Characteristics of HIV-associated cryptococcal meningitis in a tertiary Chilean hospital: An observational retrospective study.

BACKGROUND: Central nervous system opportunistic infections can be the first presentation of an HIV infection. Our aim is to describe clinical and laboratory characteristics of HIV-associated Cryptococcal Meningitis (CM), in-hospital outcomes and analyze associations of these parameters with adverse outcomes. METHODS: Observational study of local cohort of HIV-associated cryptococcal meningitis in a high complexity tertiary urban hospital in Santiago, Chile. Descriptive analysis through chart review of all episodes of HIV-associated CM in adults, from 1995 to 2019. Inclusion criteria were confirmed CM with cerebrospinal fluid culture or India ink in the appropriate clinical context and HIV diagnosis. We selected relevant variables that have been described as predictors of adverse outcomes in the literature and explore associations in our cohort. RESULTS: There were 37 HIV associated CM cases, occurring from 2000 to 2019. Majority were men (86 %) with a median age of 35 years. CM was the first HIV manifestation in 32 %. Opening pressure was measured in 10 % of patients at admission. Most CSF parameters were mildly altered, and two patients presented with completely normal CSF findings. Most patients -94,4 %- suffered adverse events secondary to antifungal therapy. Despite of recommendations against their use, steroids were frequently prescribed. Mortality was 18,9 %, and was associated with older age, and more days of headache prior to admission. CONCLUSIONS: CM clinical presentation and CSF characteristics are variable at presentation, which can lead to delayed diagnosis. Inappropriate use of corticosteroids, antifungal toxicity and suboptimal management of elevated intracranial pressure are key aspects to improve.

Criptococosis Meníngea en pacientes viviendo con HIV experiencia en cuidados intensivos / Meningeal cryptococcosis in patients living with HIV. Experience in intensive care

Resumen Introducción : La criptococosis meníngea (CM) es una causa frecuente de meningoencefalitis en personas que viven con HIV (PVHIV) y produce una importante morbi-mortalidad (20-55%). Se describen las características clínicas, la letalidad y las variables de mal pronóstico en PVHIV con CM, en unidades de cuidados intensivos (UCI). Métodos : Estudio observacional y retrospectivo. Pe ríodo 21/11/2006 a 24/05/2023. Población evaluada: 154 PVHIV adultos, admitidos en UCI con diagnóstico de CM. Los porcentajes y valores absolutos, fueron comparados mediante Chi-Cuadrado o test de Fisher y las medianas mediante test de Mann-Whitney. La asociación con mortalidad se evaluó por regresión logística. Se utilizó el programa SPSS 23.0. Un valor p<0.05 fue considerado significativo. Resultados : Los pacientes que fallecieron y los que so brevivieron fueron comparables en edad y sexo (p>0.05). El análisis univariado, observó que un estado funcional y nutricional alterado, falta de tratamiento antirretroviral previo (TARV), CD4 <100 células/μl, APACHE II ≥13 y un score pronóstico de PVHIV ≥8 puntos, requerir ventilación mecánica (VM), sufrir insuficiencia respiratoria, renal, disfunción neurológica o sepsis, podrían estar asociados (p<0.05) con mortalidad. La regresión logística estableció que un estado funcional y nutricional alterado, un score pronóstico PVHIV ≥8, necesitar VM y sufrir sepsis serían variables independientes asociadas a mortalidad. Conclusión : Los resultados indican que el estado funcional y nutricional alterado, un score pronóstico PVHIV ≥8 puntos, requerir VM y sufrir sepsis al ingreso a UCI podrían servir como variables independientes para predecir un mayor riesgo de mortalidad.

Abstract Introduction : Meningeal cryptococcosis (MC) is a frequent cause of meningoencephalitis in people living with HIV (PLHIV), leading to substantial morbidity (20- 55%). Clinical characteristics, lethality and adverse prog nostic factors in PLHIV with MC admitted to intensive care units (ICUs) are described. Methods : A retrospective observational study. Period from 11/21/2006 to 05/24/2023. It involved 154 adult PLHIV diagnosed with MC and admitted to ICUs. Percen tages and absolute values were compared by Chi-Square or Fisher's test and medians by Mann-Whitney test. The association with mortality was assessed by logistic re gression. SPSS 23.0 software was used. A p-value <0.05 was considered significant. Results : Patients who died and those who survived were comparable in age and sex (p>0.05). Univariate analysis showed that impaired functional and nutritio nal status, lack of previous highly active antiretroviral therapy, CD4 <100 cells, APACHE II ≥13 and a PLHIV prognostic score ≥8 points, requiring mechanical venti lation (MV), respiratory failure, renal failure, neurological dysfunction or sepsis could be associated (p<0.05) with mortality. Logistic regression established that impaired functional and nutritional status, a PLHIV prognostic score ≥8, need for MV and presence of sepsis would be independent variables associated with mortality. Conclusion : The results indicate that altered functio nal and nutritional status, a PLHIV prognostic score ≥ 8 points, requiring MV and suffering sepsis on admission to the ICU are more frequent in deceased patients, and they could therefore serve as independent variables to predict a higher risk of mortality.

