Habib Rehman, MBBS, FRCPC, FRCPI, FRCP (Glas), FACP

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 41-year-old man presented with pain in  the left upper quadrant for 4 days. The pain was constant, was worse on inspiration, and did not radiate. He denied fevers, night sweats, nausea, vomiting, diarrhea, and urinary symptoms. He had been diagnosed with multiple sclerosis a few years earlier, and he had undergone aortofemoral bypass surgery on the left side 2 years ago. He denied smoking or using illicit drugs and described himself as a social drinker.

In the emergency room, he appeared comfortable. He was afebrile, blood pressure 136/69 mm Hg, pulse rate 98 per minute, and respiratory rate 16. All pulses were palpable and equal, the jugular venous pressure was not elevated, and no cardiac murmurs were heard. The abdomen was tender in the left upper quadrant, with no guarding or rigidity. Examination of the nervous, musculoskeletal, and respiratory systems was unremarkable. Skin examination revealed only scars from previous surgery.

LABORATORY AND IMAGING RESULTS

• White blood cell count 7.2 × 10⁹/L (reference range 4.0–10.0) with a normal differential
• Hemoglobin 134 g/dL (140–180)
• Platelet count 167 × 10⁹/L (150–400)
• Renal and liver panels were normal
• Erythrocyte sedimentation rate 30 mm/hour
• C-reactive protein level 14.3 mg/L
• D-dimer level 2,670 ng/mL (< 500)
• International normalized ratio (INR) 1.0 (0.9–1.3)
• Activated partial thromboplastin time (aPTT) 44 seconds (25–38)
• Fibrinogen level 3.0 g/L (1.8–3.5)
• Urinalysis negative for leukocytes and casts.

Computed tomography of the abdomen showed a wedge-shaped area of hypodensity along the inferolateral aspect of the spleen measuring 6 × 3.8 cm, consistent with a recent infarct (Figure 1). There was also evidence of a previous infarct in the posterolateral aspect of the spleen. Splenic, celiac, superior mesenteric, and inferior mesenteric arteries were patent.

1. Given these findings, which of the following diagnoses should be considered?

• Subacute infective endocarditis
• Inherited thrombophilia
• Antiphospholipid syndrome

All three diagnoses should be considered in this case.

Endocarditis

Embolism from a source in the heart caused by subacute bacterial endocarditis is more common than the other two conditions listed here and must be excluded. 

Our patient lacks key features of this condition: he has no predisposing factors (artificial valve, cyanotic congenital heart disease, previous endocarditis, intravenous drug abuse); no constitutional symptoms of fever, night sweats, and weight loss; no findings on examination of skin and cardiovascular systems; and a normal white blood cell count. Nevertheless, even though the absence of these features makes bacterial endocarditis unlikely, it does not exclude it. Blood cultures and transesophageal echocardiography are indicated to rule out bacterial endocarditis.

We obtained serial blood cultures, which were negative, and transesophageal echocardiography showed normal valves and no evidence of thrombus or vegetation, thus excluding a cardiac source of emboli.

Thrombophilia

Our patient has a history of recurrent thromboembolic episodes, and this warrants testing to rule out an inherited thrombophilia. A family history of thromboembolic disease should also be sought.¹

When antiphospholipid syndrome occurs with systemic lupus erythematosus, it is termed ‘secondary’

In our patient, tests for prothrombotic activity including protein C chromogen, activated protein C ratio, free protein S, functional protein S, antithrombin factor V Leiden, and the prothrombin 20210G>A mutation were either negative or within the reference range. A negative family history of thromboembolic disease and the negative laboratory tests make inherited thrombophilia unlikely in our patient. 

Sickle cell disease, polycythemia vera, and essential thrombocythemia may also cause splenic infarction but can be ruled out in this patient on the basis of history and initial blood tests.

Antiphospholipid syndrome

A history of vascular disease (aortofemoral bypass surgery), a recent splenic infarct, and an elevated aPTT makes antiphospholipid syndrome the likeliest diagnosis in this patient.

