Background
Cryptococcal meningitis remains one of the leading causes of morbidity and mortality in patients with AIDS in resource limited settings [
1]. Up to twenty percent of patients with cryptococcal meningitis have minimal central nervous symptoms at clinical presentation and early diagnosis of meningitis is facilitated by use of cerebrospinal fluid (CSF) cryptococcal antigen (CRAG) [
2]. Cryptococcal antigen availability and use are variable in developing countries [
1]. Over the last twenty years at the University of California, San Diego (UCSD), we occasionally cared for patients with minimal or no symptoms related to the central nervous system, high serum CRAG titer (as high as 1:65,536) and ultimately fatal HIV-associated cryptococcal meningitis. This observation prompted us to study whether serum and/or CSF CRAG titers alone or in combination with other baseline clinical parameters could be used to identify AIDS patients at risk for complicated forms of cryptococcal meningitis. The study aims were to (1) establish the prevalence of complicated cryptococcal meningitis in our clinical cohort, (2) identify a parsimonious set of clinical and laboratory predictors of complicated cryptococcal meningitis, and (3) to examine the operating characteristics of quantitative predictors of complicated cryptococcal meningitis.
Results
Between 1 January 1990 and 31 August 2009, 156 patients were admitted with AIDS-related cryptoccocal meningitis at UCSD. Seventy four were excluded from the study: 40 had recurrent episodes of cryptococcal meningitis, 11 were taking antiretrovirals, 13 had no CRAG available, and 10 left against medical advice within three days of admission. Eighty-two patients with first episode of cryptococcal meningitis comprised the study population: 93% were male; 63% were non-white. By HIV transmission risk factor, 60% were men having sex with men and 11% were injection drug users.
Fourteen patients (17%) met criteria for complicated cryptococcal meningitis (death 5, prolonged altered mental status 6, focal neurologic findings 7, CSF surgical shunt placement 8), Table
1. All patients with complicated cryptococcal meningitis were treated with Amphotericin B deoxycholate (AmpBd) and 5-Fluorocytosine (5-FC) during the induction phase (or for as long as they survived) followed by oral fluconazole 800 mg during the consolidation phase. However four patients were treated with monotherapy during the first 48 hours of hospitalization (only fluconazole 2, and only AmpBd 2). The patients who received only fluconazole during the first 48 hours had no initial symptoms referable to the central nervous symptoms. All deaths occurred during the first week of hospitalization (median: day 6, range: day 4 to 7) and the patients who survived remain alive for at least 6 months after outpatient follow up. Most patients who required a CSF surgical shunt placement had the intervention done during their third week of hospitalization (median: day 21, range: day 5 to 30). The one patient that had a CSF shunt placement in the first week developed coma rapidly with signs of decortications after admission and had persistently elevated CSF opening pressures with no clinical improvement despite daily lumbar punctures. There was no difference in age, gender, race/ethnicity, HIV risk factor, CD4 cell count or HIV plasma load between patients with and without complicated cryptococcal meningitis (Table
2). On initial clinical evaluation, there was no difference in the proportion of patients with meningeal signs, altered mental status or seizures comparing patients with and without complicated cryptoccocal meningitis (Table
2). Patients with complicated cryptococcal meningitis had higher frequency of baseline focal neurological findings (50 vs. 5%, p = 0.0001), head computed tomography (CT) abnormalities (21 vs. 2%, p = 0.03) and mean values of CSF opening pressure, (43 vs. 27 cmH
20, p = 0.0001), Table
2. All patients in the present study underwent head CT evaluation except two who were in the uncomplicated group (80 out of 82). The criteria for head CT abnormalities included: (1) enlarged ventricles consistent with hydrocephalus, (2) cerebritis and (3) focal lesions with or without mass effect. In the complicated group 3 patients had abnormal head CT findings (cerebritis 3 and enlarged ventricles 1) whereas only one patient had head CT abnormalities in the uncomplicated group (focal lesion in basal ganglia without mass effect). The focal neurologic findings found at baseline in patients who had a complicated course were ocular nerve palsies 4, hearing loss 2, and blindness 1. Of note, all patients who died had normal Glasgow scale scores on admission.
