Cryptococcal meningitis in young adults: clinical characteristics and therapeutic outcomes

doi:10.21203/rs.2.1867/v1

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Cryptococcal meningitis in young adults: clinical characteristics and therapeutic outcomes

https://doi.org/10.21203/rs.2.1867/v1

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Background: The clinical characteristics of cryptococcal meningitis (CM) in young adults (≤ 40 years old) have not been reported. The purpose of this study was to delineate the clinical characteristics, laboratory findings and therapeutic outcomes of young adults with CM, and compare them with older adults (> 40 years old) with CM. Methods: Ninety-nine adult patients with CM (64 men, 35 women) were enrolled from 2002-2016, of whom 26 were ≤ 40 years old (young adult group) and 73 were > 40 years old (non-young adult group). The clinical characteristics, laboratory data and therapeutic outcomes of these two groups were compared. The prognostic factors of the young adult CM patients were analyzed, and the clinical characteristics and laboratory data between the young adult CM patients with and without acquired immune-compromised syndrome (AIDS) were compared. The modified Rankin scale (mRS) was used to evaluate the outcomes of the survivors at the time of discharge and at 1 year of follow-up. Results: The young adult CM patients had a significantly higher incidence of headache as the clinical presentation. There were no significant clinical differences between the young adult CM patients with and without AIDS. There were no significant prognostic factors in the young adult CM patients, but the young adult survivors had better outcomes (mRS score 0-2) than the non-young adult group. Conclusion: The young adult CM patients had a higher incidence of headache as the clinical presentation, and the young adult CM survivors had better clinical outcomes.

Internal Medicine Specialties

cryptococcal meningitis

young adult

AIDS

therapeutic outcome

Cryptococcal meningitis (CM) caused by Cryptococcus (C.) neoformans infection is a serious infectious disease of the central nervous system (CNS) [1, 2]. CM is associated with high rates of mortality and morbidity, and as with other CNS fungal infections, Therefore, CM has a severe economic impact on healthcare systems [2, 3]. A paediatric study of CM from China reported that the majority of patients were apparently normal, and only 23.5% had identifiable underlying conditions [4]. Paediatric cryptococcosis has been reported in both HIV-negative and -positive patients [5, 6], however other immunocompromising medical conditions are usually seen in HIV-negative patients [5]. Young adults (≤ 40 years old) are considered to be more physically healthy than very young or old individuals. Several studies have reported the clinical characteristics and therapeutic outcomes of CM [1, 2, 7-9], however the clinical characteristics and therapeutic outcomes of young adults with CM have not been examined solely in the literature. In this study, we examined the clinical and laboratory features and therapeutic outcomes of young adults with CM in order to delineate the clinical characteristics of this specific group of CM patients.

We retrospectively reviewed the clinical manifestations, laboratory data and initial neuroimaging features of adult patients (> 18 years of age) with a new diagnosis of CM admitted to Kaohsiung Chang Gung Memorial Hospital during a 15-year study period (2002–2016). During this period, 99 adult patients with CM were identified, of whom 26 were classified into the young adult group (≤ 40 years of age) and the other 73 were classified into the non-young adult group (> 40 years of age). The therapeutic outcomes of these patients were evaluated at discharge and at 1 year using the modified Rankin scale (mRS) [10], with the results being defined as a good outcome (mRS score = 0-2) or a poor outcome (mRS score ≥ 3). This study was approved by the Ethics Committee of Kaohsiung Chang Gung Memorial Hospital (IRB No:1608300002).

In this study, CM was deﬁned as either (1) isolation of C. neoformans in one or more cerebrospinal ﬂuid (CSF) cultures, a positive CSF cryptococcal antigen titre, or positive CSF India ink staining and clinical features of meningitis; or (2) isolation of C. neoformans in a blood culture with clinical presentations of meningitis and typical CSF features [1, 11]. The neuroimaging findings used for analysis were derived from initial cranial magnetic resonance imaging and/or cranial computed tomography studies as previously described [1]. During the study period, the main antifungal regimen was amphotericin B +/- flucytosine +/- fluconazole. Extra-ventricular drainage and/or ventriculo-peritoneal shunts were used to relieve hydrocephalus and/or increased intracranial pressure [1].

