, angiotensin-converting enzyme, rapid plasma reagin (RPR), herpes simplex virus, toxoplasma are generally included in the workup for the differential of uveitis, retinitis, choroiditis, etc.

►Dr. Swamy. Based on the visual changes, the patient was referred for urgent ophthalmologic evaluation. Dr. Butler, when should a generalist consider urgent ophthalmology referral?

►Dr. Butler. In general, all patients with acute (and significant) vision loss should be referred immediately to an ophthalmologist. The challenge for the general practitioner is determining the true extent of the reported vision loss. If possible, some assessment of visual acuity should be obtained, testing each eye independently and with the correct glasses correction (ie, the patient’s distance glasses if the test object is 12 feet or more from the patient or their reading glasses if the test object is held inside arm’s length). If the general practitioner does not have access to an eye chart or near card, any assessment of vision with an appropriate description will be useful (eg, the patient can quickly count fingers at 15 feet in the unaffected eye, but the eye with reported vision loss cannot reliably count fingers outside of 2 feet). Additional ocular symptoms associated with the vision loss, such as pain, redness, photophobia, new flashes or floaters, increase the urgency of the referral. The threshold for referral for any ocular complaint is lower compared with that of the general population for those with evidence of immunodeficiency, such as for this patient with HIV. Any CD4 count < 200 cells/mm³ should raise the practitioner’s concern for an ocular opportunistic infection, with the greatest concern with CD4 counts < 50 cells/mm³.

►Dr. Swamy. The patient underwent further testing in the ophthalmology clinic. Dr. Butler, can you please interpret the funduscopic exam?

►Dr. Butler. Both eyes demonstrate findings (microaneurysms and small dot-blot hemorrhages) consistent with moderate nonproliferative diabetic retinopathy (Figure 1A, white arrows). HIV-associated retinopathy could produce similar findings, but it is not generally seen with CD4 counts > 200 cells/mm³. Additionally, in the left eye, there is a diffuse patch of retinal whitening (retinitis) associated with the inferotemporal vascular arcades (Figure 1B, white arrows). The entire area involved is poorly circumscribed and the whitening is subtle in areas. Overlying some areas of deeper, ground-glass whitening there are scattered, punctate white spots (Figure 1B, green arrows). Wickremasinghe and colleagues described this pattern of retinitis and suggested that it had a high positive-predictive value in the diagnosis of ocular syphilis.⁵

►Dr. Swamy. The patient then underwent fluorescein angiography and optical coherence tomography (OCT). Dr. Butler, what did the fluorescein angiography show?

►Dr. Butler. The fluorescein angiogram in both eyes revealed leakage of dye consistent with diabetic retinopathy, with the right eye (OD) worse than the left (OS). Additionally, the areas of active retinitis in the left eye displayed gradual staining with leopard-spot changes, along with late leakage of fluorescein dye, indicating vasculopathy in the infected area (Figure 2, arrows). The patient also underwent OCT in the left eye (images not displayed) demonstrating vitreous cells (vitritis), patches of inner retinal thickening with hyperreflectivity, and hyperreflective nodules at the level of the retinal pigment epithelium with overlying photoreceptor disruption. These OCT findings are fairly stereotypic for syphilitic chorioretinitis.⁶

►Dr. Swamy. Based on the ophthalmic findings, a diagnosis of ocular syphilis was made. Dr. Serrao, what should internists consider as they evaluate and manage a patient with ocular syphilis?

►Dr. Serrao. Although isolated ocular involvement from syphilis is possible, the majority of patients (up to 85%) with HIV can present with concomitant central nervous system infection and about 30% present with symptomatic neurosyphilis (a typical late manifestation of this disease) that reflects the aggressiveness, accelerated course and propensity for wide dissemination of syphilis in this patient population.⁷

The presence of concomitant cutaneous rashes should prompt universal precautions, because transmission can occur via skin to skin contact. Clinicians should watch for the Jarisch-Herxheimer reaction during treatment, a syndrome of fever, myalgias, and headache, which results from circulating cytokines produced because of rapidly dying spirochetes that could mimic a penicillin drug reaction, yet is treated supportively.

As syphilis is sexually acquired, clinicians should test for coexistent sexually transmitted infections, vaccinate for those that are preventable (eg, hepatitis B), notify sexual partners via assistance from local departments of public health, and assess for coexistent drug use and offer counseling in order to optimize risk reduction. Special attention should be paid to virologic control of HIV since some studies have shown an increase in the propensity for breakthrough HIV viremia while on effective ART.⁹ This should warrant counseling for ongoing optimal ART adherence and close monitoring in the follow-up visits with a provider specialized in the treatment of syphilis and HIV.

►Dr. Swamy. A lumbar puncture is performed with the results listed in Table 2. Dr. Serrao, is the CSF consistent with neurosyphilis? What would you do next?

►Dr. Serrao. The lumbar puncture is inflammatory with a lymphocytic predominance, consistent with active ocular/neurosyphilis. The CSF Venereal Disease Research Laboratory test is specific but not sensitive so a negative value does not rule out the presence of central nervous system infection.¹⁰ The CSF fluorescent treponemal antibody (CSF FTA-ABS) is sensitive but not specific. In this case, the ocular findings, positive serum RPR, CSF lymphocytic predominance, and CSF FTA ABS strongly supports the diagnosis of ocular/early neurosyphilis in a patient with HIV infection in whom early aggressive treatment is warranted to prevent rapid progression/potential loss of vision.¹¹

►Dr. Swamy. Dr. Butler, how does syphilis behave in the eye as compared to other infectious or inflammatory diseases? Do visual symptoms respond well to treatment?

►Dr. Butler. As opposed to the dramatic reduction in rates and severity of CMV retinitis, HAART has had a negligible effect on ocular syphilis in the setting of HIV coinfection; in fact, rates of syphilis, including ocular syphilis, are currently surging world-wide, and HIV coinfection portends a worse prognosis.¹² This is especially true among gay men. More so, there appears to be no correlation between CD4 count and incidence of developing ocular syphilis, as opposed to CMV retinitis, which occurs far more frequently in those with CD4 counts < 50 cells/mm³. In keeping with its epithet as one of the “Great Imitators,” syphilis can affect virtually every tissue of the eye—conjunctiva, sclera, cornea, iris, lens, vitreous, retina, choroid, optic nerve—unlike other OOI, such as CMV or toxoplasma, which generally hone to the retina. Nonetheless, various findings and patterns on clinical exam and ancillary testing, such as the more recently described punctate inner retinitis (as seen in our patient) and the more classic acute syphilitic posterior placoid chorioretinitis, carry high specificity for ocular syphilis.¹³

Patients with ocular syphilis should be treated according to neurosyphilis treatment protocols. In general, these patients respond very well to treatment with resolution of the ocular findings and recovery of complete, or nearly so, visual function, as long as an excessive delay between diagnosis and proper treatment does not occur.¹⁴

►Dr. Swamy. Following this testing, the patient completed 14 days of IV penicillin with resolution of symptoms. He had no further vision complaints. He was started on Triumeq (abacavir, dolutegravir, and lamivudine) with good adherence to therapy. Dr. Serrao, in 2016 the CDC released a clinical advisory about ocular syphilis. Can you tell us about why this is an important diagnosis to be aware of today?

►Dr. Serrao. As with any disease, the epidemiologic characteristics of an infection like syphilis allow the clinician to more carefully entertain such a diagnosis in any one individual by improving the index of suspicion for a particular disease. Awareness of an increase in ocular syphilis in HIV positive MSM allows for a more timely assessment and subsequent treatment with the goal of preventing loss of vision.¹⁵

►Lakshmana Swamy, MD, chief medical resident, VA Boston Healthcare System (VABHS) and Boston Medical Center. Dr. Serrao, when you hear about vision changes in a patient with HIV, what differential diagnosis is generated? What epidemiologic or historical factors can help distinguish these entities?

