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 Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 6  |  Issue : 1  |  Page : 139-142

Cryptococcus neoformans meningitis in a Non-HIV infected, nonorgan transplant, immunocompromised individual


1 Department of Neurology, Critical Care Anesthesia, ESIC Superspeciality Hospital, ESIC Medical College, Hyderabad, Telangana, India
2 Department of Pathology, Critical Care Anesthesia, ESIC Superspeciality Hospital, ESIC Medical College, Hyderabad, Telangana, India
3 Department of Microbiology, Critical Care Anesthesia, ESIC Superspeciality Hospital, ESIC Medical College, Hyderabad, Telangana, India
4 Department of Intensivist, Critical Care Anesthesia, ESIC Superspeciality Hospital, ESIC Medical College, Hyderabad, Telangana, India

Date of Web Publication11-Jun-2018

Correspondence Address:
Prof. Sandhya Manorenj
Department of Neurology, ESIC Superspeciality Hospital, ESIC Medical College, Hyderabad, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_115_17

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  Abstract 


Cryptococcus neoformans is an opportunistic fungus and an important cause of central nervous system infections among immunocompromised individuals, especially in HIV-reactive and organ transplant recipients. Cryptococcal meningitis presenting as the initial manifestation of diabetes is rare in published literature. We present a case of C. neoformans meningitis in a patient with newly diagnosed Type II diabetes mellitus.

Keywords: Cryptococcus neoformans, diabetes mellitus, meningitis


How to cite this article:
Manorenj S, Rani VL, Suravaram S, Reddy C S. Cryptococcus neoformans meningitis in a Non-HIV infected, nonorgan transplant, immunocompromised individual. Arch Med Health Sci 2018;6:139-42

How to cite this URL:
Manorenj S, Rani VL, Suravaram S, Reddy C S. Cryptococcus neoformans meningitis in a Non-HIV infected, nonorgan transplant, immunocompromised individual. Arch Med Health Sci [serial online] 2018 [cited 2018 Jun 18];6:139-42. Available from: http://www.amhsjournal.org/text.asp?2018/6/1/139/234088




  Introduction Top


Cryptococcus neoformans is an ubiquitous encapsulated yeast, an important fungal pathogen causing CNS infection in HIV positive and organ transplant recipient individual. The infection occurs following inhalation through the respiratory pathway. The organism then disseminates via blood and has a propensity to localize to the central nervous system, causing meningitis/meningoencephalitis. Individuals with uncontrolled diabetics are prone to infections due to numerous factors as the glucose-rich blood serves as an excellent media for growth. Cryptococcal neoformans meningitis presenting initially as the sole manifestation of diabetes is rare. We report a fatal case of Cryptococcal meningitis in a de novo detected diabetic patient.


  Case Report Top


A 60-year-old male was admitted for unremitting, severe, right frontal headache associated with vomiting of 1-month duration. He had altered mental status with intractable hiccough, increased urinary frequency, generalized weakness, gait ataxia, and slurred speech in the preceding 7 days. His past medical history was unremarkable. He retired as an agriculturist 5 years before presentation. The patient's spouse denied recent travel or exposure to pets.

Computed tomography of the head showed no acute bleed or mass. T2-weighted and fluid-attenuated inversion recovery sequences of brain magnetic resonance imaging showed hyperintensity in right parietal and occipital lobe white matter, suggestive of edema [Figure 1]. Postcontrast study on T1-weighted sequence showed leptomeningeal enhancement of right occipitoparietal sulcal spaces with normal ventricular system [Figure 2]. Put together, the MRI images were consistent with asymmetric menigoencephalitis.
Figure 1: T2-weighted fluid-attenuated inversion recovery sequences of brain magnetic resonance imaging showed hyperintensity in right parietal and occipital lobe white matter, suggestive of oedema

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Figure 2: MRI brain T1 contrast sequence, coronal section showing contrast enhancement of right parieto-occipital sulci with hypodensity surrounding region suggestive of patchy menigoencephalitis

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Initial vital signs were temperature 101.2°F (38.4°C), blood pressure 110/70 mmHg, pulse 100 beats/min, and respiratory rate 28 breaths/min. Physical examination revealed a Glasgow Coma Scale score of 9 (EO-3, VR-5, MR-1). He had bilateral abducens nerve palsy and nuchal rigidity. Kerning's sign was negative, reflexes were intact, and rest of the physical examination was normal.

