Mycopathologia (2014) 177:137–141 DOI 10.1007/s11046-014-9729-5
Central Nervous System Paracoccidioidomycosis in an AIDS Patient: Case Report Mario Leo´n Silva-Vergara • Ivonete Helena Rocha • Rakel Rocha Vasconcelos • Andre´ Luiz Maltos • Fernando de Freitas Neves Luciana de Almeida Silva Teixeira • Delio Jose´ Mora
•
Received: 22 August 2013 / Accepted: 13 January 2014 / Published online: 24 January 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Up to now, over 200 patients with paracoccidioidomycosis (PCM) associated to HIV infection have already been reported; however, the central nervous system involvement in this coinfection was rarely reported. This paper presents a 35-year-old Brazilian male AIDS patient who developed pulmonary PCM successfully treated with itraconazole. At the antiretroviral therapy starting, he had 32 CD4? T cells baseline count and high viral load levels. After 9 months, he presented severe fungal meningoencephalitis diagnosed by sublenticular enhanced nodular lesion at computerized tomography and magnetic resonance brain imaging and a positive Paracoccidiodes brasiliensis smear and culture from cerebrospinal fluid. At the time, a sixfold increase in CD4? T cell count and undetectable viral load level were evidenced. The patient received amphotericin B during 1 year presenting slow but progressive clinical improvement, and he is currently asymptomatic and without neurological disabilities. To our knowledge,
M. L. Silva-Vergara I. H. Rocha R. R. Vasconcelos A. L. Maltos F. de Freitas Neves L. de Almeida Silva Teixeira D. J. Mora (&) Infectious Diseases Unit, Triaˆngulo Mineiro Federal University, Avenida Frei Paulino, 30, Uberaba, Minas Gerais CEP 38025-180, Brazil e-mail: [email protected] M. L. Silva-Vergara e-mail: [email protected]
this is the second case report of a patient with neuroparacoccidioidomycosis associated to HIV infection. Keywords Neuroparacoccidioidomycosis AIDS Meningoencephalitis Paracoccidiodes brasiliensis
Introduction Paracoccidioidomycosis (PCM) is one of the most prevalent endemic mycoses in Latin American countries where at least 10 million people are infected by the thermal dimorphic fungus Paracoccidiodes brasiliensis/Paracoccidiodes lutzii [1, 2]. The infection is acquired through fungal propagules inhalation, and most individuals in endemic areas remain asymptomatic along their lifespan [3]. Among systemic mycosis, it represents the most important cause of mortality in Brazil [4]. Classically, two different clinical forms of this mycosis are recognized, the acute/sub-acute, mostly in young people presenting severe and systemic symptoms related to the monocyte–macrophage system, mucocutaneous and bone involvement. Otherwise, the chronic form is seen in mean-age adult males who predominantly develop pulmonary and mucocutaneous lesions, although any organ or system can be isolate or concomitantly affected [5–7].
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The central nervous system (CNS) involvement in PCM was described for the first time in 1943, but it was better recognized with the advent of computerized tomography (CT) scan and magnetic resonance imaging (MRI) and can occur in 12–36 % of cases of PCM as encephalitis and rarely as meningitis alone [8–12]. Findings of autopsy and neuroimaging examination suggested that often individuals with neuro-PCM can be a symptomatic [13]. At CT imaging, hypodense enhanced lesions predominantly localized in the supratentorial compartment have been commonly described [13]. At MRI imaging, inflammatory lesions exhibit a classical pattern in conventional sequences. The core appears hyperintense on T2 WI with a hypointense rim, whereas these lesions appear hypointense with a hyperintense rim on T1 WI. A ringenhancing aspect is depicted after contrast [14, 15]. PCM neurological lesions arise after blood or lymphatic fungal dissemination either from an active pulmonary infection or quiescent foci in the CNS [14]. A recent literature review of CNS-PCM cases reported 257 patients with clinical findings of encephalitis of whom 90 % presented parenchymal inflammatory lesions at CT or MRI imaging. Focal deficits, seizures and consciousness level alterations were common clinical features. Most patients were male, median age of 43, presenting symptoms related to PCM chronic form in 98.3 % cases and a mortality rate of 44 % [10]. Since 1989, over 200 cases of PCM in HIV-infected patients have been reported [16–19]. It was described that PCM represents the fourth most common systemic mycosis associated to HIV-infected patients in South America [20]. Most patients exhibited more acute and severe symptoms of disseminated infection involving lymphatic, pulmonary and mucocutaneous sites, which suggests the overlap of features of both clinical forms. At the time of PCM diagnosis, their CD4? T count baseline values were \200 cells/mm3 [17–19]. Despite the severity observed among these patients and according to the literature reviewed, only one AIDS patient with disseminated PCM and asymptomatic brain lesion seen at MRI imaging was already described [21].
