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Original paper

Should cryptococcal antigen screening be considered as a routine procedure in antiretroviral therapy naïve severely immunocompromised HIV-seropositives – a prevalence study from Eastern India to support recent 2018 WHO guidelines

Nivedita Dutta
1
,
Rajyasree Ghosh De
1
,
Ananya Bhowmik
2
,
Sanjay Bhandary
1
,
Dolanchampa Modak
3
,
Subhasish Kamal Guha
3

1.
Centre of Excellence in HIV Care, School of Tropical Medicine, Kolkata, West Bengal, India
2.
Regional Paediatric Centre in HIV Care, Kolkata Medical College, Kolkata, West Bengal, India
3.
Department of Tropical Medicine, School of Tropical Medicine, Kolkata, West Bengal, India
HIV AIDS Rev 2020; 19, 2: 87-92
Online publish date: 2020/06/28
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Introduction

Cryptococcal meningitis (CM) has been recognized as a leading cause of adult human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS)-related mortality in sub-Saharan Africa. Data relating to the prevalence of this potentially preventable infection is sparse in South Asian countries, specifically in India. Due to paucity of prevalence data, its prevention and treatment remains ill-defined and does not get prioritized. Mortality from CM is highest in developing low-income countries, accounting for around 70-80% in low-income versus only 20-30% in high-income countries [1].
CM is known as a “sleeping disease” and is being predicted as a “mycosis of future”, but due to resource constraints and the uncertainty related to the prevalence of CM data, routine screening, evaluation, and pre-emptive treatment of pre-antiretroviral therapy (ART) subjects for cryptococcal infection are not a part of the National Program in India [2, 3].
As the mortality of CM is quite high, special attention is needed for subjects who present to antiretroviral clinics with advanced HIV infection and exceptionally low CD4 count. Data from retrospective hospital-based studies conducted in Brazil and Argentina show a high case fatality, ranging from 26% to 63% [4].
The high case fatality is related to a delay in presentation with late diagnosis. Non-availability of rapid diagnostic kits, poor accessibility, or contraindications to invasive procedures such as lumbar puncture, are the most common reasons for the delay in diagnosis [5].
CM is one of the leading opportunistic fungal infections and AIDS-defining illness in patients with CD4 count ≤ 100 cells/μl. It is caused by the encapsulated yeast of Cryptococcus neoformans or C. gattii [6]. Among these two, C. neoformans is more commonly associated with meningitis in immunocompromised patients. Cryptococcal antigenemia is considered an independent predictor of CM in HIV subjects with advanced immunosuppression [7].
In a meta-analysis, Lawn et al. observed that in sub-Saharan Africa, CM accounts for almost 20% of mortality in subjects with AIDS [8]. In a cross-sectional study from Namibia, Sawadago et al. reported an estimated prevalence of 3.3% cryptococcal antigen (CrAg) positivity on de-identified plasma specimens with CD4 ≤ 100 cells/μl [9]. According to meta-analysis by Lawn, almost 8 to 26% of deaths in people living with HIV (PLHIV) occurred in the first few months after detection and initiation of ART, of which 20% accounted for CM [8]. In Southeast Asia, CrAg prevalence in patients with CD4 ≤ 100 cells/μl is reported between 4.0% and 20.6% in both clinically suspected and asymptomatic PLHIV. In few other studies, the prevalence has been observed as high as 12.9%, where only asymptomatic, ART-naïve patients were enrolled [10-12]. The prevalence pattern is slightly more variable in India. In a study from New Delhi, North India, the prevalence of cryptococcal infection detected by conventional method (India ink and culture) was documented as high as 46% in a cohort of HIV-positive meningitis patients [13]. In a recent study by Anuradha et al. from New Delhi, latex agglutination (LA) tests of serum samples in ART naïve subjects with CD4 ≤ 100 cells/μl yielded a prevalence of 3.125% [14].
The World Health Organization (WHO) in its updated version of March 2018, strongly recommends routine CrAg screening of HIV-infected adults and adolescents with CD4 count ≤ 100 cells/μl before ART initiation, and has also considered screening at a higher CD4 cell count threshold of < 200 cells/μl. If cryptococcal antigen screening is not available, fluconazole primary prophylaxis has been advised for all individuals with CD4 count ≤ 100 cells/μl, with special consideration at a higher CD4 count of < 200 cells/μl. If CrAg-positive detected, as a strategy to reduce the development of CM, pre-emptive antifungal therapy as induction, consolidation, and maintenance treatments are recommended [15]. Previously, this screening strategy was recommended by the WHO only if the prevalence of CrAg in an area was > 3%.
The primary objective of this study was to ascertain the prevalence of CrAg positivity among ART-naïve, HIV- seropositive patients, with CD4 count of ≤ 100 cells/μl.