►Richard Serrao, MD, Infectious Disease Service, VABHS and assistant professor of medicine, Boston University School of Medicine. The differential diagnoses for vision changes in a patient with HIV is based on the overall immunosuppression of the patient: the lower the patient’s CD4 count, the higher the number of etiologies.¹ The portions of the visual pathway as well as the pattern of vision loss are useful in narrowing the differential. For example, monocular visual disturbances with dermatomal vesicles within the ophthalmic division of the trigeminal nerve strongly implicates varicella zoster retinitis or keratitis; abducens nerve palsy could suggest granulomatous basilar meningitis from cryptococcosis. Likewise, ongoing fevers in an advanced AIDS patient with concomitant colitis, hepatitis, and pneumonitis is strongly suspicious for cytomegalovirus (CMV) retinitis with wide dissemination.

Geographic epidemiologic factors can suggest pathogens more prevalent to certain regions of the world, such as histoplasma chorioretinitis in a resident of the central and eastern U.S. or tuberculosis in a returning traveler. Likewise, a cat owner or one who consumes steak tartare increases the likelihood for toxoplasma retinochoroiditis, or syphilis in men who have sex with men (MSM) in the U.S. given that the majority of new cases occur in this patient population. Other clues one should consider include the presence of splinter hemorrhages in the extremities in an intravenous drug user, raising the possibility of embolic endophthalmitis from bacterial or fungal endocarditis. A variety of other diagnoses can certainly occur as a result of drug treatment (uveitis from rifampin, for example), immune reconstitution from HAART, infections with other HIV-associated pathogens, such as Pneumocystis jiroveci, and many non-HIV-related ocular diseases.

►Dr. Swamy. Dr. Butler, what concerns do you have when you hear about an HIV-infected patient with vision loss from the ophthalmology perspective?

►Nicholas Butler, MD, Ophthalmology Service, Uveitis and Ocular Immunology, VABHS and assistant professor of ophthalmology, Harvard Medical School. Of course, patients with HIV suffer from common causes of vision loss—cataract, glaucoma, diabetes, macular degeneration, for instance—just like those without HIV infection. If there is no significant immunodeficiency, then the patient’s HIV status would be less relevant, and these more common causes of vision loss should be pursued. My first task would be to determine the patient’s most recent CD4 T-cell count.

Assuming an HIV-positive individual is experiencing visual symptoms related to his/her underlying HIV infection (especially in the setting of CD4 counts < 200 cells/mm³), ocular opportunistic infections (OOI) come to mind first. Despite a reduction in incidence of 75% to 80% in the HAART-era, CMV retinitis remains the most common OOI in patients with AIDS and carries the greatest risk of ocular morbidity.² In fact, based on enrollment data for the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), the prevalence of CMV retinitis among patients with AIDS is more than 20-fold higher than all other ocular complications of AIDS (OOIs and ocular neoplastic disease), including Kaposi sarcoma, lymphoma, herpes zoster ophthalmicus, ocular syphilis, ocular toxoplasma, necrotizing herpetic retinitis, cryptococcal choroiditis, and pneumocystis choroiditis.³ Beyond ocular opportunistic infections, the most common retinal finding in HIV-positive people is HIV retinopathy, nonspecific microvascular findings in the retina affecting nearly 70% of those with advanced HIV disease. Fortunately, HIV retinopathy is generally asymptomatic.⁴

►Dr. Swamy. Thank you for those explanations. Based on Dr. Serrao’s differential, it is worth noting that this patient is MSM. He was evaluated in urgent care with the initial examination showing a temperature of 98.0° F, pulse 83 beats per minute, and blood pressure 110/70 mm Hg. The eye exam showed no injection with normal extraocular movements. Initial laboratory data were notable for a CD4 count of 730 cells/mm³ with fewer than 20 HIV viral copies/mL. Cytomegalovirus immunoglobulin G (IgG) was positive, and immunoglobulin M (IgM) was negative. A Lyme antibody was positive with negative IgM and IgG by Western blot. Additional tests can be seen in Tables 1 and 2. The patient has good immunologic and virologic control. How does this change your thinking about the case?

►Dr. Serrao. His CD4 count is well above 350, increasing the likelihood of a relatively uncomplicated course and treatment. Cytomegalovirus antibodies reflect prior infection. As CMV generally does not manifest with disease of any variety (including CMV retinitis) at this high CD4 count, one can presume he does not have CMV retinitis as a cause for his visual changes. CMV retinitis occurs mainly when substantial CD4 depletion has occurred (typically less than 50 cells/mm³). A positive Lyme antibody screen, not specific to Lyme, can be falsely positive in other treponema diseases (eg, Treponema pallidum, the etiologic organism of syphilis) as evidenced by negative confirmatory Western blot IgG and IgM. Antineutrophil cystoplasmic antibodies, lysozyme, angiotensin-converting enzyme, rapid plasma reagin (RPR), herpes simplex virus, toxoplasma are generally included in the workup for the differential of uveitis, retinitis, choroiditis, etc.

►Dr. Swamy. Based on the visual changes, the patient was referred for urgent ophthalmologic evaluation. Dr. Butler, when should a generalist consider urgent ophthalmology referral?

►Dr. Butler. In general, all patients with acute (and significant) vision loss should be referred immediately to an ophthalmologist. The challenge for the general practitioner is determining the true extent of the reported vision loss. If possible, some assessment of visual acuity should be obtained, testing each eye independently and with the correct glasses correction (ie, the patient’s distance glasses if the test object is 12 feet or more from the patient or their reading glasses if the test object is held inside arm’s length). If the general practitioner does not have access to an eye chart or near card, any assessment of vision with an appropriate description will be useful (eg, the patient can quickly count fingers at 15 feet in the unaffected eye, but the eye with reported vision loss cannot reliably count fingers outside of 2 feet). Additional ocular symptoms associated with the vision loss, such as pain, redness, photophobia, new flashes or floaters, increase the urgency of the referral. The threshold for referral for any ocular complaint is lower compared with that of the general population for those with evidence of immunodeficiency, such as for this patient with HIV. Any CD4 count < 200 cells/mm³ should raise the practitioner’s concern for an ocular opportunistic infection, with the greatest concern with CD4 counts < 50 cells/mm³.

►Dr. Swamy. The patient underwent further testing in the ophthalmology clinic. Dr. Butler, can you please interpret the funduscopic exam?

►Dr. Butler. Both eyes demonstrate findings (microaneurysms and small dot-blot hemorrhages) consistent with moderate nonproliferative diabetic retinopathy (Figure 1A, white arrows). HIV-associated retinopathy could produce similar findings, but it is not generally seen with CD4 counts > 200 cells/mm³. Additionally, in the left eye, there is a diffuse patch of retinal whitening (retinitis) associated with the inferotemporal vascular arcades (Figure 1B, white arrows). The entire area involved is poorly circumscribed and the whitening is subtle in areas. Overlying some areas of deeper, ground-glass whitening there are scattered, punctate white spots (Figure 1B, green arrows). Wickremasinghe and colleagues described this pattern of retinitis and suggested that it had a high positive-predictive value in the diagnosis of ocular syphilis.⁵

►Dr. Swamy. The patient then underwent fluorescein angiography and optical coherence tomography (OCT). Dr. Butler, what did the fluorescein angiography show?

►Dr. Butler. The fluorescein angiogram in both eyes revealed leakage of dye consistent with diabetic retinopathy, with the right eye (OD) worse than the left (OS). Additionally, the areas of active retinitis in the left eye displayed gradual staining with leopard-spot changes, along with late leakage of fluorescein dye, indicating vasculopathy in the infected area (Figure 2, arrows). The patient also underwent OCT in the left eye (images not displayed) demonstrating vitreous cells (vitritis), patches of inner retinal thickening with hyperreflectivity, and hyperreflective nodules at the level of the retinal pigment epithelium with overlying photoreceptor disruption. These OCT findings are fairly stereotypic for syphilitic chorioretinitis.⁶

►Dr. Swamy. Based on the ophthalmic findings, a diagnosis of ocular syphilis was made. Dr. Serrao, what should internists consider as they evaluate and manage a patient with ocular syphilis?

