Asymptomatic Cryptococcal Antigenemia Research Articles

Implications of Undiagnosed Subclinical Cryptococcal Meningitis in Clinically Asymptomatic Low-Titer Cryptococcal Antigenemia Among PLWH: More Questions to Answer.

Implications of Undiagnosed Subclinical Cryptococcal Meningitis in Clinically Asymptomatic Low-Titer Cryptococcal Antigenemia Among PLWH: More Questions to Answer.

Adjunctive Single-Dose Liposomal Amphotericin to Prevent Cryptococcal Meningitis in People With Human Immunodeficiency Virus (HIV)-Associated Cryptococcal Antigenemia and Low Plasma Cryptococcal Antigen (CrAg) Titers.

Cryptococcal meningitis is a leading cause of AIDS-related mortality. Cryptococcal antigen (CrAg) predicts the development of meningitis. Historically, despite standard- of-care fluconazole, 25%-30% of asymptomatic CrAg-positive persons develop breakthrough meningitis or death. We evaluated whether adding single high-dose liposomal amphotericin B to standard pre-emptive fluconazole therapy could improve meningitis-free survival. Participants with human immunodeficiency virus (HIV) and asymptomatic cryptococcal antigenemia in Uganda were randomized to liposomal amphotericin B (10 mg/kg once) with fluconazole or fluconazole alone through 24 weeks. We compared 24-week, meningitis-free survival time between treatment groups. After the second interim review, the Data Safety and Monitoring Board recommended no further enrollment of participants with low plasma CrAg lateral flow assay titers (≤1:80) due to futility. Herein, we present the results of participants with low plasma CrAg titers. 168 participants enrolled into the ACACIA trial had low plasma CrAg titers (≤1:80). During 24 weeks of follow-up, meningitis or death occurred in 14.5% (12/83) of participants randomized to liposomal amphotericin B with fluconazole versus 10.6% (9/85) assigned to fluconazole alone (hazard ratio, 1.42; 95% CI, .60-3.36; P = .431). Adverse events were more frequent in participants assigned to the intervention versus standard-of-care (28% vs 12%; P = .011). Among CrAg-positive persons with low titers (≤1:80), the addition of single-dose liposomal amphotericin B to fluconazole as pre-emptive therapy provided no additional clinical benefit. This trial provides supportive evidence that, in asymptomatic populations with low plasma CrAg titers, lumbar punctures are likely unnecessary as administration of meningitis treatment did not improve outcomes. Clinicaltrials.gov (NCT03945448).

Frequency of cryptococcal antigenemia in hiv treatment naïve patients with CD4 count below 200/ml

Background: Cryptococcosis is a dangerous opportunistic fungal infection that poses a significant threat to individuals with advanced HIV/AIDS and compromised cellular immunity. The objective was to determine the frequency of asymptomatic cryptococcal antigenemia in treatment naïve HIV patients. Material and Methods: This cross-sectional study was conducted at The Indus Hospital and Health Network, Karachi from July to December 2022. We included all consecutive HIV patients of age > 18 years, either gender, who were treatment naïve, with CD4 counts ≤200/μL, and did not have any symptoms of cryptococcal infection. Cryptococcal antigen (CrAg) was tested in blood based on the Direct Agglutination test. Results: A total of 100 HIV patients were enrolled. The mean age was 35.12 ± 10.93 years. The majority (78%) of the subjects were males, and 2/3rd were sexually active; exposure to birds was identified in 31% of patients. Most of the patients enrolled belonged to WHO HIV stage 1 (61%), followed by stage 4 (30%). The median CD4 count was 103.5 (IQR: 56.5 – 126.5) /μL. 48 patients had CD4 count between 101 to 200/μL, while 51 patients had CD4 count ≤100/μL. Only 2 patients were found to have CrAg positive making an overall prevalence of 2%. Both patients had a CD4 count ≤ 100/μL (n = 2/51, 3.9%). 30% of patients had other opportunistic co-infections (n = 30). Conclusion: The prevalence of asymptomatic cryptococcosis in the treatment naïve HIV is low in the Pakistani population. A routine CrAg screening can be individualized and avoided in selected patients with CD4 count >100/μL in a resource-limited country like Pakistan. Keywords: AIDS, HIV stages, Asymptomatic, Opportunistic infection.

