Cryptococcal Antigen Research Articles

Prevalence of Cryptococcal Antigenemia and Associated Factors among HIV/AIDS Patients at Felege-Hiwot Referral Hospital, Bahir Dar, Northwest Ethiopia.

Background Cryptococcosis is the most common opportunistic fungal infection. High morbidity and mortality are frequently observed among hospitalized HIV/AIDS patients, particularly having CD4 count ≤100 cells/μl. Therefore, this study aimed to determine the prevalence of cryptococcal antigenemia and associated factors among HIV/AIDS patients. Methods A hospital-based cross-sectional study was conducted among 140 HIV/AIDS patients. A cryptococcal antigen test was performed for all patients along with medical chart and laboratory registration book review. Cryptococcal antigen was detected from serum by using Remel Cryptococcal Antigen Test Kit. Data related to possible associated factors were extracted from patients' charts and laboratory registration book. Data were coded, entered, and analyzed using SPSS version 20. Logistic regression analysis was done to see the association between dependent and independent variables. A P value <0.05 was considered statistically significant. Finally, data were presented in the form of texts, figures, and tables. Result Among 140 serum cryptococcal antigenemia-tested study subjects, 16 (11.43%) were positive for serum cryptococcal antigen. Of them, 43.8% (7/16) were pulmonary tuberculosis coinfected, 31.2% (5/16) were extrapulmonary tuberculosis positive, and 25% (4/16) had bacterial bloodstream infections. In addition, 68.7% (11/16) had CD4 count less than 100 cells/μl, 18.7% (3/16) had CD4 count 100–150 cells/μl, 50% (8/16) were antiretroviral therapy defaulters, and 31.3% (5/16) were naïve. In this study, the majority, 75% (12/16), of the serum cryptococcal antigen-positive subjects were clinical stage IV. Of the assessed associated factors, tuberculosis coinfection (AOR: 0.04; 95% CI [0.005–0.25]) and antiretroviral therapy status (AOR: 0.02; 95% CI [0.001–0.5]) were significantly associated factors enhancing serum cryptococcal antigenemia. Conclusion In this study, the high rate of cryptococcal antigenemia was observed among hospitalized HIV/AIDS patients, and it is alarming and highlights the need for improving CD4 status, expanding serum cryptococcal antigen screening, and strengthening regular cryptococcal antigenemia surveillance systems.

Comparison of a commercial real-time PCR panel to routine laboratory methods for the diagnosis of meningitis-encephalitis

Meningitis-encephalitis can range from a mild, self limiting illness to a life threatening disease. Rapid microbial diagnosis allows for early targeted management. This study aimed to compare the BioFire FilmArray Meningitis/Encephalitis multiplex PCR panel (ME panel) to traditional testing algorithms for accuracy and turnaround time in the diagnosis of meningitis-encephalitis. From April to November 2018, cerebrospinal fluid (CSF) samples meeting existing laboratory testing criteria for suspected community acquired meningitis-encephalitis were tested on the ME panel and by routine laboratory methods. The methods were compared for accuracy of diagnosis and turnaround time. Where an organism was not identified, the study investigators came to a consensus on whether an infective aetiology was likely based on CSF parameters, clinical features, management and final discharge diagnosis. A total of 147 CSF samples met criteria for testing. Results were concordant in 143 (97%) of cases, including 27 samples where the same organism was identified by both methods. Of the four discordant samples, three organisms identified by the ME panel alone were considered clinically insignificant. One sample, which was culture and antigen positive for Cryptococcus neoformans, was not detected on the ME panel. The ME panel and routine methods identified an organism in 55% and 58% of clinically compatible cases of infection, respectively. The median turnaround time for the ME panel was 2.9 hours, compared to 21.1 hours for routine testing. The ME panel showed high concordance with traditional testing, simplified laboratory workflow, and significantly reduced turnaround time. The failure of the ME panel to detect Cryptococcus spp. is concerning. When cryptococcal meningitis is suspected, we would recommend using culture and cryptococcal antigen testing as the investigations of choice. Despite the availability of molecular assays targeting the common causes of CNS infection, the diagnostic yield remains suboptimal.

A prospective multi-center clinical investigation of HIV-negative pulmonary cryptococcosis in China

