CRYPTOCOCCAL ANTIGENAEMIA IN ANTIRETROVIRAL THERAPY NAIVE PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION.
Human Immunodeficiency Virus (HIV) infection is a global pandemic, with cases reported from virtually every country. World Health Organization (WHO) has estimated 34.0 million (31.4-35.9) global people living with HIV in 2011. Based on HIV Sentinel Surveillance 2008-09, it is estimated that India has 23.9 lakh people infected with HIV. Human Immunodeficiency Virus infection was first reported in India in the state of Tamil Nadu in 1986, since then the cases of Cryptococcal Meningitis (CM) have also increased.  Morbidity and mortality in HIV patients is mostly caused by opportunistic infections (OI) that occur due to lowered immune defences of the patients associated with decreased CD4 counts. Among these, meningitis with HIV has an important impact causing considerable morbidity and mortality. Meningitis associated with HIV infection can be classified according to aetiologic agents as fungal, tubercular, syphilitic and pyogenic. The most common OI in HIV patients in India is either tubercular or fungal.  Cryptococcosis is a fungal disease caused by Cryptococcus neoformans (CN), which begins as droplet infection in the respiratory tract and eventually spreads to central nervous
system to produce meningitis (CM).
Cryptococcal meningitis (CM) is one of the presenting manifestations of Acquired Immune Deficiency Syndrome (AIDS).  Cryptococcal meningitis is one of the most common OI among HIV-infected individuals, with an estimated 10 lakh cases of HIV associated CM and 6 lakh deaths every year or more than 1700 deaths everyday.  Despite cryptococcal disease accounting for 13-44% of deaths in HIV-infected patients, cryptococcal diseases continue to be grossly under-diagnosed.  Recent data indicates that the incidence of cryptococcal infection is high in India.  It is the leading infectious cause of meningitis in patients with AIDS and is the initial AIDS defining diagnosis in approximately 2% of patients, mostly occurring in those with CD4 counts less than 100 cells/[mm.sup.3]. 
Cryptococcal antigen (CRAG), a biological marker for Cryptococcal infection, is detectable in sera a median of 3 weeks (range 5-234 days) before symptoms of meningitis appear.  Positive Cryptococcal antigenaemia is an independent predictor of CM and death in patients with severe immunosuppression.  This asymptomatic period before development of symptomatic meningitis provides a window of opportunity to treat patients and potentially prevent fatal Cryptococcal disease. CRAG detection is highly sensitive as compared with microscopy and culture.  The best prophylaxis to prevent OI is an immune reconstitution with anti-retro viral therapy (ART). In areas of high prevalence, the CM screening prior to ART is necessary for potential early diagnosis and treatment. This could decrease the risk of Immune Reconstitution Inflammatory Syndrome (IRIS). The WHO has recently released "Rapid Advice" guidelines for Cryptococcal disease among persons living with HIV. Early diagnosis is key to reduce mortality due to Cryptococcal disease. A major WHO recommendation is implementation of SCRAG screening and presumptive antifungal therapy (typically oral fluconazole) in those with a positive diagnostic test among ART naive adults with a CD4 count less than 100 cell/[mm.sup.3] in areas with a high prevalence of Cryptococcal disease (> 3%).
One limitation to implementing the WHO guidelines is that currently very less data exists on the extent of Cryptococcal infection in India. Hence, this prompted the study which aims at finding occurrence of and risk factors associated with Cryptococcal antigenaemia in ART naive patients with HIV. The purpose of our study was to determine the prevalence of and risk factors for Cryptococcal antigenaemia among HIV-infected adults attending ART clinic and medical emergency at SCB Medical College and Hospital, Cuttack.
MATERIALS AND METHODS
Study Design: Cross-sectional observational study with asking research questionnaire developed for this purpose.
This study was undertaken among newly diagnosed antiretroviral therapy naive HIV/AIDS infected patients at the Postgraduate Department of Medicine, SCB Medical College, Cuttack after taking written informed consent. Hundred patients admitted in the medical wards and visiting ART clinic were considered for this study from May 2016 to Apr 2017. The screening test was done for serum cryptococcal antigen (SCRAG).
ART naive patients [greater than or equal to] 18 years documented for HIV infection and confirmed by a series of 3 tests as per NACO Guidelines (First by dot immunoassay followed by two different immunochromatographic tests).
