- Email: [email protected]
A case of Cryptococcus neoformans meningitis in a patient with abnormal levels of isolated immunological markers
+ Models
MYCMED-626; No. of Pages 3 Journal de Mycologie Médicale (2016) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
CASE REPORT/CAS CLINIQUE
A case of Cryptococcus neoformans meningitis in a patient with abnormal levels of isolated immunological markers ´ ningite `a Cryptococcus neoformans chez un patient Un cas de me ´ sentant des taux anormaux de marqueurs immunologiques pre ´ es isole B. Simsek a,*, E. Guven b, R. Gumral c, G. Mert b, M.A. Saracli d, B. Besirbellioglu b, S.T. Yildiran d a
Kas½mpasa Military Hospital, Department of Medical Microbiology, Istanbul, Turkey Gulhane Military Medical Academy, Department of Infectious Diseases, Ankara, Turkey c Van Military Hospital, Department of Medical Microbiology, Van, Turkey d Gulhane Military Medical Academy, Department of Medical Mycology, Ankara, Turkey b
Received 3 January 2016; received in revised form 20 May 2016; accepted 25 May 2016
KEYWORDS Cryptococcosis; Cryptococcus neoformans; Meningitis
MOTS CLÉS Cryptococcose ; Cryptococcus neoformans ; Méningite
Summary Cryptococcal meningitis is considered rare in immunocompetent patients and is mainly a disease of immunocompromised patients. We report a case of cryptococcal meningitis, due to Cryptococcus neoformans, in an apparently healthy individual with abnormal levels of isolated immunological markers. Regardless of the patient’s immune status, the result of the disease can be serious unless the disease is diagnosed early. # 2016 Elsevier Masson SAS. All rights reserved. Résumé La cryptococcose méningée est considérée comme rare chez les patients immunocompétents et reste principalement une maladie de patients immunodéprimés. Nous rapportons un cas de méningite à cryptocoques, due à Cryptococcus neoformans, chez un individu apparemment en bonne santé avec des taux anormaux de marqueurs immunologiques isolés. Quel que soit le statut immunitaire du patient, les conséquences peuvent être assez graves si la maladie n’est pas diagnostiquée au plus tôt. # 2016 Elsevier Masson SAS. Tous droits réservés.
* Corresponding author. E-mail address: [email protected] (B. Simsek). http://dx.doi.org/10.1016/j.mycmed.2016.05.003 1156-5233/# 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Simsek B, et al. A case of Cryptococcus neoformans meningitis in a patient with abnormal levels of isolated immunological markers. Journal De Mycologie Médicale (2016), http://dx.doi.org/10.1016/j.mycmed.2016.05.003
+ Models
MYCMED-626; No. of Pages 3
2
B. Simsek et al.
Introduction Cryptococcosis is the most common fungal infection of the central nervous system in both immunocompetent and immunocompromised individuals [1]. Cryptococcus neoformans and C. gattii are the two etiologic agents of cryptococcosis. The most common risk for cryptococcosis caused by C. neoformans is AIDS and majority of cases occur in HIVinfected individuals, whereas infections caused by C. gattii are more often reported in immunocompetent patients with undefined risk than immunocompromised [5,9]. Here, we present a case of cryptococcosis in a healthy male patient having no apparent underlying immunosuppressive disease, but abnormal levels of immunological markers in blood tests.