Objective: To investigate the current status of the diagnosis and treatment of pulmonary cryptococcosis in respiratory medicine and improve the understanding of the clinical characteristics of HIV-negative pulmonary cryptococcosis in China. Methods: A prospective multi-center open cohort study was designed to screen for pulmonary cryptococcosis in the general wards and intensive care units of the Department of Respiratory Diseases in 22 hospitals. The HIV-negative patients with positive cryptococcal etiological diagnosis based on smear culture, antigen detection and histopathology were enrolled in the study. The clinical data of enrolled patients were collected and analyzed. Results: A total of 457 cases of pulmonary cryptococcosis were enrolled, among which 3.28% (15/457) were disseminated infections. The case fatality rate was 0.88% (4/457). The majority of the cases were diagnosed by histopathological examinations (74.40%, 340/457) and cryptococcus antigen detection (37.64%, 172/457). Patients with pulmonary cryptococcosis accounted for 2.04‰ (457/223 748) of the total hospitalized patients in the Department of Respiratory Diseases during the same period, and the ratio was the highest in south and east China. Meanwhile, 70.24% (321/457) of the patients had no underlying diseases, while 87.75% (401/457) were found to have immunocompetent status. Cough and expectoration were the most common clinical symptoms in patients with pulmonary cryptococcosis. However, 25.16% (115/457) of the patients had no clinical symptom or physical signs. In terms of imaging features on pulmonary CT, multiple pulmonary lesions were more common than isolated lesions, and there were more subpleural lesions than perihilar or medial lesions. Morphologically, most of the lesions were middle-sized nodules (1-5 cm) or small-sized nodules (3 mm to 1 cm). The sensitivity of serum cryptococcus antigen test was 71.99% (203/282). Moreover, antigen-positive patients differed from antigen-negative patients in terms of basic immune status, clinical symptoms, imaging features and infection types. Meanwhile, immunocompromised patients differed from immunocompetent patients in terms of clinical symptoms, physical signs, infection-related inflammation indicator levels, imaging features, serum cryptococcus antigen positive rate and prognosis. Conclusions: The majority of cases of HIV-negative pulmonary cryptococcosis in China had no underlying disease or immunocompromised status, and the overrall prognosis was favorable. However, early diagnosis of HIV-negative pulmonary cryptococcosis remains challenging due to the complicated manifestations of the disease.

The spectrum of pathogens in 187 cases of pulmonary fungal disease diagnosed by histopathology-a retrospective analysis

Objective: To investigate the spectrum of pathogens causing lung fungal disease diagnosed by histopathology through histochemical special staining, compared to the fungal culture results, and to further evaluate the diagnostic value of histochemical special staining in pulmonary fungal disease. Methods: We performed a retrospective analysis of 187 cases of pulmonary fungal disease diagnosed by histopathology in Peking Union Medical College Hospital from 2001 to 2015 (including 92 cases with pulmonary resection or open lung biopsy, 33 with percutaneous lung biopsy and 62 ones with fiberoptic bronchoscopic lung biopsy). All cases were treated with hexamine silver, PAS, mucus carmine and acid-fast staining in addition to conventional HE staining. The clinical records and the fungal culture results were reviewed. Results: There were 103 male and 84 female patients, aged from 12 to 70 years [average (48±14) years]. There were 85 cases(45.5%) of pulmonary aspergillosis(including 60 cases of invasive infection and 25 cases of aspergilloma), 51 cases(27.3%) of pulmonary cryptococosis, 6 cases (3.2%)of pulmonary mucormycosis, 3 cases(1.6%) of pulmonary histoplasmosis, 3 cases (1.6%)of pulmonary candidiasis, and 2 cases (1.1%) of pneumocystosis, while in the remaining 37 cases (19.8%) the pathogens could not be clearly classified by microscopy due to limited tissue or degeneration. Among the 88 patients with pulmonary fungal disease diagnosed by histopathology from 2011 to 2015, 35 ones (39.9%) were detected by fungal culture (including lung biopsy, intraoperative swab, blood, bronchoalveolar lavage fluid and sputum, etc.). The diagnostic results of 18 cases were completely consistent between histopathological examination and fungal culture (18/35, 51.4%), while 13 cases (13/35, 37.1%) were diagnosed by histopathology but no fungi were cultured, and in 3 cases (3/35,8.6%) the culture was positive for fungi which could not be classified clearly by histopathology. In another case the pathogen was found to be Cryptococcus histopathologically but the lavage culture grew"candida", but the patient's blood cryptococcal antigen was positive. Conclusions: Among patients with histopathological diagnosis of pulmonary fungal disease, pulmonary aspergillosis was the most common, followed by pulmonary cryptococcosis, pulmonary mucormycosis, pulmonary histoplasmosis, pulmonary candidiasis and pneumocystosis. A small number of cases could not be classified by histopathology through histochemical special staining. There was a high consistency in discovering fungal pathogens between pathological histochemical special staining and culture method, but 37% pulmonary fungal disease diagnosed by histopathology were culture negative. In practice, the role of histochemical special staining in diagnosing pulmonary fungal disease should be paid more attention.

Cryptococcal meningitis: a review for emergency clinicians.

