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Fatal aortic pseudoaneurysm from disseminated Mycobacterium kansasii infection: case report
Human Pathology (2015) 46, 467–470
www.elsevier.com/locate/humpath
Case study
Fatal aortic pseudoaneurysm from disseminated Mycobacterium kansasii infection: case report☆ Laleh Ehsani MD a,⁎, Sujan C. Reddy MD b , Mario Mosunjac MD a , Colleen S. Kraft MD a,b , Jeannette Guarner MD a,b a
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Division of Infectious Diseases, Emory University, Atlanta, GA 30322
b
Received 18 September 2014; revised 7 October 2014; accepted 4 November 2014
Keywords: Mycobacterium kansasii; Aortic pseudoaneurysm; Granuloma; Myelodysplastic syndrome; MonoMAC syndrome; GATA2
Summary Mycobacterium kansasii is a photochromogenic, slow-growing mycobacterium species that can cause pulmonary infection in patients with predisposing lung diseases, as well as extrapulmonary or disseminated disease in immunosuppressed patients. We describe a patient with a myelodysplastic syndrome, disseminated M kansasii infection, and ruptured aortic aneurysm. He had a recent diagnosis of mycobacterium cavitary lung lesions and was transferred to our facility for possible surgical intervention of an aortic aneurysm. Few hours after admission, the patient suddenly collapsed and died despite resuscitation efforts. A complete autopsy was performed and showed ruptured ascending aortic pseudoaneurysm with hemopericardium, disseminated necrotizing and nonnecrotizing granulomas with acid-fast bacilli in the aortic wall, lungs, heart, liver, spleen, and kidneys. Further genetic studies were consistent with monocytopenia and mycobacterial infection syndrome. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Disseminated nontuberculous mycobacteria have been recognized as causing distinct syndromes in immunosuppressed patients, particularly in areas where acquired immunodeficiency syndrome (AIDS) is widespread [1]. Mycobacterium kansasii has been reported to infect HIV-infected patients with an incidence of 0.14% in the United States, with a higher (0.44%) incidence in the central and southern regions of the country
☆ Competing interest: None of the authors of this study have any conflicts of interest to disclose. ⁎ Correspondence to: L. Ehsani, Emory University Hospital, 1364 Clifton Rd NE, Atlanta, GA 30322. E-mail addresses: [email protected] (L. Ehsani), [email protected] (J. Guarner).
http://dx.doi.org/10.1016/j.humpath.2014.11.005 0046-8177/© 2015 Elsevier Inc. All rights reserved.
[1,2]. Infection with M kansasii is also reported in patients with hematologic malignancies and after solid organ transplantations [3]. M kansasii is the second most common cause of nontuberculous mycobacterial disease in the United States after Mycobacterium avium complex (MAC) [4]. It can cause pulmonary infection in patients with predisposing lung diseases and disseminated infections in immunosuppressed patients. A syndrome consisting of monocytopenia with susceptibility to mycobacterial, fungal and viral infections called monocytopenia and mycobacterial infection (MonoMAC) has been recently described [5]. In the Table, we present characteristics that have been reported for the syndrome. MonoMAC is associated with loss-of-function mutations to the GATA2 gene, which is linked to myelodysplasia and macrophage dysfunction [6]. We describe here a patient with a myelodysplastic syndrome (MDS) with trisomy 8 and disseminated M kansasii infection that was complicated by an aortic pseduaneurysm.
