Q J Med 2000; 93: 245-251
© 2000 Association of Physicians
Cryptococcal meningitis in non-HIV-infected patients
From the Departments of Internal Medicine and 1 Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
Received 29 October 1999 and in revised form 10 February 2000
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Summary |
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There are few reports on cryptococcal meningitis in non-HIV-infected patients in subtropical areas. We reviewed 94 non-HIV-infected patients microbiologically diagnosed with cryptococcal meningitis and hospitalized at National Taiwan University Hospital, 1977–1996. Forty-two patients (44.7%) had underlying diseases. The main initial manifestations were headache (86.2%), vomiting (72.3%) and fever (69.1%). The 30 patients with T-cell suppression had more acute illnesses (median duration of symptoms: 14 days vs. 29 days), less typical presentations of meningitis, and reduced inflammatory responses compared with the 64 without T cell suppression. There was no statistical difference between patients who received amphotericin B treatment for 10 weeks and those received amphotericin B with subsequent fluconazole treatment, in terms of mortality rate and recurrence rate. Seventy-five patients (79.8%) had satisfactory clinical responses, and two relapsed. Eighteen patients died (19.1%) and 10 of these died within 2 weeks of hospitalization. Patients in this series had outcomes comparable with those from temperate and even tropical countries with high percentages of immunocompetent hosts. Factors significantly associated with death were lymphoma, semicoma, leukocytosis, and initial high titres of cryptococcal antigen in cerebral spinal fluid (especially
1 : 512). On multivariate analysis, lymphoma and initial high cryptococcal antigen titres were independent predictors of mortality. |
Introduction |
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Cryptococcal meningitis was a uniformly fatal disease before the introduction of amphotericin B therapy.1 Since the introduction of combination therapy of amphotericin B and flucytosine, the mortality rate has substantially reduced and clinical courses have also shortened.2 Long-term suppression therapy containing fluconazole, a triazole, is particularly helpful for patients who acquired cryptococcal meningitis secondary to acquired immunodeficiency syndrome (AIDS).3–5 However, there is still no consensus about the optimal duration of treatment in non-HIV-infected patients,2,6–10 and patient outcomes may vary between tropical and temperate countries.1,2,6,9,11–15 Taiwan is an island in the subtropical zone. Since there are few data on the clinical characteristics and prognosis of cryptococcal meningitis in subtropical countries such as Taiwan, we reviewed the clinical features and efficacy of antifungal therapy in 94 patients who were not HIV-infected, treated in a major Taiwanese hospital.
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Methods |
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Patient population
We reviewed the medical and microbiological records of patients diagnosed with cryptococcal meningitis from 1977 to 1996 at the National Taiwan University Hospital (NTUH). All had positive cultures for Cryptococcus neoformans from their cerebral spinal fluid (CSF). The underlying diseases of the patients were classified as by Dismukes et al.6 Those underlying diseases and/or medications which may affect T-cell function, such as lymphoma, prednisolone therapy >700 mg in total and/or other T-cell immunosuppressive agents for >2 weeks16,17 were deemed as T-cell suppression. Semicoma was defined as when a patient had marked confusion and somnolence, but remained rousable.
Laboratory studies
For patients with meningitis, CSF and blood were routinely sent for complete white blood cell (WBC) counts and differential counts, glucose, protein and cultures. CSF testing with India ink was also routinely done. Leukocytosis was defined as WBC in blood >104/µL. Urine, pus, lung, ascites, pleural effusion, lymph node, and/or other biopsy tissues and aspiration specimens were performed and submitted for culture when indicated. Brain computerized tomography (CT) was done when indicated and the results were reviewed and analysed by the radiologists according to the criteria defined by Rozenbaum and Goncalves.7
Microbiology methods
Brain-heart infusion agar or broth, and Sabouraund dextrose agar slants and plates were used routinely for inoculation of specimens, which were sent for fungal culture. In addition, several blood culture systems were introduced during the study for fungal culture, including an agar-slide biphasic system (Septi-Chek, Roche Diagnostics) from 1986 to 1987, and the Isolator lysis-centrifugation system (E.I. du Pont de Nemous) from 1988 to 1989.
The serum and CSF cryptococcal antigen titres were determined using commercial latex agglutination tests, including Crypto-LA (International Biological Labs) from 1982 to 1993, Calas (Meridian Diagnostics) from 1993 to 1995, and Immy Latex-Crypto Antigen (Immuno-Mycologics) since 1995. In the majority of cases, blood and CSF were collected simultaneously and processed in parallel. All the serum specimens were pre-treated by pronase and heat deactivation.
