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Copyright of Gaceta Médica de Caracas is the property of Academia Nacional de Medicina and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Atypical presentations of cryptococcal infection have been described as manifestations of immune reconstitution inflammatory syndrome (IRIS) in patients with human immunodeficiency virus (HIV) infection following the introduction of combination antiretroviral therapy (cART). We describe a patient presenting with cryptococcal bronchiolitis obliterans organizing pneumonia (BOOP) as a cryptococcal-IRIS (C-IRIS), eight weeks after cART initiation. To our knowledge, this is the first patient with HIV disease reported to have cryptococcal IRIS-related BOOP. [ABSTRACT FROM AUTHOR]

We describe the successful use of isavuconazole for treatment of an HIV-positive patient with cryptococcal meningitis following induction therapy with liposomal amphotericin B and flucytosine. Because the Cryptococcus neoformans isolate from cerebrospinal fluid had a borderline minimum inhibitory concentration of 8 mg/L, initial consolidation therapy was given with a daily dose of fluconazole 1200 mg based on area under the curve to minimum inhibitory concentration modelling data. Toxicity, and the radiological emergence of a cryptococcoma in the setting of immune reconstitution inflammatory syndrome, prompted a therapeutic switch to isavuconazole. Subsequent imaging after 19 weeks of isavuconazole shows a significant reduction in cryptococcoma size from 11 mm to complete resolution. The patient remains well after 210 days of therapy with a view to completion of treatment after 1 year. [ABSTRACT FROM AUTHOR]

Although the burden of histoplasmosis in patients with advanced HIV has been the focus of detailed estimations, knowledge about invasive fungal infections in patients living with HIV in an Amazonian context is somewhat scattered. Our goal was thus to adopt a broader view integrating all invasive fungal infections diagnosed over a decade in French Guiana. All patients hospitalized at Cayenne hospital from 1 January 2009 to 31 December 2018 with a proven diagnosis of invasive fungal infection were included (n = 227). Histoplasmosis was the most common (48.2%), followed by Cryptococcus infection (26.3%), and pneumocystosis (12.5%). For cryptococcal infection, there was a discordance between the actual diagnosis of cryptococcal meningitis n = (26) and the isolated presence of antigen in the serum (n = 46). Among the latter when the information was available (n = 34), 21(65.6%) were treated with antifungals but not coded as cryptococcocosis. Most fungal infections were simultaneous to the discovery of HIV (38%) and were the AIDS-defining event (66%). The proportion of major invasive fungal infections appeared to remain stable over the course of the study, with a clear predominance of documented H. capsulatum infections. Until now, the focus of attention has been histoplasmosis, but such attention should not overshadow other less-studied invasive fungal infections. [ABSTRACT FROM AUTHOR]

Copyright of Ciencia e Innovación en Salud is the property of Universidad Simon Bolivar (USB) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Cryptococcal meningitis, a leading opportunistic infection, causes significant morbidity and mortality in people with advanced human immunodeficiency virus (HIV). It accounts for an estimated 15% of acquired immune deficiency syndrome-related deaths globally. As recommended by the World Health Organization (WHO) 2018 guidelines, this invasive disease is preventable by routine cryptococcal antigen (CrAg) screening of all advanced HIV patients followed by pre-emptive antifungal therapy. An estimate of disease prevalence in antiretroviral treatment (ART)-naïve HIV-positive adult Indian population is essential to include this in routine screening strategy. We estimated CrAg prevalence as a guiding resource in a public health approach. Material and methods: The study design was longitudinal. ART naïve HIV-seropositive patients with CD4 count = 100 cells/µl, attending ART center at the School of Tropical Medicine, Kolkata, India were screened for CrAg using both latex agglutination and lateral flow assay kits. A total of 390 subjects were enrolled into the study, and evaluated for association of CrAg with age, sex, CD4, presence of opportunistic infections, WHO HIV staging, and clinical symptoms. Results: Of 390 subjects tested, the median CD4 count was 42 cells/µl in CrAg-positive and 46 in CrAg-negative patients. Median (IQR) age of all participants was 40 (range, 34-46) years. CrAg positivity was 12.56%, comparatively higher in those with CD4 = 50 cells/µl. Asymptomatic patients had CrAg positivity of 4.6%. Statistically significant association was noted with male sex (p = 0.03), triad symptoms of fever, headache, vomiting (p = 0.013), and altered mental status (p = 0.033). Conclusions: This study aims to estimate CrAg prevalence in India to justify the need for routine screening and pre-emptive treatment in advanced HIV infection. Incorporating this screening would definitely reduce the risk of cryptococcus meningitis-induced mortality and morbidity, as recommended by the WHO guidelines. [ABSTRACT FROM AUTHOR]

Cryptococcal meningitis persists as a significant source of morbidity and mortality in persons with HIV/AIDS, particularly in sub-Saharan Africa. Despite increasing access to antiretrovirals, persons presenting with advanced HIV disease remains common, and Cryptococcus remains the most frequent etiology of adult meningitis. We performed a literature review and herein present the most up-to-date information on the diagnosis and management of cryptococcosis. Recent advances have dramatically improved the accessibility of timely and affordable diagnostics. The optimal initial antifungal management has been newly updated after the completion of a landmark clinical trial. Beyond antifungals, the control of intracranial pressure and mitigation of toxicities remain hallmarks of effective treatment. Cryptococcal meningitis continues to present challenging complications and continued research is needed. [ABSTRACT FROM AUTHOR]

Cryptococcal meningitis remains a significant opportunistic infection among HIV-infected patients, contributing 15-20% of HIV-related mortality. A complication of initiating antiretroviral therapy (ART) following opportunistic infection is immune reconstitution inflammatory syndrome (IRIS). IRIS afflicts 10-30% of HIV-infected patients with cryptococcal meningitis (CM), but its immunopathogenesis is poorly understood. We compared circulating T cell memory subsets and cytokine responses among 17 HIV-infected Ugandans with CM: 11 with and 6 without CM-IRIS. At meningitis diagnosis, stimulation with cryptococcal capsule component, glucuronoxylomannan (GXM) elicited consistently lower frequencies of CD4+ and CD8+ T cell memory subsets expressing intracellular cytokines (IL-2, IFN-, and IL-17) among subjects who subsequently developed CM-IRIS. After ART initiation, T cells evolved to show a decreased CD8+ central memory phenotype. At the onset of CM-IRIS, stimulation more frequently generated polyfunctional IL-2+/IL-17+ CD4+ T cells in patients with CM-IRIS. Moreover, CD8+ central and effector memory T cells from CM-IRIS subjects also demonstrated more robust IL-2 responses to antigenic stimulation vs. controls. Thus, ART during CM elicits distinct differences in T cell cytokine production in response to cryptococcal antigens both prior to and during the development of IRIS, suggesting an immunologic foundation for the development of this morbid complication of CM infection. [ABSTRACT FROM AUTHOR]