468 Table
L. Ehsani et al. Characteristics of MonoMAC syndrome
Infectious
Nontuberculous mycobacteria Viral (human papilloma virus, herpes, EBV, fatal influenza) Fungal (disseminated histoplasmosis, cryptococcal meningitis, invasive aspergillosis) Cytopenias Myeloid cells (monocytes, dendritic cells) Lymphoid (natural killer and B lymphocytes) Anemia, neutropenia, thrombocytopenia Other MDS, leukemia, EBV-associated smooth muscle diseases tumors Pulmonary alveolar proteinosis, pulmonary hypertension Autoimmune phenomena: lupus-like syndrome, arthritis, erythema nodosum Primary lymphedema Bone marrow Hypocellular, with fibrosis, multilineage dysplasia, findings hemophagocytosis, abnormal plasma cells GATA2 Found in up to 60% of cases mutation NOTE. Adapted from Camargo et al [10], Calvo et al [12], and Chu et al [13]. Abbreviations: MonoMAC, monocytopenia and mycobacterial infection; EBV, Epstein-Barr virus; MDS, myelodysplastic syndrome.
breaths/min, and blood pressure of 113/64 mm Hg. On physical examination, there was no lymphadenopathy or hepatosplenomegaly. Hemoglobin was 8.8 g/dL (normal 12.9-16.1 g/dL), platelet count was 46 × l09/L (normal 150-400). The day before transfer to our institution, white blood cell count was 3.9 × l09/L (normal 4.2-9.1) with 3237 absolute neutrophils (normal 18005400), 390 absolute immature neutrophils—bands (normal 0), 156 absolute lymphocytes (normal 1300-3600), and 157 absolute monocytes (normal 300-800). His urinalysis was positive for glucose, protein, and urobilinogen. Alkaline phosphatase and aspartate aminotransferase levels were elevated, at 139 IU/L (normal 32-91 IU/L) and 55 IU/L (normal 15-41 IU/L), respectively, but alanine aminotransferase was normal at 42 IU/L. Total bilirubin and creatinine levels were elevated at 2.0 mg/dL (normal 0.3-1.2 mg/dL) and 1.4 mg/dL (normal 0.7-1.2 mg/dL), respectively. Chest radiograph demonstrated a large right pleural effusion with adjacent atelectasis or pneumonia and an air-fluid level in the right midlung, which suggested abscess or empyema. A few hours after admission to our institution, he was noted to start coughing and getting dizzy, which was quickly followed by loss of consciousness and cardiopulmonary arrest. After unsuccessful resuscitation attempts, the patient was pronounced dead.
2. Case report A 33-year-old African American man had a 9-month history of enlarging pulmonary nodules that were accompanied by a dry cough, significant unintentional weight loss, and night sweats. Prior to these symptoms, he originally came to care for an elective cholecystectomy and was found to have pancytopenia that was attributed to a MDS with trisomy 8. Two months prior to his demise, a bronchoalveolar lavage and a transbronchial biopsy showed noncaseating granulomatous inflammation suggestive of sarcoidosis as stains for acid-fast bacilli (AFB) and fungi (Grocott methenamine silver) were negative. A bone marrow biopsy also showed granulomas. He was started on prednisone 40 mg daily for treatment of sarcoidosis and was receiving blood transfusions for the pancytopenia. Approximately 2 weeks after starting treatment with prednisone, M kansasii grew from the bronchoalveolar lavage; thus, the patient started antimycobacterial treatment while stopping prednisone. He complained at that time of worsening of right-sided chest pain. Chest computed tomography revealed a new 7 × 6 × 5 cm ascending aortic aneurysm with concern for mycotic aneurysm based on his medical history, diffuse mediastinal and right hilar lymphadenopathy, moderate right-sided pleural effusion, and 2 cavitary lesions in the right lower lobe. Transthoracic echocardiography did not show any evidence of aortic insufficiency or valvular vegetation. HIV serology was negative. The patient was hemodynamically stable and was transferred to our institution for surgical intervention of the aneurysm. On the day of transfer, he had a temperature of 38.1°C, pulse rate of 103 beats/min, respiratory rate of 20
