- Email: [email protected]
Case of the Season: Disseminated Nocardiosis
Case of the Season: Disseminated Nocardiosis James H. Daniel, Jr, BS, and James G. Ravenel, MD
A
22-year-old African American female with a history of systemic lupus erythematosus nephritis treated with prednisone and cyclophosphamide presented to the emergency department with substernal chest pain, costochondral pain, and headache of 1 week duration. She also complained of night sweats and nausea, but was afebrile on admission. Admission frontal and lateral chest X-rays showed a small left pleural effusion and a nodular opacity in the right lower lung (Fig. 1A). Because of ongoing chest pain, an echocardiogram was performed and unexpectedly revealed two mobile masses measuring 0.7 and 0.8 cm near the left ventricular apex, a polypoid lesion in the left ventricular outflow tract attached to the interventricular septum, and a left ventricular intramyocardial hypoechoic area measuring 1.4 ⫻ 2.3 cm. A cardiac magnetic resonance imaging (MRI) examination confirmed an intramyocardial enhancing 1.5 ⫻ 2.0 cm lesion within the posterior lateral wall of the left ventricle (Fig. 1B). Associated findings included a moderate pericardial effusion (Fig. 1B), a 1.2 ⫻ 0.8 cm area of abnormal opacity in the right lower lobe, and small bilateral pleural effusions (Fig. 1C), multiple small rim-enhancing nodules in the subcutaneous tissues and paraspinal muscles of the thorax and upper abdomen, and multiple noncystic low signal lesions on gadolinium-enhanced sequences in the kidneys (Fig. 1D). MRI of the brain showed multiple rim enhancing lesions, the majority at the gray–white junction (Fig. 1E). Admission blood cultures returned several days later confirmed weakly Gram-positive branching bacilli consistent with Nocardia species. The patient was treated with sulfamethoxazoletrimethoprim, ciprofloxacin, and imipenem for 3 weeks and amikacin for 2 weeks. She was discharged shortly thereafter and continued treatment with sulfamethoxazole-trimethoprim orally for 12 additional months.
Diagnosis Disseminated Nocardia farcinica infection.
Department of Radiology, Medical University of South Carolina, Charleston, SC. Address reprint requests to James G. Ravenel, MD, Medical University of South Carolina, 169 Ashley Avenue, Room 297, P.O. Box 250322, Charleston, SC 29425. E-mail: [email protected]
4
0037-198X/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.ro.2006.08.006
Discussion Nocardiae is a group of aerobic Gram-positive actinomycetes that are found worldwide in soil and decaying organic matter.1 Many species of Nocardia have been identified to cause disease in humans, including but not limited to N. asteroides, N. farcinica, N. brasiliensis, N. otitidis-caviarum, N. nova, N. transvalensis, N. pseudobrasiliensis, N. abscessus, and N. africana. N. asteroides is documented as the most common pathogen; however, N. farcinica is known for its greater virulence due to its heightened ability to cause disseminated disease.1 It is estimated that 1000 new cases of Nocardia infection are documented each year in the United States and tend to be more prevalent in males and adults as opposed to women, children, and the elderly.2 Nocardia is known as an opportunistic pathogen and, in fact, case studies suggest that over 63% of all Nocardia infections occur in individuals with some degree of immunosuppression. The most common predisposing condition leading to Nocardia infection is believed to be organ transplantation.2 A relatively high number of cases have been reported in individuals with acquired immunodeficiency syndrome (AIDS) and malignancy, particularly hematologic malignancy, as well.2,3 It is believed that cellmediated immunity is essential to elimination of Nocardia, due to the species’ ability to inhibit phagocytosome formation and to interfere with oxidative killing reactions.2 Thus individuals with AIDS and those undergoing immunosuppressive or steroid therapy are at a much increased risk for Nocardiosis. Patients with systemic lupus erythematosus (SLE) are at an increased risk for opportunistic infection, not only due to prolonged courses of steroids and cytotoxic agents, the mainstay of treatment for the disease, but also due to several inherent immunologic abnormalities that patients with SLE often manifest.4 These abnormalities include a decreased number of CD8-positive lymphocytes, lymphopenia, reduced interleukin-2 and tumor necrosis factor production, impaired leukocyte migration, flawed phagocytosis, and damaged natural killer cell function.4 Coupled with the Nocardia species’ ability to evade both phagocytosis and cellular oxidative killing mechanisms, a Nocardia infection in a patient with SLE can be life-threatening.