Appropriate tests are for lupus anticoagulant, immunoglobulin G (IgG) or IgM cardiolipin antibody, and beta-2 glycoprotein 1 (beta-2 GP1) antibody, as well as the dilute Russell viper venom time (dRVVT) and the dRVVT ratio. The IgG and IgM cardiolipin antibody and beta-2 GP1 antibody tests have the same diagnostic value, and only medium to high titers should be considered positive.

Our patient’s IgG cardiolipin antibody level was in the normal range at 15 IgG phospholipid units (reference range 0–22); his IgM cardiolipin antibody level was high at 41 IgM phospholipid units (0–10). The dRVVT was 57 seconds (24–42), and the dRVVT ratio was 2.0 (0.0–1.3).

2. What further investigations are indicated before starting treatment?

• No further investigations required
• Repeat testing for phospholipid antibodies in 12 weeks
• Test for antinuclear antibodies

Antiphospholipid antibodies may appear transiently in certain infections, such as syphilis, Lyme disease, Epstein-Barr virus, cytomegalovirus, hepatitis C, and human immunodeficiency virus. Therefore, the presence of antiphospholipid antibodies must be confirmed over time, with two positive results at least 12 weeks apart.²

When repeated 12 weeks later, our patient’s IgG anticardiolipin antibody level was 14 GPL units, and the IgM anticardiolipin antibody level was 30 MPL units; the dRVVT was 55 seconds, and the dRVVT ratio was 1.8. These results, along with a history of recurrent arterial thrombosis, confirmed antiphospholipid syndrome.

The 2009 update of the International Society of Thrombosis and Haemostasis guidelines recommend two tests, the dRVVT and the aPTT, since no single test is 100% sensitive for lupus anticoagulant.³ The dRVVT has a high specificity for lupus anticoagulant in patients at high risk of thrombosis.

A SYNDROME WITH A WIDE RANGE OF EFFECTS AND COMPLICATIONS

Antiphospholipid syndrome is a systemic autoimmune disease that manifests as arterial and venous thrombosis and as obstetric complications. Thrombosis tends to be recurrent and may involve any site. For example, it can cause blurred vision in one or both eyes; amaurosis fugax; visual field defects; central or branch retinal artery or vein occlusion; deep vein thrombosis; pulmonary embolism; myocardial infarction; transient ischemic attack and stroke; cerebral vein thrombosis; and portal, renal, and mesenteric infarction involving veins or arteries.⁴ Pulmonary capillaritis may cause diffuse alveolar hemorrhage. Livedo reticularis, digital gangrene, cutaneous necrosis, splinter hemorrhages, chorea, and transverse myelopathy may also occur.

Obstetric complications of antiphospholipid syndrome include recurrent miscarriage and pregnancy loss at or after 10 weeks of gestation, eclampsia, preeclampsia, and placental insufficiency.⁵ The syndrome also has a potentially lethal variant characterized by multiorgan thrombosis affecting mainly small vessels.

The diagnosis of antiphospholipid syndrome requires relevant clinical features and symptoms and the presence of at least one of the antiphospholipid antibodies. Because the rate of false-positive tests for antiphospholipid antibodies ranges from 3% to 20% in the general population, asymptomatic patients should not be tested.⁶

Antiphospholipid syndrome may occur in the setting of other autoimmune diseases, most commonly systemic lupus erythematosus, when it is termed “secondary” antiphospholipid syndrome. Although only 40% of patients with lupus have antiphospholipid antibodies and less than 40% will have a thrombotic event, thrombotic antiphospholipid syndrome is a major adverse prognostic factor in these patients.^7,8 Therefore, it is prudent to consider systemic lupus erythematosus and to do appropriate tests if the patient has other features suggestive of lupus, such as renal, skin, or musculoskeletal lesions.

