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 ~  Abstract
 ~ Introduction
 ~ Case Report
 ~ Discussion
 ~  References

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  Table of Contents  
Year : 2018  |  Volume : 36  |  Issue : 3  |  Page : 439-440

Fatal Cryptococcus gattii meningitis with negative cryptococcal antigen test in a HIV-non-infected patient

1 Department of Microbiology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
2 Department of Medicine, Adarsha Hospital, Udupi, Karnataka, India

Date of Web Publication14-Nov-2018

Correspondence Address:
Dr. Vandana Kalwaje Eshwara
Department of Microbiology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal - 576 104, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmm.IJMM_18_164

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 ~ Abstract 

Cryptococcus gattii predominantly causes central nervous system and pulmonary infection in both immunocompromised and immunocompetent patients with substantial morbidity. We report a case of rapidly fatal meningitis by C. gattii in an HIV–non-infected man with CD4 lymphopenia who tested negative for cryptococcal antigen. This case may serve as an alert to its wider occurrence and less explored risk factors.

Keywords: Cryptococcus gatti, false-negative cryptococcal antigen test, idiopathic CD4 lymphopenia

How to cite this article:
Eshwara VK, Garg R, Chandrashekhar G S, Shaw T, Mukhopadhyay C. Fatal Cryptococcus gattii meningitis with negative cryptococcal antigen test in a HIV-non-infected patient. Indian J Med Microbiol 2018;36:439-40

How to cite this URL:
Eshwara VK, Garg R, Chandrashekhar G S, Shaw T, Mukhopadhyay C. Fatal Cryptococcus gattii meningitis with negative cryptococcal antigen test in a HIV-non-infected patient. Indian J Med Microbiol [serial online] 2018 [cited 2020 Jun 6];36:439-40. Available from:

 ~ Introduction Top

Cryptococcosis occurs not only in immunocompromised hosts mostly HIV infection but also in immunocompetent persons without any apparent underlying conditions. Infections by Cryptococcus gattii, although clinically indistinguishable from Cryptococcus neoformans, have been increasingly reported from several parts of the world.[1],[2],[3],[4] However, the available data might grossly be an underrepresentation due to non-availability of tools to identify and discriminate the pathogen in resource-constrained settings.

 ~ Case Report Top

A 26-year-old male sweet hawker on a bicycle of poor socioeconomic status, resident of rural South India near Udupi, visited a secondary-care hospital due to intermittent fever, increasing breathlessness and headache for 1 month. During the last 5 days, he also developed slurring of speech, difficulty in balancing the gait and weakness of lower limbs. Before hospitalisation in this centre, he had been treated with oral antimicrobial agents for the suspected respiratory infection by a primary care physician. His medical reports suggested HBs antigen positivity, but he did not report any symptoms of viral hepatitis. He was married for 3 years and was in good health until 1 month ago. On examination, our patient was well built and febrile. Except for bronchial breath sound in the right infraaxillary region, bilateral wheeze more over right lower zone and mildly enlarged liver, other systems were unremarkable. Neurologically, slight reduction in muscle power (4/5), ataxic gait and 1 + deep tendon reflexes were noted, while higher mental functions were normal. Fundus examinations were normal. He did not show signs of meningeal irritation at this time. Chest X-ray revealed right middle lobe consolidation. The blood leucocyte count was 12,000 cells/mm3, with neutrophils 80%, lymphocytes 12%, eosinophils 3% and monocytes 5%, and erythrocyte sedimentation rate 37 mm/h. Tests for leptospirosis, scrub typhus, dengue, malaria and enteric fever were negative. HIV antibodies were negative. Induced sputum did not show M. tuberculosis in smear. Intravenous ceftriaxone and oral doxycycline were empirically started. He remained febrile and deterioration of sensorium began by day 4 of hospitalisation.

Now, cerebrospinal fluid (CSF) examination showed 54 cells/mm3, with neutrophils 2% and lymphocytes 98%, glucose 60 mg%, protein 50 mg% and ADA 3.8 U/L. Capsulated yeasts suggestive of Cryptococcus were observed in Gram's stain and further confirmed by India ink. Interestingly, cryptococcal antigen was not detected in the serum and CSF when tested by two test kits (BIOSYNEX® CryptoPS–immunochromatographic assay and Pastorex™ Crypto Plus latex agglutination by BioRad) directly and after serial dilutions of CSF to overcome post-zone phenomenon. Culture of CSF on 5% sheep blood agar, chocolate agar and Sabouraud's dextrose agar showed mucoid colonies. However, the yeast cells appeared elongated when stained from the colonies. Isolate was identified as C. gattii by Vitek 2 (Biomeriux) that was further confirmed by 18s rRNA sequencing technique (GenBank accession number MG786812).