►Dr. Serrao. Although isolated ocular involvement from syphilis is possible, the majority of patients (up to 85%) with HIV can present with concomitant central nervous system infection and about 30% present with symptomatic neurosyphilis (a typical late manifestation of this disease) that reflects the aggressiveness, accelerated course and propensity for wide dissemination of syphilis in this patient population.⁷

The presence of concomitant cutaneous rashes should prompt universal precautions, because transmission can occur via skin to skin contact. Clinicians should watch for the Jarisch-Herxheimer reaction during treatment, a syndrome of fever, myalgias, and headache, which results from circulating cytokines produced because of rapidly dying spirochetes that could mimic a penicillin drug reaction, yet is treated supportively.

As syphilis is sexually acquired, clinicians should test for coexistent sexually transmitted infections, vaccinate for those that are preventable (eg, hepatitis B), notify sexual partners via assistance from local departments of public health, and assess for coexistent drug use and offer counseling in order to optimize risk reduction. Special attention should be paid to virologic control of HIV since some studies have shown an increase in the propensity for breakthrough HIV viremia while on effective ART.⁹ This should warrant counseling for ongoing optimal ART adherence and close monitoring in the follow-up visits with a provider specialized in the treatment of syphilis and HIV.

►Dr. Swamy. A lumbar puncture is performed with the results listed in Table 2. Dr. Serrao, is the CSF consistent with neurosyphilis? What would you do next?

►Dr. Serrao. The lumbar puncture is inflammatory with a lymphocytic predominance, consistent with active ocular/neurosyphilis. The CSF Venereal Disease Research Laboratory test is specific but not sensitive so a negative value does not rule out the presence of central nervous system infection.¹⁰ The CSF fluorescent treponemal antibody (CSF FTA-ABS) is sensitive but not specific. In this case, the ocular findings, positive serum RPR, CSF lymphocytic predominance, and CSF FTA ABS strongly supports the diagnosis of ocular/early neurosyphilis in a patient with HIV infection in whom early aggressive treatment is warranted to prevent rapid progression/potential loss of vision.¹¹

►Dr. Swamy. Dr. Butler, how does syphilis behave in the eye as compared to other infectious or inflammatory diseases? Do visual symptoms respond well to treatment?

►Dr. Butler. As opposed to the dramatic reduction in rates and severity of CMV retinitis, HAART has had a negligible effect on ocular syphilis in the setting of HIV coinfection; in fact, rates of syphilis, including ocular syphilis, are currently surging world-wide, and HIV coinfection portends a worse prognosis.¹² This is especially true among gay men. More so, there appears to be no correlation between CD4 count and incidence of developing ocular syphilis, as opposed to CMV retinitis, which occurs far more frequently in those with CD4 counts < 50 cells/mm³. In keeping with its epithet as one of the “Great Imitators,” syphilis can affect virtually every tissue of the eye—conjunctiva, sclera, cornea, iris, lens, vitreous, retina, choroid, optic nerve—unlike other OOI, such as CMV or toxoplasma, which generally hone to the retina. Nonetheless, various findings and patterns on clinical exam and ancillary testing, such as the more recently described punctate inner retinitis (as seen in our patient) and the more classic acute syphilitic posterior placoid chorioretinitis, carry high specificity for ocular syphilis.¹³

Patients with ocular syphilis should be treated according to neurosyphilis treatment protocols. In general, these patients respond very well to treatment with resolution of the ocular findings and recovery of complete, or nearly so, visual function, as long as an excessive delay between diagnosis and proper treatment does not occur.¹⁴

►Dr. Swamy. Following this testing, the patient completed 14 days of IV penicillin with resolution of symptoms. He had no further vision complaints. He was started on Triumeq (abacavir, dolutegravir, and lamivudine) with good adherence to therapy. Dr. Serrao, in 2016 the CDC released a clinical advisory about ocular syphilis. Can you tell us about why this is an important diagnosis to be aware of today?

►Dr. Serrao. As with any disease, the epidemiologic characteristics of an infection like syphilis allow the clinician to more carefully entertain such a diagnosis in any one individual by improving the index of suspicion for a particular disease. Awareness of an increase in ocular syphilis in HIV positive MSM allows for a more timely assessment and subsequent treatment with the goal of preventing loss of vision.¹⁵

►Lakshmana Swamy, MD, chief medical resident, VA Boston Healthcare System (VABHS) and Boston Medical Center. Dr. Serrao, when you hear about vision changes in a patient with HIV, what differential diagnosis is generated? What epidemiologic or historical factors can help distinguish these entities?

►Richard Serrao, MD, Infectious Disease Service, VABHS and assistant professor of medicine, Boston University School of Medicine. The differential diagnoses for vision changes in a patient with HIV is based on the overall immunosuppression of the patient: the lower the patient’s CD4 count, the higher the number of etiologies.¹ The portions of the visual pathway as well as the pattern of vision loss are useful in narrowing the differential. For example, monocular visual disturbances with dermatomal vesicles within the ophthalmic division of the trigeminal nerve strongly implicates varicella zoster retinitis or keratitis; abducens nerve palsy could suggest granulomatous basilar meningitis from cryptococcosis. Likewise, ongoing fevers in an advanced AIDS patient with concomitant colitis, hepatitis, and pneumonitis is strongly suspicious for cytomegalovirus (CMV) retinitis with wide dissemination.

Geographic epidemiologic factors can suggest pathogens more prevalent to certain regions of the world, such as histoplasma chorioretinitis in a resident of the central and eastern U.S. or tuberculosis in a returning traveler. Likewise, a cat owner or one who consumes steak tartare increases the likelihood for toxoplasma retinochoroiditis, or syphilis in men who have sex with men (MSM) in the U.S. given that the majority of new cases occur in this patient population. Other clues one should consider include the presence of splinter hemorrhages in the extremities in an intravenous drug user, raising the possibility of embolic endophthalmitis from bacterial or fungal endocarditis. A variety of other diagnoses can certainly occur as a result of drug treatment (uveitis from rifampin, for example), immune reconstitution from HAART, infections with other HIV-associated pathogens, such as Pneumocystis jiroveci, and many non-HIV-related ocular diseases.

►Dr. Swamy. Dr. Butler, what concerns do you have when you hear about an HIV-infected patient with vision loss from the ophthalmology perspective?

►Nicholas Butler, MD, Ophthalmology Service, Uveitis and Ocular Immunology, VABHS and assistant professor of ophthalmology, Harvard Medical School. Of course, patients with HIV suffer from common causes of vision loss—cataract, glaucoma, diabetes, macular degeneration, for instance—just like those without HIV infection. If there is no significant immunodeficiency, then the patient’s HIV status would be less relevant, and these more common causes of vision loss should be pursued. My first task would be to determine the patient’s most recent CD4 T-cell count.

