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Delayed relapse of paracoccidioidomycosis in the central nervous system:a case report

Delayed relapse of paracoccidioidomycosis in the central nervous system:a case report Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Delayed relapse of paracoccidioidomycosis in the central nervous system: a case report 1 2,3,4 2,3,4 Rifat Rahman, Leela Davies, Amir M. Mohareb, Paula M. Peçanha- 5 6 7 7 Pietrobom, Nirav J. Patel, Isaac H. Solomon, David M. Meredith, Harrison K. 7 8 9 9 Tsai, Jeffrey P. Guenette, Shamik Bhattacharyya, Sebastian Urday, Gustavo E. 2,10,11 Velásquez Harvard Medical School, Boston, MA Division of Infectious Diseases, Brigham and Women’s Hospital, Boston , MA Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA Division of Infectious Diseases, Universidade Federal de São Paulo, São Paulo, Brazil Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA Department of Pathology, Brigham and Women’s Hospital, Boston, MA Division of Neuroradiology, Brigham and Women’s Hospital, Boston, MA Department of Neurology, Brigham and Women’s Hospital, Boston, MA Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA Division of Global Health Equity, Brigham and Women’s Hospital, Boston , MA Corresponding Author Gustavo E el sque , MD, MP H Department of Global Health and Social Medicine Harvard Medical School 641 Huntington Avenue Boston, MA 02115 Phone: 617.732.8881 Fax: 617.732.6829 Email: gvelasquez {at} bwh.harvard.edu Alternate Author: Rifat Rahman Harvard Medical School 107 Avenue Louis Pasteur Vanderbilt Mailing Center 305 Boston, MA 02114 Phone: 910.922.7088 Email: rifat_rahman {at} hms.harvard.edu © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Author Contributions RR and GEV wrote the first draft of the manuscript. LD, AM, PP, NJP, SB, SU, and GEV provided clinical care. IS, DMM, HT were consulting pathologists. JPG was a consulting neuroradiologist. All authors revised the manuscript critically for important intellectual content and gave final approval of the version to be published. 2 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Abstract Paracoccidioidomycosis is a dimorphic fungal infection endemic in Latin America. We report a patient with a history of pulmonary paracoccidioidomycosis who presented with relapsed disease in the central nervous system four years after initial treatment. We review current treatment strategies for paracoccidioidomycosis and neuroparacoccidioidomycosis. Keywords: Paracoccidioides brasiliensis, paracoccidioidomycosis, neuroparacoccidioidomycosis, central nervous system, endemic mycosis 3 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Case Report A 49-year-old man presented to an outside hospital in fall 2017 with a 3-week history of headache, dizziness, and ataxia. He reported a past medical history of pulmonary paracoccidioidomycosis (PCM) diagnosed in 2011, for which he was treated with itraconazole for two years and underwent a right lower lobe wedge resection in 2013. The patient was originally from Brazil, where he worked in coffee and sugarcane plantations and in construction. He moved to the United States at age 29 with no international travel since immigration. He reported heavy alcohol consumption and a 40 pack-year smoking history. Prior to transfer to our hospital, a head computed tomography (CT) revealed a large right cerebellar mass with surrounding edema and mass effect. Physical examination showed an awake patient with bradycardia (52 beats per minute), inspiratory crackles in the right mid lung, dysmetria on finger-nose-finger exam, and gait instability with falling to the right side. Admission laboratories were notable for a white blood cell count of 9,600 cells/mL with normal differential, C- reactive protein of 16.9 mg/L (reference range 0.0–3.0 mg/L), negative human immunodeficiency virus (HIV) antigen/antibody, negative serum 1,3-beta-D-glucan, and negative blood cultures. Brain magnetic resonance imaging (MRI) revealed a 5.0x3.5x3.0 cm multilocular, diffusion-restricting cystic mass in the right cerebellum with