In our patient, antinuclear antibody testing was positive, with a titer of 1:320, and showed a finely speckled staining pattern. Tests for antibodies to Sjögren syndrome A and B antigens were negative. The complement C3 level was 1.28 g/L (reference range 0.74–1.85) and the C4 level was 0.24 g/L (0.16–0.44). Although the speckled staining pattern can be seen in lupus, it is more common in Sjögren syndrome, mixed connective tissue disease, scleroderma, and CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia).⁹ Moreover, normal levels of complement C3 and C4, in the absence of clinical features, make lupus unlikely. Similarly, our patient had no clinical features of other connective tissue disorders. Therefore, he had primary antiphospholipid syndrome.

3. How should this patient be managed?

• Antiplatelet therapy
• Warfarin to maintain an INR between 2.0 and 3.0
• Warfarin to maintain an INR above 3.0

The risk of recurrent thrombosis is high in patients who test positive for lupus anticoagulant, and the risk is highest in patients who are also positive for anticardiolipin and anti-beta-2 GP1 antibodies: the incidence of thrombosis is 12.2% at 1 year, 26.1% at 5 years, 44.2% at 10 years.¹⁰

Since our patient is positive for lupus anticoagulant (prolonged aPTT and elevated dRVVT, both indicating lupus anticoagulant positivity) and for anticardiolipin antibodies (anti-beta-2 GP1 not tested), his risk of recurrent thrombosis is high, and he requires lifelong anticoagulation therapy.

The intensity of anticoagulation in different subgroups of patients is controversial. Based on retrospective trials, indefinite anticoagulation at an INR of 2.0 to 3.0 has been suggested for patients with antiphospholipid syndrome presenting with venous thrombosis, and more intense anticoagulation with an INR above 3.0 in patients with recurrent or arterial thrombosis.¹¹ The combination of warfarin with an INR between 2.0 and 3.0 and aspirin 100 mg daily has also been proposed for patients with arterial thrombosis.¹²

Modifiable risk factors such as smoking, obesity, and use of estrogens should be addressed in all patients with antiphospholipid syndrome.

In pregnant women with complications such as preeclampsia, low-dose aspirin can be used, and in women with a history of miscarriage, the combination of low-dose aspirin and heparin is recommended throughout the prenatal period.⁴

In patients who have recurrent thrombosis despite adequate anticoagulation, an expert committee¹² has proposed that alternative regimens could include long-term low-molecular-weight heparin instead of warfarin, the combination of warfarin and aspirin, or warfarin and hydroxychloroquine. Adding a statin can also be considered.

Treatment of catastrophic antiphospholipid syndrome is based on expert opinion. A combination of anticoagulation, corticosteroids, plasma exchange, intravenous immunoglobulins, and rituximab has been tried, but the mortality rate remains high.¹³

OUR PATIENT'S COURSE

Our patient was started on warfarin, with a target INR above 3.0, and was doing well at 6 months of follow-up.

A 41-year-old man presented with pain in  the left upper quadrant for 4 days. The pain was constant, was worse on inspiration, and did not radiate. He denied fevers, night sweats, nausea, vomiting, diarrhea, and urinary symptoms. He had been diagnosed with multiple sclerosis a few years earlier, and he had undergone aortofemoral bypass surgery on the left side 2 years ago. He denied smoking or using illicit drugs and described himself as a social drinker.

In the emergency room, he appeared comfortable. He was afebrile, blood pressure 136/69 mm Hg, pulse rate 98 per minute, and respiratory rate 16. All pulses were palpable and equal, the jugular venous pressure was not elevated, and no cardiac murmurs were heard. The abdomen was tender in the left upper quadrant, with no guarding or rigidity. Examination of the nervous, musculoskeletal, and respiratory systems was unremarkable. Skin examination revealed only scars from previous surgery.

LABORATORY AND IMAGING RESULTS

• White blood cell count 7.2 × 10⁹/L (reference range 4.0–10.0) with a normal differential
• Hemoglobin 134 g/dL (140–180)
• Platelet count 167 × 10⁹/L (150–400)
• Renal and liver panels were normal
• Erythrocyte sedimentation rate 30 mm/hour
• C-reactive protein level 14.3 mg/L
• D-dimer level 2,670 ng/mL (< 500)
• International normalized ratio (INR) 1.0 (0.9–1.3)
• Activated partial thromboplastin time (aPTT) 44 seconds (25–38)
• Fibrinogen level 3.0 g/L (1.8–3.5)
• Urinalysis negative for leukocytes and casts.