Case report A 28-year-old male patient was admitted for intermittent fever and headache for two years and he had also meningeal signs, the unilateral involvement of cranial nerve IX, which just began one and a half months ago before admission. Past medical history of the patient did not include anything special, except he started propranolol after diagnosed with hypertension when his complaints first began. He applied different clinics, such as neurology, internal medicine and infectious diseases at different hospitals. None of them could diagnose anything certain. The history went back 45 days prior to presentation when the patient was evaluated at a hospital for coughing, fever and left hypoglossal nerve paralysis. The patient was hospitalized in the neurology clinic. At that time, magnetic resonance imaging (MRI) showed hyperintense focal signals at T2-weighted sequences in the left occipito-parietal lobe, localized cortically. According to the MRI, preliminary diagnosis was encephalitis or acute cortical infarct. Then, the patient was transferred to infectious diseases ward. At presentation, the white blood cell count was slightly high. Serum gamma glutamyltransferase (GGT) was 68 U/ L. The patient’s fever was 38.3 8C. Other initial vital signs were normal. Lumbar puncture was performed. Cerebrospinal fluid (CSF) was clear and colorless. The number of white blood cells in CSF was 470/mm3 (% 100 mononuclear leukocytes). Opening pressure of the CSF was normal. Gram stain was performed on the sediment of the CSF and no bacteria detected. Cultures were performed for aerobic and anaerobic bacteria, fungi, and Mycobacterium tuberculosis. Protein and glucose levels of CSF were 150 mg/dL and 22 mg/dL (concomitant blood glucose 115 mg/dL), respectively. Microscopic examination of the CSF using India ink showed encapsulated yeast cells. The yeast cells were also observed in Gram stained preparations. Cultures on Sabouraud dextrose agar and Staib agar (Bird seed agar) at 30 8C yielded C. neoformans. Canavanine-glycine-bromothymol blue (CGB) agar was used to distinguish whether the yeasts are C. gattii or not. The result was negative for C. gattii. At that time, the patient was also evaluated for primer immunodeficiency with phagocytic cell function tests and lymphocyte subtyping. The results were abnormal for some parameters of phagotest; phagocytosis of granulocytes was 76.2% (normal range 95—99%) and oxidative burst of
Table 1 The phagotest test results of the case patient. ´ sultats des tests de phagocytose des granulocytes du Les re patient. Phagotest test parameters
Test result (%)
Normal range of the test (%)
Phagocytosis of granulocytes Oxidative burst of granulocytes
76.2
95—99
80.8
97—100
Table 2 The lymphocyte subtyping test results of the case patient. ´ sultats du se ´ rotypage des lymphocytes du patient. Les re Lymphocyte subtyping testing
Test result (%)
Normal range of the test (%)
CD4 CD8 CD19 CD3 CD16+ 56+ CD3 HLA DR+
48.9 19.9 1.4 4.9 0.7
34—63.8 19—48 7—23 6—29 3.6—25.9
granulocytes was 80.81% (normal range 97—100%). The abnormal lymphocyte subtyping results were as follows; CD19 was 1.4% (normal range 7—23%), CD3 CD16+ 56+ was 4.9% (normal range 6—29%), and CD3 HLA DR+ was 0.7% (normal range 3.6—25.9%) (Tables 1 and 2). Rest of the parameters is in normal ranges. Also HIV antibody was found negative. The intravenous liposomal amphotericin B was started for the patient, 4 mg/kg daily for 34 days. Subsequent CSF examination carried out one month later while the patient was using intravenous liposomal amphotericin B therapy and showed no fungal growth. The patient made a good recovery and discharged on oral fluconazole, 400 mg daily for 70 days.
