Trinity Student Medical Journal 2003

A Case of Cryptococcal Meningitis in a HIV Sero-negative Patient

Ciaran Kelly, 5th year Medicine

INTRODUCTION

Cryptococcus neoformans (C.neoformans) is a saprophytic encapsulated yeast with a worldwide distribution in soil contaminated with dessicated bird excreta. C.neoformans has been recently associated with some varieties of Eucalyptus trees indigenous to Southeast Asia and Australia. It reproduces by budding and forms round cells that appear as a creamy white growth on Sabourauds agar at 37°C. Four serotypes exist (A-D) which cause disease in humans. Serotype A is included in C.neoformans variant grubii; serotypes B and D are included in C. neoformans variant gattii and serotype D is included in variant  neoformans.¹ All cryptococcal species produce phenoloxidase and are therefore able to produce melanin-like pigments. However variant gattii and variant neoformans, the principle varieties that cause disease in humans, can be distinguished by a number of other biochemical tests e.g. resistance to canavanine and resistance of their urease enzymes to EDTA.² 

There is a male predominance for infection (approximately 2:1) and infection before puberty is uncommon. Infection in humans is by inhalation of the organism and may be asymptomatic in the immunocompetent host. Host resistance to C.neoformans is mediated by phagocytosis, cell mediated immune response, and antibody production with complement fixation. In the immunocompetent host, neutrophils and macrophages phagocytose the organism making these an important first line of defence against C. neoformans. Perforin release by natural killer cells and T cells may also help in direct destruction of these organisms. Macrophages acting as antigen presenting cells cause the stimulation of specific T-lymphocytes; these lymphocytes  act in producing a cell-mediated immune response which in turn result in stimulation of B-lymphocytes and antibody production. Antibody production, which is variable, allows for opsonisation and complement fixation.

In states of decreased cell-mediated immunity the organism may disseminate haematogenously to the kidneys, lymph nodes, bone, skin, prostate gland (which may act as a reservoir) and brain (especially the meninges).³  This decrease in cell-mediated immunity is commonly associated with malignancy, diabetes mellitus, sarcoidosis, corticosteroid therapy and HIV infection.⁴  World Health Organisation guidelines indicate that cryptococcal meningitis is an "AIDS-defining illness". Before the advent of appropriate therapy cryptococcal meningitis was a uniformly lethal condition but with modern antifungal agents the mortality from this has dropped substantially^.5

CASE REPORT

This is a report of an 11 year old Vietnamese girl, K. She presented to the Centre for Tropical Diseases in Ho Chi Minh City, Vietnam in August 2002 with a 12 day history of headache, fever and progressively worsening diplopia. On examination she was found to have papilloedema and bilateral cranial nerve (CN) VI palsies. A lumbar puncture was performed and analysis revealed a low white cell count (108 cells/ml) with lymphocytic predominance, low glucose and low protein (0.7 g/l). A CAT scan of the brain showed enhancement of the meninges but no other lesions. A chest X-ray showed a diffuse pneumonia. Blood samples revealed a white blood cell count of 15x109/ml and HIV serology was negative. An Indian ink stain and culture was positive for C.neoformans and the patient was commenced on IV amphotericin therapy. For her diplopia she was commenced on IV cortisol. She improved rapidly over the next 24 hours.

Lumbar punctures were performed every two days on the patient and cerebrospinal fluid (CSF) was cultured on each occasion. Further tests showed that she had an idiopathically depleted CD4+ count of 24. The dose of amphotericin was increased to its maximum recommended limit but the CSF cultures were still found to be positive. On the 20th day of admission it was noted that her facial features had become markedly Cushingoid; she had abdominal striae and she had become euphoric. Adjunctive antifungal therapy was not available, so a decision was made to taper the steroids to prevent further immunocompromise. However when the dose of cortisol was lowered, the bilateral CN VI palsies reappeared which indicated rising intracranial pressure. The patient clinically deteriorated. No facilities were available for the insertion of a ventriculo-peritoneal shunt. As the patient was in danger of coning, the original dose of cortisol was reinitiated. She quickly improved clinically, but with reduced visual acuity of the left eye. Due to the lack of additional therapy and further options there was great concern for her prognosis.

DISCUSSION

Only in adults have there been reports of sporadic CD4+ T-lymphocyte depletion in the absence of HIV infection.⁶ Transient CD4+ lymphopœnia is seen in association with some underlying disease; however, the proportion of people who have an underlying disease in subtropical areas is much less than in temperate regions.⁷  True depletion in the absence of an underlying disease has recently become recognised as a distinct condition - idiopathic CD4+ lymphopœnia.⁸

In Vietnam, the Department of Health pays for the hospital bed but the patient must pay for any therapy or investigations that they receive. The Wellcome Trust has a research facility at the Centre for Tropical Diseases. In this case they paid for the radiological tests; an MRI scan is way beyond the means of an average Vietnamese family. An MRI scan of the brain costs about US $140 while the average monthly income is US $80. Several antifungals are available to combat cryptococcal meningitis but their costs vary widely. Amphotericin is the cheapest and most widely available antifungal agent and is often sufficient for use on its own in treating cryptococcal meningitis.⁷ In this case it was seen that this therapy alone was inadequate; however a lack of money dictated that there were few other options.

Lack of resources resulted in a poor prognosis for this patient. This only serves to highlight the enormous gaps between the standard  of health care in the developed world and that of developing nations.

REFERENCES

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2. Collier L, Balows A, Sussman M. Topley & Wilson's microbiology and microbial infections. 9th ed. New York: Arnold, 1998.

3. Levitz SM. The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis. Rev Infect Dis 1991; 13(6):1163-9.

4 Salaki JS, Louria DB, Chmel H. Fungal and yeast infections of the CNS: a clinical review. Med 1984; 63(2):108-32.

5. Bennett JE, Dismukes WE, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 1979; 301(3):126-31.

6. From the Centers for Disease Control. Unexplained CD4+ T-lymphocyte depletion in persons without evident HIV infection. JAMA 1992; 268(10):1254-5.

7. Shih CC, Chen YC, Chang SC, et al. Cryptococcal meningitis in non-HIV-infected patients. QJM 2000; 93(4):245-51.

8. Ramirez JA, Srinath L, Ahkee S, et al.  HIV-negative "AIDS" in Kentucky: a case of idiopathic CD4+ lymphopenia and cryptococcal meningitis. South Med J 1994; 87(7):751-2.