Cryptococcal Meningitis (CM) remains a high-risk clinical condition, and many patients require emergency department (ED) management for complications and stabilization. This narrative review provides an evidence-based summary of the current data for the emergency medicine evaluation and management of CM. This review evaluates the diagnosis, management, and empiric treatment of suspected CM in the ED. CM can easily evade diagnosis with a subacute presentation, and should be considered in any patient with a headache, neurological deficit, or who is immunocompromised. As a definitive diagnosis of CM will not be made in the ED, management of a patient with suspected CM includes prompt diagnostic testing and initiation of empiric treatment. Multiple types of newer Cryptococcal antigen tests provide high sensitivity and specificity both in serum and cerebrospinal fluid (CSF). Patients should be treated empirically for bacterial, fungal, and viral meningitis, specifically with amphotericin B and flucytosine for presumed CM. Additionally, appropriate resuscitation and supportive care, including advanced airway management, management of increased intracranial pressure (ICP), antipyretics, intravenous fluids, and isolation, should be initiated. Antiretroviral therapy (ART) should not be initiated in the ED for those found or known to be HIV-positive for risk of immune reconstitution inflammatory syndrome (IRIS). CM remains a rare clinical presentation, but carries significant morbidity and mortality. Physicians must rapidly diagnose these patients while evaluating for other diseases and complications. Early consultation with an infectious disease specialist is imperative, as is initiating symptomatic care.

Cryptococcal Antigen Screening Among Antiretroviral Therapy-Experienced People With HIV With Viral Load Nonsuppression in Rural Uganda.

BackgroundThe World Health Organization recommends screening for the cryptococcal antigen (CrAg), a predictor of cryptococcal meningitis, among antiretroviral therapy (ART)–naïve people with HIV (PWH) with CD4 <100 cells/mm3. CrAg positivity among ART-experienced PWH with viral load (VL) nonsuppression is not well established, yet high VLs are associated with cryptococcal meningitis independent of CD4 count. We compared the frequency and positivity yield of CrAg screening among ART-experienced PWH with VL nonsuppression and ART-naïve PWH with CD4 <100 cells/mm3 attending rural public health facilities in Uganda.MethodsWe reviewed routinely generated programmatic reports on cryptococcal disease screening from 104 health facilities in 8 rural districts of Uganda from January 2018 to July 2019. A lateral flow assay (IMMY CrAg) was used to screen for cryptococcal disease. PWH were eligible for CrAg screening if they were ART-naïve with CD4 <100 cell/mm3 or ART-experienced with an HIV VL >1000 copies/mL after at least 6 months of ART. We used Pearson’s chi-square test to compare the frequency and yield of CrAg screening.ResultsOf 71 860 ART-experienced PWH, 7210 (10.0%) were eligible for CrAg screening. Among 15 417 ART-naïve PWH, 5719 (37.1%) had a CD4 count measurement, of whom 937 (16.4%) were eligible for CrAg screening. The frequency of CrAg screening was 11.5% (830/7210) among eligible ART-experienced PWH compared with 95.1% (891/937) of eligible ART- naïve PWH (P < .001). The CrAg positivity yield was 10.5% among eligible ART-experienced PWH compared with 13.8% among eligible ART-naïve PWH (P = .035). ConclusionsThe low frequency and high positivity yield of CrAg screening among ART-experienced PWH with VL nonsuppression suggest a need for VL- directed CrAg screening in this population. Studies are needed to evaluate the cost-effectiveness and impact of CrAg screening and fluconazole prophylaxis on the outcomes of ART-experienced PWH with VL nonsuppression.

Comparison of two commercial tests (Immy vs. Dynamiker) for cryptococcal capsular antigen.

INTRODUCTION Lateral flow assay is an advanced method useful in the early diagnosis of cryptococcal meningitis. We aimed to compare two commercial tests for cryptococcal capsular antigen in the sera of asymptomatic patients with human immunodeficiency virus in Barranquilla, Colombia. METHODS Thawed (n=162) previously collected serums (2016-2019) were processed using IMMY and Dynamiker cryptococcal antigen lateral flow assay. RESULTS Compared to IMMY’s results, Dynamiker’s sensitivity, specificity, positive predictive value, negative predictive value, and kappa index were 100%, 89.9%, 48.3%, 100.0%, and 0.61, respectively.CONCLUSIONS The Dynamiker test had excellent sensitivity, acceptable specificity, and a low detection threshold for cryptococcal antigen in the tested samples.

Cost-effectiveness analysis and budgetary impact of the Cryptococcal Antigen Lateral Flow Assay (CRAG-LFA) implementation for the screening and diagnosis of cryptococcosis in asymptomatic people living with HIV in Brazil.