Computed tomography of the abdomen showed a wedge-shaped area of hypodensity along the inferolateral aspect of the spleen measuring 6 × 3.8 cm, consistent with a recent infarct (Figure 1). There was also evidence of a previous infarct in the posterolateral aspect of the spleen. Splenic, celiac, superior mesenteric, and inferior mesenteric arteries were patent.

1. Given these findings, which of the following diagnoses should be considered?

• Subacute infective endocarditis
• Inherited thrombophilia
• Antiphospholipid syndrome

All three diagnoses should be considered in this case.

Endocarditis

Embolism from a source in the heart caused by subacute bacterial endocarditis is more common than the other two conditions listed here and must be excluded. 

Our patient lacks key features of this condition: he has no predisposing factors (artificial valve, cyanotic congenital heart disease, previous endocarditis, intravenous drug abuse); no constitutional symptoms of fever, night sweats, and weight loss; no findings on examination of skin and cardiovascular systems; and a normal white blood cell count. Nevertheless, even though the absence of these features makes bacterial endocarditis unlikely, it does not exclude it. Blood cultures and transesophageal echocardiography are indicated to rule out bacterial endocarditis.

We obtained serial blood cultures, which were negative, and transesophageal echocardiography showed normal valves and no evidence of thrombus or vegetation, thus excluding a cardiac source of emboli.

Thrombophilia

Our patient has a history of recurrent thromboembolic episodes, and this warrants testing to rule out an inherited thrombophilia. A family history of thromboembolic disease should also be sought.¹

When antiphospholipid syndrome occurs with systemic lupus erythematosus, it is termed ‘secondary’

In our patient, tests for prothrombotic activity including protein C chromogen, activated protein C ratio, free protein S, functional protein S, antithrombin factor V Leiden, and the prothrombin 20210G>A mutation were either negative or within the reference range. A negative family history of thromboembolic disease and the negative laboratory tests make inherited thrombophilia unlikely in our patient. 

Sickle cell disease, polycythemia vera, and essential thrombocythemia may also cause splenic infarction but can be ruled out in this patient on the basis of history and initial blood tests.

Antiphospholipid syndrome

A history of vascular disease (aortofemoral bypass surgery), a recent splenic infarct, and an elevated aPTT makes antiphospholipid syndrome the likeliest diagnosis in this patient.

Appropriate tests are for lupus anticoagulant, immunoglobulin G (IgG) or IgM cardiolipin antibody, and beta-2 glycoprotein 1 (beta-2 GP1) antibody, as well as the dilute Russell viper venom time (dRVVT) and the dRVVT ratio. The IgG and IgM cardiolipin antibody and beta-2 GP1 antibody tests have the same diagnostic value, and only medium to high titers should be considered positive.

Our patient’s IgG cardiolipin antibody level was in the normal range at 15 IgG phospholipid units (reference range 0–22); his IgM cardiolipin antibody level was high at 41 IgM phospholipid units (0–10). The dRVVT was 57 seconds (24–42), and the dRVVT ratio was 2.0 (0.0–1.3).

2. What further investigations are indicated before starting treatment?

• No further investigations required
• Repeat testing for phospholipid antibodies in 12 weeks
• Test for antinuclear antibodies

Antiphospholipid antibodies may appear transiently in certain infections, such as syphilis, Lyme disease, Epstein-Barr virus, cytomegalovirus, hepatitis C, and human immunodeficiency virus. Therefore, the presence of antiphospholipid antibodies must be confirmed over time, with two positive results at least 12 weeks apart.²

When repeated 12 weeks later, our patient’s IgG anticardiolipin antibody level was 14 GPL units, and the IgM anticardiolipin antibody level was 30 MPL units; the dRVVT was 55 seconds, and the dRVVT ratio was 1.8. These results, along with a history of recurrent arterial thrombosis, confirmed antiphospholipid syndrome.