Amphotericin B-standard preparations and fluconazole were administered immediately after laboratory evidence of cryptococcosis. Due to economic constraints and immediate non-availability in the market, flucytosine could not be given. At this stage, his HIV infection status was reinvestigated using different test principles. Considering the unexplained and persistent lymphopenia during hospital course, together with diagnosis of cryptococcal meningitis, absence of HIV infection and no obvious clinical evidence of immunosuppression, we sought to test CD4 count that showed 66 cells/mm3. The patient's condition deteriorated further on day 5 when the total leucocyte counts were 15,300, with neutrophils 91% and lymphocytes 9%, and he developed respiratory failure needing mechanical ventilation. By the next day, he developed coma and passed away on day 8. The low CD4 count was alleged to be idiopathic CD4 lymphopenia (ICL) although subsequent retesting and confirmation of the condition was not possible due to demise of the patient.

 ~ Discussion Top

The rural ecosystem in India that contains the environmental sources and conditions for dispersion of infectious propagules of the yeast are amply sufficient to make our patient vulnerable to this infection.[5],[6] The case presented here is distinctive because of its rapid downhill clinical course, accidental diagnosis of rare immunodeficiency status and failure to detect the antigen by rapid tests of good sensitivity.[7],[8] Our patient had several risk factors for severe disease. Strikingly, frequent travelling on a bicycle between plantations of rural regions for occupational demands made him vulnerable for this environmental disease. The absence of familiar causes of immunosuppression such as HIV infection had further delayed the clinical suspicion of cryptococcosis. Concomitant-alleged ICL might be contributory to his immunosuppression making him susceptible to cryptococcosis, rather than the effect of the infection as there was no systemic evidence of chronic granulomatous infection. This possibly explains the rapid dissemination of disease to central nervous system and early fatality.[9] Inability of two test kits to detect antigen in body fluids despite the presence of capsulated yeasts in good-quantity points towards the potential flaws in these tests and further need to revise the cocktail monoclonal antibodies used in such tests for diagnosis of C. gattii infections.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

 ~ References Top

Baró T, Torres-Rodríguez JM, De Mendoza MH, Morera Y, Alía C. First identification of autochthonous Cryptococcus neoformans var. Gattii isloated from goats with predominantly severe pulmonary disease in Spain. J Clin Microbiol 1998;36:458-61.  Back to cited text no. 1
Hagen F, Colom MF, Swinne D, Tintelnot K, Iatta R, Montagna MT, et al. Autochthonous and dormant Cryptococcus gattii infections in Europe. Emerg Infect Dis 2012;18:1618-24.  Back to cited text no. 2
Harris JR, Lockhart SR, Debess E, Marsden-Haug N, Goldoft M, Wohrle R, et al. Cryptococcus gattii in the United States: Clinical aspects of infection with an emerging pathogen. Clin Infect Dis 2011;53:1188-95.  Back to cited text no. 3
Chen SC, Slavin MA, Heath CH, Playford EG, Byth K, Marriott D, et al. Clinical manifestations of Cryptococcus gattii infection: Determinants of neurological sequelae and death. Clin Infect Dis 2012;55:789-98.  Back to cited text no. 4
Lazéra MS, Cavalcanti MA, Trilles L, Nishikawa MM, Wanke B. Cryptococcus neoformans var. Gattii – evidence for a natural habitat related to decaying wood in a pottery tree hollow. Med Mycol 1998;36:119-22.  Back to cited text no. 5
Kidd SE, Bach PJ, Hingston AO, Mak S, Chow Y, MacDougall L, et al. Cryptococcus gattii dispersal mechanisms, British Columbia, Canada. Emerg Infect Dis 2007;13:51-7.  Back to cited text no. 6
Babady NE, Bestrom JE, Jespersen DJ, Jones MF, Beito EM, Binnicker MJ, et al. Evaluation of three commercial latex agglutination kits and a commercial enzyme immunoassay for the detection of cryptococcal antigen. Med Mycol 2009;47:336-8.  Back to cited text no. 7
Opota O, Desgraz B, Kenfak A, Jaton K, Cavassini M, Greub G, et al. Cryptococcus neoformans meningitis with negative cryptococcal antigen: Evaluation of a new immunochromatographic detection assay. New Microbes New Infect 2015;4:1-4.  Back to cited text no. 8
Zonios DI, Falloon J, Huang CY, Chaitt D, Bennett JE. Cryptococcosis and idiopathic CD4 lymphocytopenia. Medicine (Baltimore) 2007;86:78-92.  Back to cited text no. 9


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