Case Report A 35-year-old male Brazilian patient was admitted at the teaching hospital in March 2011 with progressive
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Mycopathologia (2014) 177:137–141
weight loss, asthenia, adynamia and cough with yellow sputum for 3 months. No other signs or symptoms were referred. He was found to be HIV positive in 2005 and since then had not received any medical care. He informed to be homosexual and an illicit drug user. At clinical examination, the patient looked emaciated with mucocutaneous pallor and was apyretic. X-ray and CT of the chest showed basal and bilateral interstitial and nodular opacities. A transbronchial biopsy was performed, and fungal structures identical to P. brasiliensis were seen at histopathology. His CD4? T cell baseline value was 32 cells/ mm3, and the viral load was above the detection limit. It was prescribed amphotericin B (AmB) for a week followed by a 400 mg daily oral dosage of itraconazole (ITR) plus (AZT ? 3TC ? efavirenz) and pneumocystis pneumonia prophylaxis with trimethoprim sulfamethoxazole (TMP–SMX). As his clinical status progressively improved, he was discharged and monthly followed up as outpatient. He remained asymptomatic for several months with good adhesion to antifungal and antiretroviral therapy (ART). In December 2011, he was readmitted with a 10-day history of dysarthria, blurred speech, phonophobia, irritability, aggressiveness, psychomotor agitation, dizziness and a syncope episode the day before. He was confused, agitated, ataxic and presented generalized hyperreflexia. The brain CT and MRI imaging evidenced diffuse cerebral edema and oval enhanced lesion localized in right internal capsule region (Fig. 1). The chest X-ray was normal. The cerebrospinal fluid (CSF) assessment showed 12 cells (93 % lymphocytes, 5 % monocytes, 2 % eosinophils), glucose 94 mg/dL, proteins 109 mg/dL and a positive latex cryptococcal antigen test (CrAg) (Immuno-Mycologics, Norman, OK, USA). At CSF smear, birefringent yeasts with multiple budding identical to P. brasiliensis were observed (Fig. 2a). After 3 weeks, culture of CSF on sabouraud glucose agar yielded colonies macro e microscopically identical to P. brasiliensis (Fig. 2b). At admission, his CD4? T cell count was 193 cells/ mm3, and the viral load was undetectable. Patient received endovenous TMP–SMX and a non-steroidal anti-inflammatory drug. Besides, efavirenz was replaced by nevirapine. After a month, he exhibited clinical improvement and was discharged with oral TMP–SMX and followed up as outpatient; 2 weeks later, he developed mucocutaneous lesions suggestive of Stevens Johnson reaction attributed to TMP–SMX
Mycopathologia (2014) 177:137–141
Fig. 1 a and b Brain CT after the contrast: enhanced oval lesion localized on the right internal capsule (posterior arm) with perilesional edema. c MRI axial flair-weighted imaging:
139
hypointense oval lesion with mild perilesional edema localized on the right internal capsule (posterior arm)
Fig. 2 a CSF India ink smear showing yeasts with multiple budding. b CSF culture on Sabouraud agar at 37 °C with giant cells containing birefringent yeast identical to P. brasiliensis. Cotton blue stain (940)
which was replaced by AmB deoxycholate. During the follow-up and despite CSF negative culture and the progressive improvement of his neurological picture, the first brain CT and MRI imaging control remained unaltered, and therefore, this therapy was kept for 1 year and then switched to 400 mg daily oral dosage of ITR. In his latest control, his viral load remains undetectable, whereas the CD4? T cell count value reached 495 cells/mm3, and at CT and MRI imaging, the CNS lesions disappeared. Currently, he receives ITR and ART and remains asymptomatic.