vasogenic edema and hydrocephalus (Figure 1). Chest and abdominal CT showed bilateral scattered pulmonary nodules and thickening of the adrenal glands (Figure 2). The patient underwent a right-sided posterior fossa craniotomy with subtotal resection of the cerebellar mass. The capsule was not entirely removed given that it was highly adherent to the brainstem and cranial nerves. Intraoperative 4 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 frozen section pathology identified yeast forms suspicious for Paracoccidioides brasiliensis, confirmed by methenamine silver staining of permanent sections (Figure 3). Fungal cultures grew Paracoccidioides brasiliensis after 21 days. The patient began treatment with a planned 4-week induction course of liposomal amphotericin B (5 mg/kg/day) with normal saline prehydration [1]. The patient’s course was complicated by acute kidney injury after two weeks of treatment with liposomal amphotericin B, which was subsequently transitioned to trimethoprim/sulfamethoxazole (TMP-SMX) dosed for glomerular filtration rate. After improvement in renal function, the patient was discharged on postoperative day 22 on oral TMP-SMX. One month after discharge, the patient reported alleviation of his presenting neurological symptoms. Repeat MRI obtained two months postoperatively demonstrated reduced edema with enhancement along the periphery of the surgical margin compatible with treatment-related involution of residual abscess (Figure 1). The target total duration of therapy was at least 18-24 months [1]. However, the patient was last seen in outpatient clinic almost 9 weeks after antifungal treatment initiation before he was lost to follow up. Discussion PCM is a dimorphic fungal infection caused by Paracoccidioides spp., which is endemic in Latin America. PCM is acquired through inhalation of conidia in soil [2]. Risk factors include agricultural work, male sex, smoking, and alcohol use disorder [1, 3]. Diagnosis relies upon serology, microscopy, and/or culture [1]. Microscopy using potassium hydroxide and calcofluor can identify the yeast form, appearing as a “pilot’s wheel” with round cells surrounded by budding daughter cell [4, 5s ]. 5 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Methenamine silver stain or periodic acid Schiff stain can identify yeast forms and granulomatous inflammation in tissue samples. Paracoccidioides spp. are cultured using Sabouraud agar incubated at room temperature and the mold form usually grows within 20-30 days [5]. Most patients initially develop an asymptomatic pulmonary infection, which may reactivate months or years later into chronic disease. PCM may disseminate to the oral mucosa, skin, adrenals, and in 9-25% of cases, to the central nervous system (CNS) [5, 6]. Neuroparacoccidioidomycosis (NPCM) most frequently localizes to the cerebral hemispheres (67%), cerebellum (25%), brain stem (25%), and spinal cord (4%) [7]. NPCM has a mortality rate of 44%; among survivors, 50% develop long- term neurological sequelae including motor deficits [8]. Individuals co-infected with HIV, with solid organ transplantation, active malignancies, or on biologic therapy have greater risk for disseminated disease, relapse, and mortality [1, 9-11]. Few randomized trials have been conducted to characterize the optimal treatment of PCM [12, 13]. There are no treatment guidelines available from professional or governmental bodies in the United States. For severe or disseminated infection, Brazilian guidelines recommend initial use of amphotericin B for 2-4 weeks followed by transition to oral antifungals, usually itraconazole or TMP-SMX [1]. Brazilian guidelines recommend TMP-SMX for 18-24 months or longer for the treatment of NPCM, given its greater CNS penetration than itraconazole [1, 14]. Ensuring regular follow up and adherence to protracted treatment regimens, particularly in the setting of disseminated disease, can be challenging for patients and clinicians. The present case is remarkable for the development of relapsed CNS disease four years after antibiotic treatment and resection of