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Case report S.E.Vernon B.C. Acar S.M. Pham D. Fertel Acanthamoeba infection in lung transplantation: report of a case and review of the literature Key words: Abstract: A 49 -year-old woman underwent bilateral lung transplantation for Authors’ a⁄liations: Acanthamoeba; lung transplantation; immunosuppression advanced idiopathic pulmonary ¢brosis. During the postoperative period she S.E.Vernon1, B.C. Acar1, S.M. Pham2, D. Fertel3 received immunosuppressive medications as well as corticosteroids. Aspergillus fumigatus grew from a sputum sample, and she was treated with nebulized am- Acknowledgement: We thank Dr G.S.Visvesvara, Centers for Disease Control and Prevention, Atlanta, GA, USA, for immuno£uorescent studies performed on tissue biopsy slides. photericin. She was discharged on tacrolimus and prednisone. After initially doing well, she required re-hospitalization for treatment of cytomegalovirus and Pseudomonas aeruginosa pneumonia. She was treated with ganciclovir and cefe- sinus debridement surgery. Aspergillus organisms were recovered and, at the periphery of the tangled masses of Aspergillus hyphae, numerous amebic cysts were also identi¢ed, which were morphologically consistent with Acanthamoeba spp. Subsequent electron microscopy and immuno£uorescent staining con¢rmed this impression. She was initially treated with intravenous amphotericin, later changed to voriconazole and caspofungin. Debridement of the sinuses 3 weeks later revealed fungal hyphae but no amebae. Infections with Acanthamoeba have rarely been reported in lung transplantation but have been recognized in bonemarrow and renal transplant patients, and have been lethal in many cases, particularly in patients with immunosuppression due to human immunode¢ciency virus infection. More recently, aggressive antimicrobial therapy has resulted in successful outcomes, as discussed herein. Acanthamoebae are ubiquitous free-living protists with a wide distribution in nature. They are perhaps best known as agents responsible for a persistent keratitis in contact lens wearers (1), and have also been widely reported as opportunistic infections in individuals with the acquired immune de¢ciency syndrome (AIDS) (2, 3). Occasional cases of granuloma- Copyright & Blackwell Munksgaard 2005 Transplant Infectious Disease . ISSN 1398 -2273 Transpl Infect Dis 2005: 7: 154^157 Printed in Denmark. All rights reserved 154 Department of Pathology 2 Department of Surgery 3 Department of Medicine, University of Miami/Jackson Memorial Hospital, Miami, Florida, USA pime and, after a 2-week hospitalization, was discharged. Seven months after transplantation she developed progressive sinusitis, treated with antibiotics and Received 1 June 2005, revised 14 October 2005, accepted for publication 24 October 2005 1 tous amebic encephalitis have been seen in immunocompetent patients, typically with fatal outcomes (3).We report here a case of Acanthamoeba rhinosinusitis, diagnosed by light and electron microscopy and con¢rmed by immuno£uorescence microscopy, in a patient with Correspondence to: Stephen E.Vernon, MD Department of Pathology University of Miami/JMH East Tower Rm. 2042 1611 NW 12th Avenue Miami, FL 33136 USA Tel: 1 305- 585- 5935 Fax: 1 305- 585-1029 e-mail: [email protected] Vernon et al: Acanthamoeba and lung transplantation bilateral lung transplantation.We also provide a brief survey of the literature on Acanthamoeba infections, with special attention to organ transplant recipients. Increased awareness of this entity and aggressive antibiotic therapies have resulted in better outcomes for this potentially fatal infection. Case report The patient was a 49 -year-old woman who underwent bilateral lung transplantation for end-stage lung disease secondary to pulmonary ¢brosis. She had been treated preoperatively with Cytoxan (cyclophosphamide) and was mildly neutropenic at the time of surgery. She underwent bilateral lung transplantation and postoperatively was treated with tacrolimus, mycophenolate mofetil, and prednisone for immunosuppression. While her initial postoperative course was fairly Fig. 1. Necrotic tissue, Aspergillus fumigatus hyphae (arrow), and numerous Acanthamoeba cysts (hematoxylin and eosin, original magni¢cation 200). uneventful, she did have one sputum culture positive for Aspergillus fumigatus, and she was given amphotericin by nebulizer in addition to her immunosuppressive medications. F|ve weeks after discharge she was again admitted to the hospital for 10 days with shortness of breath. She was believed to have cytomegalovirus (CMV) pneumonitis, and Pseudomonas aeruginosa was cultured from bronchoalveolar lavage £uid. These were treated with ganciclovir and