Case of the season
5
Figure 1 22 year old female with multiple infectious foci due to disseminated nocardiosis. (A) Posterior–anterior chest radiograph reveals right basilar nodular air-space opacity (arrow). (B) Axial T2-weighted MR image through the heart reveals focus of high signal in left ventricular myocardium (arrow) and moderate-size pericardial effusion (arrowhead). (C) Axial T2-weighted MR image inferior to (B) reveals focal area of high signal in lateral segment of right lower lobe (arrow) and small bilateral pleural effusions (arrowheads). (D) Axial T1-weighted gadolinium-enhanced MR image of upper abdomen reveals foci of decreased signal in parenchyma of both kidneys (arrowheads) along with rim-enhancing lesions within posterior pararenal space and paraspinal muscles (arrows). (E) Axial T1-weighted gadolinium-enhanced MR image of brain reveals multiple ringenhancing lesions predominately at gray–white junction in right cerebral hemisphere.
J.H. Daniel and J.G. Ravenel
6 Nocardia infections are becoming more increasingly recognized in patients with SLE, but are still extremely uncommon. While the true prevalence of Nocardia in SLE patients remains unknown, a retrospective case series in 1997 cited a prevalence of 2.8%. Furthermore, the mortality of Nocardia in SLE was found to be 35% and even higher, 75%, when the central nervous system (CNS) was involved.4 While the mortality numbers are trending downward, likely due to increased awareness of potential Nocardia infection and early institution of treatment, making the diagnosis can still be extremely difficult for a variety of reasons. First, cultures of Nocardia grow extremely slowly, often taking weeks to produce diagnostic levels, and the organism may be missed if samples are discarded prematurely. Second, Nocardia infection can mimic an acute flare of SLE, since the organisms produce few, if any, diagnostic radiological or clinical features.4 The lungs are the most common site of a primary Nocardia infection. The organisms may become airborne on soil and dust particles and an individual may become infected via inhalation or aspiration.2 A variety of clinical presentations have been described including cough, dyspnea, fever, night sweats, anorexia, weight loss, and pleuritic chest pain.2 Roentgenographic findings are unfortunately no more specific. Pulmonary nocardiosis may have a wide variety of presentations including any of the following: multifocal airspace opacities, lobar consolidation, nodules with or without cavitation, reticulonodular interstitial disease, pleural effusion, or empyema.5 Granulomas, mimicking tuberculosis, although rare, have also been reported.2 The CNS has been shown to be involved in up to 44% of patients with disseminated nocardiosis.2 Abscesses may occur in any region of the brain, and similar to pulmonary nocardiosis, clinical presentation is very nonspecific. Complaints may include headaches, seizures, focal neurological deficits, or meningismus; however, the infection itself can be subtle. Patients have few if any complaints, and fever and leukocytosis are not necessarily present.2 Typical radiological findings in a cerebral abscess include a hyperintense lesion on diffusion-weighted imaging and a ring-enhancing lesion encircling a central necrotic focus. Occasionally multiple concentric rings are seen that vary in intensity.6 While the lungs and central nervous system are the most common foci for disseminated Nocardial infections, the organism may seed virtually any organ system. There have been multiple documented cases of Nocardial endocarditis in prosthetic heart valves, but relatively few involving native valves.7 Valve replacement is often required in these circumstances, and despite aggressive treatment, mortality is often very high.7 In addition, an extensive literature search revealed no case reports identifying myocardial abscesses in disseminated Nocardiosis. The findings in this patient of an abnormal focus in the left ventricular posterior myocardium suggestive of an abscess and a polypoid lesion partially obstructing the left ventricular outflow tract are unique presen-
tations of disseminated Nocardiosis. To our knowledge, no case report has demonstrated such findings. Aggressive treatment and radiographic monitoring of myocardial abscess is essential due to the potential for myocardial rupture. Disseminated nocardiosis is diagnosed when lesions containing Nocardia are found at more than one bodily location.2 Dissemination can result from direct inoculation due to trauma or from erosion of a primary focus into a blood vessel.2 Disseminated Nocardia have the potential to invade potentially any body organ system, the most common being the lungs, CNS, eyes, kidneys, heart, bone, and skin and subcutaneous tissue.2 Disseminated Nocardia tends to behave as pyogenic bacteria and the result is typically a suppurative abscess at the embolic endpoint.2 The abscesses tend to progress and enlarge in its surrounding tissue by filamentous extension, and self-limited disease is rarely encountered at this point.2 Due to the relative rarity of the disease, disseminated Nocardiosis is infrequently included in differential diagnoses. In general, a higher level of suspicion should be maintained when an immunosuppressed individual presents with any combination of chest pain, night sweats, fever, dyspnea, and productive sputum. Further suggestive findings may include cutaneous abscesses, retinal abscess, mental status change, headaches, or focal neurological deficits. Due to the Nocardia’s potential to seed multiple organisms, full-body imaging may be necessary for diagnostic work-up. Empiric antibiotic therapy is essential in cases of suspected disseminated Nocardiosis due to the infection’s high mortality rates. Classically, the first treatment has been trimethoprim-sulfamethoxazole; however, there is much debate of the effectiveness of this combination due to increasing levels of resistance. Treatment of N. farcinica is especially problematic due to the organism’s resistance to multiple antibiotics.8 Currently the treatment of choice in disseminated N. farcinica is the combination of amikicin with imipenem.6 This combination therapy is also highly advised as empiric treatment in all patients for which there is suspicion of any disseminated Nocardia species.