ABSTRACTCryptococcal infection is a frequent cause of mortality in Brazilian HIV-infected patients. The present study aimed to evaluate the cost-effectiveness and budgetary impact of four cryptococcosis screening strategies in HIV-infected patients with CD4+ ≤ 200 cells/mm3, in Brazil. A Monte Carlo microsimulation was used to compare the following diagnostic tests: a systematic serum cryptococcal antigen (CRAG) screening with latex agglutination (CRAG-LA), a lateral flow immunochromatographic test (CRAG-LFA), India ink staining and no intervention. The rationale was that of the Unified Health System (SUS), and the time horizon was of one year for the intervention and of five years for the budgetary impact analysis (BIA). The effectiveness outcomes were years of life and years of life adjusted for quality (QALY). The cost-effectiveness analysis showed that the two cryptococcal antigen tests were cost-effective, presenting with superior results in comparison with India ink and no screening. CRAG-LFA, compared to CRAG-LA, has an incremental cost of US$0.25 and an incremental cost-effectiveness ratio of US$73.36 (considering the US dollar equal to 5 reais, the Brazilian current money). The probabilistic sensitivity analysis between CRAG-LFA and CRAG-LA, despite showing a high agreement between the two tests, indicated the superiority of CRAG-LFA. The BIA estimated that the incorporation of CRAG-LFA would have an additional cost of approximately U$S 10.4 million dollars in five years. These findings suggest that, for the group of studied patients, the adoption of CRAG-LFA and CRAG-LA are cost-effective, while the India ink test and no intervention are less effective strategies. The BIA showed that using the CRAG-LFA test for people living with HIV (PLHIV) with CD4+ ≤ 200 cells/mm3 could reduce costs for the Brazilian Unified Health System (SUS).

Evaluation of point of care serum cryptococcal antigen by lateral flow immunoassay for diagnosis of cryptococcosis and cryptococcal meningitis in HIV-positive patients.

Background:Cryptococcal meningitis (CM) is the initial acquired immunodeficiency syndrome (AIDS) defining illness in 2% of patients with CD4 levels <100/μL and a leading cause of mortality in AIDS in the developing world. It is the most common opportunistic infection of the central nervous system in AIDS in various Indian studies. Detection of serum cryptococcal antigen (SCRAG) is the most widely used diagnostic method for cryptococcosis. The presence of cerebrospinal fluid cryptococcal antigen (CSF CRAG) is diagnostic of CM. CRAG can be determined by latex agglutination (LAT), enzyme-linked immunosorbent assay and now, by lateral flow (LFA)immunoassay. LFA is a point of care test that rapidly detects CRAG.Aims and Objectives:This study compares LAT and LFA for the detection of serum CRAG and diagnosing CM.Materials and methods:Two hundred and ten patients of HIV/AIDS were submitted to SCRAG LFA by dipstick. A sample was also sent to laboratory for SCRAG by LAT. CSF examination was done for those who were positive for SCRAG LFA and those who had symptoms suggestive of meningitis. SCRAG by LFA was compared with SCRAG by LAT, CSF CRAG by LAT and LFA, CSF cryptococcal culture and CSF India ink examination for Cryptococcus.Results:Fifteen patients were found positive for SCRAG by LFA dipstick. All of them were also positive for SCRAG by LAT. Twelve of them had C. D4 count below below 100 cells/mm3. CSF CRAG was positive in all 12 SCRAG positive who were submitted to CSF examination.Conclusion:We found that serum detection of CRAG by LFA dipstick is as sensitive as CRAG detection in serum by LAT and CSF CRAG detection by LFA and LAT. It is thus a rapid test for diagnosing CM in HIV patients with low CD4 counts.

Associations of serum cryptococcal antigen with different of clinical characteristics: a comprehensive analysis of 378 pulmonary cryptococcosis patients.

Pulmonary cryptococcosis (PC) is an infection typically diagnosed in immunocompromised or immunocompetent patients, which can lead to severe disease if not treated appropriately. We aimed to determine the association between clinical manifestations, computed tomography (CT) findings, and host immune status with the serum cryptococcal antigen (CRAG) test results of PC patients. The clinical data of 378 PC patients over a 12-year period were retrospectively reviewed at Shanghai Pulmonary Hospital (Shanghai, China). Serum CRAG was detected by a latex agglutination (LA) test using CryptoTrol (Immuno-Mycologics Inc., Norman, OK, USA). Patients were categorized according to their serum LA results, and their clinical characteristics were analyzed: 244 of 378 patients showed positive serum LA results and 134 had negative results. Immunocompromised hosts (ICH) were more likely to present positive LA results. The ICH group had higher titers of LA test than the non-immunocompromised host (NICH) group. Patients with negative LA results often had no symptoms and their CT findings presented a solitary nodule or mass, while LA-positive patients had variable symptoms such as cough, expectoration, fever, etc. A large diversity of CT manifestations were observed in the LA-positive patients, such as multiple nodules, patchy shadows, interstitial infiltrates, and diffuse granular shadows. Patients with a solitary nodule or mass had lower titers than did the patients with other manifestations. The clinical characteristics of LA-positive patients were different from those of LA-negative patients. Serum CRAG test results were found to be associated with the clinical manifestations, CT findings, and host immune status of PC patients.

Point of care tests for invasive fungal infections: a blueprint for increasing availability in Africa.