cefepime, respectively, with good response. Approximately 7 months after transplantation she was re-admitted for evaluation of headaches, sinusitis, and fever. Computed tomographic scan of the sinuses showed opaci¢cation and she underwent sinus debridement. T|ssues were submitted for routine histologic processing, which by light microscopy yielded abundant hyphae with acute-angle branching consistent with Aspergillus sp. and necrotic tissue. At the periphery of the necrosis, numerous cysts were seen, subsequently identi¢ed as Acanthamoeba sp. (F|g. 1). The amebic cysts were thin- to thick- Fig. 2. Acanthamoeba cyst with nucleolus, and possible trophozoite form (inset). (Hematoxylin and eosin, original magni¢cation 400). walled structures from 12 to 15 mm in diameter, and showed what appeared to be a round nucleus, granular chromatin, and occasional cysts in the cytoplasm. Immuno£uorescent studies performed on tissue showed a centrally located nucleolus (F|g. 2). Rare amebae consistent biopsy slides at the Centers for Disease Control and Prevention in Atlan- with trophozoites were seen (F|g. 2, inset). ta were positive for Acanthamoeba spp. Immunostains developed by our laboratory (4) con¢rmed the Aspergil- Subsequently, she was treated with increased dosages of amphoteri- lus while the amebae showed no staining.The cysts were variably stained cin, voriconazole, and caspofungin. A sinus debridement 3 weeks later by Gomori’s methenamine silver stain and were also weakly stained with again revealed Aspergillus but no amebae were found, and her condition periodic acid Schi¡ stain. Fungal cultures were positive forA. fumigatus. gradually improved. Although Aspergillus could be identi¢ed in a sinus T|ssue was obtained from the para⁄n blocks and re-processed for elec- debridement 4 weeks later, no amebae have been identi¢ed in any speci- tron microscopy. Diligent search yielded a few organisms available for mens after the initial episode. examination, all cysts. Some of these demonstrated a dense cyst wall and virtually no remaining cytoplasm. Others showed a three-part wall, with a thick inner layer, a distinct outer layer, and a relatively thin amor- Discussion phous layer in between (F|g. 3). None of the cysts available for study had Infections continue to be the leading cause of death in the year following well-preserved nuclei or nucleoli. A few electron-dense bodies were seen lung transplantation. As with other transplants, the drugs used in imTransplant Infectious Disease 2005: 7: 154^157 155 Vernon et al: Acanthamoeba and lung transplantation Acanthamoebae are widely distributed in the environment and have been isolated from soil, sand, ponds and streams, tap water, seawater, physiotherapy pools, and other environmental sources.Their cysts resist dehydration, biocides, chlorination, antibiotics, and low temperatures. Mazur et al. (11) showed that cysts retained viable amebae after 24 years of storage at 41C.Wang and Feldman (12) have shown that Acanthamoebae can be recovered occasionally from throat swabs in otherwise healthy individuals. Thus, there is ample opportunity for exposure to Acanthamoebae in an ordinary household environment. Our patient had previously visited hot tubs but not for a 2-year interval before lung transplantation. Several investigators have studied the immune response to Acanthamoeba.While both antibody and complement are important in promoting recognition of amebas by phagocytic cells such as neutrophils and macrophages, killing of the amebas is dependent on lymphokine/monoFig. 3. Electron micrograph of Acanthamoeba cyst, showing inner endocyst layer and outer ectocyst layer (TEM, original magni¢cation 14,500). kine priming of the neutrophils (13, 14). Thus, the immunosuppressive munosuppression to prevent organ rejection adversely a¡ect humoral transduction and IL-2 transcription, may form the basis for human infec- and cell-mediated immune responses. The commonest infectious agents tion by Acanthamoeba in highly immunosuppressed transplant patients. tend to be bacterial, followed by viral infections, particularly CMV, and A variety of therapeutic regimens have been used in the treatment of fungal infections. These infections can represent both diagnostic and Acanthamoeba infections. Teknos et al. (15) used a combination of surgi- therapeutic challenges, and early diagnosis with prompt treatment has cal debridement, gentamicin nasal rinses, and itraconazole for one of a signi¢cant impact on survival (5). In immunocompetent individuals their HIV patients with a mixed Aspergillus/Acanthamoeba rhinosinusi- amebic keratitis has been a major concern to ophthalmologists, occur- tis, and debridement followed by intravenous pentamidine and topical ring