[Meningeal cryptococcosis in patients living with HIV. Experience in intensive care]. / Criptococosis meníngea en pacientes viviendo con HIV. Experiencia en cuidados intensivos.

INTRODUCTION: Meningeal cryptococcosis (MC) is a frequent cause of meningoencephalitis in people living with HIV (PLHIV), leading to substantial morbidity (20-55%). Clinical characteristics, lethality and adverse prognostic factors in PLHIV with MC admitted to intensive care units (ICUs) are described. METHODS: A retrospective observational study. Period from 11/21/2006 to 05/24/2023. It involved 154 adult PLHIV diagnosed with MC and admitted to ICUs. Percentages and absolute values were compared by Chi-Square or Fisher's test and medians by Mann-Whitney test. The association with mortality was assessed by logistic regression. SPSS 23.0 software was used. A p-value <0.05 was considered significant. RESULTS: Patients who died and those who survived were comparable in age and sex (p>0.05). Univariate analysis showed that impaired functional and nutritional status, lack of previous highly active antiretroviral therapy, CD4 <100 cells, APACHE II ≥ 13 and a PLHIV prognostic score ≥ 8 points, requiring mechanical ventilation (MV), respiratory failure, renal failure, neurological dysfunction or sepsis could be associated (p<0.05) with mortality. Logistic regression established that impaired functional and nutritional status, a PLHIV prognostic score ≥ 8, need for MV and presence of sepsis would be independent variables associated with mortality. CONCLUSION: The results indicate that altered functional and nutritional status, a PLHIV prognostic score ≥ 8 points, requiring MV and suffering sepsis on admission to the ICU are more frequent in deceased patients, and they could therefore serve as independent variables to predict a higher risk of mortality.

Introducción: La criptococosis meníngea (CM) es una causa frecuente de meningoencefalitis en personas que viven con HIV (PVHIV) y produce una importante morbimortalidad (20-55%). Se describen las características clínicas, la letalidad y las variables de mal pronóstico en PVHIV con CM, en unidades de cuidados intensivos (UCI). Métodos: Estudio observacional y retrospectivo. Período 21/11/2006 a 24/05/2023. Población evaluada: 154 PVHIV adultos, admitidos en UCI con diagnóstico de CM. Los porcentajes y valores absolutos, fueron comparados mediante Chi-Cuadrado o test de Fisher y las medianas mediante test de Mann-Whitney. La asociación con mortalidad se evaluó por regresión logística. Se utilizó el programa SPSS 23.0. Un valor p<0.05 fue considerado significativo. Resultados: Los pacientes que fallecieron y los que sobrevivieron fueron comparables en edad y sexo (p>0.05). El análisis univariado, observó que un estado funcional y nutricional alterado, falta de tratamiento antirretroviral previo (TARV), CD4 <100 células/µl, APACHE II ≥ 13 y un score pronóstico de PVHIV ≥ 8 puntos, requerir ventilación mecánica (VM), sufrir insuficiencia respiratoria, renal, disfunción neurológica o sepsis, podrían estar asociados (p<0.05) con mortalidad. La regresión logística estableció que un estado funcional y nutricional alterado, un score pronóstico PVHIV ≥ 8, necesitar VM y sufrir sepsis serían variables independientes asociadas a mortalidad. Conclusión: Los resultados indican que el estado funcional y nutricional alterado, un score pronóstico PVHIV ≥ 8 puntos, requerir VM y sufrir sepsis al ingreso a UCI podrían servir como variables independientes para predecir un mayor riesgo de mortalidad.

Funding for research on cryptococcal disease: an analysis based on the G-finder report.

Members of the genus Cryptococcus are the causative agents of cryptococcal meningitis, a disease mainly associated with HIV-induced immunosuppression. Patients with cryptococcal meningitis are at a serious risk of death. Most patients suffering from cryptococcosis belong to neglected populations. With reduced support for research, new therapies are unlikely to emerge. In this essay, we used the Policy Cures/G-finder platform as a reference database for funding research on cryptococcal disease. Funding for cryptococcal research started being tracked by G-finder in 2013 and has continued to appear in the annual reports ever since. In total, 15 institutions were reported as major funders for research on cryptococcal disease over the years. The US National Institutes of Health (NIH) was the main funder, followed by the UK's Wellcome Trust. The annual analysis suggested slow yearly growth in funding from 2013 to 2021. The development of new tools to prevent and fight cryptococcal disease is urgent but requires improved funding.