High prevalence of central nervous system cryptococcosis using a fingerprick whole-blood lateral flow assay in individuals with neurological symptoms and advanced HIV disease in a Brazilian emergency department.

Timely diagnosis is key in managing central nervous system (CNS) cryptococcosis in people living with HIV/AIDS (PLWHA). There are few data on implementing fingerprick whole-blood cryptococcal antigen (CrAg) lateral flow assay (LFA) as the first test for diagnosing CNS cryptococcosis. We evaluated the prevalence of CNS cryptococcosis and cryptococcal antigenemia using fingerprick whole-blood in a referral emergency department (ED) in São Paulo, Brazil. This was a prospective cohort study of consecutive adult PLWHA with advanced HIV disease and neurological symptoms. Fingerprick whole-blood CrAg LFA was performed at bedside. Seventy-four individuals were enrolled (median age=40 years; males=62%). Prevalence of CNS cryptococcosis was 17.6% (13/74); 95% confidence interval (CI), 9.4-30.0%, and prevalence of positive fingerprick whole-blood CrAg LFA was 25.7% (19/74); 95% CI, 15.5-40.1%. Among the six (8.1%) patients with positive fingerprick whole-blood CrAg LFA and negative CSF CrAg LFA, four (5.4%) had isolated asymptomatic cryptococcal antigenemia, one (1.3%) had symptomatic cryptococcal antigenemia, and one (1.3%) had cryptococcemia. Prevalence of CNS cryptococcosis and cryptococcal antigenemia using fingerprick whole-blood CrAg LFA was high. Point-of-care testing was important for diagnosing CNS cryptococcosis in an ED from a middle-income country.

Hyponatremia as a Predictor of Cryptococcal Meningitis and Death Among Asymptomatic Persons With HIV and Cryptococcal Antigenemia.

Among persons with human immunodeficiency virus-associated cryptococcal meningitis serum hyponatremia is a risk factor for mortality; however, the role of hyponatremia in persons with asymptomatic cryptococcal antigenemia is unknown. We found that serum hyponatremia ≤130 mmol/L is an independent risk factor for progression to meningitis and death in asymptomatic persons with cryptococcal antigenemia.

A multicenter survey of asymptomatic cryptococcal antigenemia among patients with advanced HIV disease in Nigeria.

As of 2018, cryptococcal antigen (CrAg) screening in patients with advanced human immunodeficiency virus (HIV) disease (AHD) was not routinely implemented in Nigeria despite being recommended in the national HIV treatment guidelines. Our aim was to determine the prevalence and risk factors for asymptomatic cryptococcal antigenemia in adult people living with HIV (PLHIV) in Nigeria to advocate for the implementation of routine CrAg screening. A descriptive cross-sectional study and CrAg screening of consecutive adult PLHIV with CD4 counts ≤200 cells/μL was conducted from April 2018 to April 2019 at HIV clinics in eleven tertiary hospitals spread across Nigeria's six geopolitical regions. Prevalence of asymptomatic cryptococcal antigenemia was estimated by facility and geopolitical zone. Logistic regression was conducted to identify risk factors for cryptococcal antigenemia. In total, 1,114 patients with AHD were screened. The overall prevalence of asymptomatic cryptococcal antigenemia was 3.9% with wide variation across facilities (range: 0/75 [0%]- 15/122 [12.3%]) and geopolitical zones (range: 0/75 [0%]-19/279 [6.8%]). Prevalence of antigenemia was highest in the South-West (19/279 [6.8%]) and lowest in the North-East (0/75 [0%]). Prevalence was 5.2% (26/512) and 3.2% (18/561) in patients with CD4<100 and CD4 of 101-200, respectively. Of all patients with antigenemia, 50% were on antiretroviral therapy (ART) at the time of having a positive CrAg test. In adjusted analysis, cryptococcal antigenemia was significantly less in patients on ART and patients who had completed any formal education. The survey showed a high overall burden of cryptococcal antigenemia in Nigeria, with variable prevalence across geopolitical regions. We provided valuable evidence for implementing routine CrAg screening of AHD patients in Nigeria which has commenced in selected centres.

