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  Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 33  |  Issue : 1  |  Page : 25-29
 

Changing paradigm of Cryptococcal meningitis: An eight-year experience from a tertiary hospital in South India


1 Department of General Medicine, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Microbiology, Christian Medical College, Vellore, Tamil Nadu, India

Date of Submission27-Aug-2013
Date of Acceptance27-Mar-2014
Date of Web Publication5-Jan-2015

Correspondence Address:
KPP Abhilash
Department of General Medicine, Christian Medical College, Vellore, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0255-0857.148372

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 ~ Abstract 

Background: Cryptococcal meningitis (CM) is a common opportunistic fungal infection causing sub-acute meningitis with the potential for complications and significant mortality. We conducted this study to describe the difference in presentation and outcome between HIV-infected and HIV-uninfected patients. Materials and Methods: Patients admitted to a tertiary care centre between 2005 and 2013 with confirmed CM were included in the analysis. Details of the clinical presentation, laboratory findings, treatment details, risk factors for infection and outcome were documented and analysed. Results: During the study period, 102 (87.2%) cases of CM occurred among HIV infected individuals, whereas 15 (12.8%) occurred among HIV-uninfected patients. HIV-infected patients with CM were younger compared with HIV-uninfected patients (38.2 ± 8.5 years vs. 45 ± 11.5 years; P = 0.07). The median duration of symptoms prior to presentation was shorter in the HIV-infected group (20 ± 32 vs. 30 ± 42; P = 0.03). There was no difference between the cerebrospinal fluid (CSF) lymphocyte counts, CSF protein counts, and CSF sugar levels in both the groups. The diagnostic yield of Cryptococcus was similar with CSF India ink smear (89% vs. 87%), CSF fungal culture (95% vs. 87%), and blood culture (100% vs. 75%) in both the groups. Case fatality rate in the HIV-infected group was 30.6%, whereas there were no deaths in the HIV-uninfected group. Conclusion: HIV-infected patients with CM have a worse outcome compared to HIV-uninfected patients. The overall trend over 3 decades shows increasingly successful rates of treatment and hence early diagnosis and treatment are of paramount importance.


Keywords: Cryptococcal meningitis, HIV, clinical profile, HIV uninfected


How to cite this article:
Abhilash K, Mitra S, Arul J, Raj P M, Balaji V, Kannangai R, Thomas S A, Abraham O C. Changing paradigm of Cryptococcal meningitis: An eight-year experience from a tertiary hospital in South India. Indian J Med Microbiol 2015;33:25-9

How to cite this URL:
Abhilash K, Mitra S, Arul J, Raj P M, Balaji V, Kannangai R, Thomas S A, Abraham O C. Changing paradigm of Cryptococcal meningitis: An eight-year experience from a tertiary hospital in South India. Indian J Med Microbiol [serial online] 2015 [cited 2019 Jul 18];33:25-9. Available from: http://www.ijmm.org/text.asp?2015/33/1/25/148372



 ~ Introduction Top


Cryptococcal meningitis (CM) is an opportunistic infection usually seen in immuno-compromised patients, but is also known to affect apparently healthy individuals. It is caused by Cryptococcus neoformans, an ubiquitous encapsulated yeast with a predilection for the central nervous system. Infection occurs via inhalation of C. neoformans spores and it disseminates haematogenously with a predilection for the central nervous system, causing meningitis/meningo-encephalitis. It clinically manifests with sub-acute onset of fever, headache, vomiting with or without focal neurological deficit and is the AIDS defining illnesses in up to 69% of patients with HIV infection. [1] If untreated, it is invariably fatal with 30-82% mortality as reported in various studies. [2],[3] Although, the incidence of CM has declined in HIV patients who are on anti-retroviral therapy, it remains a leading cause of mortality, especially in the developing countries. Studies done in the pre ART era showed HIV infection as a predisposing factor in 43.9% of patients while more recent studies done showed that up to 78.4% of patients with CM are HIV positive. [1],[2] Studies from the developed countries show that majority of CM occur in HIV un-infected patients and that the in-hospital mortality was higher among these patients. [1] This may not be the case in developing countries like India with the rapidly increasing incidence of HIV infection. We, therefore, conducted this study to describe the differences in the presentation of CM between HIV-infected and HIV-uninfected patients.