Treatment and response evaluation
Patients were divided into four groups according to therapeutic regimen, as follows: (i) amphotericin B (0.3–0.5 mg/kg/day) alone; (ii) amphotericin B (0.3–0.5 mg/kg/day) in combination with flucytosine (100 mg/kg/day); (iii) amphotericin B (0.3–0.5 mg/kg/day) and subsequent fluconazole (400 mg/day); and (iv) fluconazole (400 mg/day) alone. The treatment duration was individualized according to the response of patients and the decision of the attending physician. The times to sterile CSF, conversion of India ink stain to negative, and drop of latex agglutination test of cryptococcal antigen titre (LACT) to <1 : 8 were recorded.
Clinical symptoms, signs, and the results of cultures performed before, during and after therapy were also included to assess the response to treatment. Clinical responses were categorized according to the definition by Diamond and Bennett:18 (i) cure, two sequential negative CSF cultures results with at least a 2-week interval, a drug-free interval >1 year, and no reappearance of symptoms; (ii) improved, the same as the definition for cure but the last follow-up examination or death occurred within 1 year; (iii) fail, death due to first treated meningitis; (iv) relapse, defined as for ‘improved’ but with reappearance of symptoms with CSF culture proof after therapy has been stopped; and (v) indeterminate, death due to causes other than cryptococcal meningitis, and the treatment course was not finished. Clinical response was further classified into satisfactory (cure and improved), and unsatisfactory (all the others).
The factors for poor prognosis reported by Dismukes, Diamond and Bennett, and Saag6,18,19 were included in the univariate and multivariate analyses. These included (i) steroid usage which could not be withdrawn or with a daily required use of >20 mg prednisolone, (ii) lymphoreticular malignancy, (iii) cryptococcus growth from sites other than CSF, (iv) alteration in mental status, (v) elevated CSF pressure >20 cmH2O, (vi) hypoglycorrhachia before treatment (CSF glucose <40 mg/dl), (vii) CSF cell count <20/mm3 before treatment, (viii) negative LACT, (ix) LACT >1 : 10000, (x) CSF LACT >1 : 8 after full course of treatment, (xi) positive India ink stain after 4 weeks of treatment, and (xii) hypoglycorrhachia after 4 weeks of treatment.
Statistical methods
All continuous data were expressed either as mean and standard deviation (SD), or median and range based on the distribution. Categorical variables were analysed using the 
2 test or Fisher's exact test (two-tailed). Numerical variables were compared by using Student's t test or the Mann-Whitney rank-sum test. The independence of each variable was evaluated using a stepwise logistic regression model. A p value <0.05 was considered statistically significant.
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Results |
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Patient population
From 1977 to 1996, there were 94 patients diagnosed with cryptococcal meningitis and treated at NTUH. The average annual incidence rate was 1.75 episodes per 10 000 discharges. The incidence of cryptococcal meningitis in the hospitalized patients has not changed in the past 20 years. The majority of the patients (62.8%) were male, and ages ranged from 4 to 83 years (median 36 years). Thirteen patients were younger than 16 years.
The underlying diseases of the 94 patients are listed in Table 1
. There was no statistical difference as regards age and sex distribution between patients who had T-cell suppression and those who did not. The median ages and male : female ratios were 35 and 17 : 13 for patients with T-cell suppression, 37 and 42 : 22 for those without. The median duration of symptoms before the diagnosis of cryptococcal meningitis was 15 days (range 1–900 days) (Table 2). Headache was the most common initial manifestation (86.2%). Most also presented with nausea/vomiting (72.3%) and fever (69.1%). Patients with T-cell suppression had shorter time before diagnosis, and fewer symptoms and signs of meningitis on diagnosis (Table 2). Clinical course was similar between the two groups of patients: there was no significant difference in the time to sterile CSF (mean 25.7 days in patients without T cell suppression vs. 23.6 days in patients with T cell suppression), or treatment duration (median 76 vs. 79 days, if only survivors are included).