3. Results The main postmortem finding was a dissected, ruptured mycotic aneurysm in the ascending aorta 5 cm from the aortic valve, and hemopericardium (280 g of blood in the pericardial sac) (Fig. A). In the lungs, there were bilateral cystic cavities with yellow-green pus and necrotic debris. The right lower lobe showed a cystic cavity of 5 cm in maximum dimension and left lower lobe cystic cavity of 0.5 cm in maximum dimension. Abdominal examination revealed hepatosplenomegaly (liver 3550 g, spleen 710 g). The liver was grossly unremarkable, but the spleen demonstrated subcapsular necrotizing lesions with maximum dimension of 2.5 cm. Other organs including kidneys, pancreas, brain, and small and large intestines were grossly normal. Microscopic examination of the ascending aorta in the area of the aneurysm showed extensive wall necrosis that extended from media to adventia. The inflammatory infiltrate was composed of neutrophils and a few epithelioid histiocytes (Fig. B). AFBs were numerous at the site of the rupture (Fig. C). The lungs had thrombotic vessels with scattered necrotizing granulomas. The spleen showed thrombosis associated with the subcapsular necrosis, scattered granulomatous inflammation, and abundant AFB. Patchy perivascular nonnecrotizing granulomatous inflammation with presence of AFB was observed in the myocardium, liver, and kidneys (Fig. D). The brain and spinal cord also showed perivascular granulomatous inflammation with several necrotizing granulomata that did not demonstrate AFB. The pancreas and adipose tissue surrounding the adrenal glands showed patchy
Aortic pseudoaneurysm from Mycobacterium kansasii infection
A
B
C
D
469
Fig. A, Gross image of the heart with opened pericardial sac and ruptured mycotic aortic aneurysm (arrow) at the base the aorta. Note the hemopericardium occurred at the start of the aneurysm. B, Necrotic aortic wall with inflammation (hematoxylin and eosin, ×20). C, AFB in granuloma (Ziehl-Neelsen stain, ×100). D, Kidney with nonnecrotizing granuloma and giant cell (hematoxylin and eosin, 20X).
inflammatory foci without necrosis, and AFBs were not found. The bone marrow was hypercellular with trilineage hematopoiesis; however, no granulomas were observed. M kansasii was confirmed in paraffin-embedded tissue sections from the aortic aneurysm by using 16S polymerase chain reaction–specific for mycobacteria at the Centers for Disease Control and Prevention. To evaluate for genetic predisposition for MonoMAC, amplification of GATA2 was performed at the National Institutes of Health in a paraffinembedded material from the spleen. The patient was found to be heterozygous for a known single-nucleotide polymorphism in exon 4 (c.490 A/G); however, the use of the formalin-fixed, paraffin-embedded material did not allow amplification the intron 5 region where previously reported mutations have been found [6] (S. Holland, personal communication).
4. Discussion Nontuberculous mycobacteria are rarely pathogenic in immune competent individuals; however, they are important pathogens in immunosuppressed individuals in geographic
regions where tuberculosis is nonendemic [7]. M kansasii usually presents with nodular, bronchiectatic, or cavitary lung disease, and disseminated disease is not uncommon in patients with HIV/AIDS or in the transplant population [4]. The most common clinical presentation of disseminated disease includes fever, pancytopenia, and splenomegaly in addition to signs and symptoms pertinent to the affected body site [8]. Presentation of aortic pseudoaneurysm with disseminated M kansasii appears to be extremely rare with no reports in the English literature. In this patient, we have evidence of disseminated infection by M kansasii as AFBs were present in the heart, lungs, liver, spleen, and kidneys. In the