 ~ Materials and Methods Top


Christian Medical College, Vellore is a 2,700 bedded tertiary care and teaching hospital located in Tamilnadu state of South-India. All adult patients (age > 15 years) who were admitted with microbiologically confirmed cryptococcal meningitis (CSF fungal culture and/or a positive India ink test and/or positive cryptococcal antigen test) between the period of January 2005 to May 2013 were included in this descriptive study. Individual patient details on clinical presentation, co-morbid illnesses, HIV infection related clinical, immunological and anti-retroviral treatment details, CM treatment, and outcome were collected. Microbiological results on appropriate body fluids (CSF, blood, and bone marrow) including fungal culture, India ink preparation, and cryptococcal antigen test were gathered. All patients were initiated on a standard protocol of amphotericin B with regular monitoring of serum creatinine and potassium levels. Flucytosine was not used. High dose of fluconazole was used as an alternative if there was a contraindication to amphotericin B. The patients of CM were classified into two groups based on HIV co-infection. All the clinical and laboratory variables were analysed to compare the differences between the two groups of patients.

Laboratory tests

India ink and Gram staining were done on the CSF samples. All the samples of CSF were processed for fungal culture on Sabouraud's dextrose agar, which was incubated at 37°C and 25°C in a biological oxygen demand (BOD) incubator and processed according to a standardised protocol, which was based on the presence of any visible growth. The fungal cultures were followed for 2 weeks. The colonies of C. neoformans were identified, based on their yeast like colony morphology, the presence of spherical yeast cells without hyphae/psesudohyphae on microscopy and a positive urease test.

Statistical methods

Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software for Windows version 16.0. Descriptive data are given as mean (SD) or as median (range). Chi-square test or Fisher's exact test was used to compare dichotomous variables and t-test or Mann-Whitney test was used for continuous variables as appropriate. The association of clinical and laboratory features to the outcome were analysed by univariate analysis and their 95% confidence intervals were calculated. For all the tests, a 2-sided P value of 0.05 or less was considered statistically significant.

This study was approved by the Institutional Review Board of Christian Medical College, Vellore and patient confidentiality was maintained using unique identifiers.


 ~ Results Top


Clinical characteristics

During the study period, 117 cases of microbiologically confirmed CM were admitted in various medical units [Table 1]. Total of 102 (87.2%) cases occurred among HIV infected individual, while 15 (12.8%) occurred among HIV-uninfected patients. CM occurred more commonly among males in both the groups (82.4% and 66.7% respectively, P value = 0.17). The mean age group of the patients with CM and HIV co-infection was 38.2 ± 8.5 years, which was lower as compared to HIV-uninfected patients (45 ± 11.5 years; P value = 0.07). The median duration of symptoms prior to presentation was significantly shorter among the HIV-infected group (20 ± 32 days vs. 30 ± 42 days; P = 0.03).
Table 1: Clinical characteristics

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The most common symptom was headache (94%), followed by vomiting (85%). Fever and alteration of mentation was present in 75% and 41%, respectively. Neck stiffness was present in 84% of the patients. It is interesting to note that 21% of the CM among HIV-infected patients had seizures while HIV-uninfected patients had no seizures (P value = 0.1). All the other symptoms were not significantly different among the HIV-infected and HIV- uninfected patients.

Among HIV-infected patients, CM was the presenting HIV-AIDS defining illness in 48/102 (47.1%) of patients. Only 14/102 HIV-infected patients were on anti-retroviral therapy at the time of admission and 6 of them developed CM as an Immune Reactivation Inflammatory Syndrome (IRIS). No obvious risk factor for CM was identifiable in 6/15 patients, who were HIV uninfected but diabetes mellitus was seen in 4/15 patients. The median peripheral CD 4 T-cell count was significantly higher in the HIV-uninfected group 428 cells/μL (254.5-542.2) as compared with HIV-infected group 42 cells/μL (26.7-70.5). Case fatality rate in the HIV-infected group was 30.6%, while there were no deaths in the HIV-uninfected group.