Finger-Prick Whole Blood Cryptococcal Antigen Lateral Flow Assay for the Diagnosis of Cryptococcosis in HIV-Negative Patients: A Case Series Study in Two Tertiary Centers in São Paulo, Brazil.

Cryptococcosis in HIV-negative patients can be an opportunistic or endemic disease. There are no published studies on the use of the finger-prick whole blood (point-of-care) cryptococcal antigen lateral flow assay (CrAg LFA) for diagnosing cryptococcosis in HIV-negative patients. We conducted a case series study of HIV-negative patients with cryptococcosis in two centers in São Paulo, Brazil. The objectives were to identify the sensitivity of a finger-prick whole blood CrAg LFA and to describe the main characteristics of this population. We identified 30 HIV-negative patients with cryptococcosis [19 (63%), male; median age, 47 years]. Ten (33%) patients were immunosuppressed, ten (33%) had other comorbidities, and ten (33%) were apparently immunocompetent and without comorbidities. The distribution of the sites of cryptococcosis was as follows: the central nervous system, 90% (n = 27); pulmonary, 43% (n = 13); and other extrapulmonary sites, 40% (n = 12). The sensitivity of the finger-prick whole blood CrAg LFA for the diagnosis of cryptococcosis was 97% (29/30). Among 26 participants with cryptococcal meningitis, the sensitivity of testing cerebrospinal fluid was as follows: CrAg latex agglutination, 77% (20/26); CrAg LFA, 96% (25/26); and culture, 81% (21/26). Culture speciation identified Cryptococcus gattii in 16 (62%) cases, and all had a positive finger-prick whole blood CrAg LFA. This test presented high sensitivity to the diagnosis of cryptococcosis in HIV-negative patients, including those caused by C. gattii.

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

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

Cryptococcal meningoencephalitis: Risk factors associated to death in a hospital in Northeastern Brazil.

INTRODUCTION: Cryptococcosis is an opportunistic systemic mycosis caused by pathogenic encapsulated yeasts of the genus Cryptococcus. The objective of the present study was to evaluate the risk factors associated with death of patients diagnosed with meningitis due to Cryptococcus spp. METHODS: This retrospective cohort study included patients admitted to the São José Hospital (SJH) with Cryptococcal Meningoencephalitis (CM) who were diagnosed between 2010 and 2018. Data collection was carried out by reviewing the patients' medical records. Death during hospitalization was considered the primary outcome. RESULTS: From 2010 to 2018, 21,519 patients were admitted to the HSJ, 124 of whom were hospitalized due to CM. The CM incidence rate was 5.8 cases/103 hospitalizations. We included 112 patients in the study. Male patients were the most affected (82.1%), and the median age was 37 years [IQR: 29-45]. HIV coinfection occurred in 79.4% of the patients. Fever (65.2%) and headache (88.4%) were the most frequent symptoms. Greater cellularity in the CSF was the most related factor to CM in non-HIV individuals (p < 0.05). Death during hospitalization occurred in 28.6% (n = 32) of the patients. The independent risk factors associated with death during the hospitalization were women (p = 0.009), age > 35 years (p = 0.046), focal neurological deficits (p = 0.013), altered mental status (p = 0.018) and HIV infection (p = 0.040). The twelve-month survival was lower in HIV-positive patients (p < 0.05). CONCLUSION: Early diagnosis, optimal treatment, and clinical follow-up strategies, especially in HIV patients, should be prioritized.

Antifungal Activity, Antibiofilm and Association Studies with O-Alkylamidoximes against Cryptococcus spp.

This is the first study that describes the antifungal and anti-biofilm potential of O-alkylamidoximes against strains of Cryptococcus neoformans and Cryptococcus gattii. In vitro tests have shown that O-alkylamidoximes are capable of inhibiting fungal growth and biofilm formation of the C. neoformans and C. gattii strains, suggesting, from molecular docking, the potential for interaction with the Hsp90. The associations between O-alkylamidoximes and amphotericin B were beneficial. Therefore, O-alkylamidoximes can be a useful alternative to contribute to the limited arsenal of drugs, since they showed a powerful action against the primary agents of Cryptococcosis.

Cerebral cryptococcoma successfully treated by isavuconazole in an immunocompetent patient: A case report.

Cryptococcosis has been recognized as an increasing cause of severe systemic mycosis in immunocompetent patients in the last few years. Cerebral cryptococcomas are a more uncommon manifestation of cryptococcal meningitis, which are not usually included in the differential of brain masses. We report a case of a young, immunocompetent woman that rapidly developed severe neurological deficits. She was ultimately diagnosed with cerebral cryptococcoma caused by both Cryptococcus neoformans and Cryptococcus gattii, and was treated with amphotericin B and isavuconazole. After several complications during hospitalization, including hydrocephalus and cerebellitis, she was discharged home on isavuconazole. On follow-up, she only complained of anosmia. We review the clinical and radiological findings of similar cases. It is the first time that this form of cryptococcal meningitis is favorably treated with isavuconazole and is caused by 2 species of Cryptococcus. We emphasize that cerebral cryptococcomas should be suspected in immunocompetent patients that present with brain masses.

