1
Indian Journal of Medical Microbiology, (2015) 33(1): 25-29
Original Article
Changing paradigm of Cryptococcal meningitis: An eight-year experience from a tertiary hospital in South India *KPP Abhilash, S Mitra, JJJ Arul, PM Raj, V Balaji, R Kannangai, SA Thomas, OC Abraham
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. Key words: Cryptococcal meningitis, HIV, clinical profile, HIV uninfected
Introduction 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 *Corresponding author (email: ) Department of General Medicine (KPPA, SM, JJJA,VB, RK, SAT, OCA), Department of Microbiology (PMR), Christian Medical College, Vellore, Tamil Nadu, India Received: 27-08-2013 Accepted: 27-03-2014 Access this article online Quick Response Code:
Website: www.ijmm.org PMID: *** DOI: 10.4103/0255-0857.148372
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 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
26
Indian Journal of Medical Microbiology
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 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
vol. 33, No. 1
Table 1: Clinical characteristics HIV infected HIV uninfected P value n (%) n (%) Age (in years, SD) 38.2 (8.5) 45 (11.5) 0.07 Male (%) 84 (82.4) 10 (66.7) 0.17 Median duration 20 (±32) 30 (±42) 0.03 of symptom (days) 75 (75.8) 11 (73.3) 0.53 Fever (N=114) 83 (83.8) 14 (93.3) 0.46 Vomiting (N=114) 93 (93.9) 15 (100) 1.00 Headache (N=114) Altered sensorium 43 (43.4) 4 (26.7) 0.27 (N=114) 17 (20.7) 0 0.11 Seizure (N=95) Motor deficits 2 (2) 0 1.00 (N=115) Cranial nerve 4 (4) 1 (6.7) 0.51 deficit (N=115) Diabetes mellitus 2 (2) 4 (26.7) 0.002 (N=117) Features
SD: Standard deviation, HIV: Human immunodeficiency virus
was significantly shorter among the HIV-infected group (20 ± 32 days vs. 30 ± 42 days; P = 0.03). 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 CD4T-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
www.ijmm.org
January - March 2015
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]. 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. 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. Discussion In the decade of the 1950’s cryptococcal infection was reported in less than 500 patients globally.[1] With the advent Table 2: Comparison of CD4 T-cell count and CSF analysis HIV (median, IQR) P value 95% CI Infected Uninfected CD4 T-cell 42 428 0.005 −686.3 count (26.75-70.5) (254.5-542.25) to (cells/μL) −162.0 CSF analysis Total count 40 52 0.66 −166.4 (cells/cu. (8-140) (20-120) to 261.9 Mm) Differential 97 96 0.56 −5.9 Lymphocyte (91-99) (92-98) 10.8 count (%age of total cells) Protein 84 87 0.42 −29.5 (gm/dL) (59-153) (54-104.25) 70.6 Glucose 34 30.5 0.22 −34.7 (mg/dL) (20.25-45) (21-89) 8.7 CSF: Cerebrospinal fluid, IQR: Inter quartile range
Microbiological test India ink CSF cryptococcal antigen CSF fungal culture Blood culture
27
Abhilash, et al.: Cryptococcal meningitis in a tertiary hospital
HIV infected (no. done) 100 21 101 28
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
Table 3: Microbiological yield Positive among HIV un-infected HIV infected (n,%) (no. done) 89 (89) 15 19 (90.4) 14 96 (95) 15 28 (100) 4
CSF: Cerebrospinal fluid, HIV: Human immunodeficiency virus www.ijmm.org
Positive among HIV uninfected (n,%) 13 (86.7) 7 (50) 13 (86.7) 3 (75)
P value 0.89 0.55 0.22 0.12
28
Indian Journal of Medical Microbiology
vol. 33, No. 1
Trend of cryptococcal meningitis since 2005 25 21 20
19
19
15 9
10
10
9
8 6
5 1
2
2
0
0 2005
3
2
2006
2007
2008 HIV infected
2009
1
1
2010
2011
3 0
2012
2013
HIV uninfected
Figure 1: Number of hospital admissions due to CM since 2005
Table 4: Comparison of studies over 4 decades in India Study Khanna Prasad Our et al. et al. study Time period 1975-1995 1996-2001 2005-2012 No. of patients 41 45 116 Mean age 23.9 (15-73) 18-65 39 (19-65) HIV/non HIV 18/23 13/32 102/15 HIV percentage (%) 43.9 28.9 87.2 Headache (%) 89.5 94 Fever (%) 78.9 75 Altered sensorium (%) 23.7 41 Seizures (%) 10.5 18 Recovery (%) 38.3 55.8 73.7 In-hospital mortality (%) 38.3 18.6 20 CSF range (%) 0-1200 1-3500 CSF elevated WBC (%) 76.4 82.70 CSF: Cerebrospinal fluid, HIV: Human immunodeficiency virus, WBC: White Blood cell
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 CD4T-cell count