Discussion The patient herein described illustrates how HIV infection alters the natural history of several infections
which can present uncommon and/or atypical features and outcome [16–19]. At time of pulmonary PCM diagnosis, he was severely immune-compromised and no clinical evidence of disseminated infection to other organs was observed, and for this, it was prescribed oral ITR, the drug of choice to treat mild and moderate clinical forms of PCM in Brazil [22]. After several months on antifungal and ART, the patient presented clinical picture of fungal meningoencephalitis diagnosed by brain CT and MRI imaging which showed sublenticular enhanced nodular lesion and perilesional edema and positive CSF P. brasiliensis smear and culture. The latter has been rarely described in patients with CNS-PCM, and despite meningeal involvement evidenced by CSF changes together P. brasiliensis isolation, no meningeal thickening or enhancement were seen at MRI imaging
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[10, 23]. Of 257 cases of PCM with neurological involvement recently reviewed, 89.9 % presented pseudo-tumoral cerebral lesions at CT or MRI imaging but only 1.9 % of them exhibited P. brasiliensis positive CSF smear and culture [8, 10, 23]. In addition, the CSF positive latex CrAg test observed in this case would suggest cross-reactivity between fungal wall components of P. brasiliensis and C. neoformans as described to other microorganisms [24]. The efficacy and adhesion to ART in this case can be evidenced by the CD4? T cells sixfold increase, undetectable viral load along with whole resolution of PCM pulmonary symptoms and radiological findings under ITR therapy. However, this drug has been considered unsafe to treat patients with neuro-PCM [22], despite adequate CSF concentration levels of ITR were reported in murine models of fungal meningitis, and clinical and experimental data pointed out its efficacy similar to fluconazole [25, 26]. Inadvertently, the ART included efavirenz which could have decreased the serum levels of ITR hindering to reach CSF levels to treat quiescent P. brasiliensis foci despite a twofold dose of ITR prescribed at first admission [27, 28]. As usual, in HIV-infected patients management, he also received TMP–SMX three-times a week to prevent Pneumocystis jirovecii pneumonia what can have delayed but not avoided the starting of PCM neurological symptoms. Due to its high efficacy, this drug is commonly used to treat PCM in most Latin America countries where it is endemic and different from ITR; it reaches high CSF levels which makes it a good therapy choice to CNS-PCM [14, 22]. At admission, endovenous TMP–SMX was prescribed, and after several weeks on therapy, he developed severe allergic reaction probably associated with its use, and then, he received AmB. Most CNS-PCM cases already reported were treated with sulfa derivates as main therapy [10, 14]. Amphotericin B was kept for 12 months until the regression of his clinical symptoms and lesion at CT and MRI brain imaging. During the follow-up, no evidence of neurological disabilities have been detected, and he remains under ITR prophylaxis. Usually patients with CNS-PCM must receive specific therapy for 2 years or more depending on clinical and radiological outcome [14, 29]. To our knowledge, this is the second case report of neuroparacoccidioidomycosis in an AIDS patient.
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Mycopathologia (2014) 177:137–141
The first one was described in a pregnant HIVinfected woman who developed severe ocular lesion leading to eye enucleation which eased the P. brasiliensis infection diagnosis. Despite neurological symptoms were absent in this case, the brain MRI imaging showed a focal hypodense contrastenhanced lesions which regressed after TMP–SMX therapy [21]. Thus, as patients with PCM can have CNS asymptomatic quiescent foci, CT and MRI assessment should be routinely performed as possible, especially if they are HIV infected. ˆ ngela Azoˆr for the Acknowledgments Thanks to Mrs. A technical assistance and to Fundac¸a˜o de Amparo a Pesquisa de Minas Gerais (FAPEMIG) for the financial support. Grant: APQ 01624-12. Conflict of interest The authors report no conflict of interests.