Previously diagnosed Cryptococcosis patients on fluconazole therapy and satisfying the above criteria.
This study confirms to the ethical principles of medical research developed by the World Medical Association Declaration of Helsinki. Ethical clearance was given by the Institutional Ethics Committee of SCB Medical College, Cuttack.
Data Analysis: All data obtained with questionnaire and microbiological culture analysis were analysed using the statistical software SSPS 16.0. The Chi-square test was used to compare between two groups. Statistical significance was accepted when P value is [less than or equal to] 0.05 and the Univariate and multivariate logistic regression analyses were done to assess risk factors for a positive cryptococcal antigenaemia. Risk factors with possible significance and known to be associated with cryptococcal disease were included in the present study.
The mean age of the study population was being 36.14 [+ or -] 10.42 years (ranges 18-67 years) and median was being 35 years. The mean body mass index (BMI) of our study population was 20.54 kg/[m.sup.2] [+ or -] 2.72 (ranges 15.1 to 26.48 kg/[m.sup.2]). The present study population had mean cluster differentiation (CD4) count of 233 cells/[mm.sup.3] [+ or -] 176 (ranges 6 to 780 cells/[mm.sup.3]) (Table 1).
The maximum number of patients were from age group of 30-39 years (42%) followed by 18-30 years (24%), 40-50 years (20%) and >50 years (14%). There were 65% males (65 out of 100) and 35% (35 out of 100) females in our study and the male to female ratio was being 1.86. Maximum patients had BMI in between 18.5 to 25 kg/[m.sup.2] followed by 20% with < 18.5 kg/[m.sup.2] and 6% with >25 kg/[m.sup.2]. In the present study, 31% of individuals had CD4 count <100 cells/[mm.sup.3] and 69% >100 cells/[mm.sup.3] were observed. Signs and symptoms of meningitis were found in 17% and others were asymptomatic (Table 2).
The mean age among patients with serum cryptococcal antigen positive (SCRAG +) was 43.71 years as compared to 35.57% in cryptococcal antigen negative (SCRAG-) and this difference was statistically significant (p-0.046). The mean BMI of SCRAG+ patients and SCRAG- were 20.22 [+ or -] 2.64 kg/[m.sup.2] and 20.56 [+ or -] 2.74 respectively, which is statistically insignificant. The mean CD4 count of SCRAG- patients (246 [+ or -] 175.0) cells/[mm.sup.3] was higher than SCRAG+ patients (56.57 [+ or -] 56.0). The median CD4 count was being forty one (41 cells/[mm.sup.3]) in SCRAG+ and 203 cells/[mm.sup.3] in SCRAG- patients. The difference was statistically significant (p=0.001) (Table 3).
Out of 65 males, 5 (7.7%) were positive for SCRAG and 2 (5.7%) were positive among 35 female patients. Majority of the study population were literate (77%) and doing unskilled work (63%). Maximum cases (88, 88%) of the study population were married. The sexual transmission route for HIV infection was found to be 99% where the duration of illness is longer. The majority of SCRAG+ (6 out of 7) patients had BMI between 18.5 to 25 kg/[m.sup.2] as compared to the other groups, but the difference was not statistically significant. Out of 33 patients who had CD4 count <100 cells/[mm.sup.3], 6 (19.35%) were positive for SCRAG and significant statistically (p< 0.003). Of sixty-nine patients who had CD4 count >100 cells/[mm.sup.3], 1 (1.45%) was positive for SCRAG having statistically significance (p<0.012). Patients with cryptococcal antigenaemia were more prone to have CD4 count <100 cells/[mm.sup.3] (Table 4).
Univariate analysis showed fever (p<0.005, OR 23.368, CI 2.652-205.398), headache (p<0.010, OR 8.205, CI 1.644-40.950), vomiting (p<0.004, OR 13.200, CI 2.300-75.750), neck rigidity (p<0.014, OR 7.969, CI 1.510-42.044) and CD4 count <100 cells/[mm.sup.3] (p<0.012, OR 16.320, CI 1.871-142.374) were significantly associated with Cryptococcal antigenaemia. However, age, sex, socioeconomic status, marital status, altered mental status, duration of HIV infection, BMI and CD4 count <200 cells/[mm.sup.3] were not significantly associated with cryptococcal antigenaemia (Table 5).
