Background
Cryptococcal meningitis (CM) is a serious central nervous system infection caused by
Cryptococcus neoformans and
Cryptococcus gattii complexes [
1], and cryptococcal meningitis is a leading cause of death among HIV-infected individuals, especially in Sub-Saharan Africa [
2,
3]. Risk factors for cryptococcal infection include: HIV infection, transplant recipients, malignancy, and corticosteroid use. Due to the introduction of effective antifungal drugs and improved management of HIV, the incidence and mortality of cryptococcal meningitis in HIV-infected patients has decreased in recent years. However, the increasing population of HIV-negative patients with immunocompromised conditions has received increasing attention [
4‐
7]. Importantly, approximately 80% of cryptococcal meningitis cases in China and the US were reported in HIV-negative populations [
8,
9]. Many of these patients have underlying diseases, such as cancer, systemic lupus erythematosus, type II diabetes mellitus (DM II), nephrotic syndrome and tuberculosis [
4‐
7]. Of note, the impact of various clinical features on survival of cryptococcal meningitis in HIV-infected individuals have been adequately described in previous studies [
10,
11]. Moreover, some studies have investigated the clinical presentation and therapeutic outcomes in HIV-uninfected populations [
6,
12], but comparative assessments of cryptococcal meningitis patients with and without underlying diseases are limited.
Type II diabetes mellitus is a group of metabolic disorders characterized by a long-term elevation of blood glucose levels. China has the world’s largest type II diabetes mellitus population; according to the latest national survey, 11.6 and 50.1% of Chinese adults have diabetes and prediabetes disorders, respectively, accounting for nearly 25% of the global diabetes population [
13,
14]. Inadequate glucose management in diabetic patients increases their risk of infections and usually requires more hospitalization compared with that of the general population [
14‐
16]. The prevalence of diabetes mellitus in cryptococcosis patients varied from 2 to 25%, based on previous studies, and the diagnosis of diabetes mellitus was also associated with 1-year and overall mortality in cryptococcosis populations [
17‐
19]; therefore, understanding the differences of clinical manifestations between cryptococcal meningitis patients with and without type II diabetes mellitus may have clinical implications and contribute in ameliorating survival rate. Consequently, we conducted a retrospective study and evaluated the clinical profiles of HIV-negative cryptococcal meningitis patients with and without type II diabetes mellitus to identify factors holding prognostic values and implicated in mortality.
Methods
This study protocol was approved by the Institutional Review Board of the Jiangxi Chest Hospital (no. 20190304). Informed consent was waived by the Institutional Review Board due to the retrospective nature of the study design.
Study setting & participants
We retrospectively reviewed the medical records of patients with cryptococcal meningitis admitted to the Department of Internal Neurology, Jiangxi Chest Hospital. Between January 2012 and December 2018, HIV-negative cryptococcal meningitis patients with type II diabetes mellitus (
n = 26, DM II group) and without type II diabetes mellitus (
n = 52, non-DM II group) were enrolled. The inclusion criteria are including: confirmed cryptococcal meningitis patient with type II diabetes mellitus and without type II diabetes mellitus; Follow-up data were available. Patients receiving antifungal treatments prior to admission, those presenting recurrent cryptococcal meningitis, and aged< 18 years old were excluded from our study. The diagnosis of cryptococcal meningitis was based on positive results of cerebrospinal fluid culture, cerebrospinal fluid cryptococcal antigen test (IMMY, OK, USA), or positive cerebrospinal fluid India ink staining. Type II diabetes mellitus was defined according to the Chinese guidelines for diabetes mellitus: (1) random blood sugar test: a blood sugar level is 200 mg per deciliter (mg/dL) — 11.1 millimoles per liter (mmol/L)- or higher; (2) fasting blood sugar: a fasting blood sugar is 7 mmol/L or higher on two separate tests; (3) oral glucose tolerance test: a blood sugar level is more than 200 mg/dL (11.1 mmol/L) after 2 h [
20].
Data collection
For each patient, the following data were obtained: demographic information, sex, location, time of cryptococcal meningitis symptom emergence, time of cryptococcal meningitis confirmation, underlying diseases except type II diabetes mellitus, duration of type II diabetes mellitus course, antifungal regimen, clinical manifestations, laboratory findings, brain image, length of hospital stay (days) and outcome. Temporary drains, lumbar drains, or external ventricular drains for the control of increased intracranial pressure were also recorded. Brain image abnormalities were defined according to head computed tomography or magnetic resonance imaging scans as any parenchymal abnormality (including meningeal enhancement, bleeding, and strokes), and discharge data were used to determine the outcome. Two authors collected the clinical data, and these data were checked by the third author. Disagreements were resolved by discussion between two authors supervised by an expert.