autopsy material, we were able to identify different inflammatory reactions including abscesses, necrotizing granulomatous inflammation with giant cells, nonnecrotizing inflammation with giant cells, and nonnecrotizing inflammation with epitheliod histiocytes only. These histology features are comparable with findings by Smith et al [9] in AIDS patients infected by M kansasii. Our patient had a history of immunosuppression due to MDS. At the time the autopsy was performed, a diagnosis of MonoMAC had not been entertained; thus, fresh material in which to carry genetic testing was not obtained. Upon review of
470 the case for a conference presentation, his clinical syndrome of myelodysplasia and invasive mycobacterial disease prompted the possible diagnosis of sporadic MonoMAC syndrome, and genetic testing was performed on the formalin-fixed tissue [5,10]. Patients with MonoMAC often have profound monocytopenia and B and NK cell lymphopenia, which were present in our patient [10]. Although profound monocytopenia has been reported in patients with MonoMAC, a series of patients with GATA2 mutations and syndromes consistent with MonoMAC had absolute monocyte counts up to 380 cells/L [5,11]. Nine of the 18 patients who were first described to have MonoMAC were diagnosed as having MDS or acute myeloid leukemia [5]. Of the original 18 patients described to have MonoMAC, 78% had nontuberculous mycobacterial infection, predominately M avium complex [5]. Diagnostic criteria for MonoMAC syndrome have not been well defined, although comparisons to similar syndromes have been described [12,13]. Compared with de novo MDS, our patient's young age, monocytopenia, and invasive mycobacterial infection favor a diagnosis of MonoMAC syndrome [12]. In our case, GATA2 mutation could not be ruled out due to the inability to fully sequence the GATA2 gene, which was likely due to formalin fixation of tissues. Although GATA2 mutations have been associated with both hereditary and sporadic MonoMAC cases, these mutations are not found in all patients with MonoMAC syndrome [6]. Because of the high risk for invasive infections, identifying MonoMAC syndrome in patients with myelodysplasia may help inform decisions regarding treatment options such as allogenic hematopoietic stem cell transplantation, which have been shown to be an effective treatment [14]. Aneurysm of the thoracic aorta can occur by different mechanisms. Most commonly, the pathogenesis of the aneurysms is due to noninflammatory medial degeneration of the aortic wall. In one series of 734 patients with aortic aneurysms, only 2.3% were caused by bacterial infection, and most occurred in the abdominal aorta. The most common pathogens were Staphylococcus and Salmonella species. We believe that the pathogenesis of the mycotic aneurysm in our patient was due to septic emboli as we found disseminated evidence of the AFB. In summary, M kansasii is a rare but important cause of pulmonary and disseminated disease in patients with immunosuppression. Because of the increasing numbers of immunocompromised hosts with aging, HIV infection, cancer, and steroid therapy, this type of infection will possibly become more common and early diagnosis prompting adequate treatment is important to improve the prognosis. M kansasii should be considered in any immunosuppressed individuals with pulmonary, extrapulmonary, and systemic infection. Culture and DNA probes that can be applied to different tissues can identify this infection. Similarly, the clinical syndrome MonoMAC should be suspected in young adults with
L. Ehsani et al. myelodysplasia and invasive mycobacterial, fungal, or viral infections as early detection may expedite treatment options such as stem cell transplantation.
Acknowledgments The authors would like to acknowledge the Centers for Disease Control and Prevention and National Institutes of Health for their contribution.