Association of Antibody Immunity With Cryptococcal Antigenemia and Mortality in a South African Cohort With Advanced Human Immunodeficiency Virus Disease.

Asymptomatic cryptococcal antigenemia (positive blood cryptococcal antigen [CrAg]) is associated with increased mortality in individuals with human immunodeficiency virus (HIV) even after adjusting for CD4 count and despite receiving antifungal treatment. The association of antibody immunity with mortality in adults with HIV with cryptococcal antigenemia is unknown. Cryptococcal capsular glucuronoxylomannan (GXM)- and naturally occurring β-glucans (laminarin, curdlan)-binding antibodies were measured in blood samples of 197 South Africans with HIV who underwent CrAg screening and were followed up to 6 months. Associations between antibody titers, CrAg status, and all-cause mortality were sought using logistic and Cox regression, respectively. Compared with CrAg-negative individuals (n = 130), CrAg-positive individuals (n = 67) had significantly higher IgG1 (median, 6672; interquartile range [IQR], 4696-10 414 vs 5343, 3808-7722 μg/mL; P = .007), IgG2 (1467, 813-2607 vs 1036, 519-2012 μg/mL; P = .01), and GXM-IgG (1:170, 61-412 vs 1:117, 47-176; P = .0009) and lower curdlan-IgG (1:47, 11-133 vs 1:93, 40-206; P = .01) titers. GXM-IgG was associated directly with cryptococcal antigenemia adjusted for CD4 count and antiretroviral therapy use (odds ratio, 1.64; 95% confidence interval [CI], 1.21 to 2.22). Among CrAg-positive individuals, GXM-IgG was inversely associated with mortality at 6 months adjusted for CD4 count and tuberculosis (hazard ratio, 0.50; 95% CI, .33 to .77). The inverse association of GXM-IgG with mortality in CrAg-positive individuals suggests that GXM-IgG titer may have prognostic value in those individuals. Prospective longitudinal studies to investigate this hypothesis and identify mechanisms by which antibody may protect against mortality are warranted.

Prior Pulmonary Tuberculosis Is a Risk Factor for Asymptomatic Cryptococcal Antigenemia in a Cohort of Adults With Advanced Human Immunodeficiency Virus Disease.

The greater mortality risk among people with advanced human immunodeficiency virus disease and cryptococcal antigenemia, despite treatment, indicates an increased susceptibility to other infections. We found that prior tuberculosis was an independent risk factor for cryptococcal antigenemia (adjusted odds ratio, 2.72; 95% confidence interval, 1.13–6.52; P = .03) among patients with CD4 counts <100 cells/µL.

Asymptomatic cryptococcal antigenemia in HIV-infected patients: a review of recent studies.

The prevalence of asymptomatic cryptococcal antigenemia (ACA) in human immunodeficiency virus (HIV) infected individuals has been observed to be elevated. The prevalence of ACA ranges from 1.3% to 13%, with different rates of prevalence in various regions of the world. We reviewed studies conducted internationally, and also referred to two established expert consensus guideline documents published in China, and we have concluded that Chinese HIV-infected patients should undergo cryptococcal antigen screening when CD4 T-cell counts fall below 200 cells/μL and that the recommended treatment regimen for these patients follow current World Health Organization guidelines, although it is likely that this recommendation may change in the future. Early screening and optimized preemptive treatment for ACA is likely to help decrease the incidence of cryptococcosis, and is lifesaving. Further studies are warranted to explore issues related to the optimal management of ACA.