affected lung in an immunocompetent patient 6 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 with no repeated exposures. While PCM is rare in the United States, practitioners should consider it in immigrants from endemic areas. Past treatment does not preclude future relapse [15], and a significant fraction of cases can involve the CNS. 7 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Acknowledgments The authors thank Dr. Thomas Treadwell for his insight into the historical clinical management of this patient. Financial support G.E.V. received support from the National Institute of Allergy and Infectious Diseases (NIAID) at the U.S. National Institutes of Health (NIH) [NIH/NIAID grants K08 AI141740, L30 AI120170 and P30 AI060354], the Ronda Stryker and William Johnston Fellowship in Global Health and Social Medicine and the Dr. Lynne Reid/Drs. Eleanor and Miles Shore Fellowship at Harvard Medical School, the Burke Global Health Fellowship at the Harvard Global Health Institute, and the Harvard University Center for AIDS Research. A.M.M. received support from a postdoctoral research training award [NIH/NIAID grant T32 AI007433]. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the institutions with which the authors are affiliated. The funding source had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication. Potential conflicts of interest All authors: No reported conflicts. 8 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 References 1. Shikanai-Yasuda MA, Mendes RP, Colombo AL, et al. Brazilian guidelines for the clinical management of paracoccidioidomycosis. Rev Soc Bras Med Trop. 2017;50(5):715-740. 2. Restrepo A, McEwen JG, Castaneda E. The habitat of Paracoccidioides brasiliensis: how far from solving the riddle? Med Mycol. 2001;39(3):233-241. 3. Blotta MH, Mamoni RL, Oliveira SJ, et al. Endemic regions of paracoccidioidomycosis in Brazil: a clinical and epidemiologic study of 584 cases in the southeast region. Am J Trop Med Hyg. 1999;61(3):390-394. 4. Ameen M, Talhari C, Talhari S. Advances in paracoccidioidomycosis. Clin Exp Dermatol. 2010;35(6):576-580. 5. Brummer E, Castaneda E, Restrepo A. Paracoccidioidomycosis: an update. Clin Microbiol Rev. 1993;6(2):89-117. 6. Travassos LR, Taborda CP, Colombo AL. Treatment options for paracoccidioidomycosis and new strategies investigated. Expert Rev Anti Infect Ther. 2008;6(2):251-262. 7. Rosa Júnior M, Amorim AC, Baldon IV, et al. Paracoccidioidomycosis of the central nervous system: CT and MR imaging findings. Am J Neuroradiol. 2019;40(10):1681-1688. 8. Pedroso VS, Vilela Mde C, Pedroso ER, Teixeira AL. [Paracoccidioidomycosis compromising the central nervous system: a systematic review of the literature]. Rev Soc Bras Med Trop. 2009;42(6):691- 9 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 9. Morejón KM, Machado AA, Martinez R. Paracoccidioidomycosis in patients infected with and not infected with human immunodeficiency virus: a case- control study. Am J Trop Med Hyg. 2009;80(3):359-366. 10. Almeida FA, Neves FF, Mora DJ, et al. Paracoccidioidomycosis in Brazilian patients with and without human immunodeficiency virus infection. Am J Trop Med Hyg. 2017;96(2):368-372. 11. de Almeida JN Jr, Peçanha-Pietrobom PM, Colombo AL. Paracoccidioidomycosis in immunocompromised patients: a literature review. J Fungi (Basel). 2018;5(1). 12. Shikanai-Yasuda MA, Benard G, Higaki Y, et al. Randomized trial with itraconazole, ketoconazole and sulfadiazine in paracoccidioidomycosis. Med Mycol. 2002;40(4):411-417. 13. Queiroz-Telles F, Goldani LZ, Schlamm HT, Goodrich JM, Espinel-Ingroff A, Shikanai-Yasuda MA. An open-label comparative pilot study of oral voriconazole and itraconazole for long-term treatment of paracoccidioidomycosis. Clin Infect Dis. 2007;45(11):1462-1469. 14. de Almeida SM, Queiroz-Telles F, Teive HA, Ribeiro CE, Werneck LC. Central nervous system paracoccidioidomycosis: clinical features and laboratorial findings. J Infect. 2004;48(2):193-198. 15. Sylvestre TF, Franciscone Silva LR, Cavalcante Rde S, et al. Prevalence and serological diagnosis of relapse in paracoccidioidomycosis patients. PLoS Negl Trop Dis. 2014;8(5):e2834. 