Prevalence and Associated Factors of Cryptococcal Antigenemia in HIV-Infected Patients with CD4 < 200 Cells/µL in São Paulo, Brazil: A Bayesian Analysis

Cryptococcosis is a severe life-threatening disease and a major cause of mortality in people with advanced AIDS and CD4 ≤ 100 cells/µL. Considering the knowledge gap regarding the benefits of routine application of antigenemia tests in HIV-infected patients with 100−200 CD4 cells/µL for the prevention of cryptococcal meningitis (CM), we aimed to evaluate the prevalence of positive antigenemia through lateral flow assay (LFA) and associated factors in HIV-infected patients with CD4 < 200 cells/µL. Our findings of 3.49% of positive LFA (LFA+) patients with CD4 < 100 cells/µL and 2.24% with CD4 between 100−200 cells/µL have been included in a Bayesian analysis with 12 other studies containing similar samples worldwide. This analysis showed a proportion of 3.6% LFA+ patients (95% credible interval-Ci [2.5−5.7%]) with CD4 < 100 cells/µL and 1.1% (95%Ci [0.5−4.3%]) with CD4 between 100−200 cells/µL, without statistical difference between these groups. The difference between mortality rates in LFA+ and negative LFA groups was e = 0.05013. Cryptococcoma and CM were observed in the LFA+ group with 100−200 and <100 CD4 cells/µL, respectively. Considering the benefits of antifungal therapy for LFA+ patients, our data reinforced the recommendation to apply LFA as a routine test in patients with 100−200 CD4 cells/µL aiming to expand cost-effectiveness studies in this group.

Antifungal Potential of Synthetic Peptides against Cryptococcus neoformans: Mechanism of Action Studies Reveal Synthetic Peptides Induce Membrane-Pore Formation, DNA Degradation, and Apoptosis.

Cryptococcus neoformans is a human-pathogenic yeast responsible for pneumonia and meningitis, mainly in patients immunocompromised. Infections caused by C. neoformans are a global health concern. Synthetic antimicrobial peptides (SAMPs) have emerged as alternative molecules to cope with fungal infections, including C. neoformans. Here, eight SAMPs were tested regarding their antifungal potential against C. neoformans and had their mechanisms of action elucidated by fluorescence and scanning electron microscopies. Five SAMPs showed an inhibitory effect (MIC50) on C. neoformans growth at low concentrations. Fluorescence microscope (FM) revealed that SAMPs induced 6-kDa pores in the C. neoformans membrane. Inhibitory assays in the presence of ergosterol revealed that some peptides lost their activity, suggesting interaction with it. Furthermore, FM analysis revealed that SAMPs induced caspase 3/7-mediated apoptosis and DNA degradation in C. neoformans cells. Scanning Electron Microscopy (SEM) analysis revealed that peptides induced many morphological alterations such as cell membrane, wall damage, and loss of internal content on C. neoformans cells. Our results strongly suggest synthetic peptides are potential alternative molecules to control C. neoformans growth and treat the cryptococcal infection.

Criptococosis meníngea y pulmonar en paciente inmunocompetente

RESUMEN Presentamos el caso de un varón de 23 años, sin patologías conocidas, agricultor, procedente de la zona rural. Presenta un cuadro de 1 mes de evolución cefalea, náuseas y vómitos, además de alteración de la conciencia caracterizada por confusión. La tomografía de cráneo no muestra anomalías y la punción lumbar es compatible con meningitis, con tinta china positiva visualizándose Cryptococcus sp. Se inicia tratamiento con anfotericina B y fluconazol. Posteriormente retorna informe final de cultivo: Cryptococcus gatii. Se realizan estudios para descartar infecciones virósicas que retornan negativos. En su internación presenta neumonía nosocomial y por empeoramiento progresivo del estado de conciencia y la clínica respiratoria pasa a cuidados intensivos donde se mantuvo internado durante 21 días. En su estadía se confirmó además la presencia de C. gattii en lavado bronquioalveolar. Presentó falla multiorgánica y óbito. Es el primer caso de criptococosis en paciente inmunocompetente descrito en nuestro centro.

ABSTRACT We present the case of a 23-year-old male, with no known pathologies, a farmer, from a rural area. He presented a 1-month history of headache, nausea and vomiting, in addition to altered consciousness characterized by confusion. The skull tomography does not show abnormalities and the lumbar puncture is compatible with meningitis, with positive Chinese ink showing Cryptococcus sp. Treatment with amphotericin B and fluconazole is started. Later, the final culture report returns: Cryptococcus gatii. Studies are carried out to rule out viral infections that return negative. During his hospitalization, he presents nosocomial pneumonia and due to the progressive worsening of his state of consciousness and the respiratory symptoms goes to intensive care where he is hospitalized for 21 days. During his stay, the presence of C. gattii is also confirmed in bronchioalveolar lavage. He presents multiple organ failure and death. This is the first case of cryptococcosis in an immunocompetent patient described in our center.