References [1] Horsburgh Jr CR, Selik RM. The epidemiology of disseminated nontuberculous mycobacterial infection in the acquired immunodeficiency syndrome (AIDS). Am Rev Respir Dis 1989;139:4. [2] Campo RE, Campo CE. Mycobacterium kansasii disease in patients infected with human immunodeficiency virus. Clin Infect Dis 1997;24: 1233-8. [3] Doucette K, Fishman JA. Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients. Clin Infect Dis 2004;38:1428-39. [4] Griffth DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175: 367-416. [5] Vinh DC, Patel SY, Uzel G, et al. Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood 2010;115:1519-29. [6] Hsu AP, Sampaio EP, Khan J, et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 2011;118: 2653-5. [7] Fan MH, Hadjiliadis D. Incidence and management of mycobacterial infection in solid organ transplant recipients. Curr Infect Dis Rep 2009; 11:216-22. [8] Mazor Y, Sprecher H, Braun E. Mycobacterium kansasii disseminated disease. Isr Med Assoc J 2010;12:121-2. [9] Smith MB, Molina CP, Schnadig VJ, Boyars MC, Aronson JF. Pathologic features of Mycobacterium kansasii infection in patients with acquired immunodeficiency syndrome. Arch Pathol Lab Med 2003;127:554-60. [10] Camargo JF, Lobo SA, Hsu AP, Zerbe CS, Wormser GP, Holland SM. MonoMAC syndrome in a patient with a GATA2 mutation: case report and review of the literature. Clin Infect Dis 2013;57:697-9. [11] Pasquet M, Bellanné-Chantelot C, Tavitian S, et al. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood 2013;121:822-9. [12] Calvo KR, Vinh DC, Maric I, et al. Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications. Haematologica 2011;96:1221-5. [13] Chu VH, Curry JL, Elghetany MT, Curry CV. MonoMAC versus idiopathic CD4+ lymphocytopenia. Comment Haematol 2011;96:1221-5. Haematologica 2011;97:e9-11 [author reply e12]. [14] Cuellar-Rodriguez J, Gea-Banacloche J, Freeman AF, et al. Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. Blood 2011;118:3715-20.
www.elsevier.com/locate/humpath
Case study
Fatal aortic pseudoaneurysm from disseminated Mycobacterium kansasii infection: case report☆ Laleh Ehsani MD a,⁎, Sujan C. Reddy MD b , Mario Mosunjac MD a , Colleen S. Kraft MD a,b , Jeannette Guarner MD a,b a
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322 Division of Infectious Diseases, Emory University, Atlanta, GA 30322
b
Received 18 September 2014; revised 7 October 2014; accepted 4 November 2014
Keywords: Mycobacterium kansasii; Aortic pseudoaneurysm; Granuloma; Myelodysplastic syndrome; MonoMAC syndrome; GATA2
Summary Mycobacterium kansasii is a photochromogenic, slow-growing mycobacterium species that can cause pulmonary infection in patients with predisposing lung diseases, as well as extrapulmonary or disseminated disease in immunosuppressed patients. We describe a patient with a myelodysplastic syndrome, disseminated M kansasii infection, and ruptured aortic aneurysm. He had a recent diagnosis of mycobacterium cavitary lung lesions and was transferred to our facility for possible surgical intervention of an aortic aneurysm. Few hours after admission, the patient suddenly collapsed and died despite resuscitation efforts. A complete autopsy was performed and showed ruptured ascending aortic pseudoaneurysm with hemopericardium, disseminated necrotizing and nonnecrotizing granulomas with acid-fast bacilli in the aortic wall, lungs, heart, liver, spleen, and kidneys. Further genetic studies were consistent with monocytopenia and mycobacterial infection syndrome. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Disseminated nontuberculous mycobacteria have been recognized as causing distinct syndromes in immunosuppressed patients, particularly in areas where acquired immunodeficiency syndrome (AIDS) is widespread [1]. Mycobacterium kansasii has been reported to infect HIV-infected patients with an incidence of 0.14% in the United States, with a higher (0.44%) incidence in the central and southern regions of the country
☆ Competing interest: None of the authors of this study have any conflicts of interest to disclose. ⁎ Correspondence to: L. Ehsani, Emory University Hospital, 1364 Clifton Rd NE, Atlanta, GA 30322. E-mail addresses: [email protected] (L. Ehsani), [email protected] (J. Guarner).
http://dx.doi.org/10.1016/j.humpath.2014.11.005 0046-8177/© 2015 Elsevier Inc. All rights reserved.