mainly in patients with trauma, contact lens wearers, or corneal ketoconazole, followed by oral itraconazole in another patient with skin transplantation (1). However, Acanthamoebae are increasingly being and nasal Acanthamoebae. Oliva et al. (10) used pentamidine, 5 -£uorocy- recognized as opportunistic infections in immunosuppressed patients, in- tosine, and topical chlorhexidine gluconate/ketoconazole cream with cluding solid organ transplants, bone marrow transplants, and individ- eventual resolution of disseminated acanthamoebiasis in their lung uals infected with the human immunode¢ciency virus (HIV) (6^8). Several transplant patient. Successful treatment regimens have been few; these cases of Acanthamoeba infections in renal transplant patients have been are summarized by Marciano-Cabral and Cabral (13). However, in their reported, including both localized skin lesions and systemic disease. experience the diagnosis was often made late and multidrug toxicity To our knowledge, this report presents the third reported case of e¡ects of cyclosporine and tacrolimus, inhibiting T-lymphocyte signal complicated the disease course. Acanthamoeba infection in a lung transplant patient. Van Hamme et al. In summary, we report a third case of Acanthamoeba infection in a (9) reported a fatal case of acanthamoebiasis from Belgium in a lung lung transplant patient.While one of the previously reported cases was transplant patient, which was initially diagnosed from cutaneous le- ultimately fatal, this and another case eventually cleared the infection. sions but later became systemic. Oliva et al. (10) reported a case of widely Infections, along with bronchiolitis, continue to be the major causes of disseminated acanthamoebiasis in a single lung transplant patient, mortality during the ¢rst 5 years after lung transplantation. Early diag- successfully treated with combination antibiotic therapy. Our patient nosis and aggressive therapy seem to have played a role in the positive presented with Acanthamoeba rhinosinusitis, and the infection was con- outcomes for these patients, thus highlighting the need for recognition of trolled by surgical debridement and combination antimicrobial therapy. the distinctive morphology of Acanthamoeba infections. References 1. SEAL DV. Acanthamoeba keratitis ^ incidence, molecular epidemiology and new drugs for treatment. Eye 2003: 17: 893^905. 156 2. DUNAND VA, H AMMER SM, ROSSI R, et al. Parasitic sinusitis and otitis in patients infected with human Transplant Infectious Disease 2005: 7: 154^157 immunode¢ciency virus: report of ¢ve cases and review. Clin Infect Dis 1997: 25: 267^272. Vernon et al: Acanthamoeba and lung transplantation 3. SHUSTER FL,V IVESVARA GS. Free-living amoebae as opportunistic and nonopportunistic pathogens of humans and animals. Int J Parasit 2004: 34: 1001^1027. 4. MOSKOWITZ LB, GANJEI P, Z IEGELS W EISSMAN J, CLEARY T, P ENNEYS N, NADJI M. Immunohistologic identi¢cation of fungi in systemic and cutaneous mycoses. Arch Pathol Lab Med 1985: 110: 433^436. 5. A LEXANDER BD,TAPSON VF. Infectious complications of lung transplantation. Transpl Infect Dis 2001: 3: 128^137. 6. STEINBERG JP, GALINDO RL, K RAUS ES, GHANEM KG. Disseminated acanthamebiasis in a renal transplant recipient with osteomyelitis and cutaneous lesions: case report and literature review. Clin Infect Dis 2002: 35: e43^e49. 7. A NDERLINI P, PRZEPIORKA D, LUNA M, et al. Acanthamoeba meningoencephalitis after bone marrow transplantation. Bone Marrow Transplant 1994: 14: 459^461. 8. CARTER WW, G OMPF SG,TONEY JF, GREENE JN, CUTOLO EP. Disseminated Acanthamoeba sinusitis in a patient with AIDS: a possible role for early antiretroviral therapy. AIDS Read 2004: 14: 41^49. 9. VAN H AMME C, D UMONT M, DELOS M, LACHAPELLE JM. Cutaneous acanthamoebiasis in a lung transplant patient. Ann Dermatol Venereol 2001: 128: 1237^1240. 10. OLIVA S, JANTZ M,TIERNAN R, C OOK DL, J UDSON MA. Successful treatment of widely disseminated acanthamoebiasis. South Med J 1999: 92: 55^57. 11. M AZUR T, H ADAS E, I WANICKA I. The duration of the cyst stage and the viability and virulence of acanthamoeba isolates. Trop Med Parasitol 1995: 46: 106^108. 12. WANG SS, FELDMAN HA. Occurrence of Acanthamoeba in tissue cultures inoculated with human pharyngeal swabs. Antimicrobial Agents Chemother 1961: 1: 50^53. 13. M ARCIANO-CABRAL F, CABRAL G. Acanthamoeba spp. as agents of disease in humans. Clin Micro Rev 2003: 16: 273^307. 14. FERRANTE A. Immunity to Acanthamoeba. Rev Infect Dis 1991: 5 (Suppl.): s403^s409. 15. TEKNOS TN, P OULIN MD, LAURENTANO AM, LI KK. Acanthamoeba rhinosinusitis: characterization, diagnosis, and treatment. Am J Rhinol 2000: 21: 387^391. Transplant Infectious Disease 2005: 7: 154^157 157