Notable laboratory findings included blood glucose of 360 mg/dl (19.8 mmol/l), glycated hemoglobin (HbA1c) 8.5%, urine ketone bodies positive, serum bicarbonate 16 mEq/l, and white blood cell (WBC) count 29,000/mm 3 (93% neutrophils and 3% lymphocytes). Arterial blood gas analysis showed metabolic acidosis with a pH of 7.26 [Table 1]. HIV test (immunochromatography) and Western blot test were negative.
Table 1: Laboratory parameters

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Cerebrospinal fluid (CSF) analysis showed 800 WBC/mm 3 (90% neutrophils and 10% lymphocytes), high protein (159.7 mg/dl), and low glucose (21 mg/dl) [Table 1]. CSF Gram stain showed numerous spherical capsulated Gram-positive yeast cells. Giemsa-stained smear of CSF showed Cryptococcus neoformans characterized by rim of capsular material encircling clear space and yeast cell [Figure 3]a. On India ink stain [Figure 3]b, spherical budding yeast cells with a halo against a dark background were seen. CSF culture showed growth of C. neoformans after 36–48 h of aerobic incubation [Figure 4]. Above findings indicate Cryptococcal meningitis with secondary bacterial infection. Blood culture revealed Gram-positive organism Leuconostoc mesenteroides species grown in culture after 36–48 h aerobic incubation. These Gram-positive cocci were sensitive to penicillin, aminoglycosides, tetracyclines, imipenem, and gentamycin. CD4 absolute count was 255 cells per microliter (normal range for male in 18–65 years is 355–1215 cells per microliter). CD4% was 29%, and the normal range for CD4% in HIV-negative individual is from 25% to 65%.
Figure 3: (a) Giemsa stained smear of CSF showed Cryptococcus neoformans characterized by rim of capsular material encircling clear space and yeast cell. (b) India ink stain of CSF smear showed spherical budding yeast cells with a halo against a dark background (marked by arrow)

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Figure 4: CSF culture showing growth of Cryptococcus neoformans after 36-48 hours of aerobic incubation

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The present case was a newly detected Type II diabetic individual in diabetic ketoacidotic state with low CD4 count. Based on the above findings, a diagnosis of C. neoformans meningitis with secondary bacteremia was considered.

He was started on intravenous liposomal amphotericin B, standard dose (2–3 mg/kg/day) as induction phase along with parenteral imipenem for 2 weeks. Flucytosine was not available. Over the next 2 weeks, he significantly improved. Repeat CSF culture after 2 weeks of antifungal therapy was negative for C. neoformans. He was then advised to continue maintenance therapy with oral fluconazole of 400 mg/day for next 8 weeks. At discharge, he was alert, ambulant, and afebrile, with minimal bilateral abduction paresis of eyes. He was lost to follow-up. Subsequent telephone conversation with his son revealed that he had expired on day 40th after discharge from hospital. He had symptoms of respiratory distress a day prior.


  Discussion Top


C. neoformans meningitis is relatively uncommon among non-HIV-infected person. Kiertiburanakul et al. showed that conditions associated with Cryptococcal infection in non-HIV individual included immunosuppressive drug treatment (41%), systemic lupus erythematous (16%), malignancies (16%), and diabetes mellitus (14%).[1] Although relatively uncommon, our case has shown diabetes mellitus remains an important cause for C. neoformans meningitis. To the best of our knowledge, the present case is the first report of C. neoformans meningitis, as the initial manifestation of Type II diabetes mellitus and patient had severe immunosuppression at presentation

In diabetic patients, persistent hyperglycemic environment favors immune dysfunction, leading to dysfunction of neutrophil activity (chemotaxis and phagocytosis), reduced T lymphocyte response and humoral immunity, and depression of antioxidant system.[2] Fungal infection in diabetes mainly occurs due to neutrophil dysfunction. Studies have revealed that a deficiency of the complement C4 component in diabetes mellitus is associated with polymorphonuclear dysfunction and reduced cytokine response.[3],[4]

C. neoformans is the most common cause of fungal meningitis in HIV and non-HIV individuals.[5] It is thought to be acquired through inhaling soil contaminated with bird droppings. Two species, transmitted by inhalation, are the principal human pathogens: C. neoformans and Cryptococcus gattii.[6]C. neoformans causes cryptococcal meningitis in immunocompromised patients, whereas C. gattii is associated with illness in immunocompetent individuals.[7] Initially, we thought that C. gattii was the responsible species as our patient was neither HIV-infected nor an organ transplant recipient, and there was no history of malignancy or use of immunosuppressant drugs. However, his CD4+ count showed that he could be immunocompromised. Studies have demonstrated lymphocyte dysfunction and proliferative function of CD4 T lymphocytes and their response to antigens are impaired when the HbA1c is ≥8%.[8] In the present case, HbA1c was higher that might have caused lymphocyte dysfunction and impaired proliferation of CD4 lymphocyte and finally low CD4 count.

