Case Series and Case Reports Cryptococcal meningitis in immunocompetent Papua New Guinean children M Laman MBBS MMSci* I Hwaihwanje MBBS MMed† T M E Davis DPhil FRACP‡ L Manning MBBS FRACP‡ *Papua New Guinea Institute of Medical Research, Madang; †Paediatrics Division, Modilon General Hospital, Madang, Papua New Guinea; ‡School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, PO Box 480, Fremantle, Western Australia, Australia Correspondence to: Dr L Manning, School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, PO Box 480, Fremantle, Western Australia, Australia Email:
[email protected] TROPICAL DOCTOR 2010; 40: 61– 63 DOI: 10.1258/td.2009.090333
SUMMARY We report three cases of meningo-encephalitis caused by Cryptococcous neoformans var. gattii in apparently immunocompetent children presenting to a provincial hospital in Papua New Guinea (PNG) over a nine-month period. After a postmortem diagnosis was made in the first case, a further two were identified quickly using Indian ink staining of cerebrospinal fluid (CSF).The second case had a complicated course and recovered after relapse.The third made a full recovery with appropriate antifungal therapy. Despite the fact that an environmental reservoir has not been established, cryptococcal meningoencephalitis occurs regularly in PNG. In developing countries such as PNG, a lack of laboratory resources and limited therapeutic options can complicate the management of severe infections such as cryptococcosis. Nevertheless, with inexpensive diagnostic tests (such as Indian ink staining of CSF), a high index of suspicion and a pragmatic approach to antifungal therapy, good therapeutic outcomes can be achieved.
over a nine-month period to an observational study of severe paediatric infections admitted to the Modilon regional hospital in Madang Province. After a postmortem diagnosis of the first case, using India ink staining of cerebrospinal fluid (CSF), two subsequent children were quickly diagnosed using the same method and responded to the appropriate antifungal therapy. These cases illustrate that, although PNG is one of the least developed countries outside Africa (annual health expenditure US$24.00/person/annum),7 the application of simple laboratory techniques can have profound management implications in serious infections.
Case histories Case 1 A nine-year-old boy presented with a two-week history of fever and severe headache. Examination revealed signs of meningism. CSF showed pleocytosis with a lymphocyte density of 15 cells/mL. Gram staining was the only rapid diagnostic test available and no bacteria or other organisms were seen using this technique. Despite empirical anti-TB therapy, he deteriorated, developing signs and symptoms suggestive of raised intracranial pressure and cortical blindness. A repeat lumbar puncture was deferred due to severe papilloedema. He died on day 14 of admission. Consent was obtained from the child’s guardian for a postmortem cisternal puncture. The CSF was turbid with an increased semi-quantitative protein concentration (3.0 g/L), glucose ,5.0 mmol/L and a lymphocyte count of .1000/mL. Yeast cells with budding were seen on Gram stain. Cryptococcal meningitis was confirmed on Indian ink staining (see Figure 1). C. neoformans var. gattii was subsequently identified on CSF culture. Serological testing for HIV was negative.
Introduction Cryptococcosis was first diagnosed in Papua New Guinea (PNG) in 1946.1 Cryptococcus neoformans var. gattii is the main causative agent in PNG with an estimated annual incidence in the Central province of 42.8 per million population.2 It is usually an infection of immunocompetent young PNG adults.3 – 6 We report three cases of cryptococcosis recruited
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Figure 1 Indian ink staining of centrifuged cerebrospinal fluid (magnification 400) showing a budding form of Cryptococcus neoformans var. gattii
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Case 2 A 12-year-old boy was admitted with a 2-week history of fever, severe headache and lethargy. Neck stiffness and mild papilloedema were present and CSF microscopy showed pleocytosis with a lymphocyte density of 75/mL. CSF protein and glucose concentrations were normal, but Gram and Indian ink staining showed encapsulated yeast cells with budding. C. neoformans var. gattii was cultured from CSF. He was commenced on amphotericin B at escalating intravenous doses to 40 mg daily. His condition improved rapidly and he was discharged four weeks later to continue oral fluconazole treatment at home. He was readmitted three weeks later with persistent vomiting, photophobia, lethargy and fever. Intravenous amphotericin B was recommenced. After two weeks of therapy, he complained of diplopia. Fundoscopy showed bilateral papilloedema and a flameshaped retinal haemorrhage extending temporally to the right optic disc. The diplopia and other symptoms, including headache, improved over the following four weeks. His renal function and serum electrolyte concentrations remained normal throughout. He was discharged well six weeks after readmission. HIV testing was not performed.
Case 3 A 10-year-old girl presented to a rural health centre with severe headache and vomiting of unknown duration. After three days of chloramphenicol therapy, she became confused, irritable and lethargic. Her level of consciousness continued to decline over the next four days and she was transferred to the Modilon regional hospital. On arrival, she had a reduced level of consciousness (Blantyre coma score 3/5)8 and severe neck stiffness. Lumbar puncture showed a pleocytosis with a lymphocyte density of 540/mL and semi-quantitative CSF protein and glucose concentrations of 1 g/L and 5 mmol/L, respectively. Indian ink staining showed budding yeast cells consistent with cryptococcal infection. She was commenced on intravenous amphotericin B and responded to treatment over the following six weeks. She was discharged well with no residual neurological deficit and normal renal function. HIV testing was not performed.