In this study, we performed three separate statistical analyses. First, we compared the clinical characteristics, laboratory data and neuroimaging ﬁndings between the young adult and non-young adult groups. Second, we compared the clinical characteristics and laboratory data between the young adult CM patients with and without acquired immune-compromised syndrome (AIDS). Third, we investigated the potential prognostic factors for the young adult CM patients who survived and died. Categorical variables were analyzed using the chi-square test or Fisher’s exact test, and continuous variables were analyzed using the t-test or Mann-Whitney U-test. In the first analysis, variables with a P value < 0.05 were further analyzed using multivariate logistic regression analysis. We also compared the mRS scores at the time of discharge and after 1 year of follow-up between the survivors in the young and non-young adult groups using the Mann-Whitney U-test.

Of the 99 included adult CM patients (64 men and 35 women), 26 were ≤ 40 years of age (young adult group) and 73 were > 40 years of age (non-young adult group). The clinical characteristics, laboratory findings and neuroimaging features of these 99 adult CM patients are listed in Table 1. The young adult group included 21 men and five women with a mean age of 30.58 years (range: 20-38 years). AIDS was the most common underlying condition in eight patients, followed by autoimmune disorders (3), hematologic disorders (2), diabetes mellitus (DM) (1), and liver cirrhosis (1). Headache was the most common clinical presentation in 23 patients, followed by fever (19), altered consciousness (8), seizure (7), visual disturbance (7), and hearing impairment (3). Table 1 also shows comparisons between the young and non-young adult groups. The result showed that gender, AIDS, DM, the presence of headache, altered consciousness, level of CSF protein, presence of Indian ink stain, and presence of cryptococcemia were all potentially different between the two groups. However, after multivariate logistic regression analysis of these potential factors, only the presence of headache was significant (P = 0.047, OR = 6.228; 95% CI = 1.028-37.739).

Because eight of the 26 young adult CM patients had AIDS as the underlying condition, we compared clinical and laboratory data between the patients with and without AIDS (Table 2). The results showed that the patients with AIDS had lower CSF total protein and lactate levels, higher incidence of serum cryptococcal antigen level ≥ 1:1024, and cryptococcemia. However, none of these potential factors were significant in multivariate logistic regression analysis. Despite treatment, 10 of the 26 young adult CM patients died. Analysis of prognostic factors is shown in Table 3. The results showed that CSF/blood glucose ratio and CSF lactate level were potential factors, however none were significant in multivariate logistic regression analysis. The mRS scores of the 16 survivors in the young adult group and 50 survivors in the non-young adult group at discharge are listed in Table 4. Fifteen of the young adult CM survivors had a good outcome and one had a poor outcome at discharge and after 1 year of follow-up. With regards to the 50 non-young adult CM survivors, 29 had a good outcome and 21 had a poor outcome at discharge, compared to 28 with a good outcome and 22 with a poor outcome (including three deaths) after 1 year of follow-up. Comparisons of the median mRS scores at discharge and 1 year after discharge between the young and non-young adult CM survivors all showed significant differences (Table 4).

Because of the aging population worldwide, the health condition of young adults who are the cornerstone of the family and society has become more important. In this study, 80.8% (21/26) of the young adult CM patients were male, which is higher than that (58.9%, 43/73) of the non-young adult CM patients. In addition, 30.8% (8/26) of the young adult CM patients had AIDS as the underlying condition compared to only 5.5% (4/73) of the non-young adult CM patients. This is consistent with the study by Liao et al. [12] who reported that HIV seropositive CM patients in Taiwan were usually young males. In the current study, there were no significant differences in the clinical characteristics and laboratory findings between the young adult CM patients with and without AIDS (Table 2). DM is an important and rapidly growing medical disorder in Taiwan [13], and 10.9% of adults have been reported to have DM [14]. In the present study, 30.1% (22/73) of the non-young adult CM patients had DM as the underlying condition, which is higher than that (3.85%, 1/26) of the young adult CM patients. Nevertheless, there were no significant differences in the presence of AIDS or DM between the two groups of adult CM patients (Table 1). Headache was a significant factor to differentiate these two groups of adult CM patients. Headache is an important clinical manifestation of meningitis including CM [1, 15, 16] and it can be related to meningeal irritation and/or increased intracranial pressure.