Fungal infections are increasingly becoming common and yet often neglected in developing countries. Information on the burden of these infections is important for improved patient outcomes. The burden of serious fungal infections in Ghana is unknown. We aimed to estimate this burden. Using local, regional, or global data and estimates of population and at-risk groups, deterministic modelling was employed to estimate national incidence or prevalence. Our study revealed that about 4% of Ghanaians suffer from serious fungal infections yearly, with over 35,000 affected by life-threatening invasive fungal infections. Incidence of cryptococcal meningitis, Pneumocystis jirovecii pneumonia, and disseminated histoplasmosis cases in AIDS was estimated at 6275, 12,610 and 724, respectively. Oral and esophageal candidiasis collectively affect 27,100 Ghanaians and 42,653 adult asthmatics are estimated to have fungal asthma. We estimate a prevalence of 12,620 cases of chronic pulmonary aspergillosis (CPA and an incidence of 1254 cases of invasive aspergillosis (IA). Estimated cases of candidemia and candida peritonitis cases were 1446 and 217, respectively. The estimated prevalence of recurrent vulvovaginal candidiasis (RVVC) and tinea capitis was 442,621 and 598,840, respectively. Mucormycosis and fungal keratitis each may affect 58 and 810 Ghanaians. These data highlight the urgent need for intensified awareness to improve diagnosis and management. [ABSTRACT FROM AUTHOR]

This study characterized the genotype and phenotype of Cryptococcus gattii VGII isolates from Cucuta, an endemic region of cryptococcal disease in Colombia, and compared these traits with those from representative isolates from the Vancouver Island outbreak (VGIIa and VGIIb). Genetic diversity was assessed by multilocus sequence typing (MLST) analysis. Phenotypic characteristics, including growth capacity under different temperature and humidity conditions, macroscopic and microscopic morphology, phenotypic switching, mating type, and activity of extracellular enzymes were studied. Virulence was studied in vivo in a mouse model. MLST analysis showed that the isolates from Cucuta were highly clonal, with ST25 being the most common genotype. Phenotypically, isolates from Cucuta showed large cell and capsular sizes, and shared phenotypic traits and enzymatic activities among them. The mating type a prevailed among the isolates, which were fertile and of considerable virulence in the animal model. This study highlights the need for a continuous surveillance of C. gattii in Colombia, especially in endemic areas like Cucuta, where the highest number of cryptococcosis cases due to this species is reported. This will allow the early detection of potentially highly virulent strains that spread clonally, and can help prevent the occurrence of outbreaks in Colombia and elsewhere. [ABSTRACT FROM AUTHOR]

Abstract Fingolimod is an oral medication approved by the Food and Drug Administration in 2009 for the treatment of relapsing remitting multiple sclerosis (RRMS). Initial clinical trials did not show a significantly increased rate of serious infections with fingolimod therapy. However, a mildly increased risk of less serious infections, such as varicella zoster virus and herpes simplex virus, was reported. Recently, however, several instances of serious opportunistic infections have been reported. In the years following approval of fingolimod for use in multiple sclerosis (MS), seven cases of cryptococcal meningitis in patients undergoing treatment have been described in the literature. We present a 40-year old woman with RRMS on fingolimod therapy presenting with a rare case of cryptococcal meningitis exhibiting alterations of consciousness, which was initially diagnosed as an MS relapse. [ABSTRACT FROM AUTHOR]

Cryptococcus neoformans is a ubiquitous environmental yeast and a leading cause of invasive fungal infection in humans. The most recent estimate of global disease burden includes over 200,000 cases of cryptococcal meningitis each year. Cryptococcus neoformans expresses several virulence factors that may have originally evolved to protect against environmental threats, and human infection may be an unintended consequence of these acquired defenses. Traditionally, C. neoformans has been viewed as a purely opportunistic pathogen that targets severely immune compromised hosts; however, during the past decade the spectrum of susceptible individuals has grown considerably. In addition, the closely related strain Cryptococcus gattii has recently emerged in North America and preferentially targets individuals with intact immunity. In parallel to the changing epidemiology of cryptococcosis, an increasing role for host immunity in the pathogenesis of severe disease has been elucidated. Initially, the HIV/AIDS epidemic revealed the capacity of C. neoformans to cause host damage in the absence of adaptive immunity. Subsequently, the development and clinical implementation of highly active antiretroviral treatment (HAART) led to recognition of an immune reconstitution inflammatory syndrome (IRIS) in a subset of HIV+ individuals, demonstrating the pathological role of host immunity in disease. A post-infectious inflammatory syndrome (PIIRS) characterized by abnormal T cell-macrophage activation has also been documented in HIV-negative individuals following antifungal therapy. These novel clinical conditions illustrate the highly complex host-pathogen relationship that underlies severe cryptococcal disease and the intricate balance between tolerance and resistance that is necessary for effective resolution. In this article, we will review current knowledge of the interactions between cryptococci and mammalian hosts that result in a tolerant phenotype. Future investigations in this area have potential for translation into improved therapies for affected individuals. [ABSTRACT FROM AUTHOR]

Background: Cryptococcal meningitis accounts for 15% of AIDS-related mortality. Cryptococcal antigen (CrAg) is detected in blood weeks before onset of meningitis, and CrAg positivity is an independent predictor of meningitis and death. CrAg screening for patients with advanced HIV and preemptive treatment is recommended by the World Health Organization, though implementation remains limited. Our objective was to evaluate costs and mortality reduction (lives saved) from a national CrAg screening program across Uganda. Methods: We created a decision analytic model to evaluate CrAg screening. CrAg screening was considered for those with a CD4<100 cells/μL per national and international guidelines, and in the context of a national HIV test-and-treat program where CD4 testing was not available. Costs (2016 USD) were estimated for screening, preemptive therapy, hospitalization, and maintenance therapy. Parameter assumptions were based on large prospective CrAg screening studies in Uganda, and clinical trials from sub Saharan Africa. CrAg positive (CrAg+) persons could be: (a) asymptomatic and thus eligible for preemptive treatment with fluconazole; or (b) symptomatic with meningitis with hospitalization. Results: In the base case model for 1 million persons with a CD4 test annually, 128,000 with a CD4<100 cells/μL were screened, and 8,233 were asymptomatic CrAg+ and received preemptive therapy. Compared to no screening and treatment, CrAg screening and treatment in the base case cost $3,356,724 compared to doing nothing, and saved 7,320 lives, for a cost of $459 per life saved, with the $3.3 million in cost savings derived from fewer patients developing fulminant meningitis. In the scenario of a national HIV test-and-treat program, of 1 million HIV-infected persons, 800,000 persons were screened, of whom 640,000 returned to clinic, and 8,233 were incident CrAg positive (CrAg prevalence 1.4%). The total cost of a CrAg screening and treatment program was $4.16 million dollars, with 2,180 known deaths. Conversely, without CrAg screening, the cost of treating meningitis was $3.09 million dollars with 3,806 deaths. Thus, despite the very low CrAg prevalence of 1.4% in the general HIV-infected population, and inadequate retention-in-care, CrAg screening averted 43% of deaths from cryptococcal meningitis at a cost of $662 per death averted. Conclusion: CrAg screening and treatment programs are cost-saving and lifesaving, assuming preemptive treatment is 77% effective in preventing death, and could be adopted and implemented by ministries of health to reduce mortality in those with advanced HIV disease. Even within HIV test-and-treat programs where CD4 testing is not performed, and CrAg prevalence is only 1.4%, CrAg screening is cost-effective. [ABSTRACT FROM AUTHOR]