References 1. Marini MM, Zanforlin T, Santos PC, et al. Identification and characterization of Tc1/mariner-like DNA transposons in genomes of the pathogenic fungi of the Paracoccidioides species complex. BMC Genom. 2010;11:130. 2. Wanke B, Londero AT. Epidemiology and paracoccidioidomycosis infection. In: Franco M, Lacaz CS, RestrepoMoreno A, Del Negro G, editors. Paracoccidioidomycosis. Boca Raton, FL: CRC Press; 1994. p. 109–20. 3. Restrepo A, McEwen JG, Castaneda E. The habitat of Paracoccidiodes brasiliensis: how far from solving the riddle? Med Mycol. 2001;39:233–41. 4. Prado M, Silva MB, Laurenti R, et al. Mortality due to systemic mycoses as a primary cause of death or in association with AIDS in Brazil: a review from 1996 to 2006. Mem Inst Oswaldo Cruz. 2009;104:513–21. 5. Franco M, Montenegro MR, Mendes RP, Marques SA, et al. Paracoccidioidomycosis: a recently proposed classification of its clinical forms. Rev Soc Bras Med Trop. 1987;20: 129–32. 6. Mendes RP. The gamut of clinical manifestation. In: Franco M, da Lacaz CS, Restrepo-Moreno A, Del Negro G, editors. Paracoccidioidomicose. Boca Raton, FL: CRC Press; 1994. p. 233–58. 7. Franco M, Mendes RP, Moscardi-Bacchi M, et al. Paracoccidioidomycosis. Baillie`re’s Clin Trop Med Commun Dis. 1989;4:185–220. 8. Magalha˜es AC, Bacheschi LA, Caramelli P, et al. Paracoccidioidomycosis of the central nervous system: study of 5 cases by magnetic resonance. Rev Hosp Clin Fac Med Sa˜o Paulo. 1993;48:94–7. 9. Lambertucci JR, Lana-Peixoto MA, Pitella JE. Paracoccidioidomycosis of the central nervous system. Rev Soc Bras Med Trop. 2001;34:395–6.
Mycopathologia (2014) 177:137–141 10. Pedroso VS, Vilela MDEC, Pedroso ER, et al. Paracoccidioidomycosis compromising the central nervous system: a systematic review of the literature. Rev Soc Bras Med Trop. 2009;42:691–7. 11. Maffei WE. Micoses do Sistema Nervoso Central. An Fac Med Univ Sa˜o Paulo. 1943;29:297–327 [In Portuguese]. 12. Francesconi F, do Valle ACF, Silva MT, Costa RL, Carregal E, Thalhari S. International issue: meningoencephalitis due to Paracoccidioides brasiliensis. Neurology. 2008;71:e65–7. 13. No´brega JPS, Franc¸a AS. Neuroparacoccidioidomycosis. Franco M, Lacaz CS, Restrepo-Moreno A, Del-Negro G, editors. Paracoccidioidomycosis. Boca Raton, FL: CRC Press; 1994. p. 321–30. 14. Paniago AM, de Oliveira PA, Aguiar ES, et al. Neuroparacoccidioidomycosis: analysis of 13 cases observed in an endemic area in Brazil. Trans R Soc Trop Med Hyg. 2007;101:414–20. 15. Reis F, Collier OP, Souza TF, Lopes GP, Bronzatto E, Junior NAS, Pereira RM, Appenzeller S. Neuroparacoccidioidomycosis (NPCM): magnetic resonance imaging (MRI) findings. Mycopathologia. 2013;175:181–6. 16. Goldani LZ, Martinez R, Landell GA, et al. Paracoccidioidomycosis in a patient with acquired immunodeficiency syndrome. Mycopathologia. 1989;105:71–4. 17. Benard G, Duarte AJ. Paracoccidioidomycosis: a model for evaluation of the effects of human immunodeficiency virus infection on the natural history of endemic tropical diseases. Clin Infect Dis. 2000;31:1032–9. 18. Silva-Vergara ML, Teixeira AC, Curi VG, et al. Paracoccidioidomycosis associated with human immunodeficiency virus infection. Report of 10 cases. Med Mycol. 2003;41: 259–63. 19. Morejo´n 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;80:359–66.