In multivariate analysis, CD4 count <50 cells/[mm.sup.3] was acting as independent risk factor for cryptococcal antigenaemia (p <0.019, OR 17.769, CI 1.594-198.042) (Table 6). However, the other factors did not contribute to independent risk factors in the present study.
In the present study, overall prevalence of Cryptococcal antigenaemia is found to be 7%, which is comparable to the studies in Uganda (5-10%),  South Africa (7%)  and Kenya (7%),  which confirms that India has high rates of cryptococcal disease in HIV-infected patients in comparison to tuberculosis. The prevalence of patients with CD4 count less than 100 cells/[mm.sup.3] is 19.35% in the present study, which coincides with the study of Otella et al  in Uganda. Out of 17 meningitis cases, 4 (23.52%) cases are having cryptococcal meningitis as compared with Gomerep et al.  We observed the overall mean age being 36 years (range 18-67 years) and 43 years in SCRAG positive group as compared to 35 years in SCRAG negative group (p<0.046). On univariate analysis, we did not find advanced age as a risk factor.  There are 65 males and 35 females and the M: F ratio being 1.86:1 as compared with earlier studies.  Most of the study population has average income and literate doing unskilled work but they do not have any significant difference with positivity of SCRAG (p>0.05).
In the present study, all patients with SCRAG+ are recently diagnosed for HIV and 14 (19.71%) out of 71 have advanced disease and 25 (35.21%) patients have CD4 count less than 100 cells/[mm.sup.3], which may be due to lack of IEC (information, education and communication) activities to reach all section of population of our country.
There are 17 symptomatic patients out of which 4 (23.5%) are SCRAG+ and out of 83 asymptomatic patients 3 (3.6) are SCRAG+, which is statistically significant (p<0.015).  The symptoms of fever, headache, vomiting and neck rigidity are significantly associated with Cryptococcal antigenaemia (p<0.05). 
The mean BMI of the study population is 20.54 kg/[m.sup.2]. The SCRAG + has showed BMI 20.22 kg/[m.sup.2] whereas SCRAG-cases 20.56 kg/[m.sup.2], which is definitely higher than the previous researchers (<15.4 kg/[m.sup.2]) Oyella et. al and Micol et al.13,17 They have included patients with more advanced disease and lesser CD4 counts.
The median CD4 count of SCRAG+ individuals is 41 cells/[mm.sup.3] (mean 56, range 6-168, IQR 19.000-78.250) as compared to 203 cells/[mm.sup.3] (mean 246, range 15-780, IQR 91-370) in SCRAG- individuals (p<0.001) in Andama et al study.18 The CD4 count <100 cells/[mm.sup.3] is found in 31 patients out of which 6 (19.35%) are SCRAG+ in comparison to CD4 count >100 cells/[mm.sup.3] in which 1.45% are SCRAG+. On univariate analysis, CD4 count <100 cells/[mm.sup.3] is significantly associated with positive SCRAG (p< 0.012, OR- 16.320, 95% CI 1.871-142.374) as studied by Tenna et al,  but 67 cases in multivariate analysis do act as independent risk factor for Cryptococcal antigenaemia in Oyella et al study.  We observed high prevalence of subclinical infection 3 (3.6%) in the present study irrespective of CD4 count. Antigenaemia is not only predictive of the development of cryptococcal meningitis but also an independent predictor of mortality. 
There is a high prevalence of symptomatic Cryptococcal antigenaemia (7%) and asymptomatic Cryptococcal antigenaemia (3.6%) in ART naive HIV patients irrespective of CD4 count. There is a high prevalence of Cryptococcal antigenaemia (19.35%) in ART naive patients having CD4 count <100 cells/[mm.sup.3]. Symptoms like fever, headache, vomiting and neck rigidity have been observed in patients having CD4 count <100 cells/[mm.sup.3], significant association with Cryptococcal antigenaemia on univariate analysis seen. Cryptococcal antigenaemia is not only predictive of the development of cryptococcal meningitis in HIV patients but also an independent predictor of mortality. All ART naive adults having CD4 count <100 cells/[mm.sup.3] should be screened for serum Cryptococcal antigen followed by presumptive antifungal therapy if serum Cryptococcal antigen is positive. There is a need to strengthen IEC (information, education and communication) activities and increase routine counselling and testing of the patients attending ART clinics in Odisha.