Abstract A rare case of 70-year-old woman with adult T-cell leukemia/lymphoma who developed multifocal choroiditis from a dissemination of Cryptococcus neoformans is reported. Ophthalmologic examination revealed multiple yellowish choroidal lesions in the posterior pole of both eyes. Sequential optical coherence tomographic images disclosed the involvement of the choroid and the consecutive changes in its architecture during the course of treatment. The recognition of these ocular manifestations may be important for the rapid diagnosis of C. nerformans -disseminated diseases. Rapid diagnosis and prompt therapy with intravitreal injection as well as systemic fosfluconazole and liposomal amphotericin B led to clinical improvement of intraocular cryptococcosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to compare the quantities of oral Candida albicans in patients with primary and secondary Sjögren's syndrome before and after the use of orally administered pilocarpine hydrochloride for 1 year. METHOD AND MATERIALS: Twelve female subjects with primary (n = 4) and secondary (n = 8) Sjögren's syndrome (mean age ± SEM = 56.7 ± 5.7 years) were enrolled in the study, after meeting rigid enrollment criteria. Oropharyngeal collection of samples and culturing was performed on each subject. Cultures specific for Candida albicans were plated into a culture media tube using the Oricult kit and also by serial dilutions and plating by a streptomycin-vancomycin technique. Cultures were incubated for 48 hours at 37°C. The subjects used 5 mg of pilocarpine hydrochloride, administered orally three times daily, for 1 year, after which both of the Candida cultures were repeated. None of the subjects used antifungal medications, none smoked, and all were dentate. RESULTS: There was a significant difference in the prevalence of Candida after the use of pilocarpine hydrochloride for both groups. At the start of the study, 75% of all subjects were positive for Candida. Following the use of pilocarpine, 25% had positive cultures. There was also a decrease in the prevalence of clinical manifestations of infection from 75% of subjects to 25%. There was a significant decrease in the numbers of Candida cultured following the use of pilocarpine. CONCLUSION: Long-term administration of pilocarpine hydrochloride resulted in a significant reduction in Candida albicans colonization in patients with primary or secondary Sjögren's syndrome. [ABSTRACT FROM AUTHOR]

There are two forms of cryptococcal meningitis immune reconstitution inflammatory syndrome (CM-IRIS): paradoxical CM-IRIS and unmasking CM-IRIS. It is important to distinguish paradoxical CM-IRIS and CM relapse because mortality of CM-IRIS is higher than that of CM without IRIS, and paradoxical CM-IRIS and CM relapse requires different treatment. We report a case of paradoxical CM-IRIS that well matches the clinical findings with MR findings during three years follow-up of a HIV infected patient and new MRI finding is also introduced to help distinguish them. [ABSTRACT FROM AUTHOR]

Background: Clinicians may fail to make an early diagnosis of pulmonary cryptococcosis (PC) without HIV infection. Serum cryptococcal capsular polysaccharide antigen (CrAg) test, histopathology and culture of lung tissue play different roles in diagnosis of PC. Objective: To investigate the performance of serum CrAg test, histopathology and culture of the lung tissue in diagnosis of PC without HIV infection. Patients/methods: From January 2011 to September 2017, patients with proven PC were recruited from a teaching hospital in southern China. Those patients with HIV infection, PC confirmed by surgery or PC with probable or possible diagnosis were excluded from the study. Latex agglutination test and CrAg lateral flow assay were used for detection of serum CrAg. Lung biopsy and needle aspiration were performed under computed tomography guidance. Results: Eighty-nine patients with proven PC including 41 male (46.1%) and 48 female (53.9%) were enrolled. Fifty-one (57.3%) patients had underlying disease. Positive CrAg test was found in 83 (93.3%) cases. Among six cases with negative CrAg test, PC was confirmed by histology in two cases and positive culture in four cases. The histopathological results of 77 (86.5%) cases revealed cryptococcal granuloma and 12 cases showed chronic inflammation, which was confirmed by positive culture. Among 65 cases, the diseased tissue of 46 (70.8%) cases presented Cryptococcus neoformans in the culture and one case was diagnosed with lung cancer coexisting with PC. Conclusion: Our findings showed that serum CrAg test is rapid and sensitive in diagnosing PC, histology is important for confirming PC and culture plays a complementary role. Biopsied lung tissue should be submitted for cultures whenever feasible. [ABSTRACT FROM AUTHOR]

Fungal pathogens cause devastating infections in millions of individuals each year, representing a huge but underappreciated burden on human health. One of these, the opportunistic fungus Cryptococcus neoformans, kills hundreds of thousands of patients annually, disproportionately affecting people in resource-limited areas. This yeast is distinguished from other pathogenic fungi by a polysaccharide capsule that is displayed on the cell surface. The capsule consists of two complex polysaccharide polymers: a mannan substituted with xylose and glucuronic acid, and a galactan with galactomannan side chains that bear variable amounts of glucuronic acid and xylose. The cell wall, with which the capsule is associated, is a matrix of alpha and beta glucans, chitin, chitosan, and mannoproteins. In this review, we focus on synthesis of the wall and capsule, both of which are critical for the ability of this microbe to cause disease and are distinct from structures found in either model yeasts or the mammals afflicted by this infection. Significant research effort over the last few decades has been applied to defining the synthetic machinery of these two structures, including nucleotide sugar metabolism and transport, glycosyltransferase activities, polysaccharide export, and assembly and association of structural elements. Discoveries in this area have elucidated fundamental biology and may lead to novel targets for antifungal therapy. In this review, we summarize the progress made in this challenging and fascinating area, and outline future research questions. [ABSTRACT FROM AUTHOR]

Cryptococcal meningitis (CM) has emerged as the most common life-threatening fungal meningitis worldwide. Current management involves a sequential, longitudinal regimen of antifungals; despite a significant improvement in survival compared with uniform mortality without treatment, this drug paradigm has not led to a consistent cure. Neurapheresis therapy, extracorporeal filtration of yeasts from cerebrospinal fluid (CSF) in infected hosts, is presented here as a novel, one-time therapy for CM. In vitro filtration of CSF through this platform yielded a 5-log reduction in concentration of the yeast and a 1-log reduction in its polysaccharide antigen over 24 hours. Additionally, an analogous closed-loop system achieved 97% clearance of yeasts from the subarachnoid space in a rabbit model over 4-6 hours. This is the first publication demonstrating the direct ability to rapidly clear, both in vitro and in vivo, the otherwise slowly removed fungal pathogen that directly contributes to the morbidity and mortality seen in CM. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus- (HIV-) associated cryptococcal meningitis (CM) is one of the leading causes of deaths among patients living with HIV/AIDS in resource-limited settings, accounting for ~15-20% of AIDS-related deaths globally. We present our experience with a 25-year-old woman living with HIV who had a recurrent cryptococcal disease due to nonadherence to HIV care and lack of awareness of the benefits of adherence to secondary prophylaxis for CM. This case highlights the fact that fungal diseases awareness should not be limited only to the health professionals and public health practitioners, but also to patients, caregivers, and stakeholders. [ABSTRACT FROM AUTHOR]

