Introduction

Meningitis can be categorized as acute, subacute, and chronic onset, based on its duration of symptoms. Chronic meningitis is commonly defined as inflammation evolving during weeks to months, while acute meningitis rarely persists more than a few weeks [1].

Cryptococcal meningoencephalitis (CM) is always included in the differential diagnosis of chronic or subacute meningoencephalitis, since 75 % of CM patients present with symptoms that develop insidiously over 2 to 4 weeks [1, 2]. There are some CM happening acutely or subacutely reported previously, but nearly all of them are HIV-associated [3–8]. Until now, there has been no study performed on HIV-negative CM patients with acute/subacute onset.

In this study, we defined the HIV-negative CM patients as having no more than a month of symptoms as acute/subacute onset. After comparing their epidemiological and clinical features, as well as outcomes, with those of patients with chronic onset, we explored the independent prognosis factors and the factors related to the survival time in HIV-negative CM patients with acute/subacute onset for the first time.

Materials and methods

Data source and study population

There were 106 HIV-negative patients diagnosed with CM from Nanfang Hospital between July 1, 1998 and June 30, 2013, and they were all included in this study. The patients’ medical records were reviewed to extract demographic and clinical features, including potential risk factors, symptoms, and cerebrospinal fluid (CSF) analysis before antifungal therapy. Furthermore, the prognosis factors and factors associated with the survival time of HIV-negative CM patients with acute/subacute onset were analyzed. All patients or their family members signed a written consent in accordance with the ethical committee standards during their hospital stay or outpatient follow-up.

Study criteria

CM was defined by the following criteria from Bestard and Siddiqi [9]: “(1) isolation of cryptococcus from previous or current cerebrospinal fluid cultures, followed by a positive CSF cryptococcal antibody, positive CSF India ink staining, or positive CSF Aley new blue dye staining and clinical features of meningoencephalitis; or (2) isolation of cryptococcus in blood culture with clinical presentations of meningoencephalitis and typical CSF features.”

“With potential risk factors” was defined as when CM patients have HIV infection, malignancies, cirrhosis, organ transplantation, end-stage renal failure, autoimmune disorder, diabetes mellitus, idiopathic CH4 T-cell lymphopenia, sarcoidosis, chronic usage of corticosteroids or other immunosuppressive therapy, systemic lupus erythematosus (SLE) or other systemic autoimmune diseases, chronic kidney diseases, mycosis infection of other systems, drug addiction, etc. [10–12].

Therapy

Once patients were diagnosed with CM, intravenous administration of amphotericin B deoxycholate (AmBd) was given at 0.1 mg/kg on the first day, 0.5 mg/kg on the second day, and was increased to 1 mg/kg per day from the third day onwards, together with 100 mg/kg 5-fluorocytosine (5-FC) and 400 mg fluconazole (FCZ) per day orally, known as the induction therapy. After 4–6 weeks of induction therapy, we stopped AmBd when there was no cryptococcus found in at least three sequential CSF examinations by microscopy. FCZ and 5-FC were used continuously for 6–9 more months. Patients with persistent high CSF pressure received lumber punctures every 2–3 days.

Data analysis

For the comparison of continuous variables, such as age, CSF analysis before antifungal therapy, hospitalization length, and survival time, an independent samples t-test was performed. The Chi-square test was used to compare the categorical variables, including gender, bird/bird dropping contact history, potential risk factors, symptoms, and outcome status, between HIV-negative CM patients with acute/subacute onset and those with chronic onset. Multivariate analysis was performed for detection of the factors contributing to the prognosis in HIV-negative CM patients with acute/subacute onset. Furthermore, the Cox regression model was used to evaluate the factors related to the survival length among them. Statistical significance was defined as p < 0.05 and the data were analyzed using SPSS 16.0 software (SPSS, Chicago, IL, USA).

Results

We reviewed the data of 106 HIV-negative patients diagnosed with CM in our hospital during a 15-year period (July, 1998 to June, 2013) and found 77 patients who presented with acute/subacute onset (no more than a month) of symptoms. The mean age of these patients was 37.58 ± 16.79 years (range: 11 months to 81 years). Similar to the results obtained from the whole population [12], male predominance was also found in the patients with acute/subacute onset (54 male, 70.1 %; 23 female, 29.9 %; overall male:female ratio 2.3:1). There was no difference in the potential risk factors between CM patients with acute/subacute and those with chronic onset (Table 1).

Table 1 Demographic characteristics, contact history, and risk factors of HIV-negative CM patients with different onset process
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Compared with the HIV-negative CM patients with chronic onset, nonspecific symptoms, including headache (74.0 % vs. 79.3 %) and fever (61.0 % vs. 65.5 %) were less common in acute/subacute onset CM patients (Table 2). While specific symptoms, such as ataxia (3.9 % vs. 3.4 %), impaired consciousness (23.4 % vs.3.4 %), dizziness (2.6 % vs. 0.0 %), and psychosis (3.9 %vs. 3.4 %) were more common, only impaired consciousness showed a statistical difference (Table 2). The CSF analysis of all 106 patients showed that increased CSF pressure (81.6 % vs. 86.2 %, p = 0.774), decreased CSF glucose (51.9 % vs. 75.9 %, p = 0.026), and increased CSF protein level (70.1 % vs. 78.6 %, p = 0.392) were less prevalent in CM patients with acute/subacute onset, but they were prone to have a decreased ratio of CSF glucose/blood glucose (88.2 % vs. 80.8 %, p = 0.340) (Table 2).

