Cryptococcal Meningitis: Differences between Patients with and without HIV-Infection

Background: Cryptococcal meningitis is one of the most devastating infections, particularly in HIV-infected individuals. The increased use of immunosuppressants led to an increase in the incidence of cryptococcosis in HIV-uninfected individuals. This study aimed to compare the characteristics between groups. Methods: This retrospective cohort study was conducted from 2011 to 2021 in northern Thailand. Individuals diagnosed with cryptococcal meningitis aged ≥15 years were enrolled onto the study. Results: Out of 147 patients, 101 were individuals infected with HIV and 46 were non-infected. Factors associated with being infected with HIV included age < 45 years (OR 8.70, 95% CI 1.78–42.62), white blood cells < 5000 cells/cu.mm. (OR 7.18, 95% CI 1.45–35.61), and presence of fungemia (OR 5.86, 95% CI 1.17–42.62). Overall, the mortality rate was 24% (18% in HIV-infected vs. 37% in HIV-uninfected individuals, p-value = 0.020). Factors associated with mortality included concurrent pneumocystis pneumonia (HR 5.44, 95% CI 1.55–19.15), presence of alteration of consciousness (HR 2.94, 95% CI 1.42–6.10), infection caused by members of C. gattii species complex (HR 4.19, 95% CI 1.39–12.62), and anemia (HR 3.17, 95% CI 1.17–8.59). Conclusions: Clinical manifestations of cryptococcal meningitis differed between patients with and without HIV-infection in some aspects. Increasing awareness in physicians of this disease in HIV-uninfected individuals may prompt earlier diagnosis and timely treatment.


Introduction
Cryptococcal meningitis is a devastating neuroinfectious disease caused by members of the Cryptococcus neoformans/C. gattii species complex (CNGSC) [1]. Infection with human immunodeficiency virus (HIV) was the main underlying condition associated with this disease [2]. In 2009 the global burden of cryptococcal meningitis published was an estimated 957,900 cases of cryptococcal meningitis annually among HIV patients, resulting in 624,700 fatalities within three months of infection. Although most cases occurred in sub-Saharan Africa, 120,000 cases each year were reported in Southeast Asia with a three-month mortality rate of 55% [2]. A Thai study reported that cryptococcal meningitis was the third most common opportunistic infection after tuberculosis and pneumocystis pneumonia; however, it is the most common infection affecting the central nervous system in HIV patients [3]. During the past two decades, the prevalence of cryptococcal meningitis in HIV-uninfected patients increased due to the widespread use of immunosuppressive therapy and the increasing number of recipients receiving transplants [4][5][6][7][8]. For example, the 14-year US-based study demonstrated that in the first seven years of the study, half of the patients were HIV-infected individuals and the number dropped to less than one-third in the following seven years [8]. Several studies of cryptococcal meningitis in patients with adult-onset immunodeficiency syndrome (AOID) caused by anti-interferon-γ autoantibody (anti-IFN-γ AAb) were reported [9,10]. Comparisons of clinical characteristics of Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1). Table 1. Characteristics of cryptococcal meningitis between patients with and without HIV-infection. In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.

Characteristics
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1). Table 1. Characteristics of cryptococcal meningitis between patients with and without HIV-infection. Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1). Table 1. Characteristics of cryptococcal meningitis between patients with and without HIV-infection.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1). Table 1. Characteristics of cryptococcal meningitis between patients with and without HIV-infection.  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.

p-Value
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1). Table 1. Characteristics of cryptococcal meningitis between patients with and without HIV-infection.  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.

p-Value
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).

Laboratory Findings
In comparison with HIV-uninfected individuals, patients with HIV-infection were more anemic, had lower amounts of white blood cells, lower platelet counts, lower CD4 cell counts, higher serum cryptococcal antigen titer, and a higher rate of fungemia. (Table 2). All patients with HIV-infection were infected by members of C. neoformans species complex, whereas 8 HIV-uninfected individuals (17.4%) were infected by species of the C. gattii species complex. Following combination of the two groups, the majority of patients had a CSF opening pressure > 20 cm.H 2 O, CSF pleocytosis with a predominance of mononuclear cells, high CSF protein levels, and a low CSF: serum glucose ratio. In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to have a high opening CSF pressure, had lower cerebrospinal fluid (CSF) protein level, higher CSF to serum glucose ratio, and a high CSF cryptococcal antigen titer. Abnormal computerized tomography was found more commonly in HIV-uninfected individuals with a predominance of hydrocephalus.
Multivariate analysis revealed that factors associated with being infected with HIV in patients with cryptococcal meningitis included age < 45 years (

Induction Therapy and Outcomes
The mainstay of treatment was amphotericin B with or without fluconazole or flucytosine. There were differences in the regimen, as shown in Table 3. The dose of amphotericin B varied from 0.7 to 1.0 mg/kg/day.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.

p-Value
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.

p-Value
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.

p-Value
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1). Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.

Male
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).