In the present study 45 males and 45 females aged between 20-40 years infected with HIV were selected for study. The weight of male 30(66.6%) were between 39-45 kg, 15(33.3%) were between 46-55 kg and females 25(55.5%) were between 39-45.kg and 20(44.4%) were between 46-55 kg. The serum creatanine value was 0.80 to 0.90 in 25(55.5%) 0.90 to 1.00. 20(44.4%) in males. In females 28(62.2%) had 0.80 to 0.90, 17(37.7%) had 0.90 to 100 (µ mm) CD4 count was in 23 (51.1%) 0.83 to 100 and in 22(48.8%) 101 to 140 in males and in females 24(53.3%) had 83 to 100, 21(46.6%) had 101 to 140 CD4 count also noted. The clinical symptoms were headache 16(35.5%) in males 18(40%) in females. Fever in males 8(17.7%) in females 5(11.1%), mental confusion 5(11.1%) in males, 7(15.5%) in females, vomiting 9(20%) in males, 10(22.2%) in females, dizziness 4(8.8%) in males, 3(66%) in females, seizures. 3(6.6%) in males, 2(4.4%) in female. The associated diseases noted in HIV patients were TB 12(26.6%) in males, 14(31.1%) in females, candid 25(55.5%) in males, 20(44.4%) in females, diarrhea 6(13.3%) in males, 8(17.7%) in females, pneumonic 2(4.4%) in males, 3(6.6%) in females. The abnormalities of CSF was protein 30(66%) had 75-80 15(33.3% ) had 85-95 in males 29(64.4%) had 75-80, 16(35.5%) had 85-95 in females cells 3(71.1%) had 6-8, 13(28.8%) had 7-5 cells in males, 30,(66.6%) had 6-8 cells 15(33.3%) had 7-5 cells in females. Indian Ink staining 15(33.3%) had 20-26, 30(66.6%) had 25-19 in males cryptococcal antigen titre - 22(48.8%) had 5-10, 23(51) had 3-4 in males, 23(51%), 22(48.81%) had 3-4 cells in females. Culture base line was 39 (86.6%) had 27-29, 16(13.3%) had 20-26, in males, 40(88.8%) had 27.29, 5(11.1%) had 20-26 culture observed in female at base line. This study of CSF in HIV patients will be quite useful to pathologist and clinician to correlate the obtained values. [ABSTRACT FROM AUTHOR]

Purpose: To describe a case of bilateral endogenous cryptococcal endophthalmitis in an immunocompetent host and to review adjunctive ophthalmic imaging patterns and treatment.Methods: A retrospective case report.Results: A 45-year-old female patient with two distinct presentations of endogenous cryptococcal endophthalmitis in each eye presented initially with progressive blurred vision in the left eye, beginning more than 10 years after a craniotomy with ventriculoperitoneal shunt. Complete ophthalmic imaging was conducted and compared with data from previous literature. Administration of amphotericin-B had poorly responded; however, consolidation of fluconazole resulted in disease stabilization.Conclusions: Bilateral intraocular cryptococcal infection can present with two distinct patterns of posterior segment findings. A review of ophthalmic imaging patterns found consistency in some characteristics of A-scan ultrasonogram and fundus fluorescein angiogram. Besides conventional treatment, voriconazole is likely to play an important role in the management of cryptococcal endophthalmitis. [ABSTRACT FROM AUTHOR]

Introduction: Cryptococcal meningitis (CM) is an opportunistic fungal disease with a high mortality among HIV-positive patients with severe immunosuppression (CD4 count <100 cells/μl). Reflexed screening for cryptococcal antigen (CrAg) in remnant blood samples was initially piloted at selected CD4 testing laboratories of the National Health Laboratory Service (NHLS) prior to the implementation of a national screening programme using a lateral flow assay (LFA) (IMMY, Norman, OK, USA). The aim of this study was to assess CrAg positivity nationally, per province and district in combination with the percentage of CD4 samples tested with a CD4 count <100 cells/μl to identify areas with advanced HIV/CrAg disease burden. Methods: CrAg and CD4 laboratory result data were extracted from the NHLS corporate data warehouse. Monthly test volumes were used to assess CrAg test volumes and coverage, while bubble charts were used to display the relationship between CD4 <100 cells/μl, CrAg positivity and number of positive CrAg samples by district. ArcGIS software was used to spatially report CrAg positivity. Results: CrAg screening coverage was stable at around 96% after November 2016. Samples with a CD4 <100 cell/μl and CrAg positivity were also stable over the study period at 10% and ~5% respectively. The highest CrAg positivity was reported for the Kwa-Zulu Natal province (7.3%), which also had the lowest percentage of samples with a CD4 <100 cells/μl (7.2%). Uthungulu and Umkhanyakude districts had the highest CrAg positivity (9.3% and 8.9% respectively). Ethekwini and Johannesburg Metro districts contributed to 22% of the total number of CrAg-positive samples tested across South Africa for the period reported. Conclusion: Existing CD4 testing services were used to rapidly scale up CrAg reflex testing in South Africa. Districts with advanced HIV and CrAg disease burden were identified that need further investigation of patient management interventions. [ABSTRACT FROM AUTHOR]

Cryptococcosis remains a significant cause of morbidity and mortality world-wide, particularly among AIDS patients. Yet, to date, there are no licensed vaccines clinically available to treat or prevent cryptococcosis. In this review, we provide a rationale to support continued investment in Cryptococcus vaccine research, potential challenges that must be overcome along the way, and a literature review of the current progress underway towards developing a vaccine to prevent cryptococcosis. [ABSTRACT FROM AUTHOR]

Cryptococcus neoformans is a major opportunistic fungal pathogen. Like many dimorphic fungal pathogens, C. neoformans can undergo morphological transition from the yeast form to the hypha form, and its morphotype is tightly linked to its virulence. Although some genetic factors controlling morphogenesis have been identified, little is known about the epigenetic regulation in this process. Proteins with the plant homeodomain (PHD) finger, a structurally conserved domain in eukaryotes, were first identified in plants and are known to be involved in reading and effecting chromatin modification. Here, we investigated the role of the PHD finger family genes in Cryptococcus mating and yeast-hypha transition. We found 16 PHD finger domains distributed among 15 genes in the Cryptococcus genome, with two genes, ZNF1α and RUM1α, located in the mating type locus. We deleted these 15 PHD genes and examined the impact of their disruption on cryptococcal morphogenesis. The deletion of five PHD finger genes dramatically affected filamentation. The rum1αΔ and znf1αΔ mutants showed enhanced ability to initiate filamentation but impaired ability to maintain filamentous growth. The bye1Δ and the phd11Δ mutants exhibited enhanced filamentation, while the set302Δ mutants displayed reduced filamentation. Ectopic overexpression of these five genes in the corresponding null mutants partially or completely restored the defect in filamentation. Furthermore, we demonstrated that Phd11, a suppressor of filamentation, regulates the yeast-hypha transition through the known master regulator Znf2. The findings indicate the importance of epigenetic regulation in controlling dimorphic transition in C. neoformans [ABSTRACT FROM AUTHOR]