Epidemiology of Cryptococcal antigenemia among HIV infected patients in South-western Nigeria

Background: Cryptococcosis is a life-threatening fungal infection that presents diversely with no specific pathognomonic features. Cryptococcal disease is one of the most important opportunistic infections, and a major contributor to early mortality in HIV infected subjects. Cryptococcal antigenemia occurs in Nigeria, but the magnitude of this disease remains unclear. This study was carried out to determine the prevalence of CrAg among HIV seropositive and seronegative individuals attending Adeoyo Maternity Teaching Hospital (AMTH), Yemetu, Ibadan. Methods and materials: This was a case-control study in which 114 cases and 228 controls were recruited. Cases were HIV seropositive individuals while controls were HIV seronegative individuals receiving care at AMTH. Adult male and female (age range: 18–65 years) who agree to participate in the study were recruited. Simple random sampling was used to select subjects. Semi-structured interviewer administered questionnaire was used to collect data from subjects and retrospective review of CD4 count records in HIV infected subjects. Five millilitres venous blood was collected from each participant. Serum Cryptococcal antigen testing was done using CrAg Lateral Flow Assay. Data was analyzed using descriptive statistics and bivariate analysis at 5% level of significance. Results: Mean age of cases was 41.2 ± 10.0 years and 85 (74.6%) were females while mean age of control subjects was 38.9 ± 13.7 years 156 (68.4%) were females. The cumulative prevalence of CrAg was 8.5%. However, the prevalence of CrAg among cases was 11.4% and 7.0% among controls. Age groups 41-50 years and 21-30 years were the most affected among cases and controls respectively. HIV positive subjects were about two times more likely to test positive for CrAg. Individuals with CD4 counts of ≤100cells/μl were 20 times more likely to have positive serum cryptococcal antigen than individuals with CD4 counts >100 cells/μl (OR: 20.3, 95%CI: 5.23-78.9). Conclusion: Cryptococcal antigen was present among both cases and controls; however, the prevalence was higher among cases. Since asymptomatic cryptococcal antigenemia predicts impending cryptococcal infection (pneumonia and meningitis) with probable mortality, screening for CrAg should be part of the routine tests amongst all confirmed HIV seropositive cases

A study for precision diagnosing and treatment strategies in difficult-to-treat AIDS cases and HIV-infected patients with highly fatal or highly disabling opportunistic infections: Study protocol for the optimal early intervention for cryptococcal antigenemia in HIV-infected patients.

Background:Asymptomatic cryptococcal antigenemia is a state of cryptococcal infection commonly seen in immunocompromised HIV-infected persons. Without early intervention, a proportion of HIV-infected persons with cryptococcal antigenemia may go on to develop cryptococcosis, especially cryptococcal meningitis, which is associated with high mortality. The benefits of antifungal intervention and optimal therapeutic intervention regimens for HIV-infected persons with cryptococcal antigenemia remain controversial. We therefore designed the present study in order to investigate the necessity of, and the optimal regimens for antifungal intervention in the clinical management of cryptococcal antigenemia in HIV-infected populations.Methods/Design:This study will be an open-labeled, multi-center, prospective, randomized controlled trial, and 450 eligible participants will be randomized into a control arm and 2 intervention arms at a 1:1:1 ratio, with 150 subjects in each arm. Participants in the control arm will not receive antifungal treatment during the study period. Participants in intervention arm 1 will receive oral fluconazole 800 mg/day for 2 weeks, followed by 400 mg/day for 8 weeks and 200 mg/day for 42 weeks, and participants in intervention arm 2 will receive oral fluconazole 400 mg/day for 52 weeks. The primary outcome is the incidence of CM among the 3 groups during the study period. The secondary outcomes include the differences in all-cause mortality, proportion of patients reverting to blood CrAg negativity, change of CrAg titers, and adverse events among the 3 groups during the follow-up period.Discussion:We envisage that the results of this study will reveal the necessity of, and the optimal therapeutic regimens for, antifungal intervention in clinical management of HIV-infected patients with cryptococcal antigenemia.Trial registration:The study was registered as one of the 12 clinical trials under a general project at the Chinese Clinical Trial Registry on February 1, 2019, and the registration number of the general project is ChiCTR1900021195.

Prevalence of Asymptomatic Cryptococcal Antigenemia and Association with Follow-up Risk of Cryptococcal Meningitis and Mortality among HIV Infected Patients in North West India: A Prospective Cohort Study.