Invasive fungal infections (IFIs) such as cryptococcosis, disseminated histoplasmosis, and chronic pulmonary aspergillosis are significant causes of morbidity and mortality in Africa. Lack of laboratory infrastructure and laboratory personnel trained in diagnostic mycology hamper prompt detection and management of IFIs on the continent. Point-of-care tests (POCT) obviate the need for complex infrastructure, skilled technicians, and stable electricity and have had major impacts on the diagnosis of bacterial, viral, and parasitic infections in low- and middle-income countries. Over the last 10 years, POCTs for IFIs have become increasingly available and they have the potential to revolutionize the management of these infections if scaled up in Africa. At the beginning of 2021, the World Health Organization (WHO) Essential Diagnostic List (EDL) included a cryptococcal antigen test for the diagnosis of cryptococcosis, Histoplasma antigen test for the diagnosis of disseminated histoplasmosis, and Aspergillus-specific test for the diagnosis of chronic pulmonary aspergillosis. All of these are available in formats that may be used as POCTs and it is hoped that this will improve the diagnosis of these life-threatening IFIs, especially in low- and middle-income countries. This perspective review discusses commercially available POCTs and outlines strategies of a blueprint to achieve their roll-out in Africa. The strategies include raising awareness, conducting research that uncovers the exact burden of IFIs, increasing advocacy, integrating diagnosis of IFIs into existing public health programs, adoption of the WHO EDL at country levels, and improving logistics and supply chains.

Cryptococcosis complicating diabetes mellitus: a scoping review.

Background:A better understanding of the epidemiology of cryptococcal infection in HIV-negative individuals is an international research interest. Immune dysfunction in diabetes mellitus (DM) significantly increases the risk of acquiring and reactivation of infection due to Cryptococcus neoformans. Risk factors and outcomes of cryptococcosis in DM are not well documented.Objective:The objective of this study was to determine the clinical characteristics and outcomes of cryptococcal infections in persons living with DM.Methods:MEDLINE (via PubMed), EMBASE, and the Cochrane Library databases were searched in November 2020. The searches covered the period between 1980 and 2020.We included studies that reported confirmed cryptococcosis in patients with DM. Reference lists of included articles were also searched, and additional studies were included if appropriate. No language restriction was applied. Single case reports, case series and original articles were included whereas review articles were excluded.Results:A total of 28 studies (24 single case reports, 4 retrospectives) were included involving 47 unique patients from Asia (17 cases), North America (six cases), South America (three cases) and Africa (two cases). Men constituted 75% (n = 18) of the cases. Median age was 60.5 (range: 27–79) years. The majority of the patients had cryptococcal meningitis (68.1%, n = 32) followed by disseminated cryptococcosis (6.4%, n = 7), and others (isolated cutaneous disease one, peritonitis one, pleural one, thyroid one, adrenal one). Diagnosis was achieved through either culture and microscopy (38/47), cryptococcal antigen tests (9/47) or histopathology (9/47) singly or in a combination. All-cause mortality was 38.3% (n = 18). Among those with meningitis mortality was 36.2%.Conclusion:A wide spectrum of cryptococcal infections with varying severity occurs in DM. Mortality remains unacceptably high. There is a need for more studies to characterize better cryptococcal disease in DM.

Cryptococcal meningitis in a case of mixed connective tissue disorder: A rare case report

We report a case of cryptococcal meningitis in a 48-year-old woman with underlying mixed connective tissue disease. She presented with multiple joint pains and low-grade fever for 3 months, headache for 1 month and weakness of all four limbs for 15 days. The neck was stiff, and Kernig's sign was positive. The cerebrospinal fluid cryptococcal antigen test was positive. Autoimmune profile revealed positive antinuclear and U1 ribonucleoprotein antibodies. Magnetic resonance imaging of the brain showed T2/fluid-attenuated inversion recovery hyperintensity in the midbrain and upper pons. The patient gradually improved on antifungal therapy.

Lung Mass as a Presenting Sign of Disseminated Cryptococcus

Cryptococcosis is an invasive fungal disease that most commonly affects immunocompromised individuals, typically causing pulmonary and Central Nervous System (CNS) symptoms. The fungus that causes cryptococcosis, Cryptococcus, is globally disseminated and often transmitted through bird droppings. The two most frequent and pertinent species responsible for clinical infections in humans include Cryptococcus neoformans, which has been known to cause the majority of cryptococcosis globally until recently, during which Cryptococcus gattii has been identified and reported more frequently. A 54-year-old male with a history of renal transplant on chronic immunosuppressants and type 2 diabetes mellitus was found to have multiple lung masses within the right upper and right lower lobes. He had also been experiencing syncope and multiple falls with worsening headache, tinnitus, diplopia, and ongoing weight loss. The patient underwent a percutaneous biopsy of the lung mass in addition to a Lumbar Puncture (LP), which revealed a positive cryptococcus antigen confirmed to be C. gattii. The patient was started on amphotericin B and flucytosine to treat cryptococcal meningitis. Despite treatment, his condition continued to worsen, necessitating daily therapeutic LP and temporary placement of a lumbar drain. Once his symptoms were better managed, he was discharged from the hospital but has continued to have serial LPs outpatient while concurrently taking fluconazole to prevent reaccumulation of CSF and recurrence of symptoms. The purpose of this report is to describe the unique presentation of disseminated Cryptococcus gattii infection identified as a lung mass and subsequent management of cryptococcosis.