Background: Cryptococcal meningitis (CM) is a major cause of AIDS-related mortality in Africa. Detection of serum cryptococcal antigen (CrAg) predicts development of CM in antiretroviral (ART) naïve HIV-infected patients with severe immune depression. Systematic pre-ART CrAg screening and pre-emptive oral fluconazole is thus recommended. We postulated that a semi-quantitative CrAg screening approach could offer clinically relevant advantages. Methods: ART-naïve asymptomatic adult outpatients with <100 CD4 cells/mm³ presenting to the Yaoundé Central Hospital, Cameroon were screened for CrAg using the IMMY lateral flow assay (LFA). CrAg positive patients were consented for lumbar puncture and those with proven CM were treated with combination antifungal therapy and those with no CM were offered long-term oral fluconazole. Simultaneous onsite evaluation of CrAg detection using the new LFA Biosynex® CryptoPS test was performed and both tests were subsequently compared to a reference commercialized CrAg enzyme immunoassay (EIA). Results: Prevalence of serum CrAg in 186 screened adults was 7.5% (95%CI: 4.5-12.4). In CrAg positive patients, CM prevalence was 45.5% (95%CI: 18.3-75.7). IMMY and Biosynex CryptoPS strongly agreed in serum, plasma, and cerebrospinal fluid (Kappa: 98.4, 99.5, 100%, respectively, p < 0.001), and disagreed in urine (29 isolated positive CrAg in urine with IMMY, none with Biosynex and none of whom had proven CM). Compared to EIA, serum specificities were 96.6 and 98.3%, respectively. With Biosynex CryptoPS, all CM patients were serum T2-band positive compared to none without CM. Median EIA reciprocal titre was 160 (IQR: 13.5-718.8) and titres >160 strongly correlated with proven CM and Biosynex CryptoPS T2-band positivity. During the 1-year follow up period, there was no incident case of CM among screened patients and overall incidence of all-cause mortality was 31.5 per 100 person-years-at-risk (95%CI: 23.0-43.1). Conclusion: HIV-associated asymptomatic cryptococcosis is common in Cameroon, warranting integrated systematic screening and treatment. Biosynex CryptoPS holds promise, at point of care, for rapidly stratifying CrAg positive patients for optimal management including lumbar puncture and combination antifungal therapy when needed. Summary findings: Prevalence of CrAg and meningitis (CM) is high in Cameroon. Biosynex CryptoPS is comparable to IMMY LFA in CrAg screening. Its T2-band correlates with high antigen titres and CM, thus promising for identifying patients requiring effective induction therapy. Note: This study was presented in part at the 10th International Conference on Cryptococcus and Cryptococcosis (ICCC) in Iguazu in Brazil from 26 to 30th March 2017 and won a prize oral presentation. [ABSTRACT FROM AUTHOR]

Objective: Rare co-existance of disease or pathology Background: Cryptococcal meningitis in patients who are seronegative for the human immunodeficiency virus (HIV) and in patients who are splenectomized is rare. This report is an unusual case of meningeal and cerebellar infection due to the encapsulated yeast, Cryptococcus neoformans, which has not previously been associated with asplenia. Case Report: A 65-year-old HIV-negative patient with a previous splenectomy, presented with a three-day history of fever, vomiting, and headache. His symptoms progressed to generalized body aches, persistent fever, and neck stiffness. A lumbar puncture was performed, and cerebrospinal fluid (CSF) culture grew Cryptococcus neoformans. Treatment commenced with intravenous amphotericin B and flucytosine. The patient required serial lumbar punctures due to persistent raised intracranial pressure (ICP). Magnetic resonance imaging (MRI) of the brain showed acute meningitis and cerebellitis. Antimicrobial therapy and CSF drainage resulted in clinical improvement. Conclusions: The occurrence of meningeal and cerebellar cryptococcosis in an asplenic patient is rare, and few cases have been previously reported. This case report highlights the possibility of invasive cryptococcal infection, or cryptococcosis, in asplenic individuals in the absence of HIV infection. [ABSTRACT FROM AUTHOR]

Cryptococcus neoformans, an AIDS-defining opportunistic pathogen, is the leading cause of fungal meningitis worldwide and is responsible for hundreds of thousands of deaths annually. Cryptococcal glycans are required for fungal survival in the host and for pathogenesis. Most glycans are made in the secretory pathway, although the activated precursors for their synthesis, nucleotide sugars, are made primarily in the cytosol. Nucleotide sugar transporters are membrane proteins that solve this topological problem, by exchanging nucleotide sugars for the corresponding nucleoside phosphates. The major virulence factor of C. neoformans is an anti-phagocytic polysaccharide capsule that is displayed on the cell surface; capsule polysaccharides are also shed from the cell and impede the host immune response. Xylose, a neutral monosaccharide that is absent from model yeast, is a significant capsule component. Here we show that Uxt1 and Uxt2 are both transporters specific for the xylose donor, UDP-xylose, although they exhibit distinct subcellular localization, expression patterns, and kinetic parameters. Both proteins also transport the galactofuranose donor, UDP-galactofuranose. We further show that Uxt1 and Uxt2 are required for xylose incorporation into capsule and protein; they are also necessary for C. neoformans to cause disease in mice, although surprisingly not for fungal viability in the context of infection. These findings provide a starting point for deciphering the substrate specificity of an important class of transporters, elucidate a synthetic pathway that may be productively targeted for therapy, and contribute to our understanding of fundamental glycobiology. [ABSTRACT FROM AUTHOR]

Cutaneous Cryptococcus infection presents classically with granulomatous and gelatinous reactive patterns. Cases mimicking neutrophilic dermatoses have not been described. Conversely, neutrophilic dermatoses with degrading cells mimicking cryptococcal organisms have been reported. We report a case of cryptococcal cellulitis in an immunocompromised male with a robust neutrophilic infiltrate raising histologic consideration for a neutrophilic dermatosis. [ABSTRACT FROM AUTHOR]

Cutaneous infection with Cryptococcus neoformans is rare but can occur in the setting of rheumatoid arthritis due to immunosuppression. Risk factors include chronic kidney disease and use of tumor necrosis factor-alpha (TNF-α) inhibitor adalimumab. We report the fourth case of primary cutaneous cryptococcosis (PCC) in a diabetic female more than 60 years old living in rural Northwest Tennessee and taking adalimumab for rheumatoid arthritis. In a literature review of existing cases, this is the second case involving simultaneous chronic kidney disease and the first case in a diabetic and following extended TNF-α inhibitor immunosuppression monotherapy. Physicians should consider cryptococcal infection in a patient who develops cellulitis that is unresponsive to empiric therapy. In addition, it is imperative to monitor rheumatoid arthritis patients taking adalimumab closely and consider alternative agents in those with pre-existing immunosuppression or known risk factors for opportunistic infections as primary prevention. [ABSTRACT FROM AUTHOR]

Fas-associated death domain (FADD) and receptor interacting protein kinase 3 (RIPK3) are multifunctional regulators of cell death and immune response. Using a mouse model of cryptococcal infection, the roles of FADD and RIPK3 in anti-cryptococcal defense were investigated. Deletion of RIPK3 alone led to increased inflammatory cytokine production in the Cryptococcus neoformans-infected lungs, but in combination with FADD deletion, it led to a robust Th1-biased response with M1-biased macrophage activation. Rather than being protective, these responses led to paradoxical C. neoformans expansion and rapid clinical deterioration in Ripk3-/- and Ripk3-/-Fadd-/- mice. The increased mortality of Ripk3-/- and even more accelerated mortality in Ripk3-/-Fadd-/- mice was attributed to profound pulmonary damage due to neutrophil-dominant infiltration with prominent upregulation of pro-inflammatory cytokines. This phenomenon was partially associated with selective alterations in the apoptotic frequency of some leukocyte subsets, such as eosinophils and neutrophils, in infected Ripk3-/- Fadd-/- mice. In conclusion, our study shows that RIPK3 in concert with FADD serve as physiological "brakes," preventing the development of excessive inflammation and Th1 bias, which in turn contributes to pulmonary damage and defective fungal clearance. This novel link between the protective effect of FADD and RIPK3 in antifungal defense and sustenance of immune homeostasis may be important for the development of novel immunomodulatory therapies against invasive fungal infections. [ABSTRACT FROM AUTHOR]