Assuming an HIV-positive individual is experiencing visual symptoms related to his/her underlying HIV infection (especially in the setting of CD4 counts < 200 cells/mm³), ocular opportunistic infections (OOI) come to mind first. Despite a reduction in incidence of 75% to 80% in the HAART-era, CMV retinitis remains the most common OOI in patients with AIDS and carries the greatest risk of ocular morbidity.² In fact, based on enrollment data for the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), the prevalence of CMV retinitis among patients with AIDS is more than 20-fold higher than all other ocular complications of AIDS (OOIs and ocular neoplastic disease), including Kaposi sarcoma, lymphoma, herpes zoster ophthalmicus, ocular syphilis, ocular toxoplasma, necrotizing herpetic retinitis, cryptococcal choroiditis, and pneumocystis choroiditis.³ Beyond ocular opportunistic infections, the most common retinal finding in HIV-positive people is HIV retinopathy, nonspecific microvascular findings in the retina affecting nearly 70% of those with advanced HIV disease. Fortunately, HIV retinopathy is generally asymptomatic.⁴

►Dr. Swamy. Thank you for those explanations. Based on Dr. Serrao’s differential, it is worth noting that this patient is MSM. He was evaluated in urgent care with the initial examination showing a temperature of 98.0° F, pulse 83 beats per minute, and blood pressure 110/70 mm Hg. The eye exam showed no injection with normal extraocular movements. Initial laboratory data were notable for a CD4 count of 730 cells/mm³ with fewer than 20 HIV viral copies/mL. Cytomegalovirus immunoglobulin G (IgG) was positive, and immunoglobulin M (IgM) was negative. A Lyme antibody was positive with negative IgM and IgG by Western blot. Additional tests can be seen in Tables 1 and 2. The patient has good immunologic and virologic control. How does this change your thinking about the case?

►Dr. Serrao. His CD4 count is well above 350, increasing the likelihood of a relatively uncomplicated course and treatment. Cytomegalovirus antibodies reflect prior infection. As CMV generally does not manifest with disease of any variety (including CMV retinitis) at this high CD4 count, one can presume he does not have CMV retinitis as a cause for his visual changes. CMV retinitis occurs mainly when substantial CD4 depletion has occurred (typically less than 50 cells/mm³). A positive Lyme antibody screen, not specific to Lyme, can be falsely positive in other treponema diseases (eg, Treponema pallidum, the etiologic organism of syphilis) as evidenced by negative confirmatory Western blot IgG and IgM. Antineutrophil cystoplasmic antibodies, lysozyme, angiotensin-converting enzyme, rapid plasma reagin (RPR), herpes simplex virus, toxoplasma are generally included in the workup for the differential of uveitis, retinitis, choroiditis, etc.

►Dr. Swamy. Based on the visual changes, the patient was referred for urgent ophthalmologic evaluation. Dr. Butler, when should a generalist consider urgent ophthalmology referral?

►Dr. Butler. In general, all patients with acute (and significant) vision loss should be referred immediately to an ophthalmologist. The challenge for the general practitioner is determining the true extent of the reported vision loss. If possible, some assessment of visual acuity should be obtained, testing each eye independently and with the correct glasses correction (ie, the patient’s distance glasses if the test object is 12 feet or more from the patient or their reading glasses if the test object is held inside arm’s length). If the general practitioner does not have access to an eye chart or near card, any assessment of vision with an appropriate description will be useful (eg, the patient can quickly count fingers at 15 feet in the unaffected eye, but the eye with reported vision loss cannot reliably count fingers outside of 2 feet). Additional ocular symptoms associated with the vision loss, such as pain, redness, photophobia, new flashes or floaters, increase the urgency of the referral. The threshold for referral for any ocular complaint is lower compared with that of the general population for those with evidence of immunodeficiency, such as for this patient with HIV. Any CD4 count < 200 cells/mm³ should raise the practitioner’s concern for an ocular opportunistic infection, with the greatest concern with CD4 counts < 50 cells/mm³.

►Dr. Swamy. The patient underwent further testing in the ophthalmology clinic. Dr. Butler, can you please interpret the funduscopic exam?

►Dr. Butler. Both eyes demonstrate findings (microaneurysms and small dot-blot hemorrhages) consistent with moderate nonproliferative diabetic retinopathy (Figure 1A, white arrows). HIV-associated retinopathy could produce similar findings, but it is not generally seen with CD4 counts > 200 cells/mm³. Additionally, in the left eye, there is a diffuse patch of retinal whitening (retinitis) associated with the inferotemporal vascular arcades (Figure 1B, white arrows). The entire area involved is poorly circumscribed and the whitening is subtle in areas. Overlying some areas of deeper, ground-glass whitening there are scattered, punctate white spots (Figure 1B, green arrows). Wickremasinghe and colleagues described this pattern of retinitis and suggested that it had a high positive-predictive value in the diagnosis of ocular syphilis.⁵

►Dr. Swamy. The patient then underwent fluorescein angiography and optical coherence tomography (OCT). Dr. Butler, what did the fluorescein angiography show?

►Dr. Butler. The fluorescein angiogram in both eyes revealed leakage of dye consistent with diabetic retinopathy, with the right eye (OD) worse than the left (OS). Additionally, the areas of active retinitis in the left eye displayed gradual staining with leopard-spot changes, along with late leakage of fluorescein dye, indicating vasculopathy in the infected area (Figure 2, arrows). The patient also underwent OCT in the left eye (images not displayed) demonstrating vitreous cells (vitritis), patches of inner retinal thickening with hyperreflectivity, and hyperreflective nodules at the level of the retinal pigment epithelium with overlying photoreceptor disruption. These OCT findings are fairly stereotypic for syphilitic chorioretinitis.⁶

►Dr. Swamy. Based on the ophthalmic findings, a diagnosis of ocular syphilis was made. Dr. Serrao, what should internists consider as they evaluate and manage a patient with ocular syphilis?

►Dr. Serrao. Although isolated ocular involvement from syphilis is possible, the majority of patients (up to 85%) with HIV can present with concomitant central nervous system infection and about 30% present with symptomatic neurosyphilis (a typical late manifestation of this disease) that reflects the aggressiveness, accelerated course and propensity for wide dissemination of syphilis in this patient population.⁷

The presence of concomitant cutaneous rashes should prompt universal precautions, because transmission can occur via skin to skin contact. Clinicians should watch for the Jarisch-Herxheimer reaction during treatment, a syndrome of fever, myalgias, and headache, which results from circulating cytokines produced because of rapidly dying spirochetes that could mimic a penicillin drug reaction, yet is treated supportively.

As syphilis is sexually acquired, clinicians should test for coexistent sexually transmitted infections, vaccinate for those that are preventable (eg, hepatitis B), notify sexual partners via assistance from local departments of public health, and assess for coexistent drug use and offer counseling in order to optimize risk reduction. Special attention should be paid to virologic control of HIV since some studies have shown an increase in the propensity for breakthrough HIV viremia while on effective ART.⁹ This should warrant counseling for ongoing optimal ART adherence and close monitoring in the follow-up visits with a provider specialized in the treatment of syphilis and HIV.

►Dr. Swamy. A lumbar puncture is performed with the results listed in Table 2. Dr. Serrao, is the CSF consistent with neurosyphilis? What would you do next?

►Dr. Serrao. The lumbar puncture is inflammatory with a lymphocytic predominance, consistent with active ocular/neurosyphilis. The CSF Venereal Disease Research Laboratory test is specific but not sensitive so a negative value does not rule out the presence of central nervous system infection.¹⁰ The CSF fluorescent treponemal antibody (CSF FTA-ABS) is sensitive but not specific. In this case, the ocular findings, positive serum RPR, CSF lymphocytic predominance, and CSF FTA ABS strongly supports the diagnosis of ocular/early neurosyphilis in a patient with HIV infection in whom early aggressive treatment is warranted to prevent rapid progression/potential loss of vision.¹¹

►Dr. Swamy. Dr. Butler, how does syphilis behave in the eye as compared to other infectious or inflammatory diseases? Do visual symptoms respond well to treatment?