Discussion C. neoformans var. gattii remains an important cause of meningo-encephalitis in young immunocompetent Melanesians. These three cases highlight several issues relating to the diagnosis and management of this potentially lifethreatening infection. First, and most importantly, Indian ink staining of CSF should be considered as part of the initial laboratory investigation of a child with meningitis as cryptococcal infection is part of the differential diagnosis. Second, amphotericin remains the treatment of choice for this infection. Third, effective antifungal treatment should be continued for the complete six-week course. As shown by Case 1, a lack of basic laboratory resources can result in misdiagnosis and death. This case prompted subsequent use of Indian ink staining which resulted in early diagnosis in two further cases. Notwithstanding PNG health-care priorities,9 laboratory diagnostic facilities should include this inexpensive test which complements other
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aspects of CSF examination, including biochemistry (which may be semi-quantitative) and microscopy. As C. neoformans var. neoformans is a well recognized cause of lymphocytic meningitis in immunocompromised adults and children,10,11 HIV testing should be considered where it is available because, although in cases such as those reported here there may be little clinical evidence of immunodeficiency and/or epidemiological justification for routine HIV testing, occasionally a child may present with HIV-related disease after early childhood.3 – 6 Treatment of cryptococcosis in PNG and other developing countries can be challenging. The availability of appropriate antifungal therapy may be limited. In addition, serial monitoring through measurement of CSF cryptococcal antigen titres and serum electrolytes and renal function during amphotericin therapy may not be possible. This sometimes results in the use of treatment regimens that may not be considered adequate. Amphotericin B (1 mg/kg/d) combined with 5-flucytosine (100 mg/kg/d) for 6 weeks has been considered the treatment of choice for cryptococcosis in both Australia12 and PNG.13 In patients without immunosuppression, and with favourable prognostic features (headache, CSF leukocyte density .20/mL and low CSF cryptococcal antigen titres), the course may be shortened to 4 weeks. However, the studies justifying this approach were done in areas without C. neoformans var gattii.12 In addition, 5flucytosine was not available for use in combination with amphotericin in the cases described here despite local recommendations.13 Truncated courses of antifungal monotherapy should not be given in this situation. There are very limited data on the use of the newer oral antifungal drugs such as fluconazole and itraconazole as treatment for cryptococcosis. The PNG paediatric treatment guidelines state there is no evidence the new azoles are superior to amphotericin/5-flucytosine.13 However, there was a clinical relapse after a 4-week course of amphotericin in Case 2 and 5-flucytosine was not available. Fluconazole used as adjunctive therapy and then as outpatient monotherapy represented an attractive management option. A pragmatic approach to the use of oral azole drugs has been highlighted by their use in the majority of Australian patients with meningo-encephalitis caused by C. neoformans var. gattii despite limited evidence of efficacy in immunocompetent patients.12 The local reservoir and mode of transmission of Cryptococcus in PNG have not been identified. In Australia there is both epidemiological and environmental evidence for its presence in two Eucalypt species (Eucalyptus camaldunlensis and E. teretocornis).14 However, extensive environmental sampling of Eucalyptus trees (Forest Red Gum – E. tereticornis) in the Central province of PNG has proved negative.2,5,15 Eucalyptus trees are not part of the normal flora in Madang Province on the north coast of PNG. Although previous case reports from PNG identified cryptococcosis in a rat and a domesticated cat, both common throughout PNG,16,17 a definitive zoonotic reservoir of Cryptococcus has not been established. The three cases described here highlight many problems facing developing countries such as PNG. A lack of laboratory resources and limited therapeutic options can complicate management of serious infections such as cryptococcosis. However, with CSF staining using India ink (which costs around US$3.00/bottle), a high index of clinical suspicion
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and a pragmatic approach to antifungal therapy, good therapeutic outcomes can be achieved in children such as those in the present series.
Acknowledgements We are grateful to the children and their families for their cooperation and to staff at Modilon Hospital for their assistance with the collection of clinical data and samples. The observational study in which these children participated was funded by MalariaGEN and the National Health and Medical Research Council of Australia (grant 513782).
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6 Seaton RA, Naraqi S, Wembri JP, Warrell DA. Predictors of outcome in Cryptococcus neoformans var. gattii meningitis. QJM 1996;89:423–8 7 WHO. Western Pacific region health databank. Papua New Guinea. Country health information profile. 2006:259 8 Molyneux ME, Taylor TE, Wirima JJ, Borgstein A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. The Quarterly Journal of Medicine 1989;71:441– 59 9 Department PH. National Health Plan 2001–2010. PNG Government Printing Service 2000;IV:59 10 Fauci A, Braunwald E, Isselbacher K, et al. Harrisons Principles of Internal Medicine. 14th edn. New York: McGraw-Hill, 1998; Appendix A-1 11 Behrman R, Kliegman R. Nelson Essentials of Paediatrics. 4th edn. Pennsylvania: WB Saunders Company, 2002:387 –8 12 Mitchell DH, Sorrell TC, Allworth AM, 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 13 Shann F, Biddulph J, Vince J. Paediatrics for Doctors in Papua New Guinea. 2nd edn. Madang: Divine Word University Press, 2003:223–6 14 Sorrell TC. Cryptococcus neoformans variety gattii. Med Mycol 2001;39:155– 68 15 Laurenson I, Naraqi S, Howcroft N, Burrows I, Saulei S. Cryptococcal meningitis in Papua New Guinea: ecology and the role of eucalypts. The Medical Journal of Australia 1993; 158:213 16 Scrimgeour EM, Purohit RG. Chronic pulmonary cryptococcosis in a Rattus rattus from Rabaul, Papua New Guinea. Trans R Soc Trop Med Hyg 1984;78:827–8 17 Mumphrey JD, Fordham A, McKerrow J. Cryptococcosis in a cat in Papua New Guinea. Australian Veterinary Journal 1977;53:197
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