Cryptococcal meningitis is an important cause of morbidity and mortality in HIV infected individuals. In the era of universal antiretroviral therapy, the incidence of immune reconstitution inflammatory syndrome (IRIS) related cryptococcal meningitis has increased. Detection of serum cryptococcal antigen in asymptomatic PLHIV (People Living With HIV) and preemptive treatment with fluconazole can decrease the burden of cryptococcal disease. We conducted this study to find the prevalence of asymptomatic cryptococcal antigenemia in India and its correlation with mortality in PLHIV. This was a prospective observational study. HIV infected ART naïve patients with age of ≥ 18 years who had CD4 counts ≤ 100 /μL were included and serum cryptococcal antigen test was done. These patients were followed for six months to look for the development of Cryptococcal meningitis and mortality. A total of 116 patients were analyzed. Asymptomatic cryptococcal antigenemia was detected in 5.17% of patients and is correlated with increased risk of cryptococcal meningitis and mortality on follow-up in PLHIV. Serum cryptococcal antigen positivity is correlated with an increased risk of Cryptococcal meningitis and mortality in PLHIV. We recommend the screening of asymptomatic PLHIV with CD4 ≤ 100/μL for serum cryptococcal antigen, so that pre-emptive treatment can be initiated to reduce morbidity and mortality.

Adjunctive sertraline for asymptomatic cryptococcal antigenemia: A randomized clinical trial.

Cryptococcal antigen (CrAg) screening in HIV-infected persons with CD4<100 cells/µl can reduce meningitis and death, yet preemptive fluconazole therapy fails in ∼25%. Sertraline has in vitro and in vivo activity against Cryptococcus and is synergistic with fluconazole in mice. We evaluated the efficacy and safety of sertraline in asymptomatic cryptococcal antigenemia. We conducted a randomized trial of asymptomatic CrAg-positive Ugandans from November 2017 to February 2018. All subjects received WHO standard therapy of fluconazole 800mg for 2 weeks, then 400mg for 10 weeks, then 200mg through 24 weeks. Participants were randomized to receive adjunctive sertraline or placebo, given in once-weekly escalating 100mg/day doses up to 400mg/day, which was then given for 8 weeks, then tapered. The primary endpoint was meningitis-free 6-month survival. The data and safety monitoring board halted the trial after 21 subjects were enrolled due to safety concerns. Meningitis-free 6-month survival occurred in 9 of 11 of placebo participants and 10 of 10 of sertraline participants. However, seven serious adverse events (SAEs) occurred (n=4 sertraline group; n=3 placebo group). Three SAEs in the sertraline group presented with psychosis and aggressive behavioral changes with one meeting Hunter's criteria for serotonin syndrome while receiving 200mg/day sertraline. Two transient psychoses were associated with antecedent fluconazole and sertraline interruption. The serotonin syndrome resolved within 1 day, but psychosis persisted for 4 months after sertraline discontinuation. Sertraline was associated with excess SAEs of psychosis. Due to early stopping, we were unable to determine any efficacy for cryptococcal antigenemia.