The mortality rate of the young adult CM patients was 38.5% (10/26), but there were no significant prognostic factors for the survivors and non-survivors. This figure is higher than that (31.6%, 23/73) of the non-young adult group, but the difference did not reach statistical significance. Despite the higher mortality rate in the young adult CM group, unlike the non-young adult CM patients who survived, the young adult CM patients who survived at discharge had a better clinical outcome, and this better outcome was also noted 1 year after discharge from the hospital (Table 4).

Compared with the non-young adult CM patients, the young adult CM patients had a significantly higher incidence of headache as the clinical presentation. Although there were differences in the underlying condition and mortality rate, these factors did not show statistical significance. However, the therapeutic and follow-up results showed that the young adult CM patient who survived had a better clinical outcome at discharge and after 1 year of follow-up compared to the non-young adult patients who survived.

Author details

1Department of Neurology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

2Department of Information Management, National Sun Yat-sen University, Kaohsiung, Taiwan

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Kaohsiung Chang Gung Memorial Hospital (IRB No:1608300002). The need for informed consent was waived due to the retrospective nature of this study. The participant data was de-identified upon data collection.

Consent for publication

Not applicable.

Availability of data and material

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

None

Authors’ contribution

All authors have read and approved the submitted manuscript. CWH contributed to the conception and design, data acquisition and analysis, and drafting and revision of the manuscript. CYL, JJL and WNC contributed to the conception and design and clinical data analysis. WCT contributed to the conception and design, data analysis, and critical revision and final approval of the manuscript.

Acknowledgements

CM, cryptococcal meningitis; CNS, central nervous system; CSF, cerebrospinal ﬂuid; AIDS, acquired immune-compromised syndrome; mRS, modified Rankin scale; DM, diabetes mellitus

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Table 1. Clinical characteristics, cerebrospinal fluid and neuroimaging data of the young adults (≤ 40 years old) with CM

	Young adult (n=26)	Non-young adult (n=73)	p-value
Gender
Male	21	43
Female	5	30	0.045
Mortality at discharge	10	23	0.547
Underlying disease
AIDS	8	4	0.002
Diabetes mellitus	1	22	0.006
Liver cirrhosis	1	8	0.438
Hematologic disorders	2	10	0.727
Autoimmune disorders	3	7	0.720
Malignancy	0	9	0.107
Chronic obstructive pulmonary disease	0	5	0.322
Adrenal insufficiency	1	7	0.677
Organ transplantation	0	1	1.000
Initial presentation
Headache	23	42	0.004
Altered consciousness	8	41	0.026
Fever	19	41	0.130
Seizure	7	8	0.063
Visual disturbance	7	9	0.119
Hearing impairment	3	3	0.184
Cerebrospinal fluid (CSF) data
White blood cell count (109/L)	0.12	0.08	0.598
CSF/ blood glucose ratio	0.248	0.273	0.728
Protein (g/L)	0.715	1.208	0.003
Lactate (mmol/L)	4.01	4.52	0.744
Indian ink	12	19	0.018
CSF Cryptococcus antigen titre (≥1024)	14	24	0.062
Positive culture result	22	55	0.104
Serum Cryptococcus antigen titre (≥1024)	11	23	0.245
Cryptococcemia	13	17	0.011
Image finding
Basal meningeal enhancement	10	24	0.880
Pseudocyst/VRS dilatation	5	27	0.089
Hydrocephalus	7	26	0.395
Cerebral infarct	2	12	0.505
Cryptococcoma	1	5	1.000

CM: cryptococcal meningitis; AIDS: acquired immunodeficiency syndrome; Ag: antigen; VRS: Virchow-Robin space