Statistical analysis
IBM SPSS (version 20, International Business Machines Corporation, New York, NY, USA) was used for statistical analysis, and the categorical data were reported as the means ± standard deviations or percentages. Comparisons between groups were performed by the chi-square test, Mann-Whitney U test and logistic regression. P-values less than 0.05 were considered statistically significant.
Discussion
Cryptococcal meningitis is a common opportunistic central nervous system infection that can occur in both immunocompromised and immunocompetent patients [
21]. Many underlying diseases and conditions, such as HIV infection, organ transplantation, autoimmune disease, chronic kidney disease, and long-term steroid use, are reported as risk factors for
Cryptococcus infection [
4,
5,
11,
22]. Thus, understanding the clinical characteristics of cryptococcal meningitis patients suffering from secondary complications is important for clinical management and reducing mortality.
In this study, we found that cryptococcal meningitis patients with type II diabetes mellitus were older and more often presented with visual disorders when compared to cryptococcal meningitis patients without type II diabetes mellitus. In cerebrospinal fluid examinations, more patients had higher opening pressure and cerebrospinal fluid protein levels. In addition, the time of hospitalization was longer and mortality was higher in the type II diabetes mellitus group than in the non-type II diabetes mellitus group.
In both groups, the most common symptoms of the 78 patients were fever, headache, nausea, vomiting and consciousness disturbance, which were partially consistent with data reported in previous studies [
3]. There were no significant differences in the above mentioned symptoms between both of the groups, with the exception of vision disorders. The reasons for vision disorders include: diabetes itself can cause visual impairment, some patients have visual impairment in the diabetic stage but worsen after cryptococcal meningitis, and the other is simply caused by cryptococcal meningitis. Considering that diabetes itself can cause visual disturbance, perhaps this is the main reason for the difference between two groups [
23]. In addition, we found that type II diabetes mellitus patients presented with higher intracranial pressure. Although higher intracranial pressure has been associated with mortality among cryptococcal meningitis patients [
24,
25], we did not observe a direct relationship between intracranial pressure and mortality in the present study, probably because a ventriculoperitoneal shunt or temporary drain was used in patients with intracranial pressure or because mannitol is used as medication to reduce intracranial pressure.
Among the included 78 cryptococcal meningitis cases, 75% patients (
n = 59) received standard antifungal therapy. The antifungal regimen in the two groups was not significantly different. Five patients in the two groups were treated with voriconazole combined with flucytosine or voriconazole alone and achieved good results. Voriconazole has been found to be an effective drug for cryptococcal meningitis in some studies [
26,
27]. Although requires larger patient population, our study showed that voriconazole in combination with flucytosine might be a useful alternative therapy for cryptococcal meningitis patients.
Cryptococcal meningitis patients with type II diabetes mellitus showed higher mortality compared with non-type II diabetes mellitus group. In the type II diabetes mellitus group, 73.07% of patients were > 60 years old, and as the prevalence of diabetes mellitus also increases in the aged population, age-associated reductions in functional immune status may be a risk factor for mortality [
28]. As shown in Table
3, the presentation of nausea and vomiting was a possible risk factor for mortality type II diabetes mellitus patients. The presence of nausea and vomiting may indicates patients with higher opening pressure, which has been reported to be associated with poor prognosis [
24]. We found that 50% of type II diabetes mellitus patients had a more than 5-year history of type II diabetes mellitus, and 38% of type II diabetes mellitus patients (
n = 10) were reported to be untreated or had poor control of blood glucose despite treatment. We also found that more than half of the patients who died had a history of uncontrolled or poorly controlled blood glucose levels, indicating that blood glucose management may be a probable cause of the poor prognosis of cryptococcal meningitis, as shown in previous studies [
29‐
31].
There are several limitations of this study. First, this was a retrospective study performed in a single hospital by reviewing medical records. Secondly, we could not appropriately assess the impact of voriconazole therapy on mortality, which requires dedicated studies with large patient numbers. Thirdly, according to the different serotypes of Cryptococcus, its manifestations and prognosis are different, but this was not further assessed in this study. Further large prospective multicenter studies are needed to improve the generalizability of the data on cryptococcal meningitis .
Conclusion
In conclusion, our study demonstrated that cryptococcal meningitis patients with type II diabetes mellitus differ significantly from patients without type II diabetes mellitus with respect to clinical symptoms such as visual disorders and cerebrospinal fluid protein levels. In addition, it is necessary to note that type II diabetes mellitus patients experienced higher opening pressure, higher glucose and longer hospitalization than non- type II diabetes patients. Our data also suggested that nausea and vomiting could be related to mortality in patients with type II diabetes mellitus. We need to highlight the importance of type II diabetes mellitus management, considering that the majority of cryptococcal meningitis patients with type II diabetes mellitus who died had poorly controlled blood glucose levels.
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