►Dr. Butler. As opposed to the dramatic reduction in rates and severity of CMV retinitis, HAART has had a negligible effect on ocular syphilis in the setting of HIV coinfection; in fact, rates of syphilis, including ocular syphilis, are currently surging world-wide, and HIV coinfection portends a worse prognosis.¹² This is especially true among gay men. More so, there appears to be no correlation between CD4 count and incidence of developing ocular syphilis, as opposed to CMV retinitis, which occurs far more frequently in those with CD4 counts < 50 cells/mm³. In keeping with its epithet as one of the “Great Imitators,” syphilis can affect virtually every tissue of the eye—conjunctiva, sclera, cornea, iris, lens, vitreous, retina, choroid, optic nerve—unlike other OOI, such as CMV or toxoplasma, which generally hone to the retina. Nonetheless, various findings and patterns on clinical exam and ancillary testing, such as the more recently described punctate inner retinitis (as seen in our patient) and the more classic acute syphilitic posterior placoid chorioretinitis, carry high specificity for ocular syphilis.¹³

Patients with ocular syphilis should be treated according to neurosyphilis treatment protocols. In general, these patients respond very well to treatment with resolution of the ocular findings and recovery of complete, or nearly so, visual function, as long as an excessive delay between diagnosis and proper treatment does not occur.¹⁴

►Dr. Swamy. Following this testing, the patient completed 14 days of IV penicillin with resolution of symptoms. He had no further vision complaints. He was started on Triumeq (abacavir, dolutegravir, and lamivudine) with good adherence to therapy. Dr. Serrao, in 2016 the CDC released a clinical advisory about ocular syphilis. Can you tell us about why this is an important diagnosis to be aware of today?

►Dr. Serrao. As with any disease, the epidemiologic characteristics of an infection like syphilis allow the clinician to more carefully entertain such a diagnosis in any one individual by improving the index of suspicion for a particular disease. Awareness of an increase in ocular syphilis in HIV positive MSM allows for a more timely assessment and subsequent treatment with the goal of preventing loss of vision.¹⁵

Use of methamphetamine, an N-methyl analog of amphetamine, is a serious public health problem; throughout the world an estimated 35.7 million people use the drug recreationally.¹ Methamphetamine is easy to obtain because it is cheap to produce and can be synthesized anywhere. In the United States, methamphetamine is commonly manufactured in small-scale laboratories using relatively inexpensive, legally available ingredients. Large-scale manufacturing in clandestine laboratories also contributes to methamphetamine abuse. The drug, known as meth, crystal meth, ice, and other names, is available as a powder, tablet, or crystalline salt, and is used by various routes of administration (Table).
 

• provide a brief synopsis of the clinical presentation of patients who use methamphetamine
• describe some of the complications of methamphetamine abuse/dependence, focusing on methamphetamine-induced psychosis
• suggest ways to approach the treatment of these patients, including those with methamphetamine-induced psychosis.

Acute effects of methamphetamine use

Psychiatric symptoms. Patients under the influence of methamphetamine may present with clinical symptoms that mimic psychiatric disorders. For example, the drug can cause marked euphoria, hyperactivity, and disturbed speech patterns, thus mimicking a manic state. Patients also may present with anxiety, agitation, and irritability or aggressiveness. Although an individual may take methamphetamine for sexual enhancement, the drug can cause hyper­sexuality, which often is associated with unintended and unsafe sexual activities. These signs and symptoms are exacerbated during drug binges that can last for days, during which time large quantities of the drug are consumed.

Methamphetamine users may become preoccupied with their own thought patterns, and their actions can become compulsive and nonsensical. For example, a patient may become obsessed with an object of no specific value in his (her) environment, such as a doorknob or a cloud. Patients also may become suspicious of their friends and family members or think that police officers are after them. Less commonly, a patient also may suffer from poverty of speech, psychomotor retardation, and diminished social engagement similar to that reported in some patients with schizophrenia with deficit syndrome. Usually, acute symptoms will last 4 to 7 days after drug cessation, and then resolve completely with protracted abstinence from the drug.

Neurologic signs of methamphetamine use include hemorrhagic strokes in young people without any evidence of previous neurologic impairments. Studies have documented similarities between methamphetamine-induced neurotoxicity and traumatic brain injury.⁵ Postmortem studies have reported the presence of arteriovenous malformation in some patients with hemorrhagic strokes.

Hyperthermia is a dangerous acute effect of methamphetamine use. High body temperatures can cause both peripheral and central abnormalities, including muscular and cardiovascular dysfunction, renal failure secondary to rhabdomyolysis, heat stroke, and other heat-induced malignant syndromes. Some of the central dysfunctions may be related to heat-induced production of free radicals in various brain regions. There are no pharmacologic treatments for methamphetamine-induced thermal dysregulation.⁶ Therefore, clinicians need to focus on reducing body temperature by using cooling fans or cold water baths. Efforts should be made to avoid overhydrating patients because of the risk of developing the syndrome of inappropriate antidiuretic hormone secretion.

Chronic methamphetamine abuse

Psychosis is a long-term complication of chronic abuse of the drug.⁷ Although psychosis has been a reported complication of methamphetamine use since the 1950s,⁸ most of the subsequent literature is from Japan, where methamphetamine use was highly prevalent after World War II.^9,10 The prevalence of methamphetamine-induced psychosis in methamphetamine-dependent patients varies from 13% (in the United States¹¹) to 50% (in Asia¹²). This difference might be related to variability in the purity of methamphetamine used in different locations.

Methamphetamine users may experience a pre-psychotic state that consists of ideas of reference and delusional moods. This is followed by a psychotic state that includes hallucinations and delusions. The time it takes to develop these symptoms can vary from a few months up to >20 years after starting to use methamphetamine.^10,13 Psychosis can occur in patients who do not have a history of psychiatric illness.¹⁰

The clinical presentation of methamphetamine-induced psychosis includes delusions of reference and persecutions.^8-10 Paranoid delusions may be accompanied by violent behavior. Some patients may present with grandiose or jealousy delusions. Patients may experience auditory, tactile, or visual hallucinations. They may exhibit mania and logorrheic verbal outputs, symptoms consistent with a diagnosis of methamphetamine-induced mood disorder with manic features. Patients who use large daily doses of the drug also may report that there are ants or other parasites crawling under their skin (eg, formication, “meth mites”) and might present with infected excoriations of their skin as a result of attempting to remove insects. This is clinically important because penicillin-resistant bacteria are common in patients who use methamphetamine, and strains tend to be virulent.

Psychotic symptoms can last from a few days to several weeks after stopping methamphetamine use, although methamphetamine-induced psychosis can persist after long periods of abstinence.¹⁴ Psychotic symptoms may recur with re-exposure to the drug⁹ or repeated stressful life events.¹⁵ Patients with recurrent psychosis in the absence of a drug trigger appear to have high levels of peripheral norepinephrine.¹⁵ Patients with psychosis caused by long-term methamphetamine use will not necessarily show signs of sympathomimetic dysfunction because they may not have any methamphetamine in the body when they first present for clinical evaluation. Importantly, patients with methamphetamine-induced psychosis have been reported to have poor outcomes at follow-up.¹⁶ They have an increased risk of suicide, recurrent drug-induced psychosis, and comorbid alcohol abuse.¹⁶

Doses required to induce psychosis vary from patient to patient and may depend on the patient’s genetic background and/or environmental conditions. Methamphetamine can increase the severity of many psychiatric symptoms¹⁷ and may expedite the development of schizophrenia in first-degree relatives of patients with schizophrenia.¹⁸

The diagnosis of methamphetamine-induced psychosis should focus on differentiating it from schizophrenia. Wang et al¹⁹ found similar patterns of delusions in patients with schizophrenia and those with methamphetamine-induced psychosis. However, compared with patients with schizophrenia, patients with methamphetamine-induced psychosis have a higher prevalence of visual and tactile hallucinations, and less disorganization, blunted affect, and motor retardation. Some patients may present with depression and suicidal ideation; these features may be more prominent during withdrawal, but also may be obvious during periods of active use.¹⁶

Although these clinical features may be helpful initially, more comparative neurobiologic investigations are needed to identify potential biologic differences between schizophrenia and methamphetamine-induced psychosis because these differences will impact therapeutic approaches to these diverse population groups.