Discussion
Cryptococcal meningitis is the most common cause of opportunistic adult meningitis, particularly in areas with a high prevalence of HIV-infection, especially in Southeast Asian countries [11]. The incidence of /666 meningitis declined dramatically after the increasing availability of antiretroviral therapy [12][13][14]. However, HIV-uninfected individuals are experiencing an increase in cryptococcal meningitis due to advances in medical technology, i.e., an increase in the rate of organ/stem cell transplants or an increase in availability of immunosuppressive drugs [15]. The current study found that 54.4% of HIVuninfected individuals reported no underlying disease, which was comparable to the previous studies, which found a range of 55-67% [16][17][18][19]. Genetic factors might be a potential risk for immunocompetent HIV-uninfected patients [20]. Recent studies indicated that those of Chinese descent were more vulnerable to cryptococcal meningitis than other ethnicities [21][22][23]. In a 1970s study, 96% of HIV-uninfected Chinese Singaporeans diagnosed with cryptococcal meningitis were apparently healthy. Data from Hong Kong, Taiwan, and Shanghai also showed that most of the HIV-uninfected cryptococcal meningitis patients had apparently normal immune systems [24,25]. In addition, a recent cohort study revealed a correlation between Toll-like receptor (TLR) genes and cryptococcal infection in the Chinese population [20]. In individuals not infected with HIV, eight TLR single nucleotide polymorphisms displayed substantial genetic vulnerability to cryptococcal   Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1). Table 1. Characteristics of cryptococcal meningitis between patients with and without HIV-infection. Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.

HIV-Infected
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1). Table 1. Characteristics of cryptococcal meningitis between patients with and without HIV-infection. Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.

HIV-Infected
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1). Table 1. Characteristics of cryptococcal meningitis between patients with and without HIV-infection. Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.

HIV-Infected
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1). Table 1. Characteristics of cryptococcal meningitis between patients with and without HIV-infection. Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.

HIV-Infected
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  Out of the 46 HIV-uninfected individuals, 12 patients (26.1%) received B-cell immunosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).  nosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and re-ceived targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1). nosuppressive drugs along with steroid therapy, 5 patients (10.9%) had cancer and received targeted therapy, 3 patients (6.5%) had AOID caused by anti-IFN-γ AAb, and 1 patient (2.2%) was a solid organ transplant recipient. No underlying disease was identified in the remaining 25 patients.
In comparison with HIV-uninfected individuals, patients with HIV-infection were more likely to be younger, have a higher Charlson comorbidity index (CCI), have a higher incidence of nausea/vomiting, and were less likely to experience an alteration of consciousness (Table 1).