141 20. Bellissimo-Rodrigues F, Vitali LH, Martinez R. Serological diagnosis of paracoccidioidomycosis in HIV-coinfected patients. Mem Inst Oswaldo Cruz. 2010;105:904–7. 21. Finamor LP, Muccioli C, Martins MC, Rizzo LV, Belfort R Jr. Ocular and central nervous system paracoccidioidomycosis in a pregnant woman with acquired immunodeficiency syndrome. Am J Ophthalmol. 2002;134:456–9. 22. Shikanai-Yasuda MA, Telles Filho FQ, Mendes RP, et al. Guidelines in paracoccidioidomycosis. Rev Soc Bras Med Trop. 2006;39:297–310. 23. Lorenzoni PJ, Chang MR, Paniago AM, Salgado PR. Paracoccidioidomycosis meningitis: case report. Arq Neuropsiquiatr. 2002;60:1015–8. 24. Whittier S, Hopfer RL, Gilligan P. Elimination of falsepositive serum reactivity in latex agglutination test for cryptococcal antigen in human immunodeficiency virusinfected population. J Clin Microbiol. 1994;32:2158–61. 25. Sorensen KN, Sobel RA, Clemons KV, et al. Comparison of fluconazole and itraconazole in a rabbit model of coccidioidal meningitis. Antimicrob Agents Chemother. 2000;44: 1512–7. 26. Kamberi P, Sobel RA, Clemons KV, et al. Comparison of itraconazole and fluconazole treatments in a murine model of coccidioidal meningitis. Antimicrob Agents Chemother. 2007;51:998–1003. 27. Kethireddy S, Andes D. CNS pharmacokinetics of antifungal agents. Expert Opin Drug Metab Toxicol. 2007;3: 573–81. 28. Koo HL, Hamill RJ, Andrade RA. Dug-drug interaction between itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis. Clin Infect Dis. 2007; 45:e77–9. 29. de Almeida SM, Queiroz-Telles F, Teive HA, Ribeiro CE, Werneck LC. Central nervous system paracoccidioidomycosis: clinical features and laboratorial findings. J Infect. 2004;48:193–8.
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Central Nervous System Paracoccidioidomycosis in an AIDS Patient: Case Report Mario Leo´n Silva-Vergara • Ivonete Helena Rocha • Rakel Rocha Vasconcelos • Andre´ Luiz Maltos • Fernando de Freitas Neves Luciana de Almeida Silva Teixeira • Delio Jose´ Mora
•
Received: 22 August 2013 / Accepted: 13 January 2014 / Published online: 24 January 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Up to now, over 200 patients with paracoccidioidomycosis (PCM) associated to HIV infection have already been reported; however, the central nervous system involvement in this coinfection was rarely reported. This paper presents a 35-year-old Brazilian male AIDS patient who developed pulmonary PCM successfully treated with itraconazole. At the antiretroviral therapy starting, he had 32 CD4? T cells baseline count and high viral load levels. After 9 months, he presented severe fungal meningoencephalitis diagnosed by sublenticular enhanced nodular lesion at computerized tomography and magnetic resonance brain imaging and a positive Paracoccidiodes brasiliensis smear and culture from cerebrospinal fluid. At the time, a sixfold increase in CD4? T cell count and undetectable viral load level were evidenced. The patient received amphotericin B during 1 year presenting slow but progressive clinical improvement, and he is currently asymptomatic and without neurological disabilities. To our knowledge,
M. L. Silva-Vergara I. H. Rocha R. R. Vasconcelos A. L. Maltos F. de Freitas Neves L. de Almeida Silva Teixeira D. J. Mora (&) Infectious Diseases Unit, Triaˆngulo Mineiro Federal University, Avenida Frei Paulino, 30, Uberaba, Minas Gerais CEP 38025-180, Brazil e-mail: [email protected] M. L. Silva-Vergara e-mail: [email protected]
this is the second case report of a patient with neuroparacoccidioidomycosis associated to HIV infection. Keywords Neuroparacoccidioidomycosis AIDS Meningoencephalitis Paracoccidiodes brasiliensis
Introduction Paracoccidioidomycosis (PCM) is one of the most prevalent endemic mycoses in Latin American countries where at least 10 million people are infected by the thermal dimorphic fungus Paracoccidiodes brasiliensis/Paracoccidiodes lutzii [1, 2]. The infection is acquired through fungal propagules inhalation, and most individuals in endemic areas remain asymptomatic along their lifespan [3]. Among systemic mycosis, it represents the most important cause of mortality in Brazil [4]. Classically, two different clinical forms of this mycosis are recognized, the acute/sub-acute, mostly in young people presenting severe and systemic symptoms related to the monocyte–macrophage system, mucocutaneous and bone involvement. Otherwise, the chronic form is seen in mean-age adult males who predominantly develop pulmonary and mucocutaneous lesions, although any organ or system can be isolate or concomitantly affected [5–7].