Early clinical and microbiological predictors of outcome in hospitalized patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis causes high mortality in immunocompromised and immunocompetent patients. The objective of this study was to identify early predictors of clinical outcome, available at the first days of hospitalization, in patients with cryptococcal meningitis in a tertiary center in Brazil. METHODS: Ninety-six cases of cryptococcal meningitis with clinical, epidemiological and laboratory data, and identification and antifungal susceptibility of the strains were analyzed. Quantitative CSF yeast counts were performed by direct microscopic exam with a Fuchs-Rosenthal cell counting chamber using an institutional protocol. Univariable and multiple analyses using logistic regression were performed to identify predictors, available at the beginning of hospitalization, of in-hospital mortality. Moreover, we performed a secondary analysis for a composite outcome defined by hospital mortality and intensive care unit transfer. RESULTS: The species and the antifungal susceptibility were not associated with the outcomes evaluated. The variables significantly associated with the mortality were age (OR = 1.08, 95% CI 1.02-1.15), the cerebrospinal fluid (CSF) yeasts count (OR = 1.65, 95% CI 1.20-2.27), systemic arterial hypertension (OR = 22.63, 95% CI 1.64-312.91) and neurological impairment identified by computed tomography (OR = 41.73, 95% CI 3.10-561.65). At the secondary analysis, CSF yeast count was also associated with the composite outcome, in addition to the culture of Cryptococcus spp. from bloodstream and cerebral toxoplasmosis. The associations were consistent with survival models evaluated. CONCLUSIONS: Age and CSF yeast count were independently associated with in-hospital mortality of patients with cryptococcal meningitis but Cryptococcus species identification and antifungal susceptibility were not associated with the outcomes. Quantitative CSF yeast counts used in this study can be evaluated and implemented in other low and middle-income settings.

Características clínicas de la criptococosis cerebral en pacientes infectados por el VIH: Hospital Nacional de Paraguay años 2012 a 2020 / Clinical characteristics of cerebral cryptococcosis in HIV-infected patients: Hospital Nacional de Paraguay years 2012 to 2020

RESUMEN Introducción: el cuadro clínico de la infección por el VIH refleja la inmunodeficiencia progresiva desde fases iniciales a veces asintomáticas hasta las finales cuando clínicamente corresponde a estadios más avanzados de inmunosupresión, con linfocitos T CD4 < 100cel /µL, el síndrome de inmunodeficiencia adquirida, en el que ya aparecen las enfermedades definitorias, una de ellas la criptococosis cerebral. Objetivos: describir las características clínicas de la criptococosis cerebral en pacientes infectados por el VIH internados en el servicio de Clínica Médica del Hospital Nacional ­ Itauguá, Paraguay de 2012 a 2020. Metodología: se realizó un estudio observacional descriptivo, retrospectivo de corte transversal, en pacientes de ambos sexos mayores de 18 años. Resultados: se estudiaron 35 pacientes, 69 % fueron varones, con mediana de edad 43 años. El 100 % se hallaba sin tratamiento antirretroviral al ingreso, 74 % no se conocían infectados por el VIH y el 26 % no tenía adherencia al tratamiento. El cuadro evolutivo en promedio fue de 20 días (2 a 90 días), el 91 % de los síntomas al ingreso fueron neurológicos, siendo el predominante la cefalea, que se presentó en forma aislada en el 28 % y el resto con otro síntoma neurológico. La carga viral promedio fue 867.464 copias/mL, la mediana del nivel CD4 34 cél/mm3 y el 100 % < 150 cél/mm3. El promedio de los hallazgos del líquido cefalorraquídeo fueron glucorraquia 37 mg/dl, proteinorraquia 174 mg/dl, la celularidad 46 % ≤ 6 cél/µl, 98 % con predominio mononuclear. Todos fueron tratados con anfotericina B y de mantenimiento con fluconazol. La mediana de los días de internación fue 30 días y la mortalidad de 26 %, siendo los factores de mal pronóstico: consulta tardía, no conocidos infectados por VIH y mayor carga viral. Conclusiones: se pudo evidenciar mayoría de los casos en pacientes varones, adultos jóvenes, en estadio sida, 100 % sin tratamiento en antirretrovirales y como factores de mal pronóstico la consulta tardía y la alta carga viral. Es válida la sospecha de concomitancia criptococosis meníngea-VIH, en pacientes con cefalea crónica aun en pacientes no conocidos infectados con VIH.