Discussion As causative agents of cryptococcosis, there are two distinct species recognized according to their phenotypic and genotypic features: C. gattii (serotypes B and C) and C. neoformans (serotypes A, D and AD). C. neoformans has two different varieties; C. var. neoformans (serotype D) and C. var. grubii (serotype A), serotype AD is hybrids of two varieties [5]. C. neoformans isolation is independent from geographical location and usually infects patients with AIDS. On the other hand, C. gattii is restricted geographically to tropical and subtropical regions and affects mostly immunocompetent individuals. C. neoformans can be found in faecal materials of birds (especially pigeons) and contaminated soil with bird droppings [3,5,7,8]. Cryptococcosis is the most common mycotic infection involving the central nervous system in both immunocompetent and immunocompromised individuals who have an underlying disease, such as chronic renal disease, alcoholism, diabetes mellitus or immunosuppressive drug users [2]. C. neoformans especially
Please cite this article in press as: Simsek B, et al. A case of Cryptococcus neoformans meningitis in a patient with abnormal levels of isolated immunological markers. Journal De Mycologie Médicale (2016), http://dx.doi.org/10.1016/j.mycmed.2016.05.003
+ Models
MYCMED-626; No. of Pages 3
Cryptococcus neoformans meningitis in patient with abnormal levels of isolated immunological markers causes serious infections in immunocompromised populations. The majority of cases occur in HIV-infected individuals [9]. Cryptococcosis of central nervous system commonly presents with the symptoms of meningitis and encephalitis, such as headache, confusion, visual disturbance, staggering gait and nausea [1]. In HIV negative patients, the symptoms and signs are often slow at onset. Headache is the most common symptom and the characteristic of the pain is dull, bilateral and diffuse. Fever is often minimal or absent until late in the course of the infection [6]. The clinical picture of our patient had coherence with the clinical situation in literature. He had a dull headache with a subfebrile fever. At the end of the clinical course, a unilateral paralysis of the ninth cranial nerve developed at the patient. The diagnosis somewhat delayed in this case, because cryptococcosis was not considered during initial differential diagnosis process due to the patient’s negative HIV status. After the diagnosis of cryptococcosis was established, our patient was evaluated for the presence of primary immunodeficiency and the results showed no clinical significance although some parameters were abnormal (Tables 1 and 2). In immunocompetent patients, initial therapy should be amphotericin B deoxycholate (0.7—1 mg/kg per day) in combination with flucytosine (100 mg/kg per day in four divided doses). Amphotericin B can be administered alone (but only liposomal form) for six to ten weeks or in conjuction with flucytosine for two weeks, followed by consolidation treatment with fluconazole (400 mg/day) for a minimum of ten weeks [4,6]. Our patient was initially treated with intravenous liposomal amphotericin B alone for 34 days, and the oral fluconazole was administered for 70 days after the patient was discharged. In conclusion, the presented case emphasizes the fact that cryptococcosis can present itself with non-specific
3
symptoms (such as intermittent fever and headache) and the resulting cryptococcal meningitis may be diagnosed and treated lately in immunocompetent patients.
Disclosure of interest The authors declare that they have no competing interest.
References [1] Awasthi M, Patankar T, Shah P, Castillo M. Cerebral cryptococcosis: atypical appearances on CT. Br J Radiol 2001;74: 83—5. [2] Caldemeyer KS, Mathews VP, Edwards-Brown MK, Smith RR. Central nervous system Cryptococcosis: parenchymal calcification and large gelatinous pseudocysts. AJNR 1997;18:107—9. [3] Franzot SP, Salk½n IF, Casadevall A. Cryptococcus neoformans var. grubii: separate varietal status for Cryptococcus neoformans serotype A isolates. J Clin Microbiol 1999;37:838—40. [4] King JW, et al. Cryptococcosis. Available at: http://www. emedicine.medscape.com/article/215354-overview. Accessed on: April 17, 2015. [5] Kwon-Chung KJ, Fraser JA, Doering TL, Wang Z, Janbon G, Idnurm A, et al. Cryptococcus neoformans and Cryptococcus gattii, the etiologic agents of cryptococcosis. Cold Spring Harb Perspect Med 2014;4:a019760. [6] Richardson MD, Warnock DW. Fungal infection: diagnosis and management, . 3rd ed., Oxford: Blackwell Science; 2003: 215—29. [7] Speed B, Dunt D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin Infect Dis 1995;21:28—34. [8] Vella Zahra L, Mallia Azzopardi C, Scott G. Cryptococcal meningitis in two apparently immunocompetent Maltese patients. Mycoses 2004;47:168—73. [9] Yehia BR, Eberlein M, Sisson SD, Hager DN. Disseminated cryptococcosis with meningitis, peritonitis, and cryptococcemia in a HIV-negative patient with cirrhosis: a case report. Cases J 2009;28:170—3.