CSF analysis

Total CSF WBC count was elevated (>5 cells/cu mm) in all the HIV-uninfected patients and in 80.6% of HIV-infected patients. It ranged from 6-620/cu mm with a median of 52 (20-120) in the HIV-uninfected group, whereas the HIV-infected group had a wider range of 1-3500/cu mm with a median of 40 (8-140). There was a clear lymphocyte predominance in the CSF with 92.1% and 88.2% in the HIV-infected and HIV-uninfected groups, respectively. Comparison of both the groups showed no statistically significant difference between the CSF lymphocyte counts, CSF protein counts and CSF sugar levels [Table 2].
Table 2: Comparison of CD4 T - cell count and CSF analysis

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CSF fungal culture was positive in 112 (95.7%) patients among which 98.2% (110/112) were C. neoformans var. neoformans and 1.8% (2/112) were C. neoformans var. gattii. Both the C. neoformans var. gatti were seen in the immunosuppressed patients. The diagnostic yield of C.neoformans was similar with CSF India ink preparation (89% vs. 87%), CSF fungal culture (95% vs. 87%), and blood culture (100% vs. 75%) in both the groups [Table 3]. Cryptococcus was isolated from the bone marrow cultures of 3 patients.
Table 3: Microbiological yield

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Since 2005, the hospital admissions of newly diagnosed cases of CM have shown a declining trend among HIV co-infected individuals (P value < 0.01) as shown in [Figure 1].
Figure 1: Number of hospital admissions due to CM since 2005

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 ~ Discussion Top


In the decade of the 1950's cryptococcal infection was reported in less than 500 patients globally. [1] With the advent of the AIDS pandemic, there was an increase in the number of cases. However with the successful introduction and widespread accessibility of highly active retroviral therapy under National AIDS control program (NACP), there is a sharp decline in the incidence of new cases of invasive cryptococcal diseases. [2],[4] Other high risk groups for CM are transplant recipients on immunosuppressants and those with haematopoietic malignancies, chronic renal failure, solid organ malignancy and liver cirrhosis. Cryptococcosis has been reported from many parts of India in those with underlying risk factors and in apparently healthy individuals as well.

In our study, 88.7% (102/117) of the patients with CM had HIV infection, which is comparable to the rate (79.4%) reported in other recent studies. [1] However, a study done in South India between 1978 and 1995 showed that a much a smaller proportion of patients with CM (43.9%) were associated with HIV infection. [5] This reflects the impact of the HIV pandemic in India and supports the fact that there has been a parallel increase in the incidence of HIV and cryptococcal infections. In contrast, data from the developed countries show a higher percentage of HIV uninfected patients with CM. [1] This may be explained by a higher number of post-transplant patients and the higher use of immunosuppressant drugs.

In our hospital, out of a total of 2067 HIV related admissions from 2005-2013, 117 (5.6%) were due to CM. Lakshmi et al., reported a much lesser prevalence of 2.09% in their HIV reactive cohort in 2007. [6] Males are more commonly infected than females, which may reflect a higher prevalence of HIV infection among males and a higher exposure to cryptococcus rather than a difference in host susceptibility. CM was the AIDS defining illness in 47.1% of our patients, a rate much lesser than 78.5% reported in a study done in South India before 1995. [5] This is probably related to early diagnosis of HIV infection and widespread use of National AIDS Control Organization (NACO)-free ART.

Clinical presentation and the course of CM are usually indolent with symptoms starting over 1-3 weeks. Usual symptoms are headache and altered mental status, including personality changes, confusion, lethargy, obtundation, and coma. In our study, headache was the most common presenting complaint followed by nausea and vomiting in both the groups. Majority of HIV-uninfected patients (84.6%) presented with seizures whereas only 14.7% of HIV-infected patients had seizures at presentation. Prasad et al., reported seizures in only 10.4% of patients with CM. [7] Meningeal irritation and CNS crptococcomas, which are most commonly seen in the basal ganglia and the cerebellum are the causes of seizures. Magnetic resonance imaging (MRI) of the brain was not available in the majority of patients to determine the presence of cryptococcomas as the cause of seizures. CSF total WBC count was elevated (>5 cells/cu mm) in 80.6% of HIV infected patients, a rate much higher that reported by Atul et al., (46.43%) and Kumar et al., (55%). [8],[9] Contrary to our findings, other studies had shown that HIV-infected patients had lesser CSF pleocytosis, lower CSF protein response and a higher rate of isolation from non-neural sites. One of our patients had a CSF WBC count of 3500 cells/cu mm, probably the highest reported value for CM.