ABSTRACT Introduction: the clinical picture of HIV infection reflects the progressive immunodeficiency from the initial phases, sometimes asymptomatic to the final, when clinically it corresponds to more advanced stages of immunosuppression, with CD4 T lymphocytes <100cells / µL, the acquired immunodeficiency syndrome, in the one that already appears the defining diseases, one of them the cerebral cryptococcosis. Objectives: to describe the clinical characteristics of cerebral cryptococcosis in HIV-infected patients admitted to the Medical Clinic Service of the Hospital Nacional - Itauguá, Paraguay from 2012 to 2020. Methodology: a descriptive, retrospective, cross-sectional observational study was carried out in patients of both sexes older than 18 years. Results: 35 patients were studied, 69 % were male, with a median age of 43 years. 100 % were without antiretroviral treatment upon admission, 74 % were not known to be infected with HIV, and 26 % had no adherence to treatment. The evolutionary picture on average was 20 days (2 to 90 days), 91 % of the symptoms on admission were neurological, the predominant being headache, which occurred in isolation in 28% and the rest with another neurological symptom . The mean viral load was 867,464 copies / mL, the median CD4 level was 34 cells / mm3 and 100 % <150 cells / mm3. The mean cerebrospinal fluid findings were glucorrhachia 37 mg / dl, protein sprain 174 mg / dl, cellularity 46 % ≤ 6 cells / µl, 98% predominantly mononuclear. All were treated with amphotericin B and maintenance with fluconazole. The median number of days of hospitalization was 30 days and mortality was 26 %, with poor prognosis factors being: late consultation, unknown HIV-infected patients, and higher viral load. Conclusions: most of the cases could be evidenced in male patients, young adults, in the AIDS stage, 100 % without antiretroviral treatment, and late consultation and high viral load as poor prognostic factors. The suspicion of meningeal cryptococcosis-HIV concomitance is valid in patients with chronic headache even in unknown patients infected with HIV.

Cryptococcal Immune Reconstitution Inflammatory Syndrome: From Blood and Cerebrospinal Fluid Biomarkers to Treatment Approaches.

Immune reconstitution inflammatory syndrome (IRIS) presents as an exaggerated immune reaction that occurs during dysregulated immune restoration in immunocompromised patients in late-stage human immunodeficiency virus (HIV) infection who have commenced antiretroviral treatments (ART). Virtually any opportunistic pathogen can provoke this type of immune restoration disorder. In this review, we focus on recent developments in the identification of risk factors for Cryptococcal IRIS and on advancements in our understanding of C-IRIS immunopathogenesis. We overview new findings in blood and cerebrospinal fluid which can potentially be useful in the prediction and diagnosis of cryptococcal meningitis IRIS (CM-IRIS). We assess current therapeutic regimens and novel treatment approaches to combat CM-IRIS. We discuss the utility of biomarkers for clinical monitoring and adjusting treatment modalities in acquired immunodeficiency syndrome (AIDS) patients co-infected with Cryptococcus who have initiated ART.

Cryptococcal meningitis in non-HIV patients in the State of Amazonas, Northern Brazil.

Cryptococcosis is a life-threatening fungal infection caused by the Cryptococcus neoformans/Cryptococcus gattii species complex. Most cases are recorded in patients suffering from HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome). However, this infection also occurs in non-HIV patients with a proportion of 10-30% of all cases. The study aimed at the clinical and molecular characterization of non-HIV patients diagnosed with cryptococcosis at the Tropical Medicine Foundation (FMT-HVD) from July 2016 to June 2019. Medical records of respective patients were analyzed to describe the course of cryptococcosis in non-HIV patients. In addition, multi-locus sequence typing (MLST) was applied to identify the sequence types of the isolated Cryptococcus strains, to perform phylogenetic analysis, and to evaluate the isolates' genetic relationship to global reference strains. Antifungal susceptibility profiles to amphotericin B, fluconazole, and itraconazole were assessed by broth microdilution. From a total of 7 patients, 4 were female, the age range varied between 10 and 53 years (median of 36.3 years). Cryptococcal meningitis was the common clinical manifestation (100%). The period between onset of symptoms and confirmed diagnosis ranged from 15 to 730 days (mean value of 172.9 days), and the observed mortality was 57.1%. Of note, comorbidities of the assessed cryptococcosis patients comprised hypertension, diabetes mellitus, and intestinal tuberculosis. Genotyping applying PCR-RFLP of the URA5 gene identified all clinical isolates as C. gattii genotype VGII. Using MLST, it was possible to discriminate the sequence types ST20 (n = 4), ST5 (n = 3), and the newly identified sequence type ST560 (n = 1). The antifungals amphotericin B, fluconazole, and itraconazole showed satisfactory inhibitory activity (microdilution test) against all C. gattii VGII strains.