Please cite this article in press as: Simsek B, et al. A case of Cryptococcus neoformans meningitis in a patient with abnormal levels of isolated immunological markers. Journal De Mycologie Médicale (2016), http://dx.doi.org/10.1016/j.mycmed.2016.05.003
MYCMED-626; No. of Pages 3 Journal de Mycologie Médicale (2016) xxx, xxx—xxx
Available online at
ScienceDirect www.sciencedirect.com
CASE REPORT/CAS CLINIQUE
A case of Cryptococcus neoformans meningitis in a patient with abnormal levels of isolated immunological markers ´ ningite `a Cryptococcus neoformans chez un patient Un cas de me ´ sentant des taux anormaux de marqueurs immunologiques pre ´ es isole B. Simsek a,*, E. Guven b, R. Gumral c, G. Mert b, M.A. Saracli d, B. Besirbellioglu b, S.T. Yildiran d a
Kas½mpasa Military Hospital, Department of Medical Microbiology, Istanbul, Turkey Gulhane Military Medical Academy, Department of Infectious Diseases, Ankara, Turkey c Van Military Hospital, Department of Medical Microbiology, Van, Turkey d Gulhane Military Medical Academy, Department of Medical Mycology, Ankara, Turkey b
Received 3 January 2016; received in revised form 20 May 2016; accepted 25 May 2016
KEYWORDS Cryptococcosis; Cryptococcus neoformans; Meningitis
MOTS CLÉS Cryptococcose ; Cryptococcus neoformans ; Méningite
Summary Cryptococcal meningitis is considered rare in immunocompetent patients and is mainly a disease of immunocompromised patients. We report a case of cryptococcal meningitis, due to Cryptococcus neoformans, in an apparently healthy individual with abnormal levels of isolated immunological markers. Regardless of the patient’s immune status, the result of the disease can be serious unless the disease is diagnosed early. # 2016 Elsevier Masson SAS. All rights reserved. Résumé La cryptococcose méningée est considérée comme rare chez les patients immunocompétents et reste principalement une maladie de patients immunodéprimés. Nous rapportons un cas de méningite à cryptocoques, due à Cryptococcus neoformans, chez un individu apparemment en bonne santé avec des taux anormaux de marqueurs immunologiques isolés. Quel que soit le statut immunitaire du patient, les conséquences peuvent être assez graves si la maladie n’est pas diagnostiquée au plus tôt. # 2016 Elsevier Masson SAS. Tous droits réservés.
* Corresponding author. E-mail address: [email protected] (B. Simsek). http://dx.doi.org/10.1016/j.mycmed.2016.05.003 1156-5233/# 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Simsek B, et al. A case of Cryptococcus neoformans meningitis in a patient with abnormal levels of isolated immunological markers. Journal De Mycologie Médicale (2016), http://dx.doi.org/10.1016/j.mycmed.2016.05.003
+ Models
MYCMED-626; No. of Pages 3
2
B. Simsek et al.
Introduction Cryptococcosis is the most common fungal infection of the central nervous system in both immunocompetent and immunocompromised individuals [1]. Cryptococcus neoformans and C. gattii are the two etiologic agents of cryptococcosis. The most common risk for cryptococcosis caused by C. neoformans is AIDS and majority of cases occur in HIVinfected individuals, whereas infections caused by C. gattii are more often reported in immunocompetent patients with undefined risk than immunocompromised [5,9]. Here, we present a case of cryptococcosis in a healthy male patient having no apparent underlying immunosuppressive disease, but abnormal levels of immunological markers in blood tests.