References 1. Filice G: Nocardiosis. Harrison’s Principles of Internal Medicine (ed 16). New York, NY, McGraw-Hill, 2005, pp 934-937 2. Beaman BL, Beaman L: Nocardia species: host-parasite relationships. Clin Microbiol Rev 7:213-264, 1994 3. Torres HA, Reddy BT, Raad II, et al: Nocardiosis in cancer patients. Medicine (Baltimore) 81:388-397, 2002 4. Mok CC, Yuen KY, Lau CS: Nocardiosis in systemic lupus erythematosus. Semin Arthritis Rheum 26:675-683, 1997 5. Buckley JA, Padhani AR, Kuhlman JE: CT features of pulmonary nocardiosis. J Comput Assist Tomogr 19:726-732, 1995 6. Pyhtinen J, Pääkkö E, Jartti P: Cerebral abscess with multiple rims on MRI. Neuroradiology 39:857-859, 1997 7. Watson A, French P, Wilson M: Nocardia asteriodes native valve endocarditis. Clin Infect Dis 32:660-661, 2001 8. Hitti W, Wolff M: Two cases of multidrug-resistant Nocardia farcinica infection in immunosuppressed patients and implications for empiric therapy. Eur J Clin Microbiol Infect Dis 24:142-144, 2005
A
22-year-old African American female with a history of systemic lupus erythematosus nephritis treated with prednisone and cyclophosphamide presented to the emergency department with substernal chest pain, costochondral pain, and headache of 1 week duration. She also complained of night sweats and nausea, but was afebrile on admission. Admission frontal and lateral chest X-rays showed a small left pleural effusion and a nodular opacity in the right lower lung (Fig. 1A). Because of ongoing chest pain, an echocardiogram was performed and unexpectedly revealed two mobile masses measuring 0.7 and 0.8 cm near the left ventricular apex, a polypoid lesion in the left ventricular outflow tract attached to the interventricular septum, and a left ventricular intramyocardial hypoechoic area measuring 1.4 ⫻ 2.3 cm. A cardiac magnetic resonance imaging (MRI) examination confirmed an intramyocardial enhancing 1.5 ⫻ 2.0 cm lesion within the posterior lateral wall of the left ventricle (Fig. 1B). Associated findings included a moderate pericardial effusion (Fig. 1B), a 1.2 ⫻ 0.8 cm area of abnormal opacity in the right lower lobe, and small bilateral pleural effusions (Fig. 1C), multiple small rim-enhancing nodules in the subcutaneous tissues and paraspinal muscles of the thorax and upper abdomen, and multiple noncystic low signal lesions on gadolinium-enhanced sequences in the kidneys (Fig. 1D). MRI of the brain showed multiple rim enhancing lesions, the majority at the gray–white junction (Fig. 1E). Admission blood cultures returned several days later confirmed weakly Gram-positive branching bacilli consistent with Nocardia species. The patient was treated with sulfamethoxazoletrimethoprim, ciprofloxacin, and imipenem for 3 weeks and amikacin for 2 weeks. She was discharged shortly thereafter and continued treatment with sulfamethoxazole-trimethoprim orally for 12 additional months.
Diagnosis Disseminated Nocardia farcinica infection.