According to previous studies on HIV-infected patients with CM, a low CD 4 T-cell count <20/μL and low CSF WBC count have been found to be associated with poor prognosis where as an initial high cryptococcal antigen titre and hydrocephalus were related to poor outcomes among HIV-uninfected patients. In our study, the overall case fatality rate was 26.3% with all the deaths being in the HIV-infected group. This is in contrast to studies on CM from the developed countries where HIV-uninfected patients have a higher mortality than HIV-infected patients (13.3% vs. 10.5%; P, 0.0001). [1] Within India, the reported mortality rates due to CM have varied considerably from 18-38.3%. [5],[7] Overall, there is a trend showing a decline in incidence of CM and increasingly successful treatment of this infection from 38.33% recovery before 1995 to 73.7% recovery in our study patients [Table 4]. Early diagnosis of HIV infection and appropriate initiation of anti-retroviral therapy to maintain a higher CD 4 T-cell count may be the most important step to decrease the incidence of cryptococcal infection. Even in HIV-uninfected patients a high index of clinical suspicion and mycological surveillance is needed, as majority of patients respond well to therapy if treated early.
Table 4: Comparison of studies over 4 decades in India

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 ~ Conclusion Top


India, HIV infection continues to be an important risk factor for CM and is an important contributor to morbidity and mortality. HIV-infected patients with CM have a worse outcome compared to HIV-uninfected patients. The overall trend over 3 decades shows increasingly successful rates of treatment and hence early diagnosis and treatment are of paramount importance.

 
 ~ References Top

1.
Pyrgos V, Seitz AE, Steiner CA, Prevots DR, Williamson PR. Epidemiology of cryptococcal meningitis in the US: 1997-2009. PLoS One 2013;8:e56269.  Back to cited text no. 1
    
2.
Butler EK, Boulware DR, Bohjanen PR, Meya DB. Long term 5-year survival of persons with cryptococcal meningitis or asymptomatic subclinical antigenemia in Uganda. PLoS One 2012;7:e51291.  Back to cited text no. 2
    
3.
Yu YL, Lau YN, Woo E, Wong KL, Tse B. Cryptococcal infection of the nervous system. Q J Med 1988;66:87-96.  Back to cited text no. 3
    
4.
Dromer F, Mathoulin-Pélissier S, Fontanet A, Ronin O, Dupont B, Lortholary O, French Cryptococcosis Study Group. Epidemiology of HIV-associated cryptococcosis in France (1985-2001): Comparison of the pre- and post-HAART eras. AIDS 2004;18:555-62.  Back to cited text no. 4
    
5.
Khanna N, Chandramuki A, Desai A, Ravi V. Cryptococcal infections of the central nervous system: An analysis of predisposing factors, laboratory findings and outcome in patients from South India with special reference to HIV infection. J Med Microbiol 1996;45:376-9.  Back to cited text no. 5
    
6.
Lakshmi V, Sudha T, Teja VD, Umabala P. Prevalence of central nervous system cryptococcosis in human immunodeficiency virus reactive hospitalized patients. Indian J Med Microbiol 2007;25:146-9.  Back to cited text no. 6
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7.
Prasad KN, Agarwal J, Nag VL, Verma AK, Dixit AK, Ayyagari A. Cryptococcal infection in patients with clinically diagnosed meningitis in a tertiary care center. Neurol India 2003;51:364-6.  Back to cited text no. 7
[PUBMED]  Medknow Journal  
8.
Patel AK, Patel KK, Ranjan R, Shah S, Patel JK. Management of cryptococcal meningitis in HIV-infected patients: Experience from western India. Indian J Sex Transm Dis 2010;31:22-6.  Back to cited text no. 8
[PUBMED]  Medknow Journal  
9.
Kumar S, Wanchu A, Chakrabarti A, Sharma A, Bambery P, Singh S. Cryptococcal meningitis in HIV infected: Experience from a North Indian tertiary center. Neurol India 2008;56:444-9.  Back to cited text no. 9
[PUBMED]  Medknow Journal  


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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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