Material and methods

This longitudinal study was conducted at the Centre of Excellence in HIV Care, School of Tropical Medicine, Kolkata, India, between January 2014 to July 2017. Whole blood samples were drawn from 390 ART-naïve, HIV-seropositive subjects, who had CD4 count ≤ 100 cells/μl.
An approach of “reflex testing” was adopted for this study by which, serum CrAg testing was done on a day-to-day basis by selecting the ART-naïve subjects with CD4 counts of ≤ 100 cells/μl. Inclusion criteria included ART-naïve, HIV-seropositive adults and adolescents above 15 years of age, and written, informed consent was obtained from every participant before the enrollment. To eliminate selection bias, history and clinical examination were completed and documented only after the recruitment. A thorough history and detailed clinical examination was done for all recruited subjects, and medical records were accessed for data collection.
Baseline absolute CD4 count, WHO clinical staging for HIV/AIDS, and demographic variables were recorded. Patients who had past or ongoing history of cryptococcal disease or meningitis were excluded.
The subjects were screened for CrAg by LA using CALAS kits (Meridian Bioscience Inc., OH, USA) and lateral flow assay (LFA), namely IMMY dipsticks (Immuno Mycologics, Norman, OK, USA). LFA is an immuno-chromatographic sandwich dipstick assay. Both kits are capable of detecting the capsular polysaccharide of Cryptococcus neoformans in serum. A comparative parallel testing was done using both kits for each sample.
Modern cryptococcal antigen tests are extremely sensitive and specific [16, 17]. CrAg is detectable around 21 days prior to symptoms of CM and it has been observed that in 11% of cases, CrAg is tested positive at 100 days prior to actual clinical symptoms [18]. This window period is important for primary treatment to reduce mortality associated with this meningitis [19]. In our study, the results of LFA were interpreted according to manufacturer instructions and recorded on a standard laboratory test result form with a scale ranging from negative to 4+ positive. LFA is an overly sensitive, specific, and a point-of-care rapid diagnostic test, which needs no infrastructure or training [20, 21]. Testing for LFA was performed with IMMY LFA kits according to the manufacturer instruction. One line was interpreted as negative and two lines were considered as positive. To enumerate the predictors of CrAg positivity, a nested case-control model was used. In this, the controls were randomly selected from CrAg-negative subjects in a 4 : 1 ratio against CrAg-positive cases. At this point, the CrAg-positive patients were labelled as “cases” and CrAg-negative as “controls”.

Statistical analysis

The study results were collected manually, and all variables entered into a standardized database. CrAg prevalence was stratified by sex, age, race, education, WHO clinical staging, coexistence of other infections, and demographic parameters. Mean, median, and standard deviation were calculated for both the cases and controls. The association between CrAg positivity and these variables were analyzed using SPSS software version 20.