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138
The central nervous system (CNS) involvement in PCM was described for the first time in 1943, but it was better recognized with the advent of computerized tomography (CT) scan and magnetic resonance imaging (MRI) and can occur in 12–36 % of cases of PCM as encephalitis and rarely as meningitis alone [8–12]. Findings of autopsy and neuroimaging examination suggested that often individuals with neuro-PCM can be a symptomatic [13]. At CT imaging, hypodense enhanced lesions predominantly localized in the supratentorial compartment have been commonly described [13]. At MRI imaging, inflammatory lesions exhibit a classical pattern in conventional sequences. The core appears hyperintense on T2 WI with a hypointense rim, whereas these lesions appear hypointense with a hyperintense rim on T1 WI. A ringenhancing aspect is depicted after contrast [14, 15]. PCM neurological lesions arise after blood or lymphatic fungal dissemination either from an active pulmonary infection or quiescent foci in the CNS [14]. A recent literature review of CNS-PCM cases reported 257 patients with clinical findings of encephalitis of whom 90 % presented parenchymal inflammatory lesions at CT or MRI imaging. Focal deficits, seizures and consciousness level alterations were common clinical features. Most patients were male, median age of 43, presenting symptoms related to PCM chronic form in 98.3 % cases and a mortality rate of 44 % [10]. Since 1989, over 200 cases of PCM in HIV-infected patients have been reported [16–19]. It was described that PCM represents the fourth most common systemic mycosis associated to HIV-infected patients in South America [20]. Most patients exhibited more acute and severe symptoms of disseminated infection involving lymphatic, pulmonary and mucocutaneous sites, which suggests the overlap of features of both clinical forms. At the time of PCM diagnosis, their CD4? T count baseline values were \200 cells/mm3 [17–19]. Despite the severity observed among these patients and according to the literature reviewed, only one AIDS patient with disseminated PCM and asymptomatic brain lesion seen at MRI imaging was already described [21].
Case Report A 35-year-old male Brazilian patient was admitted at the teaching hospital in March 2011 with progressive
123
Mycopathologia (2014) 177:137–141
weight loss, asthenia, adynamia and cough with yellow sputum for 3 months. No other signs or symptoms were referred. He was found to be HIV positive in 2005 and since then had not received any medical care. He informed to be homosexual and an illicit drug user. At clinical examination, the patient looked emaciated with mucocutaneous pallor and was apyretic. X-ray and CT of the chest showed basal and bilateral interstitial and nodular opacities. A transbronchial biopsy was performed, and fungal structures identical to P. brasiliensis were seen at histopathology. His CD4? T cell baseline value was 32 cells/ mm3, and the viral load was above the detection limit. It was prescribed amphotericin B (AmB) for a week followed by a 400 mg daily oral dosage of itraconazole (ITR) plus (AZT ? 3TC ? efavirenz) and pneumocystis pneumonia prophylaxis with trimethoprim sulfamethoxazole (TMP–SMX). As his clinical status progressively improved, he was discharged and monthly followed up as outpatient. He remained asymptomatic for several months with good adhesion to antifungal and antiretroviral therapy (ART). In December 2011, he was readmitted with a 10-day history of dysarthria, blurred speech, phonophobia, irritability, aggressiveness, psychomotor agitation, dizziness and a syncope episode the day before. He was confused, agitated, ataxic and presented generalized hyperreflexia. The brain CT and MRI imaging evidenced diffuse cerebral edema and oval enhanced lesion localized in right internal capsule region (Fig. 1). The chest X-ray was normal. The cerebrospinal fluid (CSF) assessment showed 12 cells (93 % lymphocytes, 5 % monocytes, 2 % eosinophils), glucose 94 mg/dL, proteins 109 mg/dL and a positive latex cryptococcal antigen test (CrAg) (Immuno-Mycologics, Norman, OK, USA). At CSF smear, birefringent yeasts with multiple budding identical to P. brasiliensis were observed (Fig. 2a). After 3 weeks, culture of CSF on sabouraud glucose agar yielded colonies macro e microscopically identical to P. brasiliensis (Fig. 2b). At admission, his CD4? T cell count was 193 cells/ mm3, and the viral load was undetectable. Patient received endovenous TMP–SMX and a non-steroidal anti-inflammatory drug. Besides, efavirenz was replaced by nevirapine. After a month, he exhibited clinical improvement and was discharged with oral TMP–SMX and followed up as outpatient; 2 weeks later, he developed mucocutaneous lesions suggestive of Stevens Johnson reaction attributed to TMP–SMX
Mycopathologia (2014) 177:137–141
Fig. 1 a and b Brain CT after the contrast: enhanced oval lesion localized on the right internal capsule (posterior arm) with perilesional edema. c MRI axial flair-weighted imaging:
139
hypointense oval lesion with mild perilesional edema localized on the right internal capsule (posterior arm)
Fig. 2 a CSF India ink smear showing yeasts with multiple budding. b CSF culture on Sabouraud agar at 37 °C with giant cells containing birefringent yeast identical to P. brasiliensis. Cotton blue stain (940)
which was replaced by AmB deoxycholate. During the follow-up and despite CSF negative culture and the progressive improvement of his neurological picture, the first brain CT and MRI imaging control remained unaltered, and therefore, this therapy was kept for 1 year and then switched to 400 mg daily oral dosage of ITR. In his latest control, his viral load remains undetectable, whereas the CD4? T cell count value reached 495 cells/mm3, and at CT and MRI imaging, the CNS lesions disappeared. Currently, he receives ITR and ART and remains asymptomatic.
Discussion The patient herein described illustrates how HIV infection alters the natural history of several infections
which can present uncommon and/or atypical features and outcome [16–19]. At time of pulmonary PCM diagnosis, he was severely immune-compromised and no clinical evidence of disseminated infection to other organs was observed, and for this, it was prescribed oral ITR, the drug of choice to treat mild and moderate clinical forms of PCM in Brazil [22]. After several months on antifungal and ART, the patient presented clinical picture of fungal meningoencephalitis diagnosed by brain CT and MRI imaging which showed sublenticular enhanced nodular lesion and perilesional edema and positive CSF P. brasiliensis smear and culture. The latter has been rarely described in patients with CNS-PCM, and despite meningeal involvement evidenced by CSF changes together P. brasiliensis isolation, no meningeal thickening or enhancement were seen at MRI imaging
123
140
[10, 23]. Of 257 cases of PCM with neurological involvement recently reviewed, 89.9 % presented pseudo-tumoral cerebral lesions at CT or MRI imaging but only 1.9 % of them exhibited P. brasiliensis positive CSF smear and culture [8, 10, 23]. In addition, the CSF positive latex CrAg test observed in this case would suggest cross-reactivity between fungal wall components of P. brasiliensis and C. neoformans as described to other microorganisms [24]. The efficacy and adhesion to ART in this case can be evidenced by the CD4? T cells sixfold increase, undetectable viral load along with whole resolution of PCM pulmonary symptoms and radiological findings under ITR therapy. However, this drug has been considered unsafe to treat patients with neuro-PCM [22], despite adequate CSF concentration levels of ITR were reported in murine models of fungal meningitis, and clinical and experimental data pointed out its efficacy similar to fluconazole [25, 26]. Inadvertently, the