375. Cryptococcal Antigenemia in Advanced HIV Infection

BackgroundDiagnostic importance of asymptomatic cryptococcal antigenemia is being increasingly recognized in the last few years. Recently, WHO (World Health Organization) has recommended routine screening of CrAg (cryptococcal antigen) among PLHA with CD4 ≤100/mm3, albeit this procedure is not yet adopted by many developing countries including India.MethodsWe conducted a prospective observational study in a large tertiary care center of North India, upon ethical clearance. Latex agglutination test was performed to assess serum CrAg levels, followed by the lumbar puncture for detection of CrAg levels in the CSF. We analyzed the prevalence and treatment outcomes of cryptococcal antigenemia among PLHA with CD4 ≤ 100 cells/mm3. Detailed clinical examination was conducted, with follow-up of upto 3 months. Multivariate analysis was performed for the estimation of risk factors.ResultsThe mean age (years) and BMI (kg/m2) of all the participants were 41.4 ± 11.2 and 22.1 ± 2.6, respectively. Notably, the mean CD4 count (cu.mm) at the time of recruitment was 62.3 ± 20.5. Noteworthy, 62 (60.8%) of the patients were ART naïve. We found 9.8% (n = 10) of the patients were positive for serum CrAg, and only 2.9% (n = 3) had clinical features of meningitis and 6.8% (n = 7) were asymptomatic (subclinical) CrAg positive. Strikingly, 3.9% (n = 4) of the asymptomatic cryptococcal antigenemia patients were also positive for CrAg in CSF, with 1.9% (n = 2) were only serum CrAg positive, and 1 patient was lost to follow-up (Graph 1). Multivariate analysis revealed that patients with long duration of HIV (P = 0.04), headache symptoms (P = 0.004) and possessing features of meningismus (P value=0.08) are more likely to be CrAg positive. Conversely, patients on fluconazole were protective against cryptococcal antigenemia (P = 0.1) as shown in Table 1. Overall mortality observed was 11.3% among advanced HIV patients. Moreover, mortality in CrAg-positive patients was 33.3% in comparison to CrAg-negative patients who had 9% (P = 0.06) in 3-months follow-up.ConclusionCryptococcal antigenemia is common (9.8%) among patients with CD4 count ≤100/mm3 in India. Screening for CrAg should be made routine for PLHA with CD4 count ≤100/mm3 and if required preemptive treatment to be given in this regard. Disclosures All authors: No reported disclosures.

Epidemiology of Cryptococcal antigenemia among HIV infected patients in southwestern Nigeria

Cryptococcosis is a life-threatening fungal infection that presents diversely with no specific pathognomonic features. Cryptococcal disease is one of the most important opportunistic infections, and a significant contributor to early mortality in HIV infected subjects. Cryptococcal antigenemia occurs in Nigeria, but the magnitude of this disease remains unclear. This study was carried out to determine the prevalence of CrAg among HIV infected and HIV seronegative subjects and to assess the relationship between CD4 count and CrAg in HIV-positive subjects attending Adeoyo Maternity Teaching Hospital, Yemetu, Ibadan. In an hospital-based case-control study using simple random sampling, 114 HIV-seropositive individuals (cases) and 228 HIV-seropositive individuals (controls) were recruited. A semi-structured interviewer-administered questionnaire was used to collect data from subjects and retrospective review of CD4 count records in HIV infected subjects. Five millilitres of venous blood were collected from each participant. Serum Cryptococcal antigen testing was done using CrAg Lateral Flow Assay. Data was analyzed using descriptive statistics and bivariate analysis at 5% level of significance. Mean age of cases was 41.2 ± 10.0 years and 85 (74.6%) were females while mean age of controls was 38.9 ± 13.7 years and 156 (68.4%) were females. The prevalence of CrAg among cases was 11.4% and 7.0% among controls. Cases were about two times more likely to test positive for CrAg. However, the association was not statistically significant (OR: 1.71, 95%CI: 0.79 - 3.68). Individuals with CD4 counts of ≤100 cells/µl were 20 times more likely to have positive serum cryptococcal antigen than individuals with CD4 counts >100 cells/µl (OR: 20.3, 95%CI: 5.23-78.9). This study has demonstrated significant prevalence of Cryptococcal antigenemia among the study population; however, prevalence was higher among cases. Screening for CrAg should therefore be part of routine tests amongst all confirmed HIV seropositive cases, since asymptomatic cryptococcal antigenemia predicts impending cryptococcal infection with probable mortality.

Identification of Cryptococcus antigen in human immunodeficiency virus-positive Turkish patients by using the Dynamiker® lateral flow assay.