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Laboratory data
The results of laboratory findings are also shown in Table 2
. Twenty out of 94 patients had C. neoformans isolated from specimens other than CSF, including blood (13), sputum (four), urine (two), and lung tissue (one). Brain CT scan was performed in only 64 patients. The most common findings were meningeal enhancement (31) and hydrocephalus (27), but 18 had normal findings. Patients with T-cell suppression had lower cell count in CSF, fewer lymphocytes in the blood, and fewer CT findings.
Of 67 patients who had initial CSF LACT data, 63 had LACT1 : 8 and four had LACT<1 : 8 (one had negative result for LACT). Eight patients had results negative for LACT in their blood, while their CSF LACT ranged from 0 (only one patient) to 1 : 4096. These observations indicate the discrepancy between blood and CSF LACT. Furthermore, our data also showed that the LACT titre in blood was usually less than that in CSF: 30/60 (50.0%) had CSF titres >blood titres vs. 14/60 (23.3%) with blood titres >CSF titres.
Complications
Decreased visual acuity, visual field defect and/or blindness were found in 21 patients. Twenty-one patients required ventriculo-peritoneal shunt (VP shunt) to lower intracranial pressures. Other complications included hearing impairment (eight patients), impaired functions of other cranial nerves (11 patients), hemiplegia (five patients) and permanent change in mental status (11 patients).
Treatment and outcome
Fluconazole was introduced to NTUH in late 1990, and there has been an obvious change in the therapeutic regimen from amphotericin B plus flucytosine to amphotericin B with subsequent fluconazole treatment since then (Table 3).
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Compared with that before 1990, the median duration of treatment was significantly longer after 1991 (151.5 vs. 73 days). The duration of the amphotericin B regimen decreased significantly after 1991 (53 vs. 72.5 days) because of an early shift from amphotericin B to fluconazole. Lumbar punctures were done every 1–2 weeks in the majority of patients. The median durations of anti-fungal treatment to sterile CSF, conversion of India ink stain, and to LACT titre <1 : 8 were 20 (4–150), 44 (7–180), and 44.5 (8–388) days, respectively. CSF culture remained positive in 68.0% (51/75), 8.6% (6/70), and 1.8% (1/55) after 2, 6, and 10 weeks of anti-fungal treatment, respectively, and the positive India ink stain rates at 2, 6, and 10 weeks were 85.5% (65/76), 47.8% (33/69), and 25.9% (14/54), respectively. There remained 25.3% (19/75) and 45.8% (22/48) of patients who had a satisfactory response to treatment but still showed positive India ink stain and CSF LACT titre
1 : 8 at the end of treatment. The clinical responses of the first course of treatment for the 94 patients were: cure in 59 patients, improvement in 16, failure in 17, and relapse in two. Two patients who had T-cell suppression (systemic lupus erythematosis and lymphoma) recurred within 2 months after completion of the first course of treatment.
The crude mortality rate was 19.1% (18/94). Seven patients died before starting antifungal treatment, due to delayed diagnosis. Those who died during the course of treatment usually died within 10 weeks (10/11, 90.9%). As shown in Table 4, those patients with conditions such as lymphoma, semicoma, leukocytosis and high initial LACT of CSF on admission had higher mortality rates. Lymphoma and CSF titres 1 : 512 were found to be independent predictors of fatal outcome after multivariate analysis. None of the factors for poor prognosis reported in previous studies6,16,17 was significantly correlated with death in our study.
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Discussion |
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Cryptococcal meningitis may affect people of any age. However, the average age ranges from 30 to 40 years,7,9,11,18 and men are more affected than women.1,6–810,12,18 Our observations are similar to those reported previously. Geographic and climate factors do play some roles in the differences in underlying patient status,2,6,9,11–14 which may be associated with the distribution of eucalyptus trees and variant gattii.20,21 Forty-two of 94 patients had documented underlying diseases in our series, and 30 of them had T-cell suppression. In contrast to our series and reports from Australia9 and the USA2,6 (in which 40.5–70.3% of the patients had underlying diseases), few patients with cryptococcal meningitis reported in tropical areas have identifiable underlying diseases (0–8.3%).11–14 Because our study was retrospective, only 12 isolates were available for subtyping. By the methods proposed by Kwon-Chung et al., Salkin et al., and Ikeda et al., 22–24 four of these 12 isolates were var. neoformans and eight isolates were var. gattii. Among the eight isolates of var. gattii, four patients had T-cell suppression and one had no underlying disease. However, due to the limited data, we can draw no conclusions about the relationship between patients' underlying immune status and the subtype of the infecting isolate.