ART included efavirenz which could have decreased the serum levels of ITR hindering to reach CSF levels to treat quiescent P. brasiliensis foci despite a twofold dose of ITR prescribed at first admission [27, 28]. As usual, in HIV-infected patients management, he also received TMP–SMX three-times a week to prevent Pneumocystis jirovecii pneumonia what can have delayed but not avoided the starting of PCM neurological symptoms. Due to its high efficacy, this drug is commonly used to treat PCM in most Latin America countries where it is endemic and different from ITR; it reaches high CSF levels which makes it a good therapy choice to CNS-PCM [14, 22]. At admission, endovenous TMP–SMX was prescribed, and after several weeks on therapy, he developed severe allergic reaction probably associated with its use, and then, he received AmB. Most CNS-PCM cases already reported were treated with sulfa derivates as main therapy [10, 14]. Amphotericin B was kept for 12 months until the regression of his clinical symptoms and lesion at CT and MRI brain imaging. During the follow-up, no evidence of neurological disabilities have been detected, and he remains under ITR prophylaxis. Usually patients with CNS-PCM must receive specific therapy for 2 years or more depending on clinical and radiological outcome [14, 29]. To our knowledge, this is the second case report of neuroparacoccidioidomycosis in an AIDS patient.
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Mycopathologia (2014) 177:137–141
The first one was described in a pregnant HIVinfected woman who developed severe ocular lesion leading to eye enucleation which eased the P. brasiliensis infection diagnosis. Despite neurological symptoms were absent in this case, the brain MRI imaging showed a focal hypodense contrastenhanced lesions which regressed after TMP–SMX therapy [21]. Thus, as patients with PCM can have CNS asymptomatic quiescent foci, CT and MRI assessment should be routinely performed as possible, especially if they are HIV infected. ˆ ngela Azoˆr for the Acknowledgments Thanks to Mrs. A technical assistance and to Fundac¸a˜o de Amparo a Pesquisa de Minas Gerais (FAPEMIG) for the financial support. Grant: APQ 01624-12. Conflict of interest The authors report no conflict of interests.
References 1. Marini MM, Zanforlin T, Santos PC, et al. Identification and characterization of Tc1/mariner-like DNA transposons in genomes of the pathogenic fungi of the Paracoccidioides species complex. BMC Genom. 2010;11:130. 2. Wanke B, Londero AT. Epidemiology and paracoccidioidomycosis infection. In: Franco M, Lacaz CS, RestrepoMoreno A, Del Negro G, editors. Paracoccidioidomycosis. Boca Raton, FL: CRC Press; 1994. p. 109–20. 3. Restrepo A, McEwen JG, Castaneda E. The habitat of Paracoccidiodes brasiliensis: how far from solving the riddle? Med Mycol. 2001;39:233–41. 4. Prado M, Silva MB, Laurenti R, et al. Mortality due to systemic mycoses as a primary cause of death or in association with AIDS in Brazil: a review from 1996 to 2006. Mem Inst Oswaldo Cruz. 2009;104:513–21. 5. Franco M, Montenegro MR, Mendes RP, Marques SA, et al. Paracoccidioidomycosis: a recently proposed classification of its clinical forms. Rev Soc Bras Med Trop. 1987;20: 129–32. 6. Mendes RP. The gamut of clinical manifestation. In: Franco M, da Lacaz CS, Restrepo-Moreno A, Del Negro G, editors. Paracoccidioidomicose. Boca Raton, FL: CRC Press; 1994. p. 233–58. 7. Franco M, Mendes RP, Moscardi-Bacchi M, et al. Paracoccidioidomycosis. Baillie`re’s Clin Trop Med Commun Dis. 1989;4:185–220. 8. Magalha˜es AC, Bacheschi LA, Caramelli P, et al. Paracoccidioidomycosis of the central nervous system: study of 5 cases by magnetic resonance. Rev Hosp Clin Fac Med Sa˜o Paulo. 1993;48:94–7. 9. Lambertucci JR, Lana-Peixoto MA, Pitella JE. Paracoccidioidomycosis of the central nervous system. Rev Soc Bras Med Trop. 2001;34:395–6.
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