[1,2]. Infection with M kansasii is also reported in patients with hematologic malignancies and after solid organ transplantations [3]. M kansasii is the second most common cause of nontuberculous mycobacterial disease in the United States after Mycobacterium avium complex (MAC) [4]. It can cause pulmonary infection in patients with predisposing lung diseases and disseminated infections in immunosuppressed patients. A syndrome consisting of monocytopenia with susceptibility to mycobacterial, fungal and viral infections called monocytopenia and mycobacterial infection (MonoMAC) has been recently described [5]. In the Table, we present characteristics that have been reported for the syndrome. MonoMAC is associated with loss-of-function mutations to the GATA2 gene, which is linked to myelodysplasia and macrophage dysfunction [6]. We describe here a patient with a myelodysplastic syndrome (MDS) with trisomy 8 and disseminated M kansasii infection that was complicated by an aortic pseduaneurysm.
468 Table
L. Ehsani et al. Characteristics of MonoMAC syndrome
Infectious
Nontuberculous mycobacteria Viral (human papilloma virus, herpes, EBV, fatal influenza) Fungal (disseminated histoplasmosis, cryptococcal meningitis, invasive aspergillosis) Cytopenias Myeloid cells (monocytes, dendritic cells) Lymphoid (natural killer and B lymphocytes) Anemia, neutropenia, thrombocytopenia Other MDS, leukemia, EBV-associated smooth muscle diseases tumors Pulmonary alveolar proteinosis, pulmonary hypertension Autoimmune phenomena: lupus-like syndrome, arthritis, erythema nodosum Primary lymphedema Bone marrow Hypocellular, with fibrosis, multilineage dysplasia, findings hemophagocytosis, abnormal plasma cells GATA2 Found in up to 60% of cases mutation NOTE. Adapted from Camargo et al [10], Calvo et al [12], and Chu et al [13]. Abbreviations: MonoMAC, monocytopenia and mycobacterial infection; EBV, Epstein-Barr virus; MDS, myelodysplastic syndrome.
breaths/min, and blood pressure of 113/64 mm Hg. On physical examination, there was no lymphadenopathy or hepatosplenomegaly. Hemoglobin was 8.8 g/dL (normal 12.9-16.1 g/dL), platelet count was 46 × l09/L (normal 150-400). The day before transfer to our institution, white blood cell count was 3.9 × l09/L (normal 4.2-9.1) with 3237 absolute neutrophils (normal 18005400), 390 absolute immature neutrophils—bands (normal 0), 156 absolute lymphocytes (normal 1300-3600), and 157 absolute monocytes (normal 300-800). His urinalysis was positive for glucose, protein, and urobilinogen. Alkaline phosphatase and aspartate aminotransferase levels were elevated, at 139 IU/L (normal 32-91 IU/L) and 55 IU/L (normal 15-41 IU/L), respectively, but alanine aminotransferase was normal at 42 IU/L. Total bilirubin and creatinine levels were elevated at 2.0 mg/dL (normal 0.3-1.2 mg/dL) and 1.4 mg/dL (normal 0.7-1.2 mg/dL), respectively. Chest radiograph demonstrated a large right pleural effusion with adjacent atelectasis or pneumonia and an air-fluid level in the right midlung, which suggested abscess or empyema. A few hours after admission to our institution, he was noted to start coughing and getting dizzy, which was quickly followed by loss of consciousness and cardiopulmonary arrest. After unsuccessful resuscitation attempts, the patient was pronounced dead.