Results

A total of 390 eligible subjects were screened. Of them, 49 patients (12.56%) were tested positive for CrAg by both the test kits. No discordance was encountered with the two different test kit (LA and LFA) results. In other words, all those who tested CrAg-positive with LFA were also positive with LA kit.
Within a range of 1-100, the median CD4 count was 42 cells/μl in CrAg-positive cases and 46 cells/μl in CrAg-nega¬tive controls. CrAg positivity was comparatively higher in the subgroup of CrAg-positive cases, with CD4 < 50 cells/μl (59.1%) as compared to the range of 50-100 cells/μl (40.8%).
Of all subjects tested, 81.3% were males, and approximately 92% of CrAg-positive patients were male. The median age for the positive subjects was 38 years (Table 1). Hete¬rosexual transmission was the commonest mode for HIV infection. The majority (42.8%) of CrAg-positive cases were from rural area and married (71.4%), with an education up to secondary level (69.4%). Initial clinical examination and staging revealed that more than 80% of those who were later detected as CrAg-positive were of WHO HIV clinical stage 3 or 4.
The presence of only fever could not be correlated with CM, but the triad symptoms of fever, headache, and vomiting had a strong association with CrAg positivity.
Tuberculosis and oro-esophageal candidiasis were the commonest opportunistic infections. In CrAg positive patients, oral candidiasis was noted in 21 (42.8%) and esophageal candidiasis was documented in 5 cases (10.2%). Active TB was more prevalent among CrAg-negative patients (44.4%), as compared to CrAg-positive subjects (32.6%) (Table 1).
Following the WHO December 2011 guidelines, all 38 consented CrAg-positive patients were treated with an induction therapy of intravenous amphotericin B for 2 weeks with high-dose of oral fluconazole, followed by oral fluconazole in consolidation phase for 8 weeks (if CM symptoms were present) or pre-emptively with only oral fluconazole (if CM symptoms were not evident). Not all of 11 CrAg-positive cases who had declined the empirical therapy were asymptomatic. Six presented a history of low-grade fever for more than 3 weeks, associated with headache, cough, and vomiting. Of these 11 positive patients declining therapy, 6 were diagnosed with TB meningitis and were started on anti-TB drugs as per national guidelines (Table 2). Among the rest five patients with CrAg positivity, three had a history of headache with convulsions and underwent an MRI with gadolinium contrast; they were diagnosed as toxoplasmosis of brain and positive anti-toxoplasma IgG. Among those who declined antifungal therapy, only 2 patients were truly asymptomatic, and they were reluctant to get admitted for the empirical antifungal treatment, as they thought they were apparently doing well. Though most, that is 75% of 49 positive cases were either 3+ or 2+ in LA test titre (Table 3) but according to the existing NACO guidelines for treatment of opportunistic infections, treatment is not offered to any asymptomatic cryptococcal-positive subjects.
Immediate ART initiation is not recommended for CrAg-positive HIV-seropositive patients as, according to WHO guidelines, there is a high-risk of mortality due to development of central nervous system (CNS) immune reconstruction inflammatory syndrome (IRIS). The median time to ART initiation from date of CrAg testing was 28 days (range, 14-42 days). ART was postponed by 2 weeks in 3 subjects who were CrAg-positive, relatively asymptomatic, and received oral fluconazole only. ART initiation was delayed by 3-6 weeks in CM-confirmed patients who received amphotericin B and high-dose of fluconazole. The compliance to amphotericin B and high-dose of fluconazole was 100%, and ART adherence was mostly above 95%. Following the induction and consolidation phase, the maintenance treatment with only oral fluconazole was advised until the CD4 count increased to level of above 200 cells/μl. Cerebrospinal fluid (CSF) evaluation was done in 22 of 49 CrAg-positive (44.8%) cases (Table 4). In the rest of patients, it was either not completed due to operational issues or to subjects’ refusal to perform the test.
All enrolled subjects were followed up for 12 months and the outcomes of CM mortality or relapse were recorded. Among the patients who were treated for cryptococcal infection, 8 (21%) subjects died but among the survivors, none had a relapse within 12 months of follow-up (Table 2).
Among the 11 odd subjects who declined empirical treatment, one week following ART initiation, two of them were hospital admitted with severe meningitis at 14 weeks and 21 weeks from date of CrAg testing.
We observed a 12.56% of prevalence of CrAg positivity among the ART-naïve, HIV-positive subjects with CD4 ≤ 100 cells/μl. The ART center had an average of 680 annual new ART initiators during the study period, of whom approxi¬mately 15% had CD4 count ≤ 100 cells/μl. In these 3 years of study period, average new ART initiations were recorded as 180,000 all over the country. If the prevalence data is extrapolated to estimate CrAg-positive subjects in ART-naïve PLHIV all over India, which would roughly be 3,391 subjects who need pre-emptive treatment to reduce emergence of meningitis, with its morbidity and mortality.