90. Incidence and Risk Factors for Inappropriate Use of Non-culture Based Fungal Assays: Implication for Diagnostic Stewardship

BackgroundCulture-based diagnostic tests are the gold standard for diagnosing invasive fungal diseases (IFDs). Because these tests have low sensitivity, non-culture-based fungal assays (NCBFAs) have been used increasingly to help diagnose IFDs. However, little is known about inappropriate use of NCBFAs. We aimed to investigate inappropriate use of NCBFAs in a tertiary academic hospital in Tokyo, Japan.MethodsThis retrospective cohort study included all patients who underwent testing with beta-D glucan (BDG) between January and March 2018, or galactomannan antigen (GMA) or cryptococcal antigen (CRAG) between January and June 2018. Patients who had received hematopoietic stem cell or solid organ transplantations were excluded. Appropriateness was assessed according to the previously published study. We compared patients with appropriate and inappropriate use of NCBFAs. Risk factors for inappropriate use were evaluated using multivariate logistic regression analysis.ResultsOf 1,140 patients (BDG, 1,009; GMA 273; CRAG, 310) who underwent tests, 470 patients (BDG, 394; GMA, 138; CRAG, 164) were included in this study. Four hundred thirty-eight patients (93.2%) were aged 18 or older. About 80% of NCBFAs (BDG, 334 patients [74.8%]; GMA, 117 patients [74.8%]; CRAG, 146 patients [89.0%]) were deemed inappropriate. The factors associated with inappropriate NCBFAs use included specialties of ordering physicians, risk factors for fungal infections, and recommendation from infectious disease physicians (Table). Sixty-four patients (13.6%) underwent three inappropriate NCBFAs simultaneously. Furthermore, during the study period, 408 patients (35.8%) with inappropriate NCBFAs underwent the same assays repeatedly during the study period; 643 times for BDG, 163 times for GMA, and 192 times for CRAG.The Factors Associated with Inappropriate Use of Non-Culture Based Fungal Assays ConclusionWe found a large proportion of NCBFAs were deemed inappropriate and it was mostly driven by ordering physicians who generally care for transplant patients. Because inappropriate use of NCBFAs could lead to additional inappropriate tests and treatment with substantial costs to patients and health systems, diagnostic stewardship targeting NCBFAs is urgently needed.Disclosures All Authors: No reported disclosures

776. The prevalence of HIV among hospitalized persons with acute febrile illness in rural Uganda, August 2019-June 2020

BackgroundIn Uganda, in the early PEPFAR era, HIV coinfections were responsible for most hospitalizations with febrile illness (as high as 85% in 2006). Currently, national guidelines recommend universal antiretroviral therapy ideally before the development of AIDS. We evaluated the prevalence of HIV among patients admitted to two regional referral hospitals with febrile illness in the era of ‘Treat All.’MethodsParticipants admitted to two regional referral hospitals in Uganda were enrolled at emergency departments or medical wards. Participants uniformly received blood cultures, malaria (rapid diagnostic test), and tuberculosis (Xpert MTB/RIF Ultra), hepatitis A IgM, hepatitis B sAg, and HIV fourth generation testing were performed. Among participants with HIV, cryptococcal antigen testing and urine lipoarabinomannan (LAM) were performed.ResultsFrom August 2019-June 2020, 95 participants (58% female) with an average age of 36.2 (SD 14.1) years, presented from 11 districts in Uganda. Participants presented at facilities 4.9 days (SD: 2.5) after onset of symptoms. Additionally, 16.1% of participants had a qSOFA (quick Sepsis Related Organ Failure Assessment) severity score of 2 or greater. By 28 days, 11.0% (n=7) died and 10.8% were lost to follow-up. On admission, 25.3% (n=24) of participants had a known history of HIV, the majority (87.5%) were on ART on hospital presentation. Of the 9.5% (n=9) who were newly diagnosed with HIV during the admission 6 were started on ART during hospitalization or within a month after hospitalization. Microbiologic and rapid diagnostic test results included positive results for tuberculosis (2.1%, 2/95 PCR; 3/16 urine LAM), malaria (29.5%, 28/95), cryptococcal antigen positive (12.5%; 2/15), hepatitis A (1.1%, 1/95), and hepatitis B (5.3%, 5/95). Blood cultures were positive in 11.1% of patients (10/90) with S. pneumoniae being most common isolate (N=4).ConclusionIn the universal ART era, the proportion of hospitalized febrile patients with HIV has decreased. Overall, 10% have newly diagnosed infection emphasizing the importance of continuing to test all hospitalized febrile patients. Diagnostic evaluations are needed to assess the burden of other causes of febrile illness in order to reprioritize potential differential diagnoses.Disclosures All Authors: No reported disclosures