Table 1
Distribution of Complicated Meningitis Outcome Components
Only persistent altered mental status | 1 |
Only CSF shunting procedure | 4 |
Persistent focal finding and CSF shunting | 3 |
Persistent focal finding and death | 1 |
Persistent altered mental status and death | 2 |
Persistent altered mental status and persistent focal finding and CSF shunting | 1 |
Persistent altered mental status and persistent focal finding and death | 2 |
Table 2
Demographic, Clinical and Laboratory Characteristics of Study Patients with AIDS-Related Cryptococcal Meningitis
|
n = 82
|
n = 68
|
n = 14
| |
Age | 38 (19 - 57) | 38 (19 - 57) | 36 (25-48) | 0.54 |
Race/ethnicity | | | | |
White | 30(36.7) | 28(41.2) | 2(14.3) | |
Latino | 31(37.8) | 24(35.3) | 7(50.00) | |
Black | 17(20.7) | 13(19.1) | 4(28.6) | 0.17 |
Asian | 2(2.4) | 1(1.5) | 1(7.1) | |
Other | 2(2.4) | 2(2.9) | 0 | |
HIV risk factor | | | | |
MSM | 49 (59.8) | 38(55.8) | 11 (78.7) | |
Heterosexual | 18 (22.0) | 17 (25.0) | 1 (7.1) | |
IVDA | 13 ( 15.8) | 11 (16.2) | 2 (14.2) | 0.51 |
Hemophilia | 1 ( 1.2) | 1 (1.5) | 0 | |
Unknown/other | 1 (1.2) | 1 (1.5) | 0 | |
CD4 cell count (× 106/l) | 39.4 (2-256) | 38.7 (2-256) | 42.7 (3-139) | 0.77 |
HIV plasma load, log10 copies/ml a | 5.3 (4.1-6.2) | 5.3 (4.1-6.2) | 5.5 (4.8-5.9) | 0.48 |
Meningeal signsb | 12 (14.6) | 8 (11.8) | 4 (28.6) | 0.21 |
Initial altered mental status(Glasgow scale ≤ 13)b, | 21 (25.6) | 15 (22.1) | 6 (42.9) | 0.18 |
Focal neurological findingsb | 10 (12.2) | 3 (4.4) | 7 (50) | 0.0001 |
Seizures b | 5 (6.1) | 3 (4.4) | 2 (14.3) | 0.20 |
CSF opening pressure (cmH20)c | 30 (5-61) | 26.9 (5-57) | 43.4 (15-61) | 0.0001 |
CSF | | | | |
wbc (/μl) | 45.9 (0-500) | 49.9 ( 0-500) | 26.3 (0-210) | 0.36 |
glucose(mg/dl) | 41.5 (2-122) | 40.7 ( 2-103) | 45.8 (11-122) | 0.34 |
protein (mg/dl) | 77.2 (25-278) | 77.9 (27-278) | 73.9 ( 25-178) | 0.79 |
CSF India ink positive | 71 (88) | 57 (85) | 14 (100) | 0.20 |
CSF culture positive | 78 (98) | 64 (97) | 14 (100) | 1.0 |
Blood culture positive for Cryptococcus speciesd | 43 (75) | 35 (75) | 8 (80) | 1.0 |
Baseline log 2 serum CRAG | 11 (3-16) | 11 (3-16) | 14 (8-16) | 0.001 |
Baseline log 2 CSF CRAG | 10 (1-18) | 9 (1-18) | 13 (10-16) | 0.001 |
Initial abnormal head CTe | 4 (4.9) | 1 (1.5) | 3 (21.4) | 0.03 |
OUTCOMES
f
| | | | |
Persistent (≥ 14 days) altered mental status | 6 (7) | 0 | 6 (43) | 0.0001 |
Persistent (≥ 14 days) focal neurological findings | 7(9) | 0 | 7(50) | 0.0001 |
Required CSF surgical shunt | 8 (10) | 0 | 8 (57) | 0.0001 |
Death | 5 (6) | 0 | 5 (36) | 0.0001 |
Patients with complicated forms of cryptococcal meningitis had higher baseline CRAG titers in serum and CSF (p = 0.001, Table
2). ROC, 95% confidence intervals (CI) area of log
2 serum CRAG to predict complicated forms of cryptococcal meningitis was comparable to that of log
2 CSF CRAG, 0.78 (95%CI:0.66 to 0.90) vs. 0.78 (95% CI:0.67 to 0.89), respectively (χ
2, p = 0.95). The ROC areas to predict the outcome were similar for both CSF opening pressure and log
2 CSF CRAG (ROC area difference 0.04 (95% CI -0.12 to 0.20, p = 0.64)). There was a significant correlation between log
2 CSF CRAG and CSF opening pressure (Spearman rho = 0.42, p = 0.0003) and also between log
2 serum CRAG and CSF opening pressure (Spearman rho = 0.31, p = 0.01).
In bivariate categorical analysis, complicated forms of cryptococcal meningitis were strongly associated with the presence of baseline focal neurological findings [odds ratio (OR) 21.7, 95% CI: 3.7-149.3, p = 0.00001], CSF opening pressure ≥ 30 cm H
20 (OR 4.3, 95% CI: 1.02-19, p = 0.02), log
2 CSF CRAG titer (OR 1.5, 95% CI:1.1-1.9) and head CT abnormalities (OR 17.7, 95% CI: 1.2-944, p = 0.002). Multiple logistic regression models identified focal neurologic findings, log
2 CSF antigen titer, and head CT abnormalities as independent predictors of complicated cryptococcal meningitis (Table
3). Values of CSF opening pressure were not available in 14 patients (one with complicated and 13 without complicated course). Logistic regression models yielded similar results when performed with and without patients with missing CSF opening pressure values. Although CSF opening pressure ≥ 30 cm H
20 was strongly associated with the outcome in bivariate analysis, this effect was not detected when controlling for baseline focal neurologic deficit, CT abnormality, and CSF antigen titer.