Discussion
Cryptococcal meningitis is the most common cause of opportunistic adult meningitis, particularly in areas with a high prevalence of HIV-infection, especially in Southeast Asian countries [11]. The incidence of /666 meningitis declined dramatically after the increasing availability of antiretroviral therapy [12][13][14]. However, HIV-uninfected individuals are experiencing an increase in cryptococcal meningitis due to advances in medical technology, i.e., an increase in the rate of organ/stem cell transplants or an increase in availability of immunosuppressive drugs [15]. The current study found that 54.4% of HIV-uninfected individuals reported no underlying disease, which was comparable to the previous studies, which found a range of 55-67% [16][17][18][19]. Genetic factors might be a potential risk for immunocompetent HIV-uninfected patients [20]. Recent studies indicated that those of Chinese descent were more vulnerable to cryptococcal meningitis than other ethnicities [21][22][23]. In a 1970s study, 96% of HIV-uninfected Chinese Singaporeans diagnosed with cryptococcal meningitis were apparently healthy. Data from Hong Kong, Taiwan, and Shanghai also showed that most of the HIV-uninfected cryptococcal meningitis patients had apparently normal immune systems [24,25]. In addition, a recent cohort study revealed a correlation between Toll-like receptor (TLR) genes and cryptococcal infection in the Chinese population [20]. In individuals not infected with HIV, eight TLR single nucleotide polymorphisms displayed substantial genetic vulnerability to cryptococcal infection, whereas two polymorphisms were related to disease severity. These mutations enhanced the reaction to exposure to cryptococcal glucuronoxylomannan, resulting in a decrease in fungal clearance and an elevation in inflammatory cytokines. This evidence may indicate that people with Chinese ancestry are more easily susceptible to cryptococcal meningitis even in the absence of the risk of underlying disease [20].
Data from an earlier study showed that 63 out of 111 excreta samples from pigeons were found to be positive for Cryptococcus spp. [26]. This finding led to the assumption that pigeons and other bird species might harbor Cryptococcus spp., and contact with them would be associated with infection. In addition, northern Thailand, an area largely covered by moist deciduous forests, is a potential harbor for species of the C. gattii species complex [27,28]. However, data regarding environmental exposure were missing in the current study. Patients infected with species of the C. gattii species complex were all HIV-uninfected individuals (eight patients), and 75% of those (six patients) were apparently healthy. C. gattii species complex comprises five species: VGI (C. gattii), VGII (C. deuterogattii), VGIII (C. bacillisporus), VGIV (C. tetragattii), and VCIV/VCIIIc (C. decagattii). It was shown that VGI, VGII, and VGIII infect immunocompetent people, but VGIV mostly affects immunocompromised individuals [29,30]. In Asia, including Thailand, 73% of all isolates are VGI, followed by VGII at 19%; these incidence findings were similar to those related to Australia and New Zealand [29,30]. In contrast, VGII and VGIII predominate in America, whilst VGIV does so in Africa [30].
Consistent with previous studies, patients with HIV-infection were younger than HIV-uninfected individuals [19,31]. Patients with cryptococcal meningitis do not always have the classic signs associated with meningitis, specifically fever, nuchal rigidity, and altered sensorium [31][32][33]. However, we observed that alteration of consciousness was less prevalent in patients with HIV-infection, which is concordant with previous reports [18,19]. Typically, the duration of symptoms from onset to presentation is subacute [1]. However, this current study revealed that HIV-uninfected individuals came to hospitals earlier than individuals described within the previous reports (2 weeks in the current study vs. 6-12 weeks in a previous study) [1].
Laboratory indices from CSF also differed between patients with and without HIVinfection. Patients with HIV-infection were more likely to have anemia and leukopenia at the time of diagnosis, had a higher opening CSF pressure, higher serum cryptococcal antigen titer, and were more likely to have fungemia than patients without HIV-infection. Anemia and leukopenia may indicate chronic illness due to HIV-infection [34]. Higher opening CSF pressure, higher serum cryptococcal antigen titer, and the presence of fungemia represent a higher fungal load and disseminated infection in patients with HIV-infection due to low CD4 cell count [35,36]. However, HIV-uninfected individuals appeared to have a higher CSF protein concentration and a lower CSF: serum sugar ratio, which may indicate a more robust inflammatory response in immunocompetent hosts [37,38]. In this study, all HIV-infected patients were infected with members of C. neoformans species complex, whereas 17.4% of HIV-uninfected individuals were infected with C. gattii. This supported previous reports that C. gattii infected HIV-uninfected individuals more frequently than patients with HIV-infection [30,31,[39][40][41]. Brain imaging was frequently abnormal, especially in HIV-uninfected individuals. Hydrocephalus appeared to be the most frequent abnormality seen in HIV-uninfected individuals, which corresponded to the findings in previous studies [31,42,43].
Amphotericin B combined with flucytosine is the induction therapy of choice for patients with cryptococcal meningitis regardless of HIV-serostatus [44]. However, as flucytosine was unavailable in the hospital before the year 2020, fluconazole was mainly used in combination with amphotericin B during the study period.
Compared to the study carried out in 2005-2010, in-hospital, 90-day, and 1-year mortality rates in patients with HIV-infection were shown to have declined dramatically in the current study (1.0% vs. 24.1%, 13.9% vs. 32.4%, and 17.8% vs. 52.2%, respectively) [45]. Mortality rate among patients without HIV-infection was higher than HIV-infected patients and was driven by the 1-year mortality. This might be explained by the fact that patients with HIV-infection have immune restoration after initiation of antiretroviral therapy [46,47]. In contrary, some patients without HIV-infection in this study may receive long-term immunosuppressive agents and may suffer from their underlying diseases or other opportunistic infections contributing to death. However, HIV-serostatus was not found to be associated with mortality after adjusting for confounders. Factors associated with mortality from multivariate analysis included infections caused by the presence of alteration of consciousness, the concurrence of pneumocystis pneumonia, infection caused by species of the C. gattii species complex, and anemia. The presence of alteration of consciousness may indicate a high opening CSF pressure due to a high fungal burden [16,31,48]. Concurrent pneumocystis pneumonia may reflect the low CD4 cell count and may put patients at risk of other opportunistic infections during a 1-year period and may lead to higher mortality. An association between cryptococcal meningitis caused by species of the C. gattii species complex and high mortality in comparison to members of C. neoformans species complex were reported [30,[48][49][50][51][52]. As also observed in this study, infection caused by species of the C. gattii species complex occurred in HIV-uninfected individuals and may lead to a delay in diagnosis and treatment. In addition, species of the C. gattii species complex may not respond as well to amphotericin B in comparison to members of C. neoformans species complex [53]. Hypoalbuminemia and older age were reported in association with mortality in other studies [54,55].
There were several limitations in this study. First, due to the nature of all retrospective studies, some data may be missing and lead to misinterpretation of the results. Second, due to the small sample size, if other factors associated with mortality existed, some correlations may not have been captured.

Conclusions
The incidence of cryptococcal meningitis in patients with and without HIV-infection differed in some aspects. Patients infected with HIV were more likely to be younger, have leukopenia, and fungemia. An awareness of these differences may help to improve patient care for people with cryptococcal meningitis. Informed Consent Statement: Patient consent was waived as the data were retrieved from medical records, as is the common procedure in a retrospective study.
Data Availability Statement: Some of the data will be shared upon request.