HIV-Associated Cryptococcal Meningitis Patients Treated with Amphotericin B Deoxycholate Plus Flucytosine under Routine Care Conditions in a Referral Center in São Paulo, Brazil.

BACKGROUND: Cryptococcal meningitis remains a common cause of mortality in low- and middle-income countries, where amphotericin B deoxycholate (amphotericin) plus fluconazole is the most common treatment. Flucytosine is almost uniformly absent as is outcome data on flucytosine use in routine care. The main goal of this study was identified the cumulative mortality at 2, 4, and 10 weeks after hospital admission. METHODS: We conducted a retrospective, observational cohort study among HIV-infected adults with cryptococcal meningitis receiving amphotericin plus flucytosine as induction therapy in Brazil. We assessed cumulative mortality at 2, 4, and 10 weeks and the cumulative proportion discontinuating amphotericin or flucytosine due to toxicity at 2 weeks. We performed multiple logistic regression to identify variables associated with in-hospital mortality. RESULTS: In total, 77 individuals (n = 66 men) were included with median baseline CD4 of 29 (IQR, 9-68) cells/mcL. Twenty (26%) had at least one concurrent neurological disease diagnosed. Sixty (78%) patients received at least 14 days of amphotericin plus flucytosine. Cumulative mortality was 5% (4/77) at 2 weeks, 8% (6/77) at 4 weeks, and 19% (15/77) at 10 weeks. Cumulative proportion of patients that discontinuated amphotericin or flucytosine due to toxicity was 20% (16/77) at 2 weeks. In addition, in-hospital mortality was associated with receiving ≤ 10 days of induction therapy (odds ratio = 4.5, 95% CI 1.2-17.1, P = 0.028) or positive cerebrospinal fluid fungal culture after 2 weeks (odds ratio = 3.8, 95% CI 1.1-13.5, P = 0.035). CONCLUSION: In this "real-world" study, amphotericin plus flucytosine shows low early mortality of patients with HIV-associated cryptococcal meningitis. Early discontinuation due to adverse events was moderate. More effective and safe antifungals are needed in order to improve the outcome of cryptococcal meningitis.

Cryptococcosis by Cryptococcus neoformans/Cryptococcus gattii Species Complexes in non-HIV-Infected Patients in Southeastern Brazil

Abstract INTRODUCTION: The clinical manifestations of cryptococcosis are usually associated with the infecting agents Cryptococcus neoformans (CN) and C. gattii (CG) species complexes and the host. In this study, non-HIV-infected patients, at a university hospital in southeastern Brazil, had epidemiological and clinical data associated with cryptococcal disease and isolated Cryptococcus species: CN - 24 patients and CG - 12 patients. METHODS: The comparison was comprised of demographic data, predisposing factors, clinical and laboratory manifestations, and outcomes of cryptococcosis patients treated between 2000 and 2016. Immunocompetent and immunosuppressed patients were also compared, irrespective of the infecting species. Cryptococcus spp. were genotyped by PCR-RFLP analysis of the URA5 gene. RESULTS: Infections by the CN species complex (100% VNI genotype) were associated with drug immunosuppression and fungemia, and patients infected with the CG species complex (83% VG II and 17% VGI genotypes) had more evident environmental exposure and higher humoral response. CN and CG affected patients with or without comorbidities. CONCLUSIONS: Diabetes mellitus, other chronic non-infectious diseases, and alcoholism were likely predisposing factors for infection by both CN and CG species. Immunocompetent patients, independent of the infecting Cryptococcus species complexes, showed a higher occurrence of meningitis and a trend toward less fungal dissemination and longer survival than immunosuppressed hosts.

Production of a latex agglutination reagent for the rapid diagnosis of cryptococcal meningitis / Producción de un reactivo de látex para el diagnóstico rápido de criptococosismeníngea

Abstract Cryptococcosis is a fungal disease affecting more than one million people per yearworldwide. Its main etiological agents are Cryptococcus neoformans species complex and Cryp-tococcus gattii species complex. Cryptococcal meningitis (CM) is considered an AIDS-definingcondition. Rapid diagnosis by cryptococcal antigen assays, either the latex agglutination test(LA) or the lateral flow assay, is key to decreasing mortality due to cryptococcal disease. Theaim of the study was to develop a latex agglutination reagent (LA-ANLIS) for the rapid and reliable diagnosis of cryptococcosis in Argentina. This reagent will be produced in order to supplythe NMLN (National Mycology Laboratory Network). The evaluation of LA-ANLIS performanceand its comparison with the Cryptococcus Antigen Latex Agglutination Test System (LA-IMMY)(Immuno-Mycologics, Inc., USA) were conducted in 94 samples of cerebrospinal fluid. LA-ANLISand LA-IMMY compared exhibited 100% positive agreement and 97% negative agreement. LA-ANLIS showed 94% sensitivity and 97% specificity with the positive and negative predictivevalues of 94% and 97%, respectively. The LA-ANLIS is a reliable, reproducible and cost-effectivereagent, especially useful in countries where the commercial kit is not generally available andmust be obtained at a high cost. National production of reagents is the best choice for a reliableaccess to the rapid diagnosis of CM in Argentina.