Discussion

For a long time, diagnosis of CM was cumbersome and dependent on direct visualization under the microscope by India ink (nigrosine) staining or culture confirmation on Saboraud dextrose agar media. Though, the culture technique is the gold standard, but the long time needed for its reporting made early diagnosis and treatment difficult. With the advent of new antigen tests like enzyme immunoassay (EIA), LA, and the most recent LFA, it is much easier to obtain a rapid diagnosis. In particular, LFA is an easy, point-of-care, and relatively cheap test, which is a very useful tool for diagnosis in a resource-limited setting.
As a part of national guidelines for integral screening for HIV care, CrAg screening and treatment is presently implemented in several countries, including South Africa, Rwanda, Zimbabwe, Uganda, Namibia, and Mozambique. In a recently published meta-analysis, Nathan et al. have supported current recommendations to screen all PLHIV who have a CD4 count ≤ 100 cells/µl for CrAg, and suggested that screening may be considered at CD4 cell count ≤ 200 cells/µl [22]. WHO of 2018 guidelines have recommended cryptococcal screening followed by pre-emptive antifungal treatment for all HIV-positive adults and adolescents who present CD4 count of less than 100 cells/µl as well as screening those with CD4 less than 200 cells/μl. In places where this testing is not available, fluconazole primary prophylaxis has been advised.
In India, as per NACO guidelines, pre-emptive antifungal treatment is not recommended. Also, the program does not support a routine primary prophylaxis for subjects with CD4 of less than 100 cells/μl. Hence presently, we are not able to estimate the benefits from preventive strategies, which is a debatable issue in a resource-limited country like India. This study showed a CrAg prevalence of 12.56% in de-identified serum samples. The prevalence of CrAg serum positivity in apparently symptomless subjects was 4.6% (18/390), which is closer to the global pooled prevalence of 6.4% observed in systematic review of 60 observational studies in subjects with CD4 < 100 cells/μl [22].
The main objective of this ‘reflex testing’ method study was to yield valuable information whether the implementation of the screen-and-treat program would be effective to reduce mortality and morbidity in our country as a part of the National AIDS Control Program. For this, an assessment of the current prevalence in India would certainly help to evaluate the need for any of such recommendations. Adaptation of the point-of-care and the screen-and-treat strategies would need several key infrastructural services but would definitely be helpful in reducing morbidity and mortality.
In comparison to CrAg screening, the cost of treatment of symptomatic CM is substantially greater, but the relative morbidity and mortality is also high. On an average, the cost of LFA testing is Rs 350 (INR) or $5 per person, and the cost of LA is Rs 300 (INR) or roughly $4.2 per person. Pre-emptive treatment of CrAg-positive patients with amphotericin B and fluconazole poses less financial burden, as these drugs are available free of cost in the majority of government hospitals in India with antiretroviral centers. Therefore, the test-and-treat costs are relatively meagre as compared to no routine screening, with the in-patient treatment costs, morbidity, and mortality associated with meningitis. Patients often present with too advanced diseases to be effectively treated, leading to high mortality. The efficacy of this screening also needs to be evaluated as well as the cost of this test and treatment, which is the target of our follow-up studies.
According to the findings in the present study, with a high prevalence of CrAg positivity of around 12.6% in ART-naïve PLHIV (4.6% of asymptomatic patients), routine screening and pre-emptive treatment should be considered as a part of the National Programme in India, which are consistent with the WHO guidelines. In ART-naïve subjects with CD4 ≤ 100 cells/μl, routine screening has a potential to prevent CM-related morbidity and mortality.

Acknowledgements

This work was supported by research grants from the National AIDS Control Organization (NACO) of India to the Centre of Excellence in HIV Care, School of Tropical Medicine, Kolkata.
Institutional and National AIDS Control Organization ethics committee approval was accordingly taken before the initiation of the study.

Conflict of interest

The authors declare no conflict of interest with respect to the research, authorship, and/or publication of this article.