1164. Epidemiology of Cryptococcal Infections in Non-HIV Patients: A 20-year Single Center Experience

Background Cryptococcus has a worldwide distribution, with C. neoformans and C. gattii being two of the most common species causing disease. Despite advances in therapy, disseminated infection often results in significant morbidity and mortality.MethodsWe conducted a single center retrospective cohort study over a twenty-year period spanning from January 2000 through May 2020 to determine epidemiology and outcomes of non-HIV-associated cryptococcosis at Northwestern Memorial Hospital. Cases were identified by positive culture data or positive cryptococcal antigen in the serum or cerebrospinal fluid (CSF). Epidemiology of risk factors, morbidity, and mortality was evaluated.Results81 cases were identified of which, 67 had Cryptococcus spp isolated from culture and the remaining patients diagnosed by cryptococcal antigen and/or histopathology. The cohort was primarily Caucasian (56.8%, n=46) and male gender (67.9%, n=55), with a median age of 59.5 (IQR: 52.75-66.25) years old. Common predisposing conditions were diabetes (37%, n=30), chronic kidney disease (34.6%, n=28), and liver disease (28.4%, n=23). Solid organ transplant recipients and use of immunosuppression accounted for, respectively, 32.1% (n=26) and 29.6% (n=24) of the cohort. Sites of infection include lung (65.4%. n=53), central nervous system (33.3%, n=27), blood (30.9%, n=25), peritoneum (6.2%, n=5), musculoskeletal (2.5%, n=2), and prostate (1.2%, n=1). Mean opening pressure on lumbar puncture was 25.3 mmHg (range: 9 -52 mmHg). In hospital mortality at time of diagnosis was 27.2% (n=22), and mortality at 12 months post diagnosis was 51.9% (n=42).ConclusionAt our center, those with cryptococcosis commonly had risk factors such as immunosuppression either secondary to solid organ transplant or otherwise. Morbidity and mortality remain high.Disclosures Sudhir Penugonda, MD, MPH, AbbVie, Inc. (Employee, Other Financial or Material Support, ownership and/or investment interests) Michael Angarone, DO, Abbvie (Other Financial or Material Support, Data Safety Monitoring Board)Allergan (Speaker’s Bureau)

113. Advanced HIV Disease Among Adults in the African Cohort Study (AFRICOS)

BackgroundIn the “test and treat” era, early ART may decrease the prevalence of advanced HIV disease (AHD), defined as having a CD4 cell count < 200 cells/µL or World Health Organization (WHO) clinical stage III or IV disease. We assessed trends in AHD and ART coverage and describe factors associated with AHD among adults living with HIV (LWH) across four countries before and during the “test and treat” era.MethodsThe African Cohort Study (AFRICOS) is a prospective cohort enrolling adults at risk for HIV or LWH from 12 facilities in Uganda, Kenya, Tanzania and Nigeria. Clinical history review and laboratory testing were performed at enrollment and every 6 months. Serum cryptococcal antigen screening (CrAg) was performed in a subset with CD4 < 200 at enrollment. Logistic regression was used to estimate odds ratios for factors associated with CD4 < 200.ResultsFrom January 2013–December 2019, 2934 adults LWH were enrolled (median age 38 years [interquartile range, 31–46 years], 41.5% men). Of 2903 with CD4 results at enrollment, 567 (19.5%) had CD4 < 200. Despite consistent increases in ART coverage since 2016, across all countries the prevalence of AHD did not decline below levels observed in 2013 until 2019. The prevalence of CD4 < 200 did not significantly decline from 11.9% (range 9.1–25.0%) in 2013 to 10.3% (range 0–16%) in 2019, p=0.7, while ART coverage increased from 74.7% (range 68.3–93.8%) in 2013 to 97.5% (range 86–100%) in 2019, p= < 0.01 (Figure 1). Factors associated with a higher risk of CD4 < 200 at enrollment were being enrolled in Tanzania, male sex, age >29 years, having a primary or some secondary education or above, and WHO stage II disease or higher. Factors associated with a lower risk of CD4 < 200 were >1 year since HIV diagnosis and being on ART for at least 6 months (Table 1). Among those with CD4 < 200 at enrollment, the most commonly reported comorbidities included HIV wasting syndrome (9.3%) and tuberculosis (TB) (2.3%); 19 (3.4%) of 564 adults screened were CrAg positive.Figure 1: Trends in Percentage of Participants with CD4 <200 and ART coverage at Study Enrollment by Country and Year Table 1: Factors associated with CD4 <200 cells/mm3 at Study Enrollment ConclusionDespite the scale-up of ART in the era of “test and treat”, AHD prevalence has only recently trended downward. Continued efforts towards early HIV diagnosis and timely ART initiation are needed to reduce the risk for CD4< 200. Strategies to increase TB screening, prophylaxis, and treatment are essential to reduce morbidity.Disclosures All Authors: No reported disclosures

Diagnostic Accuracy of the Biosynex CryptoPS Cryptococcal Antigen Semiquantitative Lateral Flow Assay in Patients with Advanced HIV Disease.