Neurologic complications. Chronic methamphetamine users may develop various neurologic disorders.²⁰ They may present with stereotypies involving finger movements or repeated rubbing of mouth or face, orofacial dyskinesia, and choreoathetoid movements reminiscent of classical neurologic disorders. These movement disorders can persist after cessation of methamphetamine use. In some cases, these movement abnormalities may respond to dopamine receptor antagonists such as haloperidol.

Neuropsychological findings. Chronic methamphetamine users show mild signs of cognitive decline that affects a broad range of neuropsychological functions.^21-23 There are deficits in several cognitive processes that are dependent on the function of frontostriatal and limbic circuits.^24-26 Specifically, episodic memory, executive functions, complex information processing speed, and psychomotor functions all have been reported to be negatively impacted.

Methamphetamine use often results in psychiatric distress that impacts users’ interpersonal relationships.²⁷ Additionally, impulsivity may exacerbate their psychosocial difficulties and promote maintenance of drug-seeking behaviors.²⁸ Cognitive deficits lead to poor health outcomes, high-risk behaviors, employment difficulties, and repeated relapse.^29,30

Partial recovery of neuropsychological functioning and improvement in affective distress can be achieved after sustained abstinence from methamphetamine, but recovery may not be complete. Because cognitive dysfunction can influence treatment outcomes, clinicians need to be fully aware of the cognitive status of those patients, and a thorough neuropsychological evaluation is necessary before initiating treatment.

Treatment

Methamphetamine abuse. Because patients who abuse methamphetamine are at high risk of developing psychosis, neuro­logic complications, and neuropsychological disorders, initiating treatment early in the course of their addiction is of paramount importance. Treatment of methamphetamine addiction is complicated by the fact that these patients have a high prevalence of comorbid psychiatric disorders, which clinicians need to keep in mind when selecting therapeutic interventions.

There are no FDA-approved agents for treating methamphetamine abuse.³¹ Several drugs have been tried with varying degrees of success, including bupropion, modafinil, and naltrexone. A study of modafinil found no clinically significant effects for treating methamphetamine abuse; however, only approximately one-half of participants in this study took modafinil as instructed.³² Certain selective serotonin reuptake inhibitors, including fluoxetine and paroxetine, have not been shown to be effective in treating these patients. Naltrexone may be a reasonable medication to consider because of the high prevalence of comorbid alcohol abuse among methamphetamine users.

Other treatments for methamphetamine addiction consist of behavioral interventions such as cognitive-behavioral therapy. Clinical experience has shown that the risk of relapse depends on how long the patient has been abstinent prior to entering a treatment program, the presence of attention and memory deficits, and findings of poor decision-making on neuropsychological tests.

The presence of cognitive abnormalities has been reported to impact methamphetamine abusers’ response to treatment.³³ These findings suggest the need to develop approaches that might improve cognition in patients who are undergoing treatment for methamphetamine abuse. The monoaminergic agent modafinil and similar drugs need to be evaluated in large populations to increase the possibility of identifying characteristics of patients who might respond to cognitive enhancement.³⁴

Methamphetamine-induced psychosis. First-generation antipsychotics, such as haloperidol or fluphenazine, need to be used sparingly in patients with methamphetamine-induced psychosis because of the risk of developing extrapyramidal symptoms (EPS) and because these patients are prone to develop motor complications as a result of methamphetamine abuse. Second-generation antipsychotics, such as risperidone and olanzapine, may be more appropriate because of the lower risks of EPS.³⁵ The presence of high norepinephrine levels in some patients with recurrent methamphetamine psychosis suggests that drugs that block norepinephrine receptors, such as prazosin or propranolol, might be of therapeutic benefit if they are shown to be effective in controlled clinical trials.

Use of methamphetamine, an N-methyl analog of amphetamine, is a serious public health problem; throughout the world an estimated 35.7 million people use the drug recreationally.¹ Methamphetamine is easy to obtain because it is cheap to produce and can be synthesized anywhere. In the United States, methamphetamine is commonly manufactured in small-scale laboratories using relatively inexpensive, legally available ingredients. Large-scale manufacturing in clandestine laboratories also contributes to methamphetamine abuse. The drug, known as meth, crystal meth, ice, and other names, is available as a powder, tablet, or crystalline salt, and is used by various routes of administration (Table).
 

• provide a brief synopsis of the clinical presentation of patients who use methamphetamine
• describe some of the complications of methamphetamine abuse/dependence, focusing on methamphetamine-induced psychosis
• suggest ways to approach the treatment of these patients, including those with methamphetamine-induced psychosis.

Acute effects of methamphetamine use

Psychiatric symptoms. Patients under the influence of methamphetamine may present with clinical symptoms that mimic psychiatric disorders. For example, the drug can cause marked euphoria, hyperactivity, and disturbed speech patterns, thus mimicking a manic state. Patients also may present with anxiety, agitation, and irritability or aggressiveness. Although an individual may take methamphetamine for sexual enhancement, the drug can cause hyper­sexuality, which often is associated with unintended and unsafe sexual activities. These signs and symptoms are exacerbated during drug binges that can last for days, during which time large quantities of the drug are consumed.

Methamphetamine users may become preoccupied with their own thought patterns, and their actions can become compulsive and nonsensical. For example, a patient may become obsessed with an object of no specific value in his (her) environment, such as a doorknob or a cloud. Patients also may become suspicious of their friends and family members or think that police officers are after them. Less commonly, a patient also may suffer from poverty of speech, psychomotor retardation, and diminished social engagement similar to that reported in some patients with schizophrenia with deficit syndrome. Usually, acute symptoms will last 4 to 7 days after drug cessation, and then resolve completely with protracted abstinence from the drug.

Neurologic signs of methamphetamine use include hemorrhagic strokes in young people without any evidence of previous neurologic impairments. Studies have documented similarities between methamphetamine-induced neurotoxicity and traumatic brain injury.⁵ Postmortem studies have reported the presence of arteriovenous malformation in some patients with hemorrhagic strokes.

Hyperthermia is a dangerous acute effect of methamphetamine use. High body temperatures can cause both peripheral and central abnormalities, including muscular and cardiovascular dysfunction, renal failure secondary to rhabdomyolysis, heat stroke, and other heat-induced malignant syndromes. Some of the central dysfunctions may be related to heat-induced production of free radicals in various brain regions. There are no pharmacologic treatments for methamphetamine-induced thermal dysregulation.⁶ Therefore, clinicians need to focus on reducing body temperature by using cooling fans or cold water baths. Efforts should be made to avoid overhydrating patients because of the risk of developing the syndrome of inappropriate antidiuretic hormone secretion.

Chronic methamphetamine abuse

Psychosis is a long-term complication of chronic abuse of the drug.⁷ Although psychosis has been a reported complication of methamphetamine use since the 1950s,⁸ most of the subsequent literature is from Japan, where methamphetamine use was highly prevalent after World War II.^9,10 The prevalence of methamphetamine-induced psychosis in methamphetamine-dependent patients varies from 13% (in the United States¹¹) to 50% (in Asia¹²). This difference might be related to variability in the purity of methamphetamine used in different locations.

Methamphetamine users may experience a pre-psychotic state that consists of ideas of reference and delusional moods. This is followed by a psychotic state that includes hallucinations and delusions. The time it takes to develop these symptoms can vary from a few months up to >20 years after starting to use methamphetamine.^10,13 Psychosis can occur in patients who do not have a history of psychiatric illness.¹⁰

The clinical presentation of methamphetamine-induced psychosis includes delusions of reference and persecutions.^8-10 Paranoid delusions may be accompanied by violent behavior. Some patients may present with grandiose or jealousy delusions. Patients may experience auditory, tactile, or visual hallucinations. They may exhibit mania and logorrheic verbal outputs, symptoms consistent with a diagnosis of methamphetamine-induced mood disorder with manic features. Patients who use large daily doses of the drug also may report that there are ants or other parasites crawling under their skin (eg, formication, “meth mites”) and might present with infected excoriations of their skin as a result of attempting to remove insects. This is clinically important because penicillin-resistant bacteria are common in patients who use methamphetamine, and strains tend to be virulent.