There is generally a delay in establishing the diagnosis of cryptococcal meningitis,7,12,13,15 but a shorter duration of symptom onset to diagnosis in immunocompromised hosts has been reported.9,13 In our study, there was a tendency for more acute onset in patients with T-cell suppression (median 14 vs. 29 days). However, less typical clinical manifestations of cryptococcal meningitis in the T-cell-suppressed patients (such as headache, diplopia, altered mental status, meningeal sign and CT scan findings) were seen in our series. Impaired immune responses such as lower CSF cell counts, and lower systemic lymphocyte counts may explain why there were fewer typical presentations in patients with T-cell suppression. The acute and atypical clinical manifestations in patients with T-cell suppression indicated the importance of early consideration of this disease, because the number of patients with T-cell suppression increased progressively.
CSF cultures remained positive in 68.0% of our patients after 2 weeks of treatment, but in only 1.8% of patients after 10 weeks of treatment. Other investigators have suggested similar treatment duration (10 weeks) and they found recurrences in only a few cases.5,7,14 Before the introduction of fluconazole in late 1990, the median treatment duration of amphotericin B and flucytosine was 73 days in our patients, and the recurrence rate was also very low, which is similar to other investigators' findings. Although the duration of treatment extended to 151.5 days after the introduction of fluconazole, there were no identifiable factors, such as underlying disease, recurrence rate, mortality rate, LACT, or time to sterile CSF, to indicate the necessity of long-term use. The prolongation of the treatment duration appears to be simply because fluconazole is easy to use and physicians like to maintain suppression therapy. Although LACT <1 : 8 has been suggested as a treatment end-point,6 only 54.2% of our patients reached this standard after treatment. Further, of 75 patients with satisfactory responses, 25.3% still showed positive India ink stain in CSF at the end of treatment. Therefore, from our data and previous reports,11,20 we believed that negative India ink stain or LACT <1 : 8 are not necessarily the best criteria for ending treatment. Our results also indicate that LACT of CSF was more sensitive (98.5%) than that observed in serum (85.5%). Therefore, cryptococcal meningitis can not be ruled out by negative serum LACT results.
Mortality rates have varied from 0 to 47% in non-HIV-infected patients in previous reports.1,2,6–1518,25–27 Although a high prevalence of underlying diseases was found in our patients (42/94, 44.7%), our mortality rate is comparable with that in tropical countries (0–38%) where a low percentage of patients had underlying diseases.7,8,27 Our low relapse rate (2%) was also similar to those reported from Brazil (2%),7 Australia (6%, 7%),8,9 and Papua New Guinea (7%, 10%).13,14
Effective control of underlying disease, the fungus load at initial presentations as evaluated by large numbers of yeast in India ink examination and high titre of LACT, poor inflammatory response, and mental status on admission may all affect outcome.28 Our data showed the initial presentation on admission (semicoma, leukocytosis), underlying disease (lymphoma), and fungus burden (higher CSF LACT results, and CSF LACT 1 : 512), rather than treatment regimen or rapidity of response to treatment (time to sterile CSF), were associated with death. Under multivariate analysis, lymphoma and initial high CSF LACT were the independent factors for mortality, which indicated that both the underlying diseases and microbiological burden were important, rather than the treatment regimen.
In summary, our patients with T-cell suppression had more acute onset, more atypical presentation, and more obscure CT findings, which may be due to reduced immune and inflammatory responses. Neither conversion of India ink stain nor LACT 1 : 8 was a good indicator for treatment end-point. About half of our patients had underlying diseases, as high as those populations in temperate countries. Nonetheless, the mortality rate in our series is comparable with that in other countries, including those in tropical areas, where high percentages of the patients are immunocompetent. Lymphoma and initial LACT1 : 512 were independent predictors of mortality.
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Acknowledgments |
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This study was supported by a grant from the National Science Council (NSC 86–2413-B002– 054). The authors thank Ms Yueh-Shya Pan, Department of Laboratory Medicine, National Taiwan University Hospital, for data collection and Dr Jer-Shown Tsai, Koo Foundation Sun Yat-Sen Cancer Center, for assistance with the English.
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Notes |
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Address correspondence to Dr S.-C. Chang, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. e-mail: sc4030{at}ha.mc.ntu.edu.tw
Present address: Department of Internal Medicine, Koo Foundation, Sun Yat-Sen Cancer Center Hospital
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