10 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 1 Figures 3 Figure 1. (A) Non-contrast T2-weighted, (B) contrast-enhanced T1-weighted, and (C) diffusion-weighted magnetic 4 resonance (MR) images from the time of presentation demonstrate a large, rim-enhancing, multilocular cystic mass with 5 areas of central diffusion restriction and adjacent edema. The mass effaces the fourth ventricle. Obstructive 6 hydrocephalus with transependymal flow was also present (not shown). (D) Contrast-enhanced T1-weighted MR image 7 obtained 2 months postoperatively demonstrates resolved mass effect with heterogeneous enhancement along the 8 margins of the resection cavity, consistent with treatment-related involution of the residual abscess. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 10 Figure 2. Axial contrast-enhanced computed tomography images from the time of presentation demonstrate (A-C) several 11 scattered pulmonary nodules in bilateral lungs, some of which are tubular in configuration and peribronchial in distribution, 12 and (D) thickening of the adrenal glands. A B C D Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 15 Figure 3. Histopathologic findings from right cerebellar mass resection. (A) Hematoxylin 16 and eosin (H&E) stained smear preparation from the intraoperative pathology 17 consultation showed scattered medium to large-sized yeast with multiple buds. 18 Permanent sections (B, C, D) showed numerous yeast (negatively stained by H&E) in a 19 background of necrosis (B) and associated with granulomatous inflammation (C), 20 including engulfment by multinucleated giant cells (arrow). (D) Grocott's methenamine 21 silver stain highlighted multiple yeast forms including the classic "pilot’s wheel" 22 appearance characteristic of Paracoccidioides brasiliensis. All images were taken with 23 40x objective. Accepted Manuscript http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Delayed relapse of paracoccidioidomycosis in the central nervous system:a case report

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Abstract

Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Delayed relapse of paracoccidioidomycosis in the central nervous system: a case report 1 2,3,4 2,3,4 Rifat Rahman, Leela Davies, Amir M. Mohareb, Paula M. Peçanha- 5 6 7 7 Pietrobom, Nirav J. Patel, Isaac H. Solomon, David M. Meredith, Harrison K. 7 8 9 9 Tsai, Jeffrey P. Guenette, Shamik Bhattacharyya, Sebastian Urday, Gustavo E. 2,10,11 Velásquez Harvard Medical School, Boston, MA Division of Infectious Diseases, Brigham and Women’s Hospital, Boston , MA Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA Division of Infectious Diseases, Universidade Federal de São Paulo, São Paulo, Brazil Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA Department of Pathology, Brigham and Women’s Hospital, Boston, MA Division of Neuroradiology, Brigham and Women’s Hospital, Boston, MA Department of Neurology, Brigham and Women’s Hospital, Boston, MA Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA Division of Global Health Equity, Brigham and Women’s Hospital, Boston , MA Corresponding Author Gustavo E el sque , MD, MP H Department of Global Health and Social Medicine Harvard Medical School 641 Huntington Avenue Boston, MA 02115 Phone: 617.732.8881 Fax: 617.732.6829 Email: gvelasquez {at} bwh.harvard.edu Alternate Author: Rifat Rahman Harvard Medical School 107 Avenue Louis Pasteur Vanderbilt Mailing Center 305 Boston, MA 02114 Phone: 910.922.7088 Email: rifat_rahman {at} hms.harvard.edu © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Author Contributions RR and GEV wrote the first draft of the manuscript. LD, AM, PP, NJP, SB, SU, and GEV provided clinical care. IS, DMM, HT were consulting pathologists. JPG was a consulting neuroradiologist. All authors revised the manuscript critically for important intellectual content and gave final approval of the version to be published. 