SCRAG--serum cryptococcal antigenaemia, CD4--cluster differentiation, HIV--Human Immunodeficiency Virus, WHO--World Health Organization, CM--Cryptococcal meningitis, OI--opportunistic infections, AIDS--Acquired Immune Deficiency Syndrome, IQR--Interquartile range, CD4--cluster differentiation (cells/[mm.sup.3]) and BMI--body mass index and C.I-95% Confidence Intervals of Odds Ratios.
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Dibya Prasana Mohanty (1), Dharma Niranjan Mishra (2), Dillip Kumar Pradhan (3)
(1) Assistant Professor, Department of Microbiology, Utkal University, SCB Medical College, Cuttack.
(2) Assistant Professor, Department of Anatomy, Utkal University, SCB Medical College, Cuttack.
(3) Senior Resident, Department of Medicine, Utkal University, SCB Medical College, Cuttack.
'Financial or Other Competing Interest': None.
Submission 12-10-2017, Peer Review 05-11-2017, Acceptance 11-11-2017, Published 20-11-2017.
Dharma Niranjan Mishra, Flat No. 3-B, Neelamani Enclave, Professor Pada, Post- College Square, Cuttack-753003.
Table 1. Age, BMI and CD4 Count Characteristics Distribution of Study Population Characteristic No. Mean [+ or -] SD Median Age in years 100 36.14 [+ or -] 10.42 35 BMI(kg/[m.sup.2]) 100 20.54 [+ or -] 2.72 20.271 CD4 count cells/ 100 233.06 [+ or -] 176.13 196 [mm.sup.3] Characteristic Range Min-Max I Q Range Age in years 18-67 30.0-42 BMI(kg/[m.sup.2]) 15.1-26.48 19.13-22.36 CD4 count cells/ 6-780 70.5-355.5 [mm.sup.3] I. Q. R.--Interquartile range, CD4--cluster differentiation (cells/[mm.sup.3]) and BMI--body mass index Table 2. Demographic and Clinical Characteristics of the Study Population Age in years Number(n) Percentage 18-29 24 24% 30-39 42 42% 40-49 20 20% [greater than or equal to]50 14 14% Male 65 65% Female 35 35% BMI (kg/[m.sup.2])<18.5 20 20% BMI (kg/[m.sup.2])18.5-25 74 74% BMI (kg/[m.sup.2])>25 06 6% CD4 count <100 (cells/[mm.sup.3]) 31 31% CD4 count >100 (cells/[mm.sup.3]) 69 69% Signs and symptoms Meningitis 17 17% Asymptomatic 83 83% BMI--body mass index, CD-cluster differentiation Table 3. Age, BMI and CD4 Count Characteristics Distribution of SCRAG Positive and SCRAG Negative Patients Type SCRAG Positive(n=7) Characteristic Age in years BMI (kg/[m.sup.2]) Mean [+ or -] S.D 43.71 [+ or -] 13.94 20.22 [+ or -] 2.64 Median 40 19.1 Range 26-67 16.9-23.9 I Q Range 35.5-52.25 18.7-22.8 P value 0.046 0.750 Type SCRAG Positive(n=7) SCRAG Negative(n=93) Characteristic CD4 count (cells/ Age in years [mm.sup.3]) Mean [+ or -] S.D 56.57 [+ or -] 56.0 35.57 [+ or -] 9.978 Median 41 35 Range 6-168 18-64 I Q Range 19.0-78.3 29.75-42.0 P value 0.001 0.046 Type SCRAG Negative(n=93) Characteristic BMI (kg/[m.sup.2]) CD4 count (cells/ [mm.sup.3]) Mean [+ or -] S.D 20.56 [+ or -] 2.74 246.34 [+ or -] 175.0 Median 20.5 203 Range 15.1-26.5 15-780 I Q Range 19.3-22.4 91-370.0 P value 0.750 0.001 SCRAG--serum cryptococcal antigen, I Q Range--Interquartile range, CD4 count-cluster differentiation count (cells/[mm.sup.3]), P value Table 4. Comparison of Different Parameters in SCRAG+ and