The 2009 update of the International Society of Thrombosis and Haemostasis guidelines recommend two tests, the dRVVT and the aPTT, since no single test is 100% sensitive for lupus anticoagulant.³ The dRVVT has a high specificity for lupus anticoagulant in patients at high risk of thrombosis.

A SYNDROME WITH A WIDE RANGE OF EFFECTS AND COMPLICATIONS

Antiphospholipid syndrome is a systemic autoimmune disease that manifests as arterial and venous thrombosis and as obstetric complications. Thrombosis tends to be recurrent and may involve any site. For example, it can cause blurred vision in one or both eyes; amaurosis fugax; visual field defects; central or branch retinal artery or vein occlusion; deep vein thrombosis; pulmonary embolism; myocardial infarction; transient ischemic attack and stroke; cerebral vein thrombosis; and portal, renal, and mesenteric infarction involving veins or arteries.⁴ Pulmonary capillaritis may cause diffuse alveolar hemorrhage. Livedo reticularis, digital gangrene, cutaneous necrosis, splinter hemorrhages, chorea, and transverse myelopathy may also occur.

Obstetric complications of antiphospholipid syndrome include recurrent miscarriage and pregnancy loss at or after 10 weeks of gestation, eclampsia, preeclampsia, and placental insufficiency.⁵ The syndrome also has a potentially lethal variant characterized by multiorgan thrombosis affecting mainly small vessels.

The diagnosis of antiphospholipid syndrome requires relevant clinical features and symptoms and the presence of at least one of the antiphospholipid antibodies. Because the rate of false-positive tests for antiphospholipid antibodies ranges from 3% to 20% in the general population, asymptomatic patients should not be tested.⁶

Antiphospholipid syndrome may occur in the setting of other autoimmune diseases, most commonly systemic lupus erythematosus, when it is termed “secondary” antiphospholipid syndrome. Although only 40% of patients with lupus have antiphospholipid antibodies and less than 40% will have a thrombotic event, thrombotic antiphospholipid syndrome is a major adverse prognostic factor in these patients.^7,8 Therefore, it is prudent to consider systemic lupus erythematosus and to do appropriate tests if the patient has other features suggestive of lupus, such as renal, skin, or musculoskeletal lesions.

In our patient, antinuclear antibody testing was positive, with a titer of 1:320, and showed a finely speckled staining pattern. Tests for antibodies to Sjögren syndrome A and B antigens were negative. The complement C3 level was 1.28 g/L (reference range 0.74–1.85) and the C4 level was 0.24 g/L (0.16–0.44). Although the speckled staining pattern can be seen in lupus, it is more common in Sjögren syndrome, mixed connective tissue disease, scleroderma, and CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia).⁹ Moreover, normal levels of complement C3 and C4, in the absence of clinical features, make lupus unlikely. Similarly, our patient had no clinical features of other connective tissue disorders. Therefore, he had primary antiphospholipid syndrome.

3. How should this patient be managed?

• Antiplatelet therapy
• Warfarin to maintain an INR between 2.0 and 3.0
• Warfarin to maintain an INR above 3.0

The risk of recurrent thrombosis is high in patients who test positive for lupus anticoagulant, and the risk is highest in patients who are also positive for anticardiolipin and anti-beta-2 GP1 antibodies: the incidence of thrombosis is 12.2% at 1 year, 26.1% at 5 years, 44.2% at 10 years.¹⁰

Since our patient is positive for lupus anticoagulant (prolonged aPTT and elevated dRVVT, both indicating lupus anticoagulant positivity) and for anticardiolipin antibodies (anti-beta-2 GP1 not tested), his risk of recurrent thrombosis is high, and he requires lifelong anticoagulation therapy.