Indian Journal of Medical Microbiology, (2015) 33(1): 25-29
Original Article
Changing paradigm of Cryptococcal meningitis: An eight-year experience from a tertiary hospital in South India *KPP Abhilash, S Mitra, JJJ Arul, PM Raj, V Balaji, R Kannangai, SA Thomas, OC Abraham
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. Key words: Cryptococcal meningitis, HIV, clinical profile, HIV uninfected
Introduction 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 *Corresponding author (email: ) Department of General Medicine (KPPA, SM, JJJA,VB, RK, SAT, OCA), Department of Microbiology (PMR), Christian Medical College, Vellore, Tamil Nadu, India Received: 27-08-2013 Accepted: 27-03-2014 Access this article online Quick Response Code:
Website: www.ijmm.org PMID: *** DOI: 10.4103/0255-0857.148372
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 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
26
Indian Journal of Medical Microbiology
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 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
vol. 33, No. 1
Table 1: Clinical characteristics HIV infected HIV uninfected P value n (%) n (%) Age (in years, SD) 38.2 (8.5) 45 (11.5) 0.07 Male (%) 84 (82.4) 10 (66.7) 0.17 Median duration 20 (±32) 30 (±42) 0.03 of symptom (days) 75 (75.8) 11 (73.3) 0.53 Fever (N=114) 83 (83.8) 14 (93.3) 0.46 Vomiting (N=114) 93 (93.9) 15 (100) 1.00 Headache (N=114) Altered sensorium 43 (43.4) 4 (26.7) 0.27 (N=114) 17 (20.7) 0 0.11 Seizure (N=95) Motor deficits 2 (2) 0 1.00 (N=115) Cranial nerve 4 (4) 1 (6.7) 0.51 deficit (N=115) Diabetes mellitus 2 (2) 4 (26.7) 0.002 (N=117) Features
SD: Standard deviation, HIV: Human immunodeficiency virus
was significantly shorter among the HIV-infected group (20 ± 32 days vs. 30 ± 42 days; P = 0.03). 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 CD4T-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
www.ijmm.org
January - March 2015
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]. 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. 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. Discussion In the decade of the 1950’s cryptococcal infection was reported in less than 500 patients globally.[1] With the advent Table 2: Comparison of CD4 T-cell count and CSF analysis HIV (median, IQR) P value 95% CI Infected Uninfected CD4 T-cell 42 428 0.005 −686.3 count (26.75-70.5) (254.5-542.25) to (cells/μL) −162.0 CSF analysis Total count 40 52 0.66 −166.4 (cells/cu. (8-140) (20-120) to 261.9 Mm) Differential 97 96 0.56 −5.9 Lymphocyte (91-99) (92-98) 10.8 count (%age of total cells) Protein 84 87 0.42 −29.5 (gm/dL) (59-153) (54-104.25) 70.6 Glucose 34 30.5 0.22 −34.7 (mg/dL) (20.25-45) (21-89) 8.7 CSF: Cerebrospinal fluid, IQR: Inter quartile range
Microbiological test India ink CSF cryptococcal antigen CSF fungal culture Blood culture
27
Abhilash, et al.: Cryptococcal meningitis in a tertiary hospital
HIV infected (no. done) 100 21 101 28
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
Table 3: Microbiological yield Positive among HIV un-infected HIV infected (n,%) (no. done) 89 (89) 15 19 (90.4) 14 96 (95) 15 28 (100) 4
CSF: Cerebrospinal fluid, HIV: Human immunodeficiency virus www.ijmm.org
Positive among HIV uninfected (n,%) 13 (86.7) 7 (50) 13 (86.7) 3 (75)
P value 0.89 0.55 0.22 0.12
28
Indian Journal of Medical Microbiology
vol. 33, No. 1
Trend of cryptococcal meningitis since 2005 25 21 20
19
19
15 9
10
10
9
8 6
5 1
2
2
0
0 2005
3
2
2006
2007
2008 HIV infected
2009
1
1
2010
2011
3 0
2012
2013
HIV uninfected
Figure 1: Number of hospital admissions due to CM since 2005
Table 4: Comparison of studies over 4 decades in India Study Khanna Prasad Our et al. et al. study Time period 1975-1995 1996-2001 2005-2012 No. of patients 41 45 116 Mean age 23.9 (15-73) 18-65 39 (19-65) HIV/non HIV 18/23 13/32 102/15 HIV percentage (%) 43.9 28.9 87.2 Headache (%) 89.5 94 Fever (%) 78.9 75 Altered sensorium (%) 23.7 41 Seizures (%) 10.5 18 Recovery (%) 38.3 55.8 73.7 In-hospital mortality (%) 38.3 18.6 20 CSF range (%) 0-1200 1-3500 CSF elevated WBC (%) 76.4 82.70 CSF: Cerebrospinal fluid, HIV: Human immunodeficiency virus, WBC: White Blood cell
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 CD4T-cell count