Department of Radiology, Medical University of South Carolina, Charleston, SC. Address reprint requests to James G. Ravenel, MD, Medical University of South Carolina, 169 Ashley Avenue, Room 297, P.O. Box 250322, Charleston, SC 29425. E-mail: [email protected]
4
0037-198X/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.ro.2006.08.006
Discussion Nocardiae is a group of aerobic Gram-positive actinomycetes that are found worldwide in soil and decaying organic matter.1 Many species of Nocardia have been identified to cause disease in humans, including but not limited to N. asteroides, N. farcinica, N. brasiliensis, N. otitidis-caviarum, N. nova, N. transvalensis, N. pseudobrasiliensis, N. abscessus, and N. africana. N. asteroides is documented as the most common pathogen; however, N. farcinica is known for its greater virulence due to its heightened ability to cause disseminated disease.1 It is estimated that 1000 new cases of Nocardia infection are documented each year in the United States and tend to be more prevalent in males and adults as opposed to women, children, and the elderly.2 Nocardia is known as an opportunistic pathogen and, in fact, case studies suggest that over 63% of all Nocardia infections occur in individuals with some degree of immunosuppression. The most common predisposing condition leading to Nocardia infection is believed to be organ transplantation.2 A relatively high number of cases have been reported in individuals with acquired immunodeficiency syndrome (AIDS) and malignancy, particularly hematologic malignancy, as well.2,3 It is believed that cellmediated immunity is essential to elimination of Nocardia, due to the species’ ability to inhibit phagocytosome formation and to interfere with oxidative killing reactions.2 Thus individuals with AIDS and those undergoing immunosuppressive or steroid therapy are at a much increased risk for Nocardiosis. Patients with systemic lupus erythematosus (SLE) are at an increased risk for opportunistic infection, not only due to prolonged courses of steroids and cytotoxic agents, the mainstay of treatment for the disease, but also due to several inherent immunologic abnormalities that patients with SLE often manifest.4 These abnormalities include a decreased number of CD8-positive lymphocytes, lymphopenia, reduced interleukin-2 and tumor necrosis factor production, impaired leukocyte migration, flawed phagocytosis, and damaged natural killer cell function.4 Coupled with the Nocardia species’ ability to evade both phagocytosis and cellular oxidative killing mechanisms, a Nocardia infection in a patient with SLE can be life-threatening.
Case of the season
5
Figure 1 22 year old female with multiple infectious foci due to disseminated nocardiosis. (A) Posterior–anterior chest radiograph reveals right basilar nodular air-space opacity (arrow). (B) Axial T2-weighted MR image through the heart reveals focus of high signal in left ventricular myocardium (arrow) and moderate-size pericardial effusion (arrowhead). (C) Axial T2-weighted MR image inferior to (B) reveals focal area of high signal in lateral segment of right lower lobe (arrow) and small bilateral pleural effusions (arrowheads). (D) Axial T1-weighted gadolinium-enhanced MR image of upper abdomen reveals foci of decreased signal in parenchyma of both kidneys (arrowheads) along with rim-enhancing lesions within posterior pararenal space and paraspinal muscles (arrows). (E) Axial T1-weighted gadolinium-enhanced MR image of brain reveals multiple ringenhancing lesions predominately at gray–white junction in right cerebral hemisphere.
J.H. Daniel and J.G. Ravenel
6 Nocardia infections are becoming more increasingly recognized in patients with SLE, but are still extremely uncommon. While the true prevalence of Nocardia in SLE patients remains unknown, a retrospective case series in 1997 cited a prevalence of 2.8%. Furthermore, the mortality of Nocardia in SLE was found to be 35% and even higher, 75%, when the central nervous system (CNS) was involved.4 While the mortality numbers are trending downward, likely due to increased awareness of potential Nocardia infection and early institution of treatment, making the diagnosis can still be extremely difficult for a variety of reasons. First, cultures of Nocardia grow extremely slowly, often taking weeks to produce diagnostic levels, and the organism may be missed if samples are discarded prematurely. Second, Nocardia infection can mimic an acute flare of SLE, since the organisms produce few, if any, diagnostic radiological or clinical features.4 The lungs are the most common site of a primary Nocardia infection. The organisms may become airborne on soil and dust particles and an individual may become infected via inhalation or aspiration.2 A variety of clinical presentations have been described including cough, dyspnea, fever, night sweats, anorexia, weight loss, and pleuritic chest pain.2 Roentgenographic findings are unfortunately no more specific. Pulmonary