Cryptococcus neoformans causes life-threatening meningoencephalitis, particularly in human immunodeficiency virus (HIV)-positive individuals with low CD4 levels (<100 cells/μL). Although the burden of cryptococcal meningoencephalitis (CM) in Turkey is low (0.13 cases per 100000 persons), asymptomatic individuals at risk of cryptococcosis should be screened for antigenemia to prevent the disease and/or promote early CM diagnosis. A lateral flow assay (LFA) is used to detect Cryptococcus antigen (CrAg) in cerebrospinal fluid and serum. We determined Cryptococcus antigenemia prevalence in serum samples of HIV-positive and HIV-negative adult patients by using Dynamiker® CrAg-LFA, a point-of-care dipstick test. Patients' demographic data, CD4 count, HIV-RNA levels and anti-retroviral therapy status were recorded. CrAg was detected in 28 (11%) of 254 HIV-positive patients screened but not in 100 HIV-negative control individuals; a significant difference was observed in the CrAg-LFA positivity rate between HIV-positive and HIV-negative groups (x2 =11.970; P<.05). In CrAg-positive patients, the median CD4 level was 666cells/μL (115-1344cells/μL), with a median viral load of 23copies/mL (0-3.69×106 copies/mL). In HIV-positive CrAg-negative patients, the median CD4 level was 633cells/μL (31-2953cells/μL) and the median viral load was 12copies/mL (0-1.95×106 copies/mL; P>.05). Results indicate that HIV-positive patients with both low (<200cells/μL) and high (>200cells/μL) CD4 counts should be screened for asymptomatic cryptococcal antigenemia. HIV-associated asymptomatic cryptococcosis is not uncommon in Turkey, which warrants systematic screening. Updated strategies for CM prevention among HIV-positive patients should be used even in non-endemic countries.

Antibody Responses in HIV-Infected Patients With Advanced Immunosuppression and Asymptomatic Cryptococcal Antigenemia.

BackgroundThere are no host biomarkers of risk for HIV-associated cryptococcal meningitis (CM) except CD4+ T-cell deficiency. At present, serum cryptococcal antigen (CrAg) screening of those with CD4 <100 cells/µL is used to identify persons at risk for HIV-associated CM. We determined if plasma antibody profiles could discriminate CrAg+ from CrAg- patients.MethodsWe performed serological analyses of 237 HIV-infected asymptomatic Zimbabwean patients with CD4 <100 cells/µL; 125 CrAg- and CrAg+ but cerebrospinal fluid CrAg- by CrAg lateral flow assay. We measured plasma immunoglobulin M (IgM), immunoglobulin G (IgG) 1, and IgG2 concentrations by Luminex, and titers of Cryptococcus neoformans (Cn) glucuronoxylomannan (GXM) polysaccharide and naturally occurring Laminarin (natural Lam, a β-(1–3)-glucan linked polysaccharide)-binding IgM and IgG by enzyme-linked immunosorbent assay.ResultsGXM-IgG, -IgM, and -IgG2 levels were significantly higher in CrAg+ patients, whereas natural Lam-IgM and Lam-IgG were higher in CrAg- patients before and after adjustment for age, sex, and CD4 T-cell count, despite overlap of values. To address this variability and better discriminate the groups, we used Akaike Information Criteria to select variables that independently predicted CrAg+ status and included them in a receiver operating characteristic curve to predict CrAg status. By inclusion of CD4, GXM-IgG, GXM-IgM, and Lam-IgG, -IgG2, and -IgM, this model had an 80.4% probability (95% confidence interval, 0.75–0.86) of predicting CrAg+ status.ConclusionsStatistical models that include multiple serological variables may improve the identification of patients at risk for CM and inform new directions in research on the complex role that antibodies may play in resistance and susceptibility to CM.

Routine Cryptococcal Antigen Screening in Solid Organ Transplant Recipients: Is it Time to Save Lives and Money?