References

1. Rajasingham R, Smith RM, Park BJ, et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis 2017; 17: 873-881.
2. HIV Sentinel Surveillance and HIV Estimation. NACO, 2006.
3. Kauffman L, Blumer S. Proceedings of the 4th International Conference on mycosis. Washington: Pan American Health Organisation and Science publication; 1978, 176-187.
4. Vidal JE, Penalva de Oliveira AC, Dauar RF, Boulware DR. Strategies to reduce mortality and morbidity due to AIDS-related cryptococcal meningitis in Latin America. Braz J Infect Dis 2013; 17: 353-362.
5. WHO. Rapid advice: Diagnosis, prevention and management of cryptococcal disease in HIV infected adults, adolescents and children. 2011
6. Cox GM, Perfect JR. Cryptococcus neoformans var. neoformans and gattii and Trichosporon species. In: Ajello, Land-May RJ (eds.). Topley and Wilson’s Microbiology and Microbial Infections. London: Arnold; 1999, 461-484.
7. Boulware DR, Meya DB, Muzoora C, et al.; COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014, 370: 2487-2498.
8. Lawn S, Harries A, Anglaret X, Myer L, Wood R. Early mortality among adults accessing antiretroviral treatment programs in sub-Saharan Africa. AIDS 2008; 22: 1897-1908.
9. Sawadogo S, Makumbi B, Purfield A, et al. Estimated prevalence of cryptococcus antigenemia (CrAg) among HIV-infected adults with advanced immunosuppression in Namibia justifies routine screening and preemptive treatment. PLoS One 2016; 11: e0161830.
10. Pongsai P, Atamasirikul K, Sungkanuparph S. The role of serum cryptococcal antigen screening for the early diagnosis of cryptococcosis in HIV-infected patients with different ranges of CD4 cell counts. J Infect 2010; 60: 474-477.
11. Micol R, Lortholary O, Sar B, et al. Prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in Cambodian HIV-infected patients. J Acquir Immune Defic Syndr 2007; 45: 555-559.
12. Kwan CK, Leelawiwat W, Intalapaporn P, et al. Utility of cryptococcal antigen screening and evolution of asymptomatic cryptococcal antigenemia among HIV-infected women starting antiretroviral therapy in Thailand. J Int Assoc Provid AIDS Care 2014; 13: 434-437.
13. Thakur R, Sarma S, Kushwaha S. Prevalence of HIV-associated cryptococcal meningitis and utility of microbiological determinants for its diagnosis in a tertiary care center. Indian J Pathol Microbiol 2008; 51: 212-214.
14. Anuradha S, Narayana A, Dewan R, Kaur R, Rajeshwari K. Asymptomatic cryptococcal antigenemia in people living with HIV (PLHIV) with severe immunosuppression: is routine CrAg screening indicated in India? J Assoc Phys India 2017; 65: 14-17.
15. WHO, March 2018; Guidelines for the Diagnosis, Prevention and Management of Cryptococcal disease in HIV infected adults, adolescents and children. India 2017; 65.
16. Tanner DC, Weinstein MP, Fedorciw B, Joho KL, Thorpe JJ, Reller L. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol 1994; 32: 1680-1684.
17. Temstet A, Roux P, Poirot JL, Ronin O, Dromer F. Evaluation of a monoclonal antibody-based latex agglutination test for the diagnosis of cryptococcosis: comparison with two tests using polyclonal antibodies. J Clin Microbiol 1992; 30: 2544-2550.
18. French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 2002; 16: 1031-1038.
19. McKenney J, Smith RM, Chiller TM, et al.; Centers for Disease Control and Prevention. Prevalence and correlates of cryptococcal antigen positivity among AIDS patients – United States, 1986-2012. MMWR Morb Mortal Wkly Rep 2014; 63: 585-587.
20. Lindsley MD, Mekha N, Baggett HC, et al. Evaluation of a newly developed lateral flow immunoassay for the diagnosis of cryptococcosis. Clin Infect Dis 2011; 53: 321-325.
21. Jarvis JN, Percival A, Bauman S, et al. Evaluation of a novel point of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis. Clin Infect Dis 2011; 53: 1019-1023.
22. Ford N, Shubber Z, Jarvis JN, et al. CD4 cell count threshold for cryptococcal antigen screening of HIV-infected individuals: a systematic review and meta-analysis. Clin Infect Dis 2018; 66 (Suppl 2): S152-159.