The intensity of anticoagulation in different subgroups of patients is controversial. Based on retrospective trials, indefinite anticoagulation at an INR of 2.0 to 3.0 has been suggested for patients with antiphospholipid syndrome presenting with venous thrombosis, and more intense anticoagulation with an INR above 3.0 in patients with recurrent or arterial thrombosis.¹¹ The combination of warfarin with an INR between 2.0 and 3.0 and aspirin 100 mg daily has also been proposed for patients with arterial thrombosis.¹²

Modifiable risk factors such as smoking, obesity, and use of estrogens should be addressed in all patients with antiphospholipid syndrome.

In pregnant women with complications such as preeclampsia, low-dose aspirin can be used, and in women with a history of miscarriage, the combination of low-dose aspirin and heparin is recommended throughout the prenatal period.⁴

In patients who have recurrent thrombosis despite adequate anticoagulation, an expert committee¹² has proposed that alternative regimens could include long-term low-molecular-weight heparin instead of warfarin, the combination of warfarin and aspirin, or warfarin and hydroxychloroquine. Adding a statin can also be considered.

Treatment of catastrophic antiphospholipid syndrome is based on expert opinion. A combination of anticoagulation, corticosteroids, plasma exchange, intravenous immunoglobulins, and rituximab has been tried, but the mortality rate remains high.¹³

OUR PATIENT'S COURSE

Our patient was started on warfarin, with a target INR above 3.0, and was doing well at 6 months of follow-up.

A 41-year-old man presented with pain in  the left upper quadrant for 4 days. The pain was constant, was worse on inspiration, and did not radiate. He denied fevers, night sweats, nausea, vomiting, diarrhea, and urinary symptoms. He had been diagnosed with multiple sclerosis a few years earlier, and he had undergone aortofemoral bypass surgery on the left side 2 years ago. He denied smoking or using illicit drugs and described himself as a social drinker.

In the emergency room, he appeared comfortable. He was afebrile, blood pressure 136/69 mm Hg, pulse rate 98 per minute, and respiratory rate 16. All pulses were palpable and equal, the jugular venous pressure was not elevated, and no cardiac murmurs were heard. The abdomen was tender in the left upper quadrant, with no guarding or rigidity. Examination of the nervous, musculoskeletal, and respiratory systems was unremarkable. Skin examination revealed only scars from previous surgery.

LABORATORY AND IMAGING RESULTS

• White blood cell count 7.2 × 10⁹/L (reference range 4.0–10.0) with a normal differential
• Hemoglobin 134 g/dL (140–180)
• Platelet count 167 × 10⁹/L (150–400)
• Renal and liver panels were normal
• Erythrocyte sedimentation rate 30 mm/hour
• C-reactive protein level 14.3 mg/L
• D-dimer level 2,670 ng/mL (< 500)
• International normalized ratio (INR) 1.0 (0.9–1.3)
• Activated partial thromboplastin time (aPTT) 44 seconds (25–38)
• Fibrinogen level 3.0 g/L (1.8–3.5)
• Urinalysis negative for leukocytes and casts.

Computed tomography of the abdomen showed a wedge-shaped area of hypodensity along the inferolateral aspect of the spleen measuring 6 × 3.8 cm, consistent with a recent infarct (Figure 1). There was also evidence of a previous infarct in the posterolateral aspect of the spleen. Splenic, celiac, superior mesenteric, and inferior mesenteric arteries were patent.

1. Given these findings, which of the following diagnoses should be considered?

• Subacute infective endocarditis
• Inherited thrombophilia
• Antiphospholipid syndrome

All three diagnoses should be considered in this case.

Endocarditis

Embolism from a source in the heart caused by subacute bacterial endocarditis is more common than the other two conditions listed here and must be excluded. 

Our patient lacks key features of this condition: he has no predisposing factors (artificial valve, cyanotic congenital heart disease, previous endocarditis, intravenous drug abuse); no constitutional symptoms of fever, night sweats, and weight loss; no findings on examination of skin and cardiovascular systems; and a normal white blood cell count. Nevertheless, even though the absence of these features makes bacterial endocarditis unlikely, it does not exclude it. Blood cultures and transesophageal echocardiography are indicated to rule out bacterial endocarditis.

