Cost-effectiveness of cryptococcal antigen screening at CD4 counts of 101–200 cells/µL in Botswana

Background: Cryptococcal antigen (CrAg) screening in individuals with advanced HIV reduces cryptococcal meningitis (CM) cases and deaths. The World Health Organization recently recommended increasing screening thresholds from CD4 ≤100 cells/µL to ≤200 cells/µL. CrAg screening at CD4 ≤100 cells/µL is cost-effective; however, the cost-effectiveness of screening patients with CD4 101–200 cells/µL requires evaluation. Methods: Using a decision analytic model with Botswana-specific cost and clinical estimates, we evaluated CrAg screening and treatment among individuals with CD4 counts of 101–200 cells/µL. We estimated the number of CM cases and deaths nationally and treatment costs without screening. For screening we modeled the number of CrAg tests performed, number of CrAg-positive patients identified, proportion started on pre-emptive fluconazole, CM cases and deaths. Screening and treatment costs were estimated and cost per death averted or disability-adjusted life year (DALY) saved compared with no screening. Results: Without screening, we estimated 142 CM cases and 85 deaths annually among individuals with CD4 101–200 cells/µL, with treatment costs of $368,982. With CrAg screening, an estimated 33,036 CrAg tests are performed, and 48 deaths avoided (1,017 DALYs saved). While CrAg screening costs an additional $155,601, overall treatment costs fall by $39,600 (preemptive and hospital-based CM treatment), yielding a net increase of $116,001. Compared to no screening, high coverage of CrAg screening and pre-emptive treatment for CrAg-positive individuals in this population avoids one death for $2440 and $114 per DALY saved. In sensitivity analyses assuming a higher proportion of antiretroviral therapy (ART)-naïve patients (75% versus 15%), cost per death averted was $1472; $69 per DALY saved. Conclusions: CrAg screening for individuals with CD4 101–200 cells/µL was estimated to have a modest impact, involve additional costs, and be less cost-effective than screening populations with CD4 counts ≤100 cells/µL. Additional CrAg screening costs must be considered against other health system priorities.

1376. Cryptococcal Infection Presenting Solely as a Pleural Effusion

Background Cryptococcal infections are frequently seen in immunosuppressed hosts. To date, few cases of cryptococcal infections presenting solely as pleural effusion have been described in liver transplant recipients. To our knowledge, this is the first case of cryptococcal pleuritis presenting with acute respiratory failure early post liver transplant. Methods 51- year old male with non- alcoholic cirrhosis complicated by chronic right hydrothorax underwent deceased donor liver transplantation with methylprednisolone induction. A week later, he developed acute respiratory failure requiring intubation. Pleural fluid was exudative with lymphocyte predominance; aerobic culture grew C. neoformans. Serum cryptococcal antigen was initially negative (prozone phenomenon was excluded) and subsequently turned positive titer 1:16. He was started on liposomal amphotericin and flucytosine, but developed acute kidney injury; induction therapy was changed to fluconazole with flucytosine for 2 weeks followed by fluconazole consolidation for 8 weeks. He remains on maintenance therapy. Donor serum cryptococcal antigen was negative, and recipients of other organs from the donor were clinically well. Results Pleural effusions are common in cirrhotic patients with ascites from hepatic hydrothorax. Although rare, Cryptococcal infection can manifest as isolated pleural effusion. Our patient was diagnosed with Cryptococcal empyema early post-transplant, though likely had subclinical or latent infection pre-transplant; evaluation for donor-derived infection was negative. Diagnosis of isolated pleural disease may be missed if only serum Cryptococcal antigen is tested, as antigen may not be detectable. Diagnosis is mainly established by pleural fluid culture and may be delayed, as pleural fluid is not routinely cultured when effusions are attributed to hepatic hydrothorax. Cryptococcal antigen in the pleural fluid may have a better diagnostic yield. Conclusion Cryptococcal infection should be considered in patients with cirrhosis and liver transplant recipients presenting with pleural effusion without any other abnormalities on chest imaging. Diagnosis may be missed if only serum cryptococcal antigen is used. Disclosures All Authors: No reported disclosures

Application and evaluation of nucleic acid sequence-based amplification, PCR and cryptococcal antigen test for diagnosis of cryptococcosis