Case report A 28-year-old male patient was admitted for intermittent fever and headache for two years and he had also meningeal signs, the unilateral involvement of cranial nerve IX, which just began one and a half months ago before admission. Past medical history of the patient did not include anything special, except he started propranolol after diagnosed with hypertension when his complaints first began. He applied different clinics, such as neurology, internal medicine and infectious diseases at different hospitals. None of them could diagnose anything certain. The history went back 45 days prior to presentation when the patient was evaluated at a hospital for coughing, fever and left hypoglossal nerve paralysis. The patient was hospitalized in the neurology clinic. At that time, magnetic resonance imaging (MRI) showed hyperintense focal signals at T2-weighted sequences in the left occipito-parietal lobe, localized cortically. According to the MRI, preliminary diagnosis was encephalitis or acute cortical infarct. Then, the patient was transferred to infectious diseases ward. At presentation, the white blood cell count was slightly high. Serum gamma glutamyltransferase (GGT) was 68 U/ L. The patient’s fever was 38.3 8C. Other initial vital signs were normal. Lumbar puncture was performed. Cerebrospinal fluid (CSF) was clear and colorless. The number of white blood cells in CSF was 470/mm3 (% 100 mononuclear leukocytes). Opening pressure of the CSF was normal. Gram stain was performed on the sediment of the CSF and no bacteria detected. Cultures were performed for aerobic and anaerobic bacteria, fungi, and Mycobacterium tuberculosis. Protein and glucose levels of CSF were 150 mg/dL and 22 mg/dL (concomitant blood glucose 115 mg/dL), respectively. Microscopic examination of the CSF using India ink showed encapsulated yeast cells. The yeast cells were also observed in Gram stained preparations. Cultures on Sabouraud dextrose agar and Staib agar (Bird seed agar) at 30 8C yielded C. neoformans. Canavanine-glycine-bromothymol blue (CGB) agar was used to distinguish whether the yeasts are C. gattii or not. The result was negative for C. gattii. At that time, the patient was also evaluated for primer immunodeficiency with phagocytic cell function tests and lymphocyte subtyping. The results were abnormal for some parameters of phagotest; phagocytosis of granulocytes was 76.2% (normal range 95—99%) and oxidative burst of
Table 1 The phagotest test results of the case patient. ´ sultats des tests de phagocytose des granulocytes du Les re patient. Phagotest test parameters
Test result (%)
Normal range of the test (%)
Phagocytosis of granulocytes Oxidative burst of granulocytes
76.2
95—99
80.8
97—100
Table 2 The lymphocyte subtyping test results of the case patient. ´ sultats du se ´ rotypage des lymphocytes du patient. Les re Lymphocyte subtyping testing
Test result (%)
Normal range of the test (%)
CD4 CD8 CD19 CD3 CD16+ 56+ CD3 HLA DR+
48.9 19.9 1.4 4.9 0.7
34—63.8 19—48 7—23 6—29 3.6—25.9
granulocytes was 80.81% (normal range 97—100%). The abnormal lymphocyte subtyping results were as follows; CD19 was 1.4% (normal range 7—23%), CD3 CD16+ 56+ was 4.9% (normal range 6—29%), and CD3 HLA DR+ was 0.7% (normal range 3.6—25.9%) (Tables 1 and 2). Rest of the parameters is in normal ranges. Also HIV antibody was found negative. The intravenous liposomal amphotericin B was started for the patient, 4 mg/kg daily for 34 days. Subsequent CSF examination carried out one month later while the patient was using intravenous liposomal amphotericin B therapy and showed no fungal growth. The patient made a good recovery and discharged on oral fluconazole, 400 mg daily for 70 days.