We obtained serial blood cultures, which were negative, and transesophageal echocardiography showed normal valves and no evidence of thrombus or vegetation, thus excluding a cardiac source of emboli.

Thrombophilia

Our patient has a history of recurrent thromboembolic episodes, and this warrants testing to rule out an inherited thrombophilia. A family history of thromboembolic disease should also be sought.¹

When antiphospholipid syndrome occurs with systemic lupus erythematosus, it is termed ‘secondary’

In our patient, tests for prothrombotic activity including protein C chromogen, activated protein C ratio, free protein S, functional protein S, antithrombin factor V Leiden, and the prothrombin 20210G>A mutation were either negative or within the reference range. A negative family history of thromboembolic disease and the negative laboratory tests make inherited thrombophilia unlikely in our patient. 

Sickle cell disease, polycythemia vera, and essential thrombocythemia may also cause splenic infarction but can be ruled out in this patient on the basis of history and initial blood tests.

Antiphospholipid syndrome

A history of vascular disease (aortofemoral bypass surgery), a recent splenic infarct, and an elevated aPTT makes antiphospholipid syndrome the likeliest diagnosis in this patient.

Appropriate tests are for lupus anticoagulant, immunoglobulin G (IgG) or IgM cardiolipin antibody, and beta-2 glycoprotein 1 (beta-2 GP1) antibody, as well as the dilute Russell viper venom time (dRVVT) and the dRVVT ratio. The IgG and IgM cardiolipin antibody and beta-2 GP1 antibody tests have the same diagnostic value, and only medium to high titers should be considered positive.

Our patient’s IgG cardiolipin antibody level was in the normal range at 15 IgG phospholipid units (reference range 0–22); his IgM cardiolipin antibody level was high at 41 IgM phospholipid units (0–10). The dRVVT was 57 seconds (24–42), and the dRVVT ratio was 2.0 (0.0–1.3).

2. What further investigations are indicated before starting treatment?

• No further investigations required
• Repeat testing for phospholipid antibodies in 12 weeks
• Test for antinuclear antibodies

Antiphospholipid antibodies may appear transiently in certain infections, such as syphilis, Lyme disease, Epstein-Barr virus, cytomegalovirus, hepatitis C, and human immunodeficiency virus. Therefore, the presence of antiphospholipid antibodies must be confirmed over time, with two positive results at least 12 weeks apart.²

When repeated 12 weeks later, our patient’s IgG anticardiolipin antibody level was 14 GPL units, and the IgM anticardiolipin antibody level was 30 MPL units; the dRVVT was 55 seconds, and the dRVVT ratio was 1.8. These results, along with a history of recurrent arterial thrombosis, confirmed antiphospholipid syndrome.

The 2009 update of the International Society of Thrombosis and Haemostasis guidelines recommend two tests, the dRVVT and the aPTT, since no single test is 100% sensitive for lupus anticoagulant.³ The dRVVT has a high specificity for lupus anticoagulant in patients at high risk of thrombosis.

A SYNDROME WITH A WIDE RANGE OF EFFECTS AND COMPLICATIONS

Antiphospholipid syndrome is a systemic autoimmune disease that manifests as arterial and venous thrombosis and as obstetric complications. Thrombosis tends to be recurrent and may involve any site. For example, it can cause blurred vision in one or both eyes; amaurosis fugax; visual field defects; central or branch retinal artery or vein occlusion; deep vein thrombosis; pulmonary embolism; myocardial infarction; transient ischemic attack and stroke; cerebral vein thrombosis; and portal, renal, and mesenteric infarction involving veins or arteries.⁴ Pulmonary capillaritis may cause diffuse alveolar hemorrhage. Livedo reticularis, digital gangrene, cutaneous necrosis, splinter hemorrhages, chorea, and transverse myelopathy may also occur.