Background: Honokiol, a compound extracted from Magnolia officinalis, has antifungal activities by inducing mitochondrial dysfunction and triggering apoptosis in Candida albicans. However, the mechanism of honokiol-induced oxidative stress is poorly understood. The present investigation was designed to determine the specific mitochondrial reactive oxygen species (ROS)-generation component. Methods/results: We found that honokiol induced mitochondrial ROS accumulation, mainly superoxide anions (O2•−) measured by fluorescent staining method. The mitochondrial respiratory chain complex I (C I) inhibitor rotenone completely blocked O2•− production and provided the protection from the killing action of honokiol. Moreover, respiratory activity and the C I enzyme activity was significantly reduced after honokiol treatment. The differential gene-expression profile also showed that genes involved in oxidoreductase activity, electron transport, and oxidative phosphorylation were upregulated. Conclusions: The present work shows that honokiol may bind to mitochondrial respiratory chain C I, leading to mitochondrial dysfunction, accompanied by increased cellular superoxide anion and oxidative stress. General significance: This work not only provides insights on the mechanism by which honokiol interferes with fungal cell, demonstrating previously unknown effects on mitochondrial physiology, but also raises a note of caution on the use of M. officinalis as a Chinese medicine due to the toxic for mitochondria and suggests the possibility of using honokiol as chemosensitizer. [ABSTRACT FROM AUTHOR]

The article discusses the 2016 Global Funding of Innovation for Neglected Diseases of Policy Cures which shows that cryptococcal meningitis ranks amongst the most poorly funded neglected diseases in the world. It mentions cryptococcal meningitis disproportionately affects people in low- and middle-income countries (LMICs). It notes that cryptococcal meningitis is a deadly invasive fungal infection that continues to affect hundreds of thousands of HIV patients with advanced disease.

Background: HIV-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.Methods: Participants 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.Results: Cryptococcal 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).Conclusion: Significant 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. [ABSTRACT FROM AUTHOR]

The article presents the study which examines the improvement in the specificity of urinary cryptococcal antigen testing through preheating of urine using the lateral flow assay. Details of the physical procedure to increase the specificity without compromising test sensitivity are offered. The inclusion of a prospective cohort study involving HIV-positive patients over 18 years of age with CD4 T cell counts is also discussed.

Cryptococcal meningitis (CM) is a life-threatening infection in HIV-infected patients, especially in resource-limited settings. Cytokine patterns in the cerebrospinal fluid (CSF) and sera may be related to clinical outcomes. This study aimed to evaluate cytokine patterns in the CSF and sera of HIV-infected patients with CM as well as the cytokines produced by peripheral blood mononuclear cells (PBMCs) when stimulated with LPS and cryptococcal GXM. CSF and serum levels of IL-2, IL-4, IL-8, IL-10, IL-12p40, IL-17A, INF-γ, TNF-α and CXCL-10 were measured in HIV-infected patients with CM (CM+ HIV+) at various time points. Cytokine levels were evaluated in the PBMC culture supernatants and the baseline values were compared to those of HIV-infected patients without CM (CM- HIV+) and healthy controls (CM- HIV-). CSF cytokine levels at admission (n = 33) were higher than levels among the 23 survivors at week 2, but statistically significant differences were observed for IL-8 and IFN-γ (p<0.05). CSF and serum levels of IL-4 and IL-17A at week 10 (n = 16) were lower than the baseline values, whereas IL-2 levels increased compared to week 2 (p<0.05). At week 16 (n = 15), CSF and serum levels of IL-4, IL-10 and CXCL-10 were decreased compared to the baseline values (p<0.05). PBMCs from CM- HIV- individuals produced significantly higher levels of proinflammatory cytokines in response to LPS, with the exception of TNF-α, which showed higher levels among CM+ HIV+ patients. The PBMCs of CM patients produced higher levels of IL-4 than those of CM- HIV- patients in response to GXM stimulation, and levels progressively decreased during treatment (p<0.05). Then, a progressive shift in cytokine expression favoring a Th1 pattern was observed, which is crucial in controlling cryptococcal infection. A better understanding of the protective immune response against Cryptococcus neoformans will help to develop novel strategies to improve the outcomes of patients with cryptococcosis. [ABSTRACT FROM AUTHOR]

Aim This retrospective cohort study analyzes the impact of possible risk factors on the survival chance of patients with cryptococcal meningitis. These factors include the patient's socio-economic background, age, gender, presenting symptoms, comorbidities, laboratory findings and, in particular, non-adherence versus adherence to therapy. Methods Data were collected from all adult patients admitted to Kalafong Hospital with laboratory confirmed cryptococcal meningitis over a period of 24 months. We analyzed the data by the presentation of descriptive summary statistics, logistic regression was used to assess factors which showed association between outcome of measure and factor. Furthermore, multivariable logistic regression analysis using all the factors that showed significant association in the cross tabulation was applied to determine which factors had an impact on the patients' mortality risk. Results A total of 87 patients were identified. All except one were HIV-positive, of which 55.2% were antiretroviral therapy naïve. A history of previous tuberculosis was given by 25 patients (28.7%) and 49 (56.3%) were on tuberculosis treatment at admission or started during their hospital stay. In-hospital mortality was 31%. Statistical analysis showed that antiretroviral therapy naïve patients had 9.9 (CI 95% 1.2-81.2, p < 0.0032) times greater odds of dying compared to those on antiretroviral therapy, with 17 from 48 patients (35.4%) dying compared with 1 out of 21 patients (4.8%) on treatment. Defaulters had 14.7 (CI 95% 1.6-131.6, p < 0.016) times greater odds of dying, with 9 from 18 patients dying (50%), compared to the non-defaulters. In addition, patients who presented with nausea and vomiting had a 6.3 (95% CI 1.7-23.1, p < 0.005) times greater odds of dying (18/47, 38.3%); this remained significant when adjusted for antiretroviral therapy naïve patients and defaulters. Conclusion Cryptococcal meningitis is still a common opportunistic infection in people living with HIV/AIDS resulting in hospitalization and a high mortality. Defaulting antiretroviral therapy and presentation with nausea and vomiting were associated with a significantly increased mortality risk. [ABSTRACT FROM AUTHOR]

Introduction: The first-line combination therapy for HIV-associated cryptococcal meningitis (CM), a condition of high mortality particularly in the first two weeks of treatment, consists of amphotericin B plus flucytosine (5-FC). Given that 5-FC remains unavailable in many countries, the knowledge of factors influencing mycological clearance in patients treated with second-line therapy could contribute to effective management. Objectives: To determine the factors associated with the clearance of Cryptococcus sp. from the cerebrospinal fluid by the second week of effective antifungal therapy (early mycological clearance) in HIV-associated CM. Methods: Retrospective cohort study based on secondary data corresponding to HIV-associated CM cases hospitalized at a tertiary health care center in Lima, Peru where 5-FC remains unavailable. Risk factors associated with early mycological clearance were analyzed by generalized linear regression models. Results: From January 2000 to December 2013, 234 individuals were discharged with a diagnosis of HIV-associated CM; in 215 we retrieved the required data. The inpatient mortality was 20% (43/215), 15 of them in the first two weeks of treatment. In the final model (157 cases), adjusted for age, previous episode of CM, ART use, type of antifungal treatment, raised intracranial pressure, frequency of therapeutic lumbar punctures, baseline fungal burden and treatment period, the factors associated with early mycological clearance were: Amphotericin B deoxycholate plus fluconazole as combination therapy (RR, 1.56; 95% CI, 1.14–2.14); severe baseline intracranial pressure (≥35 cm H2O) (RR, 0.57; 95% CI, 0.33–0.99); and baseline fungal burden over 4.5 log10 CFU/mL (RR, 0.61 95% CI: 0.39–0.95). Conclusions: In a setting without access to first-line therapy for CM, the combination therapy with amphotericin B deoxycholate plus fluconazole was positively associated with early mycological clearance, while high fungal burden and severe baseline intracranial pressure were negatively associated, and thus related to failure. [ABSTRACT FROM AUTHOR]