Table 3
Unadjusted and Adjusted Risk Factors for Developing Complicated Cryptococcal Meningitis within Two Weeks of Admission
Baseline focal neurologic findings | 21.7(3.7-149.3) | .00001 | 17.2(2.6-114.9) | .003 |
CSF opening pressurea | |
.04
| |
.44
|
≥ 30 cmH20 | 4.3(1.2-15.1) | .03 | 1.9(0.36-10.7) | .44 |
Missing CSF opening pressureb | 0.6(0.1-5.8) | .67 | 0.37(0.02-6.7) | .51 |
Baseline log2 CSF CRAG | 1.5(1.1-1.9) | .004 | 1.5(1.1-2.2) | .02 |
Initial abnormal head CT | 17.7(1.2-944) | .002 | 32.6(1.1-927.8) | .04 |
Discussion
The present study to assess AIDS patients at risk for complicated forms of cryptococcal meningitis found that: (1) focal neurologic deficit, CT imaging abnormality, and CSF CRAG at the time of initial hospital evaluation independently predict the outcome of complicated forms of cryptococcal meningitis following two weeks from antifungal therapy.;(2) Serum and CSF CRAG as measures of fungal burden were comparable in their ability to discriminate between those with and without outcome; (3) CSF CRAG and initial opening pressure were comparable in ROC discrimination and (4) CRAG (both serum and CSF) was moderately correlated with initial CSF opening pressure.
AIDS related cryptococcal meningitis (in the absence of immune reconstitution) is often clinically characterized by a massive fungal burden with minimal CSF pleocytosis but with elevated CSF pressure [
6,
7]. Intracranial hypertension results is consequence of inflammatory cells invading and disrupting the architecture of the arachnoid granulations which then facilitate blockage of CSF reabsorption at the arachnoid granulations by the fungal organism [
8]. The present study showed that the fungal burden correlates with CSF pressure, as has been shown before by a clinical and a pathologic study [
8,
9]. Our study adds that this association is present irrespective of whether fungal burden is assessed using serum or CSF CRAG. CRAG and India ink are common markers of fungal burden [
10,
11]. In this study only CRAG was associated with complicated cryptococcal meningitis. Indian ink is widely available in developing countries whereas CRAG is not [
1]. We believe that the enhanced diagnostic sensitivity of antigen testing over India ink as well as the prognostic value quantitative antigen measurement demonstrated in this and other studies provide further evidence to support wider availability of quantitative antigen testing in developing settings.
Although, having a baseline CSF opening pressure ≥ 30 cmH
20 was associated with complicated forms of cryptococcal meningitis in bivariate analysis, it was not significant in multivariate analysis. Nonetheless, the severity of intracranial hypertension at baseline has been associated with fatal outcomes within two weeks of initiation of therapy in some studies [
12], but not in all [
9]. This difference may be explained by a number of factors: (1) lack of statistical power to detect a meaningful biological difference; (2)in those studies where no association was found, patients were enrolled in an aggressive CSF pressure management protocol with frequent lumbar punctures if found to have intracranial hypertension at baseline [
9]; and (3) the wide distribution of normal CSF opening pressure values in the general population [
3] may preclude detection of an association between intracranial hypertension and complications of AIDS-related cryptococcal meningitis. Nevertheless, current guidelines recommend measurement of CSF pressure in every AIDS patient undergoing clinical evaluation for meningitis [
13]. We acknowledge selection bias in ascertainment of initial opening pressure. It is clear from both bivariate and multivariate models that those with unrecorded opening pressure had a prognosis similar to those with measured opening pressures < 30 cm H
20. We also note that in our cohort almost thirty percent of patients who developed a complicated course had no focal neurologic findings and only minimal central nervous system referable symptoms at time of presentation.
Death is not the only relevant outcome of this opportunistic infection [
14]. Our definition of complicated cryptococcal meningitis includes death but also incorporates two elements of long term morbidity: (1) persistently (≥ 14 days) abnormal neurologic exam either by altered mental status or focal neurologic findings, and (2) surgical intervention to control intractable intracranial hypertension.
This was an observational retrospective study and important limitations need to be recognized. First, fourteen patients had no baseline opening CSF pressure measurement. Among those who had no CSF pressure documented, all but one had an uncomplicated course. The main reasons for missing CSF pressure documentation included: technical challenges that arose during lumbar puncture while performed in the emergency room and the illness episode occurred between 1990 and 1995 when routine measurement of CSF opening pressure was not as widely accepted as currently. Second, certain variables (Table
1) have missing data: (1) HIV viral loads were missing in 39% of patients, most of them diagnosed when viral loads were not widely available for patient care; (2) fungal blood cultures were not available in 17% of patients, which is due to the observational and retrospective nature of the study.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
ERC carried out study design, data collection, statistical analysis and draft manuscript. HJ and SK performed data collection and filled case report forms. JC and AMS, carried out data reconciliation by chart reviews. WCM participated in every single step of study from conception, design, statistical analysis and drafting of manuscript. All authors review and approved final version of manuscript.