2. Case report A 33-year-old African American man had a 9-month history of enlarging pulmonary nodules that were accompanied by a dry cough, significant unintentional weight loss, and night sweats. Prior to these symptoms, he originally came to care for an elective cholecystectomy and was found to have pancytopenia that was attributed to a MDS with trisomy 8. Two months prior to his demise, a bronchoalveolar lavage and a transbronchial biopsy showed noncaseating granulomatous inflammation suggestive of sarcoidosis as stains for acid-fast bacilli (AFB) and fungi (Grocott methenamine silver) were negative. A bone marrow biopsy also showed granulomas. He was started on prednisone 40 mg daily for treatment of sarcoidosis and was receiving blood transfusions for the pancytopenia. Approximately 2 weeks after starting treatment with prednisone, M kansasii grew from the bronchoalveolar lavage; thus, the patient started antimycobacterial treatment while stopping prednisone. He complained at that time of worsening of right-sided chest pain. Chest computed tomography revealed a new 7 × 6 × 5 cm ascending aortic aneurysm with concern for mycotic aneurysm based on his medical history, diffuse mediastinal and right hilar lymphadenopathy, moderate right-sided pleural effusion, and 2 cavitary lesions in the right lower lobe. Transthoracic echocardiography did not show any evidence of aortic insufficiency or valvular vegetation. HIV serology was negative. The patient was hemodynamically stable and was transferred to our institution for surgical intervention of the aneurysm. On the day of transfer, he had a temperature of 38.1°C, pulse rate of 103 beats/min, respiratory rate of 20
3. Results The main postmortem finding was a dissected, ruptured mycotic aneurysm in the ascending aorta 5 cm from the aortic valve, and hemopericardium (280 g of blood in the pericardial sac) (Fig. A). In the lungs, there were bilateral cystic cavities with yellow-green pus and necrotic debris. The right lower lobe showed a cystic cavity of 5 cm in maximum dimension and left lower lobe cystic cavity of 0.5 cm in maximum dimension. Abdominal examination revealed hepatosplenomegaly (liver 3550 g, spleen 710 g). The liver was grossly unremarkable, but the spleen demonstrated subcapsular necrotizing lesions with maximum dimension of 2.5 cm. Other organs including kidneys, pancreas, brain, and small and large intestines were grossly normal. Microscopic examination of the ascending aorta in the area of the aneurysm showed extensive wall necrosis that extended from media to adventia. The inflammatory infiltrate was composed of neutrophils and a few epithelioid histiocytes (Fig. B). AFBs were numerous at the site of the rupture (Fig. C). The lungs had thrombotic vessels with scattered necrotizing granulomas. The spleen showed thrombosis associated with the subcapsular necrosis, scattered granulomatous inflammation, and abundant AFB. Patchy perivascular nonnecrotizing granulomatous inflammation with presence of AFB was observed in the myocardium, liver, and kidneys (Fig. D). The brain and spinal cord also showed perivascular granulomatous inflammation with several necrotizing granulomata that did not demonstrate AFB. The pancreas and adipose tissue surrounding the adrenal glands showed patchy
Aortic pseudoaneurysm from Mycobacterium kansasii infection
A
B
C
D
469
Fig. A, Gross image of the heart with opened pericardial sac and ruptured mycotic aortic aneurysm (arrow) at the base the aorta. Note the hemopericardium occurred at the start of the aneurysm. B, Necrotic aortic wall with inflammation (hematoxylin and eosin, ×20). C, AFB in granuloma (Ziehl-Neelsen stain, ×100). D, Kidney with nonnecrotizing granuloma and giant cell (hematoxylin and eosin, 20X).
inflammatory foci without necrosis, and AFBs were not found. The bone marrow was hypercellular with trilineage hematopoiesis; however, no granulomas were observed. M kansasii was confirmed in paraffin-embedded tissue sections from the aortic aneurysm by using 16S polymerase chain reaction–specific for mycobacteria at the Centers for Disease Control and Prevention. To evaluate for genetic predisposition for MonoMAC, amplification of GATA2 was performed at the National Institutes of Health in a paraffinembedded material from the spleen. The patient was found to be heterozygous for a known single-nucleotide polymorphism in exon 4 (c.490 A/G); however, the use of the formalin-fixed, paraffin-embedded material did not allow amplification the intron 5 region where previously reported mutations have been found [6] (S. Holland, personal communication).