Discussion As causative agents of cryptococcosis, there are two distinct species recognized according to their phenotypic and genotypic features: C. gattii (serotypes B and C) and C. neoformans (serotypes A, D and AD). C. neoformans has two different varieties; C. var. neoformans (serotype D) and C. var. grubii (serotype A), serotype AD is hybrids of two varieties [5]. C. neoformans isolation is independent from geographical location and usually infects patients with AIDS. On the other hand, C. gattii is restricted geographically to tropical and subtropical regions and affects mostly immunocompetent individuals. C. neoformans can be found in faecal materials of birds (especially pigeons) and contaminated soil with bird droppings [3,5,7,8]. Cryptococcosis is the most common mycotic infection involving the central nervous system in both immunocompetent and immunocompromised individuals who have an underlying disease, such as chronic renal disease, alcoholism, diabetes mellitus or immunosuppressive drug users [2]. C. neoformans especially
Please cite this article in press as: Simsek B, et al. A case of Cryptococcus neoformans meningitis in a patient with abnormal levels of isolated immunological markers. Journal De Mycologie Médicale (2016), http://dx.doi.org/10.1016/j.mycmed.2016.05.003
+ Models
MYCMED-626; No. of Pages 3
Cryptococcus neoformans meningitis in patient with abnormal levels of isolated immunological markers causes serious infections in immunocompromised populations. The majority of cases occur in HIV-infected individuals [9]. Cryptococcosis of central nervous system commonly presents with the symptoms of meningitis and encephalitis, such as headache, confusion, visual disturbance, staggering gait and nausea [1]. In HIV negative patients, the symptoms and signs are often slow at onset. Headache is the most common symptom and the characteristic of the pain is dull, bilateral and diffuse. Fever is often minimal or absent until late in the course of the infection [6]. The clinical picture of our patient had coherence with the clinical situation in literature. He had a dull headache with a subfebrile fever. At the end of the clinical course, a unilateral paralysis of the ninth cranial nerve developed at the patient. The diagnosis somewhat delayed in this case, because cryptococcosis was not considered during initial differential diagnosis process due to the patient’s negative HIV status. After the diagnosis of cryptococcosis was established, our patient was evaluated for the presence of primary immunodeficiency and the results showed no clinical significance although some parameters were abnormal (Tables 1 and 2). In immunocompetent patients, initial therapy should be amphotericin B deoxycholate (0.7—1 mg/kg per day) in combination with flucytosine (100 mg/kg per day in four divided doses). Amphotericin B can be administered alone (but only liposomal form) for six to ten weeks or in conjuction with flucytosine for two weeks, followed by consolidation treatment with fluconazole (400 mg/day) for a minimum of ten weeks [4,6]. Our patient was initially treated with intravenous liposomal amphotericin B alone for 34 days, and the oral fluconazole was administered for 70 days after the patient was discharged. In conclusion, the presented case emphasizes the fact that cryptococcosis can present itself with non-specific
3
symptoms (such as intermittent fever and headache) and the resulting cryptococcal meningitis may be diagnosed and treated lately in immunocompetent patients.
Disclosure of interest The authors declare that they have no competing interest.
References [1] Awasthi M, Patankar T, Shah P, Castillo M. Cerebral cryptococcosis: atypical appearances on CT. Br J Radiol 2001;74: 83—5. [2] Caldemeyer KS, Mathews VP, Edwards-Brown MK, Smith RR. Central nervous system Cryptococcosis: parenchymal calcification and large gelatinous pseudocysts. AJNR 1997;18:107—9. [3] Franzot SP, Salk½n IF, Casadevall A. Cryptococcus neoformans var. grubii: separate varietal status for Cryptococcus neoformans serotype A isolates. J Clin Microbiol 1999;37:838—40. [4] King JW, et al. Cryptococcosis. Available at: http://www. emedicine.medscape.com/article/215354-overview. Accessed on: April 17, 2015. [5] Kwon-Chung KJ, Fraser JA, Doering TL, Wang Z, Janbon G, Idnurm A, et al. Cryptococcus neoformans and Cryptococcus gattii, the etiologic agents of cryptococcosis. Cold Spring Harb Perspect Med 2014;4:a019760. [6] Richardson MD, Warnock DW. Fungal infection: diagnosis and management, . 3rd ed., Oxford: Blackwell Science; 2003: 215—29. [7] Speed B, Dunt D. Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin Infect Dis 1995;21:28—34. [8] Vella Zahra L, Mallia Azzopardi C, Scott G. Cryptococcal meningitis in two apparently immunocompetent Maltese patients. Mycoses 2004;47:168—73. [9] Yehia BR, Eberlein M, Sisson SD, Hager DN. Disseminated cryptococcosis with meningitis, peritonitis, and cryptococcemia in a HIV-negative patient with cirrhosis: a case report. Cases J 2009;28:170—3.
Please cite this article in press as: Simsek B, et al. A case of Cryptococcus neoformans meningitis in a patient with abnormal levels of isolated immunological markers. Journal De Mycologie Médicale (2016), http://dx.doi.org/10.1016/j.mycmed.2016.05.003