Background Cryptococcosis is a major opportunistic invasive mycosis in immunocompromised patients, but it is also increasingly seen in immunocompetent patients. In the early stages of cryptococcosis, limitations of the detection method may hinder the diagnosis. A molecular diagnostic technique based on nucleic acid sequence-based amplification (NASBA) method was developed to fulfil the need for efficient diagnosis of cryptococcosis. Methods We compared the diagnostic performance of NASBA, PCR and cryptococcal antigen (CrAg) test (colloidal gold method) in clinical samples from 25 cryptococcosis patients (including 8 cryptococcal meningoencephalitis and 17 pulmonary cryptococcosis) who were categorized as proven cases (n = 10) and probable cases (n = 15) according to the revised EORTC/MSG definitions. 10 patients with non-Cryptococcus infection and 30 healthy individuals were categorized as control group. Results The lowest detection limit of NASBA was 10 CFU/mL, and RNA of non-target bacteria or fungi was not amplified. The sensitivity of NASBA, PCR and colloidal gold method was 92.00% (95% CI 72.50–98.60%), 64.00% (95% CI 42.62–81.29%), 100.00% (95% CI 83.42–100.00%), and the specificity was 95.00% (95% CI 81.79–99.13%), 80.00% (95% CI 63.86–90.39%) and 82.50% (95% CI 66.64–92.11%) respectively. The highest specificity (97.50%), accuracy (95.38%) and k value (0.90) were achieved when both NASBA and colloidal gold results were positive. Conclusions NASBA is a new alternative detection method for cryptococcosis which is both accurate and rapid without expensive equipment and specialised personnel. It may be used as a tool for confirming current infection as well as monitoring the effectiveness of antifungal treatment. The use of NASBA to detect Cryptococcus RNA in blood samples is of great significance for the diagnosis of pulmonary cryptococcosis. The combination of NASBA and colloidal gold can improve the diagnostic accuracy of cryptococcosis.

Cryptococcal antigen carriage among HIV infected children aged 6 months to 15 years at Laquintinie Hospital in Douala

Background Up to 15% of deaths of people living with HIV is attributable to meningeal cryptococcosis, with nearly 75% occuring in sub-Saharan Africa. Although rare in children, it is a major cause of morbidity and mortality in people living with HIV. A strong association between cryptococcal antigenemia and the development of meningeal cryptococcosis has been shown in adults. Thus, in 2018, the World Health Organization published an updated version of its guidelines for the diagnosis, prevention and management of cryptococcal infection in adults, adolescents and the HIV-infected child. Goal To determine the prevalence of cryptococcal antigenemia and to identify its determinants in children infected with HIV. Methods An analytical cross-sectional study was carried out at the approved treatment center of Laquintinie hospital in Douala over a period of 4 months. Children were recruited consecutively after informed parental consent. Cryptococcal antigenemia and CD4 assay were performed using a Cryptops® immunochromatographic rapid diagnostic test and flow cytometry, respectively. The data collected included the socio-demographic, clinical and paraclinical variables of the children, as well as their antecedents. Data analysis was performed using Epiinfo software version 3.1 and SPSS 21.0. The significance threshold was set at 5%. Results A total of 147 children were enrolled. The mean age was 9.8 ± 4.09 years. The majority were on antiretroviral therapy (142, 96.60%). Only 13 (8.80%) were in severe immunosuppression. No child showed signs of meningeal cryptococcosis. The prevalence of cryptococcal antigenemia was 6.12%. Severe immunosuppression [OR: 10.03 (1.52–65.91), p = 0.016] and contact with pigeons [OR: 9.76 (1.14–83.65), p = 0.037] were independent factors significantly associated with the carriage of the cryptococcal antigen. Conclusion We recommend screening for cryptococcal antigenemia and routine treatment with fluconazole of all HIV positive children with cryptococcal antigen whether symptomatic or not.

Evaluation of the Diagnostic Performance of a Semi-Quantitative Cryptococcal Antigen Point-of-Care Assay among HIV-infected Persons with Cryptococcal Meningitis

Introduction: A newly developed cryptococcal antigen (CrAg) semi-quantitative (SQ) lateral flow assay (LFA) provides a semi-quantitative result in a rapid, one-step test instead of performing serial dilutions to determine CrAg titer. Methodology: We prospectively compared the diagnostic performance of the CrAgSQ assay (IMMY) with the CrAg LFA (IMMY) on cerebrospinal fluid (CSF) samples collected from persons with HIV-associated meningitis. The CrAgSQ grades (1+ to 5+) were compared with CrAg LFA titers and quantitative CSF fungal cultures. Results: Among 87 participants screened for HIV-associated meningitis, 60 had cryptococcal meningitis (59 CrAg+ by LFA and 1 false negative due to prozone with CrAg LFA titer of 1:1,310,000 and culture positivity), and 27 had no cryptococcal meningitis by CrAg LFA or culture. The CrAgSQ on CSF had 100% (60/60) sensitivity and 100% specificity (27/27). CSF CrAg titers ranged from 1:5 to 1:42 million. CrAgSQ grade of 1+, 2+, 3+, 4+, and 5+ corresponded to median CrAg LFA titers of 1:<10, 1:60, 1:7,680, 1:81,920, and 1:1,474,000, respectively. CSF CrAgSQ 3+ or higher were always CSF culture positive. Mortality at 14 days for those with low CrAgSQ grade (1+ to 3+) was 5% (1/22) versus 21% (8/38) with high CrAgSQ grades (4+ to 5+) (P=.084). Conclusion: The CrAgSQ demonstrates excellent diagnostic performance, maintaining both the sensitivity and specificity of the CrAg LFA, and counters false negative prozone effects. The CrAgSQ assay reading is more complex but does provide useful clinical information about disease burden and probability of culture positivity in a single rapid diagnostic test.