4. Discussion Nontuberculous mycobacteria are rarely pathogenic in immune competent individuals; however, they are important pathogens in immunosuppressed individuals in geographic
regions where tuberculosis is nonendemic [7]. M kansasii usually presents with nodular, bronchiectatic, or cavitary lung disease, and disseminated disease is not uncommon in patients with HIV/AIDS or in the transplant population [4]. The most common clinical presentation of disseminated disease includes fever, pancytopenia, and splenomegaly in addition to signs and symptoms pertinent to the affected body site [8]. Presentation of aortic pseudoaneurysm with disseminated M kansasii appears to be extremely rare with no reports in the English literature. In this patient, we have evidence of disseminated infection by M kansasii as AFBs were present in the heart, lungs, liver, spleen, and kidneys. In the autopsy material, we were able to identify different inflammatory reactions including abscesses, necrotizing granulomatous inflammation with giant cells, nonnecrotizing inflammation with giant cells, and nonnecrotizing inflammation with epitheliod histiocytes only. These histology features are comparable with findings by Smith et al [9] in AIDS patients infected by M kansasii. Our patient had a history of immunosuppression due to MDS. At the time the autopsy was performed, a diagnosis of MonoMAC had not been entertained; thus, fresh material in which to carry genetic testing was not obtained. Upon review of
470 the case for a conference presentation, his clinical syndrome of myelodysplasia and invasive mycobacterial disease prompted the possible diagnosis of sporadic MonoMAC syndrome, and genetic testing was performed on the formalin-fixed tissue [5,10]. Patients with MonoMAC often have profound monocytopenia and B and NK cell lymphopenia, which were present in our patient [10]. Although profound monocytopenia has been reported in patients with MonoMAC, a series of patients with GATA2 mutations and syndromes consistent with MonoMAC had absolute monocyte counts up to 380 cells/L [5,11]. Nine of the 18 patients who were first described to have MonoMAC were diagnosed as having MDS or acute myeloid leukemia [5]. Of the original 18 patients described to have MonoMAC, 78% had nontuberculous mycobacterial infection, predominately M avium complex [5]. Diagnostic criteria for MonoMAC syndrome have not been well defined, although comparisons to similar syndromes have been described [12,13]. Compared with de novo MDS, our patient's young age, monocytopenia, and invasive mycobacterial infection favor a diagnosis of MonoMAC syndrome [12]. In our case, GATA2 mutation could not be ruled out due to the inability to fully sequence the GATA2 gene, which was likely due to formalin fixation of tissues. Although GATA2 mutations have been associated with both hereditary and sporadic MonoMAC cases, these mutations are not found in all patients with MonoMAC syndrome [6]. Because of the high risk for invasive infections, identifying MonoMAC syndrome in patients with myelodysplasia may help inform decisions regarding treatment options such as allogenic hematopoietic stem cell transplantation, which have been shown to be an effective treatment [14]. Aneurysm of the thoracic aorta can occur by different mechanisms. Most commonly, the pathogenesis of the aneurysms is due to noninflammatory medial degeneration of the aortic wall. In one series of 734 patients with aortic aneurysms, only 2.3% were caused by bacterial infection, and most occurred in the abdominal aorta. The most common pathogens were Staphylococcus and Salmonella species. We believe that the pathogenesis of the mycotic aneurysm in our patient was due to septic emboli as we found disseminated evidence of the AFB. In summary, M kansasii is a rare but important cause of pulmonary and disseminated disease in patients with immunosuppression. Because of the increasing numbers of immunocompromised hosts with aging, HIV infection, cancer, and steroid therapy, this type of infection will possibly become more common and early diagnosis prompting adequate treatment is important to improve the prognosis. M kansasii should be considered in any immunosuppressed individuals with pulmonary, extrapulmonary, and systemic infection. Culture and DNA probes that can be applied to different tissues can identify this infection. Similarly, the clinical syndrome MonoMAC should be suspected in young adults with
L. Ehsani et al. myelodysplasia and invasive mycobacterial, fungal, or viral infections as early detection may expedite treatment options such as stem cell transplantation.
Acknowledgments The authors would like to acknowledge the Centers for Disease Control and Prevention and National Institutes of Health for their contribution.
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