Psychotic symptoms can last from a few days to several weeks after stopping methamphetamine use, although methamphetamine-induced psychosis can persist after long periods of abstinence.¹⁴ Psychotic symptoms may recur with re-exposure to the drug⁹ or repeated stressful life events.¹⁵ Patients with recurrent psychosis in the absence of a drug trigger appear to have high levels of peripheral norepinephrine.¹⁵ Patients with psychosis caused by long-term methamphetamine use will not necessarily show signs of sympathomimetic dysfunction because they may not have any methamphetamine in the body when they first present for clinical evaluation. Importantly, patients with methamphetamine-induced psychosis have been reported to have poor outcomes at follow-up.¹⁶ They have an increased risk of suicide, recurrent drug-induced psychosis, and comorbid alcohol abuse.¹⁶

Doses required to induce psychosis vary from patient to patient and may depend on the patient’s genetic background and/or environmental conditions. Methamphetamine can increase the severity of many psychiatric symptoms¹⁷ and may expedite the development of schizophrenia in first-degree relatives of patients with schizophrenia.¹⁸

The diagnosis of methamphetamine-induced psychosis should focus on differentiating it from schizophrenia. Wang et al¹⁹ found similar patterns of delusions in patients with schizophrenia and those with methamphetamine-induced psychosis. However, compared with patients with schizophrenia, patients with methamphetamine-induced psychosis have a higher prevalence of visual and tactile hallucinations, and less disorganization, blunted affect, and motor retardation. Some patients may present with depression and suicidal ideation; these features may be more prominent during withdrawal, but also may be obvious during periods of active use.¹⁶

Although these clinical features may be helpful initially, more comparative neurobiologic investigations are needed to identify potential biologic differences between schizophrenia and methamphetamine-induced psychosis because these differences will impact therapeutic approaches to these diverse population groups.

Neurologic complications. Chronic methamphetamine users may develop various neurologic disorders.²⁰ They may present with stereotypies involving finger movements or repeated rubbing of mouth or face, orofacial dyskinesia, and choreoathetoid movements reminiscent of classical neurologic disorders. These movement disorders can persist after cessation of methamphetamine use. In some cases, these movement abnormalities may respond to dopamine receptor antagonists such as haloperidol.

Neuropsychological findings. Chronic methamphetamine users show mild signs of cognitive decline that affects a broad range of neuropsychological functions.^21-23 There are deficits in several cognitive processes that are dependent on the function of frontostriatal and limbic circuits.^24-26 Specifically, episodic memory, executive functions, complex information processing speed, and psychomotor functions all have been reported to be negatively impacted.

Methamphetamine use often results in psychiatric distress that impacts users’ interpersonal relationships.²⁷ Additionally, impulsivity may exacerbate their psychosocial difficulties and promote maintenance of drug-seeking behaviors.²⁸ Cognitive deficits lead to poor health outcomes, high-risk behaviors, employment difficulties, and repeated relapse.^29,30

Partial recovery of neuropsychological functioning and improvement in affective distress can be achieved after sustained abstinence from methamphetamine, but recovery may not be complete. Because cognitive dysfunction can influence treatment outcomes, clinicians need to be fully aware of the cognitive status of those patients, and a thorough neuropsychological evaluation is necessary before initiating treatment.

Treatment

Methamphetamine abuse. Because patients who abuse methamphetamine are at high risk of developing psychosis, neuro­logic complications, and neuropsychological disorders, initiating treatment early in the course of their addiction is of paramount importance. Treatment of methamphetamine addiction is complicated by the fact that these patients have a high prevalence of comorbid psychiatric disorders, which clinicians need to keep in mind when selecting therapeutic interventions.

There are no FDA-approved agents for treating methamphetamine abuse.³¹ Several drugs have been tried with varying degrees of success, including bupropion, modafinil, and naltrexone. A study of modafinil found no clinically significant effects for treating methamphetamine abuse; however, only approximately one-half of participants in this study took modafinil as instructed.³² Certain selective serotonin reuptake inhibitors, including fluoxetine and paroxetine, have not been shown to be effective in treating these patients. Naltrexone may be a reasonable medication to consider because of the high prevalence of comorbid alcohol abuse among methamphetamine users.

Other treatments for methamphetamine addiction consist of behavioral interventions such as cognitive-behavioral therapy. Clinical experience has shown that the risk of relapse depends on how long the patient has been abstinent prior to entering a treatment program, the presence of attention and memory deficits, and findings of poor decision-making on neuropsychological tests.

The presence of cognitive abnormalities has been reported to impact methamphetamine abusers’ response to treatment.³³ These findings suggest the need to develop approaches that might improve cognition in patients who are undergoing treatment for methamphetamine abuse. The monoaminergic agent modafinil and similar drugs need to be evaluated in large populations to increase the possibility of identifying characteristics of patients who might respond to cognitive enhancement.³⁴

Methamphetamine-induced psychosis. First-generation antipsychotics, such as haloperidol or fluphenazine, need to be used sparingly in patients with methamphetamine-induced psychosis because of the risk of developing extrapyramidal symptoms (EPS) and because these patients are prone to develop motor complications as a result of methamphetamine abuse. Second-generation antipsychotics, such as risperidone and olanzapine, may be more appropriate because of the lower risks of EPS.³⁵ The presence of high norepinephrine levels in some patients with recurrent methamphetamine psychosis suggests that drugs that block norepinephrine receptors, such as prazosin or propranolol, might be of therapeutic benefit if they are shown to be effective in controlled clinical trials.

Use of methamphetamine, an N-methyl analog of amphetamine, is a serious public health problem; throughout the world an estimated 35.7 million people use the drug recreationally.¹ Methamphetamine is easy to obtain because it is cheap to produce and can be synthesized anywhere. In the United States, methamphetamine is commonly manufactured in small-scale laboratories using relatively inexpensive, legally available ingredients. Large-scale manufacturing in clandestine laboratories also contributes to methamphetamine abuse. The drug, known as meth, crystal meth, ice, and other names, is available as a powder, tablet, or crystalline salt, and is used by various routes of administration (Table).
 

• provide a brief synopsis of the clinical presentation of patients who use methamphetamine
• describe some of the complications of methamphetamine abuse/dependence, focusing on methamphetamine-induced psychosis
• suggest ways to approach the treatment of these patients, including those with methamphetamine-induced psychosis.

Acute effects of methamphetamine use

Psychiatric symptoms. Patients under the influence of methamphetamine may present with clinical symptoms that mimic psychiatric disorders. For example, the drug can cause marked euphoria, hyperactivity, and disturbed speech patterns, thus mimicking a manic state. Patients also may present with anxiety, agitation, and irritability or aggressiveness. Although an individual may take methamphetamine for sexual enhancement, the drug can cause hyper­sexuality, which often is associated with unintended and unsafe sexual activities. These signs and symptoms are exacerbated during drug binges that can last for days, during which time large quantities of the drug are consumed.

Methamphetamine users may become preoccupied with their own thought patterns, and their actions can become compulsive and nonsensical. For example, a patient may become obsessed with an object of no specific value in his (her) environment, such as a doorknob or a cloud. Patients also may become suspicious of their friends and family members or think that police officers are after them. Less commonly, a patient also may suffer from poverty of speech, psychomotor retardation, and diminished social engagement similar to that reported in some patients with schizophrenia with deficit syndrome. Usually, acute symptoms will last 4 to 7 days after drug cessation, and then resolve completely with protracted abstinence from the drug.