Table 2 Clinical features and outcome of HIV-negative CM patients with different onset process
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Evaluating the CM patients demonstrated that those with acute/subacute onset were more inclined to die (48.6 % vs. 27.6 %, p = 0.052), but no statistical difference was found. There is no difference in both the hospitalization length and survival time between CM patients with and without acute/subacute onset (Table 2).

As reported in previous studies, there are five major prognosis factors: older than 55 years, a CSF opening pressure greater than or equal to 250mmH2O, a decreased ratio of CSF glucose/blood glucose, consciousness level, and the duration of intensive care unit stay [12–17]. We chose age, ratio of CSF glucose/blood glucose, consciousness level, CSF pressure, CSF glucose, CSF protein, and hospitalization length to explore the prognosis factors in CM patients with acute/subacute onset. In our multivariate analysis, the ratio of CSF glucose/blood glucose [odds ratio (OR) 0.04, 95 % confidence interval (CI) 0.004–0.262, p = 0.02], impaired consciousness (OR 5.09, 95 % CI 1.477–17.522, p = 0.01), and hospitalization length (OR 0.98, 95 % CI 0.977–0.999, p = 0.04) were independently significant with regards to prognosis (Table 3).

Table 3 Multivariate conditional logistic analysis of prognosis factors related to HIV-negative CM patients with acute/subacute onset
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Cox regression analysis of our study indicated that the ratio of CSF glucose/blood glucose (p = 0.019, 95 % CI 0.006–0.631, OR 0.059), impaired consciousness (p < 0.001, 95 % CI 0.109–0.534, OR 0.241), and hospitalization length (p < 0.001, 95 % CI 0.963–0.987, OR 0.975) were the factors significantly related to the survival time in HIV-negative CM patients with acute/subacute onset (Table 4).

Table 4 Cox regression analysis of factors related to survival length in HIV-negative CM patients with acute/subacute onset
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Discussion

CM affects individuals with impaired cell-mediated immunity (such as HIV infection), malignancies, organ transplant recipients, users of chronic corticosteroids or other immunosuppressive regimens, as well as individuals with a competent immune system [11, 18, 19]. Being present in more than 90 % cases of immunocompromised patients, particularly those with AIDS with a more acute course, CM mostly manifests as a subacute or chronic process in HIV-negative patients [2, 20]. In this study, we focus on the HIV-negative CM patients with acute/subacute onset. We analyzed their epidemiological and clinical features, and the outcomes among HIV-negative CM patients, and explored the independent prognosis factors and the factors related to the survival time of patients with acute/subacute onset for the first time.

There is no difference between age, contact history, potential risk factors, mortality, hospitalization length, and survival time between HIV-negative CM patients with acute/subacute onset and those with chronic onset. This result indicated that contact history and potential history risk factors (such as history of use of corticosteroids and/or immunosuppressants, history of SLE or other autoimmune diseases, history of kidney diseases, history of hematopathy, history of diabetes mellitus, history of tuberculosis, history of malignant cancer, or history of organ transplantation) did not affect the onset process of HIV-negative CM patients, regardless of their gender or age. Furthermore, the mortality, hospitalization length, and survival time of the HIV-negative CM patients did not relate to the onset process of their symptoms.

Similar to previous studies in China [11, 12], nonspecific symptoms, such as headache and fever, were the most common symptoms in HIV-negative CM patients with acute/subacute onset. Impaired consciousness, one of the most common clinical manifestations of central nervous system (CNS) infection [21], is the only symptom having a statistical difference between HIV-negative CM patients with acute/subacute onset and those with chronic onset. It is probably because consciousness level, which was strongly associated with therapeutic effect and prognosis, caused more attention among patients and clinical workers than other specific symptoms [15, 16].

Compared to patients with chronic onset, fewer patients with acute/subacute onset had increased CSF pressure (>200 mmH2O), decreased CSF glucose (<2.25 mmol/L), and increased CSF protein (>0.45 g/L). This result indicated that the abnormal CSF analysis was probably directly related to the length of time symptoms persisted.

Unlike previous studies [13, 14], we carried out multivariate analysis on age, CSF analysis, consciousness level, and hospitalization length to find the prognosis factors related to the HIV-negative CM patients with acute/subacute onset and found that the ratio of CSF glucose/blood glucose, impaired consciousness, and hospitalization length were associated with the prognosis. Similar to what we previously reported [12], in patients (inclusive of both HIV-negative and HIV-positive patients), decreased ratio of CSF glucose/blood glucose was an independent prognosis factor: the ratio of CSF glucose/blood glucose of patients who died was 0.04 times that of those who survived. Similar to what Darzé et al. [15] found previously, patients with impaired consciousness were 5.09-fold more likely to die over those without, and impaired consciousness was, therefore, another prognosis factor. In addition, the hospitalization length of patients who died was 0.98 times shorter than that of those who survived, showing that professional care was important to CM patients. This result was consistent to what Chen et al. [13] indicated in 2015. On our Cox regression analysis, these three prognosis factors were also significantly related to the survival time of HIV-negative CM patients with acute/subacute onset. These results demonstrated that the ratio of CSF glucose/blood glucose, consciousness level, and hospitalization length of the HIV-negative CM patients with acute/subacute onset should receive greater focus, in the hope to decrease mortality.

Although we focused on the onset progress of HIV-negative CM patients and explored the independent prognosis factors and the factors related to the survival time of HIV-negative CM patients with acute/subacute onset, there were some limitations to this approach. A larger sample size may allow more prognosis factors to be detected. A better method of communication to avoid lost cases due to any inconveniences in maintaining contact should be accounted for in future studies. Furthermore, a multicenter study should be performed for a more detailed study.