Background. An infectious disease (ID) consultation (consult) is often obtained to treat patients with cryptococcosis due to the complex nature of the disease, but has never been demonstrated to impact outcomes. Methods. We assembled a retrospective cohort of 147 consecutive cases of cryptococcosis in patients without human immunodeficiency virus. Patients who were diagnosed <24 hours prior to death were excluded. Survival analysis was performed with Cox regression with survival censored past 90 days. Results. The patients with an ID consult had a higher fungal burden but a lower 90-day mortality compared with patients without ID involvement (27% vs 45%; P < .001), with an adjusted hazard ratio of not receiving an ID consult of 4.2 (95% confidence interval, 2.2-7.6). The ID consult group was more likely to receive an indicated lumbar puncture (86% vs 32%; P < .001), and more likely to be treated with amphotericin B (AmB) (87% vs 24%; P < .001) and flucytosine (5-FC) (57% vs 16%; P < .001) when indicated. The duration of therapy with AmB (14 vs 11 days; P = .05) and 5-FC (7.5 days vs 1 day; P < .001) was longer in the ID consult group. Conclusions. Patients who received an ID consult were significantly less likely to die in the 90 days following diagnosis. Patients seen by ID physicians were more likely to be managed according to evidence-based practice established by randomized controlled trials and published in Infectious Diseases Society of America guidelines. These data suggest that an ID consult should be an integral part of clinical care of patients with cryptococcosis. [ABSTRACT FROM AUTHOR]

Altered mental status in cryptococcal meningitis results in poorer survival, but underlying causes of altered mentation are poorly understood. Within two clinical trials, we assessed risk factors for altered mental status (GCS score<15) considering baseline clinical characteristics, CSF cytokines/chemokines, and antiretroviral therapy. Among 326 enrolled participants, 97 (30%) had GCS<15 and these patients had lower median CSF cryptococcal antigen titers (P = .042) and CCL2 (P = .005) but higher opening pressures (320 vs. 269 mm H2O; P = .016), IL-10 (P = .044), and CCL3 (P = .008) compared with persons with GCS=15. Altered mental status may be associated with host immune response rather than Cryptococcus burden. [ABSTRACT FROM AUTHOR]

Introduction: Cryptococcal meningitis is a major cause of mortality and morbidity in countries with high HIV prevalence, primarily affecting patients whose CD4 are < = 100 cells/μl. Routine Cryptococcal Antigen (CrAg) screening is thus recommended in the South African HIV treatment guidelines for all patients with CD4 counts < = 100 cells/μl, followed by pre-emptive anti-fungal therapy where CrAg results are positive. A laboratory-based reflexed CrAg screening approach, using a Lateral Flow Assay (LFA) on remnant EDTA CD4 blood samples, was piloted at three CD4 laboratories. Objectives: This study aimed to assess the cost-per-result of laboratory-based reflexed CrAg screening at one pilot CD4 referral laboratory. Methods: CD4 test volumes from 2014 were extracted to estimate percentage of CD4 < = 100 cells/μl. Daily average volumes were derived, assuming 12 months per/year and 21.73 working days per/month. Costing analyses were undertaken using Microsoft Excel and Stata with a provider prospective. The cost-per-result was estimated using a bottom-up method, inclusive of test kits and consumables (reagents), laboratory equipment and technical effort costs. The ZAR/$ exchange of 14.696/$1 was used, where applicable. One-way sensitivity analyses on the cost-per-result were conducted for possible error rates (3%– 8%, reductions or increases in reagent costs as well as test volumes (ranging from -60% to +60%). Results: The pilot CD4 laboratory performed 267000 CD4 tests in 2014; ~ 9.3% (27500) reported CD4< = 100 cells/μl, equivalent to 106 CrAg tests performed daily. A batch of 30-tests could be performed in 1.6 hours, including preparation and analysis time. A cost-per-result of $4.28 was reported, with reagents contributing $3.11 (72.8%), while technical effort and laboratory equipment overheads contributed $1.17 (27.2%) and $0.03 (<1%) respectively. One-way sensitivity analyses including increasing or decreasing test volumes by 60% revealed a cost-per-result range of $3.84 to $6.03. Conclusion: A cost-per-result of $4.28 was established in a typical CD4 service laboratory to enable local budgetary cost projections and programmatic cost-effectiveness modelling. Varying reagent costs linked to currency exchange and varying test volumes in different levels of service can lead to varying cost-per-test and technical effort to manage workload, with an inverse relationship of higher costs expected at lower volumes of tests. [ABSTRACT FROM AUTHOR]

Biofilm formation on dental biomaterials is implicated in various oral health problems. Thus the challenge is to prevent the formation of this consortium of microorganisms using a safe approach such as antimicrobial and anti-adhesive natural products. Indeed, in the present study, the effects of an antifungal extract of Bacillus sp., isolated from plant rhizosphere, on the surface physicochemical properties of cobalt and nickel based dental alloys were studied using the contact angle measurements. Furthermore, in order to predict the adhesion of Candida albicans to the treated and untreated dental alloys, the total free energy of adhesion was calculated based on the extended Derjaguin-Landau-Verwey-Overbeek approach. Results showed hydrophobic and weak electron-donor and electron-acceptor characteristics of both untreated dental alloys. After treatment with the antifungal extract, the surface free energy of both dental alloys was influenced significantly, mostly for cobalt based alloy. In fact, treated cobalt based alloy became hydrophilic and predominantly electron donating. Those effects were time-dependent. Consequently, the total free energy of adhesion of C . albicans to this alloy became unfavorable after treatment with the investigated microbial extract. A linear relationship between the electron-donor property and the total free energy of adhesion has been found for both dental alloys. Also, a linear relationship has been found between this latter and the hydrophobicity for the cobalt based alloy. However, the exposure of nickel based alloy to the antifungal extract failed to produce the same effect. [ABSTRACT FROM AUTHOR]

Cryptococcal meningitis is a very rare type of infection in healthy adults. Such patients may present with the symptoms of increased intracranial pressure. Rapid diagnosis of infection, rapid intervention to reduce intracranial pressure and appropriate antifungal therapy are important to reduce mortality. In here we report a case of cryptococcal meningitis infection. An immunocompetent patient presented to our clinic with the complaints of headache and dizziness for a month. The findings of the physical examination supported with meningitis. Cryptococcus neoformans growth was observed on blood and cerebrospinal fluid culture. Despite the appropriate antifungal therapy, patient died because of the delaying in the diagnosis. [ABSTRACT FROM AUTHOR]

The article discusses Human immunodeficiency virus associated Cryptococcal Meningitis Immune Reconstitution Inflammatory Syndrome. Topics discussed include mortality rate in amphotericin-based treatments recommended clinical trials; survival of initial illness and initiate antiretroviral therapy (ART) suffered with Immune reconstitution inflammatory syndrome; and uncertain role of antibody- mediated protection in HIV-related cryptococcal infection.