2 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Abstract Paracoccidioidomycosis is a dimorphic fungal infection endemic in Latin America. We report a patient with a history of pulmonary paracoccidioidomycosis who presented with relapsed disease in the central nervous system four years after initial treatment. We review current treatment strategies for paracoccidioidomycosis and neuroparacoccidioidomycosis. Keywords: Paracoccidioides brasiliensis, paracoccidioidomycosis, neuroparacoccidioidomycosis, central nervous system, endemic mycosis 3 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Case Report A 49-year-old man presented to an outside hospital in fall 2017 with a 3-week history of headache, dizziness, and ataxia. He reported a past medical history of pulmonary paracoccidioidomycosis (PCM) diagnosed in 2011, for which he was treated with itraconazole for two years and underwent a right lower lobe wedge resection in 2013. The patient was originally from Brazil, where he worked in coffee and sugarcane plantations and in construction. He moved to the United States at age 29 with no international travel since immigration. He reported heavy alcohol consumption and a 40 pack-year smoking history. Prior to transfer to our hospital, a head computed tomography (CT) revealed a large right cerebellar mass with surrounding edema and mass effect. Physical examination showed an awake patient with bradycardia (52 beats per minute), inspiratory crackles in the right mid lung, dysmetria on finger-nose-finger exam, and gait instability with falling to the right side. Admission laboratories were notable for a white blood cell count of 9,600 cells/mL with normal differential, C- reactive protein of 16.9 mg/L (reference range 0.0–3.0 mg/L), negative human immunodeficiency virus (HIV) antigen/antibody, negative serum 1,3-beta-D-glucan, and negative blood cultures. Brain magnetic resonance imaging (MRI) revealed a 5.0x3.5x3.0 cm multilocular, diffusion-restricting cystic mass in the right cerebellum with vasogenic edema and hydrocephalus (Figure 1). Chest and abdominal CT showed bilateral scattered pulmonary nodules and thickening of the adrenal glands (Figure 2). The patient underwent a right-sided posterior fossa craniotomy with subtotal resection of the cerebellar mass. The capsule was not entirely removed given that it was highly adherent to the brainstem and cranial nerves. Intraoperative 4 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 frozen section pathology identified yeast forms suspicious for Paracoccidioides brasiliensis, confirmed by methenamine silver staining of permanent sections (Figure 3). Fungal cultures grew Paracoccidioides brasiliensis after 21 days. The patient began treatment with a planned 4-week induction course of liposomal amphotericin B (5 mg/kg/day) with normal saline prehydration [1]. The patient’s course was complicated by acute kidney injury after two weeks of treatment with liposomal amphotericin B, which was subsequently transitioned to trimethoprim/sulfamethoxazole (TMP-SMX) dosed for glomerular filtration rate. After improvement in renal function, the patient was discharged on postoperative day 22 on oral TMP-SMX. One month after discharge, the patient reported alleviation of his presenting neurological symptoms. Repeat MRI obtained two months postoperatively demonstrated reduced edema with enhancement along the periphery of the surgical margin compatible with treatment-related involution of residual abscess (Figure 1). The target total duration of therapy was at least 18-24 months [1]. However, the patient was last seen in outpatient clinic almost 9 weeks after antifungal treatment initiation before he was lost to follow up. Discussion PCM is a dimorphic fungal infection caused by Paracoccidioides spp., which is endemic in Latin America. PCM is acquired through inhalation of conidia in soil [2]. Risk factors include agricultural work, male sex, smoking, and alcohol use disorder [1, 3]. Diagnosis relies upon serology, microscopy, and/or culture [1]. Microscopy using potassium hydroxide and calcofluor can identify the yeast form, appearing as a “pilot’s wheel” with round cells surrounded by budding daughter cell [4, 5s ]. 