Neurologic signs of methamphetamine use include hemorrhagic strokes in young people without any evidence of previous neurologic impairments. Studies have documented similarities between methamphetamine-induced neurotoxicity and traumatic brain injury.⁵ Postmortem studies have reported the presence of arteriovenous malformation in some patients with hemorrhagic strokes.

Hyperthermia is a dangerous acute effect of methamphetamine use. High body temperatures can cause both peripheral and central abnormalities, including muscular and cardiovascular dysfunction, renal failure secondary to rhabdomyolysis, heat stroke, and other heat-induced malignant syndromes. Some of the central dysfunctions may be related to heat-induced production of free radicals in various brain regions. There are no pharmacologic treatments for methamphetamine-induced thermal dysregulation.⁶ Therefore, clinicians need to focus on reducing body temperature by using cooling fans or cold water baths. Efforts should be made to avoid overhydrating patients because of the risk of developing the syndrome of inappropriate antidiuretic hormone secretion.

Chronic methamphetamine abuse

Psychosis is a long-term complication of chronic abuse of the drug.⁷ Although psychosis has been a reported complication of methamphetamine use since the 1950s,⁸ most of the subsequent literature is from Japan, where methamphetamine use was highly prevalent after World War II.^9,10 The prevalence of methamphetamine-induced psychosis in methamphetamine-dependent patients varies from 13% (in the United States¹¹) to 50% (in Asia¹²). This difference might be related to variability in the purity of methamphetamine used in different locations.

Methamphetamine users may experience a pre-psychotic state that consists of ideas of reference and delusional moods. This is followed by a psychotic state that includes hallucinations and delusions. The time it takes to develop these symptoms can vary from a few months up to >20 years after starting to use methamphetamine.^10,13 Psychosis can occur in patients who do not have a history of psychiatric illness.¹⁰

The clinical presentation of methamphetamine-induced psychosis includes delusions of reference and persecutions.^8-10 Paranoid delusions may be accompanied by violent behavior. Some patients may present with grandiose or jealousy delusions. Patients may experience auditory, tactile, or visual hallucinations. They may exhibit mania and logorrheic verbal outputs, symptoms consistent with a diagnosis of methamphetamine-induced mood disorder with manic features. Patients who use large daily doses of the drug also may report that there are ants or other parasites crawling under their skin (eg, formication, “meth mites”) and might present with infected excoriations of their skin as a result of attempting to remove insects. This is clinically important because penicillin-resistant bacteria are common in patients who use methamphetamine, and strains tend to be virulent.

Psychotic symptoms can last from a few days to several weeks after stopping methamphetamine use, although methamphetamine-induced psychosis can persist after long periods of abstinence.¹⁴ Psychotic symptoms may recur with re-exposure to the drug⁹ or repeated stressful life events.¹⁵ Patients with recurrent psychosis in the absence of a drug trigger appear to have high levels of peripheral norepinephrine.¹⁵ Patients with psychosis caused by long-term methamphetamine use will not necessarily show signs of sympathomimetic dysfunction because they may not have any methamphetamine in the body when they first present for clinical evaluation. Importantly, patients with methamphetamine-induced psychosis have been reported to have poor outcomes at follow-up.¹⁶ They have an increased risk of suicide, recurrent drug-induced psychosis, and comorbid alcohol abuse.¹⁶

Doses required to induce psychosis vary from patient to patient and may depend on the patient’s genetic background and/or environmental conditions. Methamphetamine can increase the severity of many psychiatric symptoms¹⁷ and may expedite the development of schizophrenia in first-degree relatives of patients with schizophrenia.¹⁸

The diagnosis of methamphetamine-induced psychosis should focus on differentiating it from schizophrenia. Wang et al¹⁹ found similar patterns of delusions in patients with schizophrenia and those with methamphetamine-induced psychosis. However, compared with patients with schizophrenia, patients with methamphetamine-induced psychosis have a higher prevalence of visual and tactile hallucinations, and less disorganization, blunted affect, and motor retardation. Some patients may present with depression and suicidal ideation; these features may be more prominent during withdrawal, but also may be obvious during periods of active use.¹⁶

Although these clinical features may be helpful initially, more comparative neurobiologic investigations are needed to identify potential biologic differences between schizophrenia and methamphetamine-induced psychosis because these differences will impact therapeutic approaches to these diverse population groups.

Neurologic complications. Chronic methamphetamine users may develop various neurologic disorders.²⁰ They may present with stereotypies involving finger movements or repeated rubbing of mouth or face, orofacial dyskinesia, and choreoathetoid movements reminiscent of classical neurologic disorders. These movement disorders can persist after cessation of methamphetamine use. In some cases, these movement abnormalities may respond to dopamine receptor antagonists such as haloperidol.

Neuropsychological findings. Chronic methamphetamine users show mild signs of cognitive decline that affects a broad range of neuropsychological functions.^21-23 There are deficits in several cognitive processes that are dependent on the function of frontostriatal and limbic circuits.^24-26 Specifically, episodic memory, executive functions, complex information processing speed, and psychomotor functions all have been reported to be negatively impacted.

Methamphetamine use often results in psychiatric distress that impacts users’ interpersonal relationships.²⁷ Additionally, impulsivity may exacerbate their psychosocial difficulties and promote maintenance of drug-seeking behaviors.²⁸ Cognitive deficits lead to poor health outcomes, high-risk behaviors, employment difficulties, and repeated relapse.^29,30

Partial recovery of neuropsychological functioning and improvement in affective distress can be achieved after sustained abstinence from methamphetamine, but recovery may not be complete. Because cognitive dysfunction can influence treatment outcomes, clinicians need to be fully aware of the cognitive status of those patients, and a thorough neuropsychological evaluation is necessary before initiating treatment.

Treatment

Methamphetamine abuse. Because patients who abuse methamphetamine are at high risk of developing psychosis, neuro­logic complications, and neuropsychological disorders, initiating treatment early in the course of their addiction is of paramount importance. Treatment of methamphetamine addiction is complicated by the fact that these patients have a high prevalence of comorbid psychiatric disorders, which clinicians need to keep in mind when selecting therapeutic interventions.

There are no FDA-approved agents for treating methamphetamine abuse.³¹ Several drugs have been tried with varying degrees of success, including bupropion, modafinil, and naltrexone. A study of modafinil found no clinically significant effects for treating methamphetamine abuse; however, only approximately one-half of participants in this study took modafinil as instructed.³² Certain selective serotonin reuptake inhibitors, including fluoxetine and paroxetine, have not been shown to be effective in treating these patients. Naltrexone may be a reasonable medication to consider because of the high prevalence of comorbid alcohol abuse among methamphetamine users.

Other treatments for methamphetamine addiction consist of behavioral interventions such as cognitive-behavioral therapy. Clinical experience has shown that the risk of relapse depends on how long the patient has been abstinent prior to entering a treatment program, the presence of attention and memory deficits, and findings of poor decision-making on neuropsychological tests.

The presence of cognitive abnormalities has been reported to impact methamphetamine abusers’ response to treatment.³³ These findings suggest the need to develop approaches that might improve cognition in patients who are undergoing treatment for methamphetamine abuse. The monoaminergic agent modafinil and similar drugs need to be evaluated in large populations to increase the possibility of identifying characteristics of patients who might respond to cognitive enhancement.³⁴

Methamphetamine-induced psychosis. First-generation antipsychotics, such as haloperidol or fluphenazine, need to be used sparingly in patients with methamphetamine-induced psychosis because of the risk of developing extrapyramidal symptoms (EPS) and because these patients are prone to develop motor complications as a result of methamphetamine abuse. Second-generation antipsychotics, such as risperidone and olanzapine, may be more appropriate because of the lower risks of EPS.³⁵ The presence of high norepinephrine levels in some patients with recurrent methamphetamine psychosis suggests that drugs that block norepinephrine receptors, such as prazosin or propranolol, might be of therapeutic benefit if they are shown to be effective in controlled clinical trials.