Obstetric complications of antiphospholipid syndrome include recurrent miscarriage and pregnancy loss at or after 10 weeks of gestation, eclampsia, preeclampsia, and placental insufficiency.⁵ The syndrome also has a potentially lethal variant characterized by multiorgan thrombosis affecting mainly small vessels.

The diagnosis of antiphospholipid syndrome requires relevant clinical features and symptoms and the presence of at least one of the antiphospholipid antibodies. Because the rate of false-positive tests for antiphospholipid antibodies ranges from 3% to 20% in the general population, asymptomatic patients should not be tested.⁶

Antiphospholipid syndrome may occur in the setting of other autoimmune diseases, most commonly systemic lupus erythematosus, when it is termed “secondary” antiphospholipid syndrome. Although only 40% of patients with lupus have antiphospholipid antibodies and less than 40% will have a thrombotic event, thrombotic antiphospholipid syndrome is a major adverse prognostic factor in these patients.^7,8 Therefore, it is prudent to consider systemic lupus erythematosus and to do appropriate tests if the patient has other features suggestive of lupus, such as renal, skin, or musculoskeletal lesions.

In our patient, antinuclear antibody testing was positive, with a titer of 1:320, and showed a finely speckled staining pattern. Tests for antibodies to Sjögren syndrome A and B antigens were negative. The complement C3 level was 1.28 g/L (reference range 0.74–1.85) and the C4 level was 0.24 g/L (0.16–0.44). Although the speckled staining pattern can be seen in lupus, it is more common in Sjögren syndrome, mixed connective tissue disease, scleroderma, and CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia).⁹ Moreover, normal levels of complement C3 and C4, in the absence of clinical features, make lupus unlikely. Similarly, our patient had no clinical features of other connective tissue disorders. Therefore, he had primary antiphospholipid syndrome.

3. How should this patient be managed?

• Antiplatelet therapy
• Warfarin to maintain an INR between 2.0 and 3.0
• Warfarin to maintain an INR above 3.0

The risk of recurrent thrombosis is high in patients who test positive for lupus anticoagulant, and the risk is highest in patients who are also positive for anticardiolipin and anti-beta-2 GP1 antibodies: the incidence of thrombosis is 12.2% at 1 year, 26.1% at 5 years, 44.2% at 10 years.¹⁰

Since our patient is positive for lupus anticoagulant (prolonged aPTT and elevated dRVVT, both indicating lupus anticoagulant positivity) and for anticardiolipin antibodies (anti-beta-2 GP1 not tested), his risk of recurrent thrombosis is high, and he requires lifelong anticoagulation therapy.

The intensity of anticoagulation in different subgroups of patients is controversial. Based on retrospective trials, indefinite anticoagulation at an INR of 2.0 to 3.0 has been suggested for patients with antiphospholipid syndrome presenting with venous thrombosis, and more intense anticoagulation with an INR above 3.0 in patients with recurrent or arterial thrombosis.¹¹ The combination of warfarin with an INR between 2.0 and 3.0 and aspirin 100 mg daily has also been proposed for patients with arterial thrombosis.¹²

Modifiable risk factors such as smoking, obesity, and use of estrogens should be addressed in all patients with antiphospholipid syndrome.

In pregnant women with complications such as preeclampsia, low-dose aspirin can be used, and in women with a history of miscarriage, the combination of low-dose aspirin and heparin is recommended throughout the prenatal period.⁴

In patients who have recurrent thrombosis despite adequate anticoagulation, an expert committee¹² has proposed that alternative regimens could include long-term low-molecular-weight heparin instead of warfarin, the combination of warfarin and aspirin, or warfarin and hydroxychloroquine. Adding a statin can also be considered.

Treatment of catastrophic antiphospholipid syndrome is based on expert opinion. A combination of anticoagulation, corticosteroids, plasma exchange, intravenous immunoglobulins, and rituximab has been tried, but the mortality rate remains high.¹³

OUR PATIENT'S COURSE

Our patient was started on warfarin, with a target INR above 3.0, and was doing well at 6 months of follow-up.