5 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Methenamine silver stain or periodic acid Schiff stain can identify yeast forms and granulomatous inflammation in tissue samples. Paracoccidioides spp. are cultured using Sabouraud agar incubated at room temperature and the mold form usually grows within 20-30 days [5]. Most patients initially develop an asymptomatic pulmonary infection, which may reactivate months or years later into chronic disease. PCM may disseminate to the oral mucosa, skin, adrenals, and in 9-25% of cases, to the central nervous system (CNS) [5, 6]. Neuroparacoccidioidomycosis (NPCM) most frequently localizes to the cerebral hemispheres (67%), cerebellum (25%), brain stem (25%), and spinal cord (4%) [7]. NPCM has a mortality rate of 44%; among survivors, 50% develop long- term neurological sequelae including motor deficits [8]. Individuals co-infected with HIV, with solid organ transplantation, active malignancies, or on biologic therapy have greater risk for disseminated disease, relapse, and mortality [1, 9-11]. Few randomized trials have been conducted to characterize the optimal treatment of PCM [12, 13]. There are no treatment guidelines available from professional or governmental bodies in the United States. For severe or disseminated infection, Brazilian guidelines recommend initial use of amphotericin B for 2-4 weeks followed by transition to oral antifungals, usually itraconazole or TMP-SMX [1]. Brazilian guidelines recommend TMP-SMX for 18-24 months or longer for the treatment of NPCM, given its greater CNS penetration than itraconazole [1, 14]. Ensuring regular follow up and adherence to protracted treatment regimens, particularly in the setting of disseminated disease, can be challenging for patients and clinicians. The present case is remarkable for the development of relapsed CNS disease four years after antibiotic treatment and resection of affected lung in an immunocompetent patient 6 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 with no repeated exposures. While PCM is rare in the United States, practitioners should consider it in immigrants from endemic areas. Past treatment does not preclude future relapse [15], and a significant fraction of cases can involve the CNS. 7 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 Acknowledgments The authors thank Dr. Thomas Treadwell for his insight into the historical clinical management of this patient. Financial support G.E.V. received support from the National Institute of Allergy and Infectious Diseases (NIAID) at the U.S. National Institutes of Health (NIH) [NIH/NIAID grants K08 AI141740, L30 AI120170 and P30 AI060354], the Ronda Stryker and William Johnston Fellowship in Global Health and Social Medicine and the Dr. Lynne Reid/Drs. Eleanor and Miles Shore Fellowship at Harvard Medical School, the Burke Global Health Fellowship at the Harvard Global Health Institute, and the Harvard University Center for AIDS Research. A.M.M. received support from a postdoctoral research training award [NIH/NIAID grant T32 AI007433]. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the institutions with which the authors are affiliated. The funding source had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication. Potential conflicts of interest All authors: No reported conflicts. 8 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 References 1. Shikanai-Yasuda MA, Mendes RP, Colombo AL, et al. Brazilian guidelines for the clinical management of paracoccidioidomycosis. Rev Soc Bras Med Trop. 2017;50(5):715-740. 2. Restrepo A, McEwen JG, Castaneda E. The habitat of Paracoccidioides brasiliensis: how far from solving the riddle? Med Mycol. 2001;39(3):233-241. 3. Blotta MH, Mamoni RL, Oliveira SJ, et al. Endemic regions of paracoccidioidomycosis in Brazil: a clinical and epidemiologic study of 584 cases in the southeast region. Am J Trop Med Hyg. 1999;61(3):390-394. 4. Ameen M, Talhari C, Talhari S. Advances in paracoccidioidomycosis. Clin Exp Dermatol. 2010;35(6):576-580. 5. Brummer E, Castaneda E, Restrepo A. Paracoccidioidomycosis: an update. Clin Microbiol Rev. 1993;6(2):89-117. 