Introduction: Clinically, increased cerebrospinal fluid (CSF) adenosine deaminase (ADA) level is an important diagnostic clue of tuberculous meningitis. However, increased CSF ADA level can be caused by other neurological diseases. Case description: We report a case of a 67-year-old woman with cryptococcal meningitis presented with increased ADA level of the CSF. In parallel with her recovery, the ADA level of CSF decreased steadily. This is the first case described the chronological change in CSF ADA level of the patient with cryptococcal meningitis in detail. Discussion and Evaluation: Clinically, increased CSF ADA level is an important diagnostic clue of tuberculous meningitis. However, previously, it was reported that increased CSF ADA level can be caused by other neurological diseases. In this case, the patient was diagnosed with cryptococcal meningitis, and the possibility of coinfection with tuberculous meningitis has been discarded by the negative PCR, negative cultures and the clinical course. In addition, the chronological change in CSF ADA level was useful for follow-up assessment. Conclusions: Cryptococcal meningitis should be considered for the differential diagnosis for diseases presented increased CSF ADA. [ABSTRACT FROM AUTHOR]

Objective: To determine the prevalence of asymptomatic cryptococcal antigen (CRAG) using lateral flow assay (LFA) in hospitalised HIV-infected patients with CD4 counts <200 cells/μl.Methods: Hospitalised HIV-infected patients were prospectively recruited at Instituto de Infectologia Emilio Ribas, a tertiary referral hospital to HIV-infected patients serving the São Paulo State, Brazil. All patients were >18 years old without prior cryptococcal meningitis, without clinical suspicion of cryptococcal meningitis, regardless of antiretroviral (ART) status, and with CD4 counts <200 cells/μl. Serum CRAG was tested by LFA in all patients, and whole blood CRAG was tested by LFA in positive cases.Results: We enrolled 163 participants of whom 61% were men. The duration of HIV diagnosis was a median of 8 (range, 1-29) years. 26% were antiretroviral (ART)-naïve, and 74% were ART-experienced. The median CD4 cell count was 25 (range, 1-192) cells/μl. Five patients (3.1%; 95%CI, 1.0-7.0%) were asymptomatic CRAG-positive. Positive results cases were cross-verified by performing LFA in whole blood.Conclusions: 3.1% of HIV-infected inpatients with CD4 <200 cells/μl without symptomatic meningitis had cryptococcal antigenemia in São Paulo, suggesting that routine CRAG screening may be beneficial in similar settings in South America. Our study reveals another targeted population for CRAG screening: hospitalised HIV-infected patients with CD4 <200 cells/μl, regardless of ART status. Whole blood CRAG LFA screening seems to be a simple strategy to prevention of symptomatic meningitis. [ABSTRACT FROM AUTHOR]

Disseminated cryptococcal infection carries a high risk of morbidity and mortality. Typical patients include HIV individuals with advanced immunosuppression or solid organ or hematopoietic transplant recipients. We report a case of disseminated cryptococcal disease in a 72-year-old male who was immunocompromised with chronic lymphocytic leukemia and ongoing chemotherapy. The patient presented with a subacute history of constitutional symptoms and headache after he received five cycles of FCR chemotherapy (fludarabine/cyclophosphamide/rituximab). Diagnosis of disseminated cryptococcal disease was made based on fungemia in peripheral blood cultures with subsequent involvement of the brain, lungs, and eyes. Treatment was started with liposomal amphotericin, flucytosine, and fluconazole as induction. He was discharged after 4 weeks of hospitalization on high dose fluconazole for consolidation for 2 months, followed by maintenance therapy. [ABSTRACT FROM AUTHOR]

Purpose Cryptococcosis is a devastating opportunistic disease commonly encountered in organ transplant recipients and patients with acquired immunodeficiency syndrome (AIDS). Few studies have profiled the disease in immunocompetent patients. We sought to characterize the neuroimaging findings of cryptococcal meningitis among immunocompetent patients in China. Materials and methods Retrospective review of all patients diagnosed with cryptococcal meningitis at our institute, on the basis of CSF culture or India Ink test, between November 2011 and February 2016, was performed. Only apparently immunocompetent patients, for whom at least one brain MRI examination was performed, were included in the analysis. The MRI results were available for all these patients before CSF diagnosis. Data related to variables such as patient demographics, clinical features, neuroimaging characteristics and CSF findings were analyzed. Results Eighteen apparently immunocompetent patients, for whom brain MRI radiographs were available, were included in the analysis. Abnormal MRI findings were observed in 16 patients. These included multiple intraparenchymal lesions with or without enhancement, prominent basal ganglia involvement, miliary distribution of parenchymal nodules, multiple dilated Virchow-Robin spaces and leptomeningeal enhancement. Six patients had ventriculomegaly. Conclusion In our study, intraparenchymal findings were more common than leptomeningeal enhancement and perivascular lesions. Cryptococcal meningitis should be considered in the differential diagnosis of immunocompetent patients with brain MRI findings of prominent parenchymal involvement such as bilateral patchy lesions in basal ganglia or miliary distribution of parenchymal nodules. [ABSTRACT FROM AUTHOR]

Cryptococcosis is mainly caused by members of the Cryptococcus gattii/ Cryptococcus neoformans species complexes. Here, we report the molecular characterisation and in vitro antifungal susceptibility of Danish clinical cryptococcal isolates. Species, genotype, serotype and mating type were determined by amplified fragment length polymorphism (AFLP) fingerprinting and qPCR. EUCAST E.Def 7.2 MICs were determined for amphotericin B, flucytosine, fluconazole, voriconazole and isavuconazole. Most isolates were C. neoformans (serotype A; n = 66) and belonged to genotype AFLP1/VNI ( n = 61) or AFLP1B/VNII ( n = 5) followed by Cryptococcus deneoformans (serotype D; genotype AFLP2, n = 20), C. neoformans × C. deneoformans hybrids (serotype AD; genotype AFLP3, n = 13) and Cryptococcus curvatus ( n = 2). Six isolates were C. gattii sensu lato, and one isolate was a C. deneoformans × C. gattii hybrid (genotype AFLP8). All isolates were amphotericin B susceptible. Flucytosine susceptibility was uniform MIC50 of 4-8 mg l−1 except for C. curvatus (MICs >32 mg l−1). Cryptococcus gattii sensu lato isolates were somewhat less susceptible to the azoles. MICs of fluconazole (>32 mg l−1), voriconazole (≥0.5 mg l−1) and isavuconazole (0.06 and 0.25 mg l−1 respectively) were elevated compared to the wild-type population for 1/19 C. deneoformans and 1/2 C. curvatus isolates. Flucytosine MIC was elevated for 1/61 C. neoformans (>32 mg l−1). Antifungal susceptibility revealed species-specific differential susceptibility, but suggested acquired resistance was an infrequent phenomenon. [ABSTRACT FROM AUTHOR]