High cryptococcal antigen (CrAg) titers in blood are associated with subclinical meningitis and mortality in CrAg-positive individuals with advanced HIV disease (AHD). We evaluated a novel semiquantitative lateral flow assay (LFA), CryptoPS, that may be able to identify individuals with high CrAg titers in a cohort of AHD patients undergoing CrAg screening. In a prospective cohort of patients with AHD (CD4 cell count, ≤200/μl) receiving CD4 count testing, whole blood was tested for CrAg by CryptoPS and the IMMY LFA; the two assays were conducted by two different operators, each blind to the results of the other assay. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CryptoPS were assessed against the IMMY LFA as a reference. CryptoPS low-titer (T1 band) and high-titer (T2 band) results were compared with IMMY LFA titers obtained through serial dilution. A total of 916 specimens were tested. The sensitivity of the CryptoPS assay was 61.0% (25/41) (95% confidence interval [95% CI], 44.5 to 75.8%), its specificity was 96.6% (845/875) (95% CI, 95.1 to 97.7%), its PPV was 45.5% (95% CI, 32.0 to 59.4%), and its NPV was 98.1% (95% CI, 97.0 to 98.9%). All (16/16) CryptoPS false-negative results were obtained for samples with IMMY titers of ≤1:160. Of 29 patients (30 specimens) who tested positive by CryptoPS but negative by the IMMY LFA, none developed cryptococcal meningitis over 3 months of follow-up without fluconazole. Median CrAg titers were 1:20 (interquartile range [IQR], 0 to 1:160) in CryptoPS T1-positive samples and 1:2,560 (IQR, 1:1,280 to 1:10,240) in T2-positive samples. We conclude that the diagnostic accuracy of the CryptoPS assay was suboptimal in the context of CrAg screening, with poor sensitivity at low CrAg titers. However, the CryptoPS assay reliably detected individuals with high titers, which are associated with poor outcomes.

Benefits of enhanced infection prophylaxis at antiretroviral therapy initiation by cryptococcal antigen status.

To assess baseline prevalence of cryptococcal antigen (CrAg) positivity; and its contribution to reductions in all-cause mortality, deaths from cryptococcus and unknown causes, and new cryptococcal disease in the REALITY trial. Retrospective CrAg testing of baseline and week-4 plasma samples in all 1805 African adults/children with CD4+ cell count less than 100 cells/μl starting antiretroviral therapy who were randomized to receive 12-week enhanced-prophylaxis (fluconazole 100 mg/day, azithromycin, isoniazid, cotrimoxazole) vs. standard-prophylaxis (cotrimoxazole). Proportional hazards models were used to estimate the relative impact of enhanced-prophylaxis vs. standard-cotrimoxazole on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24 weeks, by baseline CrAg positivity. Excluding 24 (1.4%) participants with active/prior cryptococcal disease at enrolment (all treated for cryptococcal disease), 133/1781 (7.5%) participants were CrAg-positive. By 24 weeks, 105 standard-cotrimoxazole vs. 78 enhanced-prophylaxis participants died. Of nine standard-cotrimoxazole and three enhanced-prophylaxis cryptococcal deaths, seven and two, respectively, were CrAg-positive at baseline. Among deaths of unknown cause, only 1/46 standard-cotrimoxazole and 1/28 enhanced-prophylaxis were CrAg-positive at baseline. There was no evidence that relative reductions in new cryptococcal disease associated with enhanced-prophylaxis varied between baseline CrAg-positives [hazard-ratio = 0.36 (95% confidence interval 0.13-0.98), incidence 19.5 vs. 56.5/100 person-years] and CrAg-negatives [hazard-ratio = 0.33 (0.03-3.14), incidence 0.3 vs. 0.9/100 person-years; Pheterogeneity = 0.95]; nor for all deaths, cryptococcal deaths or unknown deaths (Pheterogeneity > 0.3). Relative reductions in cryptococcal disease/death did not depend on CrAg status. Deaths of unknown cause were unlikely to be cryptococcus-related; plausibly azithromycin contributed to their reduction. Findings support including 100 mg fluconazole in an enhanced-prophylaxis package at antiretroviral therapy initiation where CrAg screening is unavailable/impractical.