6. Travassos LR, Taborda CP, Colombo AL. Treatment options for paracoccidioidomycosis and new strategies investigated. Expert Rev Anti Infect Ther. 2008;6(2):251-262. 7. Rosa Júnior M, Amorim AC, Baldon IV, et al. Paracoccidioidomycosis of the central nervous system: CT and MR imaging findings. Am J Neuroradiol. 2019;40(10):1681-1688. 8. Pedroso VS, Vilela Mde C, Pedroso ER, Teixeira AL. [Paracoccidioidomycosis compromising the central nervous system: a systematic review of the literature]. Rev Soc Bras Med Trop. 2009;42(6):691- 9 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 9. Morejón KM, Machado AA, Martinez R. Paracoccidioidomycosis in patients infected with and not infected with human immunodeficiency virus: a case- control study. Am J Trop Med Hyg. 2009;80(3):359-366. 10. Almeida FA, Neves FF, Mora DJ, et al. Paracoccidioidomycosis in Brazilian patients with and without human immunodeficiency virus infection. Am J Trop Med Hyg. 2017;96(2):368-372. 11. de Almeida JN Jr, Peçanha-Pietrobom PM, Colombo AL. Paracoccidioidomycosis in immunocompromised patients: a literature review. J Fungi (Basel). 2018;5(1). 12. Shikanai-Yasuda MA, Benard G, Higaki Y, et al. Randomized trial with itraconazole, ketoconazole and sulfadiazine in paracoccidioidomycosis. Med Mycol. 2002;40(4):411-417. 13. Queiroz-Telles F, Goldani LZ, Schlamm HT, Goodrich JM, Espinel-Ingroff A, Shikanai-Yasuda MA. An open-label comparative pilot study of oral voriconazole and itraconazole for long-term treatment of paracoccidioidomycosis. Clin Infect Dis. 2007;45(11):1462-1469. 14. de Almeida SM, Queiroz-Telles F, Teive HA, Ribeiro CE, Werneck LC. Central nervous system paracoccidioidomycosis: clinical features and laboratorial findings. J Infect. 2004;48(2):193-198. 15. Sylvestre TF, Franciscone Silva LR, Cavalcante Rde S, et al. Prevalence and serological diagnosis of relapse in paracoccidioidomycosis patients. PLoS Negl Trop Dis. 2014;8(5):e2834. 10 of 10 Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 1 Figures 3 Figure 1. (A) Non-contrast T2-weighted, (B) contrast-enhanced T1-weighted, and (C) diffusion-weighted magnetic 4 resonance (MR) images from the time of presentation demonstrate a large, rim-enhancing, multilocular cystic mass with 5 areas of central diffusion restriction and adjacent edema. The mass effaces the fourth ventricle. Obstructive 6 hydrocephalus with transependymal flow was also present (not shown). (D) Contrast-enhanced T1-weighted MR image 7 obtained 2 months postoperatively demonstrates resolved mass effect with heterogeneous enhancement along the 8 margins of the resection cavity, consistent with treatment-related involution of the residual abscess. Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 10 Figure 2. Axial contrast-enhanced computed tomography images from the time of presentation demonstrate (A-C) several 11 scattered pulmonary nodules in bilateral lungs, some of which are tubular in configuration and peribronchial in distribution, 12 and (D) thickening of the adrenal glands. A B C D Accepted Manuscript Downloaded from https://academic.oup.com/ofid/advance-article-abstract/doi/10.1093/ofid/ofaa077/5771108 by guest on 05 March 2020 15 Figure 3. Histopathologic findings from right cerebellar mass resection. (A) Hematoxylin 16 and eosin (H&E) stained smear preparation from the intraoperative pathology 17 consultation showed scattered medium to large-sized yeast with multiple buds. 18 Permanent sections (B, C, D) showed numerous yeast (negatively stained by H&E) in a 19 background of necrosis (B) and associated with granulomatous inflammation (C), 20 including engulfment by multinucleated giant cells (arrow). (D) Grocott's methenamine 21 silver stain highlighted multiple yeast forms including the classic "pilot’s wheel" 22 appearance characteristic of Paracoccidioides brasiliensis. All images were taken with 23 40x objective. Accepted Manuscript

Journal

Open Forum Infectious Diseases – Oxford University Press

Published: Apr 1, 2020

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