1. Rajasingham R, Smith RM, Park BJ, et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis 2017; 17: 873-881.
2. HIV Sentinel Surveillance and HIV Estimation. NACO, 2006.
3. Kauffman L, Blumer S. Proceedings of the 4th International Conference on mycosis. Washington: Pan American Health Organisation and Science publication; 1978, 176-187.
4. Vidal JE, Penalva de Oliveira AC, Dauar RF, Boulware DR. Strategies to reduce mortality and morbidity due to AIDS-related cryptococcal meningitis in Latin America. Braz J Infect Dis 2013; 17: 353-362.
5. WHO. Rapid advice: Diagnosis, prevention and management of cryptococcal disease in HIV infected adults, adolescents and children. 2011
6. Cox GM, Perfect JR. Cryptococcus neoformans var. neoformans and gattii and Trichosporon species. In: Ajello, Land-May RJ (eds.). Topley and Wilson’s Microbiology and Microbial Infections. London: Arnold; 1999, 461-484.
7. Boulware DR, Meya DB, Muzoora C, et al.; COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014, 370: 2487-2498.
8. Lawn S, Harries A, Anglaret X, Myer L, Wood R. Early mortality among adults accessing antiretroviral treatment programs in sub-Saharan Africa. AIDS 2008; 22: 1897-1908.
9. Sawadogo S, Makumbi B, Purfield A, et al. Estimated prevalence of cryptococcus antigenemia (CrAg) among HIV-infected adults with advanced immunosuppression in Namibia justifies routine screening and preemptive treatment. PLoS One 2016; 11: e0161830.
10. Pongsai P, Atamasirikul K, Sungkanuparph S. The role of serum cryptococcal antigen screening for the early diagnosis of cryptococcosis in HIV-infected patients with different ranges of CD4 cell counts. J Infect 2010; 60: 474-477.
11. Micol R, Lortholary O, Sar B, et al. Prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in Cambodian HIV-infected patients. J Acquir Immune Defic Syndr 2007; 45: 555-559.
12. Kwan CK, Leelawiwat W, Intalapaporn P, et al. Utility of cryptococcal antigen screening and evolution of asymptomatic cryptococcal antigenemia among HIV-infected women starting antiretroviral therapy in Thailand. J Int Assoc Provid AIDS Care 2014; 13: 434-437.
13. Thakur R, Sarma S, Kushwaha S. Prevalence of HIV-associated cryptococcal meningitis and utility of microbiological determinants for its diagnosis in a tertiary care center. Indian J Pathol Microbiol 2008; 51: 212-214.
14. Anuradha S, Narayana A, Dewan R, Kaur R, Rajeshwari K. Asymptomatic cryptococcal antigenemia in people living with HIV (PLHIV) with severe immunosuppression: is routine CrAg screening indicated in India? J Assoc Phys India 2017; 65: 14-17.
15. WHO, March 2018; Guidelines for the Diagnosis, Prevention and Management of Cryptococcal disease in HIV infected adults, adolescents and children. India 2017; 65.
16. Tanner DC, Weinstein MP, Fedorciw B, Joho KL, Thorpe JJ, Reller L. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol 1994; 32: 1680-1684.
17. Temstet A, Roux P, Poirot JL, Ronin O, Dromer F. Evaluation of a monoclonal antibody-based latex agglutination test for the diagnosis of cryptococcosis: comparison with two tests using polyclonal antibodies. J Clin Microbiol 1992; 30: 2544-2550.
18. French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 2002; 16: 1031-1038.
19. McKenney J, Smith RM, Chiller TM, et al.; Centers for Disease Control and Prevention. Prevalence and correlates of cryptococcal antigen positivity among AIDS patients – United States, 1986-2012. MMWR Morb Mortal Wkly Rep 2014; 63: 585-587.
20. Lindsley MD, Mekha N, Baggett HC, et al. Evaluation of a newly developed lateral flow immunoassay for the diagnosis of cryptococcosis. Clin Infect Dis 2011; 53: 321-325.
21. Jarvis JN, Percival A, Bauman S, et al. Evaluation of a novel point of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis. Clin Infect Dis 2011; 53: 1019-1023.
22. Ford N, Shubber Z, Jarvis JN, et al. CD4 cell count threshold for cryptococcal antigen screening of HIV-infected individuals: a systematic review and meta-analysis. Clin Infect Dis 2018; 66 (Suppl 2): S152-159.
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