The most common manifestations of central nervous system (CNS) cryptococcosis are meningitis and menigoencephalitis and are usually subacute or chronic in nature. Headache and confusion is the most common feature; classical meningism occurs in <20% of patients.[9] Cranial nerve palsies and seizure occur with raised intracranial pressure. Neurological infection may be complicated by mass lesions (cryptococcomas) that occur more commonly with C. gattii than C. neoformans. The present case had asymmetrical menigoencephalitis with predominant involvement of right parietal and occipital lobe.

Our patient had de novo detected diabetic state and he was in diabetic ketoacidotic state during presentation with CNS cryptococcal infection and secondary bacterial sepsis. Although he recovered initially and repeat CSF culture at 2 weeks was negative, still he succumbed with symptoms suggestive of respiratory tract infection. Probably, the cause may be respiratory cryptococcosis or secondary bacterial infection. IDSA 2010 guidelines recommended 2 weeks of combination of amphotericin (0.7–1 mg/kg/day) and flucytosine (100 mg/kg/day) for most cases of cryptococcal meningitis but also suggested at least 4–6 weeks of same combination for induction therapy in non-HIV infected, nontransplant hosts and at least 6 weeks for those with cerebral cryptococcomas.[10] Hence, in the present case ideally, he should have received at least 4 weeks amphotericin even if CSF cultures were negative. Second, since flucytosine was unavailable, the combination of amphotericin B with fluconazole is recommended during induction phase as per guidelines.


  Conclusion Top


Cryptococcal meningitis should be considered in the differential diagnosis for all individuals, including non-HIV patients, presenting with chronic headache, altered sensorium in the presence of fever. Non-HIV, nontransplant recipient requires a longer duration of combination therapy than HIV-infected individuals. Diabetic patients are at increased risk of opportunistic infection similar to HIV patients. Strict hyperglycemic control and longer parenteral antifungal should be a goal to prevent mortality.

Declaration of patient consent

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

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kiertiburanakul S, Wirojtananugoon S, Pracharktam R, Sungkanuparph S. Cryptococcosis in human immunodeficiency virus-negative patients. Int J Infect Dis 2006;10:72-8.  Back to cited text no. 1
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2.
Casqueiro J, Casqueiro J, Alves C. Infections in patients with diabetes mellitus: A review of pathogenesis. Indian J Endocrinol Metab 2012;16 Suppl 1:S27-36.  Back to cited text no. 2
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3.
Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol Med Microbiol 1999;26:259-65.  Back to cited text no. 3
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4.
Stoeckle M, Kaech C, Trampuz A, Zimmerli W. The role of diabetes mellitus in patients with bloodstream infections. Swiss Med Wkly 2008;138:512-9.  Back to cited text no. 4
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5.
Pappas PG. Therapy of cryptococcal meningitis in non-HIV-infected patients. Curr Infect Dis Rep 2001;3:365-70.  Back to cited text no. 5
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6.
Byrnes EJ 3rd, Bartlett KH, Perfect JR, Heitman J. Cryptococcus gattii: An emerging fungal pathogen infecting humans and animals. Microbes Infect 2011;13:895-907.  Back to cited text no. 6
    
7.
Mitchell DH, Sorrell TC, Allworth AM, Heath CH, McGregor AR, Papanaoum K, et al. Cryptococcal disease of the CNS in immunocompetent hosts: Influence of cryptococcal variety on clinical manifestations and outcome. Clin Infect Dis 1995;20:611-6.  Back to cited text no. 7
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8.
Peleg AY, Weerarathna T, McCarthy JS, Davis TM. Common infections in diabetes: Pathogenesis, management and relationship to glycaemic control. Diabetes Metab Res Rev 2007;23:3-13.  Back to cited text no. 8
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9.
Mwaba P, Mwansa J, Chintu C, Pobee J, Scarborough M, Portsmouth S, et al. Clinical presentation, natural history, and cumulative death rates of 230 adults with primary cryptococcal meningitis in Zambian AIDS patients treated under local conditions. Postgrad Med J 2001;77:769-73.  Back to cited text no. 9
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10.
Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America. Clin Infect Dis 2010;50:291-322.  Back to cited text no. 10
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