SCRAG- Study Group Parameters SCRAG+ (n=7) SCRAG- (93) Male 5 (7.7) 60 (92.3%) Female 2 (5.7%) 33 (94.3%) Illiterate 2 (8.7%) 21 (91.3%) Education <10th standard 2 (4.5%) 42 (95.5%) Education >10th standard 3 (9.1%) 30 (90.9%) Skilled worker 3 (8.1%) 34 (91.9%) Unskilled worker 4 (6.3%) 59 (93.7%) Married 6 (6.8%) 82 (93.2%) Unmarried 1 (8.3%) 11 (91.7%) Recent onset of the disease 7 (9.9%) 64 (90.1%) Past history of the disease 0 (0%) 29 (100%) BMI <18.5 kg/[m.sup.2] 1 (4.5%) 19 (95.5%) BMI 18.5-25.0 kg/[m.sup.2] 6 (8.2%) 68 (91.8%) BMI >25.1 kg/m[m.sup.2] 0 (0%) 6 (100%) CD4<100 cells/[mm.sup.3] 6 (19.35%) 27 (80.65%) CD4>100 cells/[mm.sup.3] 1 (1.45%) 68 (98.55%) Symptomatic Cr Ag 4 (23.5%) 13 (76.5%) Asymptomatic Cr Ag 3 (3.6%) 80 (96.4%) Parameters Total P Value Male 65 (100%) 1.00 Female 35 (100%) 1.00 Illiterate 23 (100%) 0.660 Education <10th standard 44 (100%) 0.660 Education >10th standard 33 (100%) 0.660 Skilled worker 37 (100%) 0.708 Unskilled worker 63 (100%) 0.708 Married 88 (100%) 1.00 Unmarried 12 (100%) 1.00 Recent onset of the disease 71 (100%) 0.104 Past history of the disease 29 (100%) 0.104 BMI <18.5 kg/[m.sup.2] 20 (100%) 0.700 BMI 18.5-25.0 kg/[m.sup.2] 74 (100%) 0.700 BMI >25.1 kg/m[m.sup.2] 6 (100%) 0.700 CD4<100 cells/[mm.sup.3] 33 (100%) 0.001 CD4>100 cells/[mm.sup.3] 69 (100%) 0.001 Symptomatic Cr Ag 17 (76.5%) 0.015 Asymptomatic Cr Ag 83 (96.4%) 0.015 CD--cluster differentiation, SCRAG--serum cryptococcal antigen Table 5. Univariate Analysis of Risk Factors for Cryptococcal Antigenaemia among HIV-infected Patients Odds 95% CI for Odds Ratio Risk Factor P value Ratio Lower Upper Age in years 0.055 1.072 0.999 1.151 Male sex 0.713 0.727 0.134 3.957 Education < 8th 0.489 0.488 0.064 3.712 standard Education > 8th 0.913 1.086 0.167 7.085 standard Married 0.847 0.805 0.088 7.237 BMI kg/[m.sup.2] 0.747 0.954 0.718 1.268 CD4 count <50cells/ 0.001 20.750 3.548 121.385 [mm.sup.3] CD4 count <100 0.012 16.320 1.871 142.374 cells/[mm.sup.3] CD4 count <200 0.053 17.414 0.967 313.749 cells/[mm.sup.3] Fever 0.005 23.368 2.652 205.368 Headache 0.010 8.205 1.644 40.950 vomiting 0.004 13.200 2.300 75.750 Neck rigidity 0.014 7.969 1.510 42.044 Altered mental 0.617 1.771 0.189 16.595 status C.I-95% Confidence Intervals of Odds Ratios Table 6. Multivariate Analysis of Risk Factors for Cryptococcal Antigenaemia Among HIV-infected Patients Risk factor P value Odds Ratio Fever 0.074 12.736 Headache 0.991 1.022 vomiting 0.293 4.474 Neck rigidity 0.568 17.761 CD4 count <50 cells/ 0.019 17.769 [mm.sup.3] Risk factor 95% C.I for Odds Ratio Fever 0.780 208.014 Headache 0.022 47.211 vomiting 0.274 73.150 Neck rigidity 1.594 198.042 CD4 count <50 cells/ 1.594 198.042 [mm.sup.3] 95% Confidence Intervals of Odds Ratios
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|Title Annotation:||Original Research Article|
|Author:||Mohanty, Dibya Prasana; Mishra, Dharma Niranjan; Pradhan, Dillip Kumar|
|Publication:||Journal of Evolution of Medical and Dental Sciences|
|Date:||Nov 20, 2017|
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