nocardiosis may have a wide variety of presentations including any of the following: multifocal airspace opacities, lobar consolidation, nodules with or without cavitation, reticulonodular interstitial disease, pleural effusion, or empyema.5 Granulomas, mimicking tuberculosis, although rare, have also been reported.2 The CNS has been shown to be involved in up to 44% of patients with disseminated nocardiosis.2 Abscesses may occur in any region of the brain, and similar to pulmonary nocardiosis, clinical presentation is very nonspecific. Complaints may include headaches, seizures, focal neurological deficits, or meningismus; however, the infection itself can be subtle. Patients have few if any complaints, and fever and leukocytosis are not necessarily present.2 Typical radiological findings in a cerebral abscess include a hyperintense lesion on diffusion-weighted imaging and a ring-enhancing lesion encircling a central necrotic focus. Occasionally multiple concentric rings are seen that vary in intensity.6 While the lungs and central nervous system are the most common foci for disseminated Nocardial infections, the organism may seed virtually any organ system. There have been multiple documented cases of Nocardial endocarditis in prosthetic heart valves, but relatively few involving native valves.7 Valve replacement is often required in these circumstances, and despite aggressive treatment, mortality is often very high.7 In addition, an extensive literature search revealed no case reports identifying myocardial abscesses in disseminated Nocardiosis. The findings in this patient of an abnormal focus in the left ventricular posterior myocardium suggestive of an abscess and a polypoid lesion partially obstructing the left ventricular outflow tract are unique presen-
tations of disseminated Nocardiosis. To our knowledge, no case report has demonstrated such findings. Aggressive treatment and radiographic monitoring of myocardial abscess is essential due to the potential for myocardial rupture. Disseminated nocardiosis is diagnosed when lesions containing Nocardia are found at more than one bodily location.2 Dissemination can result from direct inoculation due to trauma or from erosion of a primary focus into a blood vessel.2 Disseminated Nocardia have the potential to invade potentially any body organ system, the most common being the lungs, CNS, eyes, kidneys, heart, bone, and skin and subcutaneous tissue.2 Disseminated Nocardia tends to behave as pyogenic bacteria and the result is typically a suppurative abscess at the embolic endpoint.2 The abscesses tend to progress and enlarge in its surrounding tissue by filamentous extension, and self-limited disease is rarely encountered at this point.2 Due to the relative rarity of the disease, disseminated Nocardiosis is infrequently included in differential diagnoses. In general, a higher level of suspicion should be maintained when an immunosuppressed individual presents with any combination of chest pain, night sweats, fever, dyspnea, and productive sputum. Further suggestive findings may include cutaneous abscesses, retinal abscess, mental status change, headaches, or focal neurological deficits. Due to the Nocardia’s potential to seed multiple organisms, full-body imaging may be necessary for diagnostic work-up. Empiric antibiotic therapy is essential in cases of suspected disseminated Nocardiosis due to the infection’s high mortality rates. Classically, the first treatment has been trimethoprim-sulfamethoxazole; however, there is much debate of the effectiveness of this combination due to increasing levels of resistance. Treatment of N. farcinica is especially problematic due to the organism’s resistance to multiple antibiotics.8 Currently the treatment of choice in disseminated N. farcinica is the combination of amikicin with imipenem.6 This combination therapy is also highly advised as empiric treatment in all patients for which there is suspicion of any disseminated Nocardia species.
References 1. Filice G: Nocardiosis. Harrison’s Principles of Internal Medicine (ed 16). New York, NY, McGraw-Hill, 2005, pp 934-937 2. Beaman BL, Beaman L: Nocardia species: host-parasite relationships. Clin Microbiol Rev 7:213-264, 1994 3. Torres HA, Reddy BT, Raad II, et al: Nocardiosis in cancer patients. Medicine (Baltimore) 81:388-397, 2002 4. Mok CC, Yuen KY, Lau CS: Nocardiosis in systemic lupus erythematosus. Semin Arthritis Rheum 26:675-683, 1997 5. Buckley JA, Padhani AR, Kuhlman JE: CT features of pulmonary nocardiosis. J Comput Assist Tomogr 19:726-732, 1995 6. Pyhtinen J, Pääkkö E, Jartti P: Cerebral abscess with multiple rims on MRI. Neuroradiology 39:857-859, 1997 7. Watson A, French P, Wilson M: Nocardia asteriodes native valve endocarditis. Clin Infect Dis 32:660-661, 2001 8. Hitti W, Wolff M: Two cases of multidrug-resistant Nocardia farcinica infection in immunosuppressed patients and implications for empiric therapy. Eur J Clin Microbiol Infect Dis 24:142-144, 2005