Table 2. Clinical characteristics, cerebrospinal fluid and neuroimaging data of the young adults with CM with or without AIDS

	AIDS (n=8)	Without AIDS (n=18)	p-value
Gender
Male	8	13
Female	0	5	0.281
Mortality at discharge	3	7	1.000
Underlying disease
Diabetes mellitus	0	1	1.000
Liver cirrhosis	0	1	1.000
Hematologic disorders	0	2	1.000
Autoimmune disorders	0	3	0.529
Adrenal insufficiency	0	1	1.000
Initial presentation
Headache	7	16	1.000
Altered consciousness	1	7	0.360
Fever	6	13	1.000
Seizure	1	6	0.375
Visual disturbance	2	5	1.000
Hearing impairment	0	3	0.529
Cerebrospinal fluid (CSF) data
White blood cell count (109/L)	0.005	0.137	0.055
CSF/ blood glucose ratio	0.353	0.185	0.237
Protein (g/L)	0.51	0.84	0.024
Lactate (mmol/L)	2.90	5.55	0.011
Indian ink	5	7	0.642
CSF Cryptococcus antigen titre (≥1024)	6	8	0.388
Positive culture result	6	16	1.000
Serum Cryptococcus antigen titre (≥1024)	5	6	0.035
Cryptococcemia	7	6	0.030
Image finding
Basal meningeal enhancement	2	8	1.000
Pseudocyst/VRS dilatation	0	5	0.281
Hydrocephalus	1	6	0.375
Cerebral infarct	1	1	1.000
Cryptococcoma	0	1	1.000

CM: cryptococcal meningitis; AIDS: acquired immunodeficiency syndrome; Ag: antigen; VRS: Virchow-Robin space

Table 3. Prognostic factors of the young adults (≤ 40 years old) with CM

	Survived (n=16)	Expired (n=10)	p-value
Gender
Male	12	9
Female	4	1	0.617
Underlying disease
AIDS	5	3	1.000
Diabetes mellitus	0	1	0.385
Liver cirrhosis	0	1	0.385
Hematologic disorders	0	2	0.138
Autoimmune disorders	1	2	0.538
Adrenal insufficiency	1	0	1.000
Initial presentation
Headache	14	9	1.000
Altered consciousness	3	5	0.189
Fever	11	8	0.668
Seizure	2	5	0.069
Visual change	3	4	0.369
Hearing impairment	1	2	0.538
Cerebrospinal fluid (CSF) data
White blood cell count (109/L)	0.094	0.158	0.452
CSF/ blood glucose ratio	0.376	0.027	0.036
Protein (g/L)	0.69	0.76	0.928
Lactate (mmol/L)	3.47	6.45	0.006
Indian ink	7	5	1.000
CSF Cryptococcus antigen titre (≥1024)	8	6	0.678
Positive culture result	14	8	1.000
Serum Cryptococcus antigen titre (≥1024)	7	4	1.000
Cryptococcemia	7	6	0.420
Image finding
Basal meningeal enhancement	8	2	0.628
Pseudocyst/VRS dilatation	1	4	0.055
Hydrocephalus	4	3	1.000
Cerebral infarct	1	1	1.000
Cryptococcoma	1	0	1.000

CM: cryptococcal meningitis; AIDS: acquired immunodeficiency syndrome; Ag: antigen; VRS: Virchow-Robin space

Table 4. mRS scores of the young adult and non-young adult survivors with cryptococcal meningitis

	At discharge		After 1 year of follow-up
mRS scores	Young adult (n=16)	Non-young adult (n=50)	Young adult (n=16)	Non-young adult (n=50)
Good outcome 0	12	18	11	17
1	3	9	4	8
2 Poor outcome	0	2	0	3
3	0	2	0	2
4	0	10	0	6
5	1	9	1	11
6	0	0	0	3
Median mRS	0.00 p=0.005	1.00	0.00 p=0.005	1.50

mRS: modified Rankin scale

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Cryptococcal meningitis in young adults: clinical characteristics and therapeutic outcomes

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