BackgroundCryptococcosis affects 1 in 270 solid organ transplant (SOT) recipients with high mortality. In HIV-infected patients, cryptococcal antigen (CRAG) is detectable in blood weeks to months before symptomatic infection and screening is recommended. No screening guidelines exist for SOT recipients.MethodsWe performed a cost-effectiveness analysis of CRAG screening amongst SOT recipients. We estimated costs of screening from Medicare reimbursement of $16.49 for CPT 87899 (Infectious agent antigen detection by immunoassay). We determined the number at risk from a large cohort of 42,634 adult SOT recipients from ICD-9 CM billing data from HCUP State Inpatient Databases of Florida (2006–2012), New York (2006–2011), and California (2004–2010). Cost of screening was compared with the cost of inpatient hospitalization.ResultsAmong 42,634 adult SOT recipients, 158 (0.37%) developed cryptococcosis at a median time of 15.5 months (range 0.1 -80) after transplant. During the 43 month follow-up, there was approximately 2.5% annual mortality. The estimated cost of hospital care for cryptococcal meningitis per person is approximately $70,000 in 2016 with current explosive cost of flucytosine at ~$29,000 per 2 weeks. Thus, the total estimated cost of hospital care in the cohort would be $11.0 million in 2016. In comparison, the cost to screen all 42,634 SOT recipients every three months would be $8.8 million. If CRAG screening could detect 75% of asymptomatic cryptococcal antigenemia prior to symptomatic disease requiring prolonged hospitalization, it would be approximately cost neutral ($11.5 million), and even cost saving if above 80% of hospitalizations are averted. Alternatively stated, for every one hospitalization avoided, 4245 persons could be CRAG screened for similar cost and likely better outcome.ConclusionAssuming the ability of routine screening to identify 75% of patients who would develop invasive cryptococcosis; CRAG screening every 3 months among SOT recipients likely would be at least cost neutral to the healthcare system. Antecedent duration of cryptococcal antigenemia prior to symptomatic disease in Non-HIV/SOT cohorts to inform optimal screening intervals should be further studied. Prospective SOT cohorts should validate this approach to save lives in a cost-effective manner.Disclosures All authors: No reported disclosures.

Neurocognitive function in HIV-infected persons with asymptomatic cryptococcal antigenemia: a comparison of three prospective cohorts

BackgroundHIV-infected persons with detectable cryptococcal antigen (CrAg) in blood have increased morbidity and mortality compared with HIV-infected persons who are CrAg-negative. This study examined neurocognitive function among persons with asymptomatic cryptococcal antigenemia.MethodsParticipants from three prospective HIV cohorts underwent neurocognitive testing at the time of antiretroviral therapy (ART) initiation. Cohorts included persons with cryptococcal meningitis (N = 90), asymptomatic CrAg + (N = 87), and HIV-infected persons without central nervous system infection (N = 125). Z-scores for each neurocognitive test were calculated relative to an HIV-negative Ugandan population with a composite quantitative neurocognitive performance Z-score (QNPZ-8) created from eight tested domains. Neurocognitive function was measured pre-ART for all three cohorts and additionally after 4 weeks of ART (and 6 weeks of pre-emptive fluconazole) treatment among asymptomatic CrAg + participants.ResultsCryptococcal meningitis and asymptomatic CrAg + participants had lower median CD4 counts (17 and 26 cells/μL, respectively) than the HIV-infected control cohort (233 cells/μL) as well as lower Karnofsky performance status (60 and 70 vs. 90, respectively). The composite QNPZ-8 for asymptomatic CrAg + (−1.80 Z-score) fell between the cryptococcal meningitis cohort (−2.22 Z-score, P = 0.02) and HIV-infected controls (−1.36, P = 0.003). After four weeks of ART and six weeks of fluconazole, the asymptomatic CrAg + cohort neurocognitive performance improved (−1.0 Z-score, P < 0.001).ConclusionSignificant deficits in neurocognitive function were identified in asymptomatic CrAg + persons with advanced HIV/AIDS even without signs or sequelae of meningitis. Neurocognitive function in this group improves over time after initiation of pre-emptive fluconazole treatment and ART, but short term adherence support may be necessary.

Survival in HIV-infected Asymptomatic Cryptococcal Antigenemia without CSF Positivity Treated with Fluconazole Did Not Differ from Cryptococcal Antigen (CrAg) Negative with CD4 &lt;150.

Survival in HIV-infected Asymptomatic Cryptococcal Antigenemia without CSF Positivity Treated with Fluconazole Did Not Differ from Cryptococcal Antigen (CrAg) Negative with CD4 &lt;150.