Resumen La criptococosis es una enfermedad fúngica que afecta a más de un millón de personas por año en todo el mundo. Los principales agentes etiológicos pertenecen a los complejos de especies Cryptococcus neoformans y Cryptococcus gattii. La criptococosis meníngea (CM) se considera una enfermedad marcadora de sida. El diagnóstico rápido de esta enfermedad a través de la detección del antígeno de Cryptococcus, ya sea por aglutinación en partículas de látex o por inmunocromatografía, es clave para disminuir la mortalidad. El objetivo del presente estudio fue desarrollar un reactivo de aglutinación en partículas de látex para el diagnóstico rápido y certero de la CM en Argentina. Este reactivo (denominado en adelante LA-ANLIS) será producido para abastecer a la Red Nacional de Laboratorios de Micología. Se evaluó el desempeno del reactivo LA-ANLIS, y se realizó una comparación con el reactivo comercial Immuno-Mycologics, Inc. (en adelante, LA-IMMY) utilizando 94 muestras de líquido cefalorraquídeo. Hubo un 100% de acuerdo positivo y un 97% de acuerdo negativo entre los resultados obtenidos con los reactivos LA-ANLIS y LA-IMMY. El reactivo LA-ANLIS mostró una sensibilidad del 94% y una especificidad del 97%; los valores predictivos positivo y negativo fueron del 94 y del 97%, respectivamente. Se concluye que el LA-ANLIS es un reactivo confiable y rentable, que arroja resultados reproducibles, por lo que es especialmente útil en países donde los reactivos comerciales generalmente no están disponibles o sus costos son elevados. La producción nacional de reactivos es la mejor opción para asegurar el acceso de todos los hospitales al diagnóstico rápido de la CM en Argentina.

Achados Epidemiológicos de Neurocriptococose em Pacientes Imunocompetentes: Relato de Casos de um Hospital Público de Joinville, Brasil / Epidemiological Findings of Neurocriptococcosis in Immunocompetent Patients: Case Reports from a Public Hospital in Joinville, Brazil / Hallazgos epidemiológicos de la neurocriptococosis en pacientes inmunocompetentes: relato de casos de un hospital público en Joinville, Brasil

Justificativa e Objetivos: Neurocriptococose é uma doença fúngica que acomete principalmente pacientes imunocomprometidos. Casos em pacientes imunocompetentes têm sido descritos em alguns relatos de casos; no entanto, por não ser uma doença de notificação compulsória no Brasil até 2020, ainda pouco se sabe sobre sua epidemiologia no sul do país. O presente estudo teve como objetivo descrever aspectos epidemiológicos relacionados à doença em pacientes supostamente imunocompetentes. Métodos: Estudo retrospectivo, observacional, baseado em uma série de casos atendidos entre 2018 e 2019, em um hospital público de Joinville, Santa Catarina, Brasil. Pacientes com diagnóstico clínico confirmado pela presença do fungo do gênero Cryptococcus spp. no líquido cefalorraquidiano pelo método tinta da China foram avaliados quanto aos aspectos clínicos, tratamento e complicações durante o período de internação. Resultados: Houve dois pacientes em 2018 e seis pacientes em 2019 com diagnóstico confirmado. Todos sem fatores aparentes para imunocomprometimento e sem fator de risco ambiental evidente. A maioria eram homens com média de idade de 39 anos. Febre e confusão mental foram os achados mais comuns na apresentação. A variante C. neoformans foi encontrada em 75% dos casos. Todos receberam Anfotericina B, no mínimo, durante 13 dias, associado ou não a Fluconazol. Seis pacientes apresentaram nefrotoxicidade pela Anfotericina B, dois evoluíram para óbito intra-hospitalar e dois permaneceram com sequelas neurológicas. Conclusão: A mortalidade e as complicações relacionadas ao tratamento da neurocriptococose em pessoas imunocompetentes foram altas na amostra estudada. A recente inclusão da doença como uma patologia de notificação compulsória poderá aprimorar dados epidemiológicos para o melhor entendimento e a prevenção dessa doença.(AU)

Background and Objectives: Neurocryptococcosis is a fungal disease that affects mainly immunocompromised patients. Cases in immunocompetent patients have been described in some case reports. However, as its reporting was not mandatory in Brazil until 2020, little is known about its epidemiology in the South Region of the country. The present study had the objective of describing epidemiological aspects related to the disease in presumably immunocompetent patients. Methods: A retrospective and observational study was developed, based on cases of patients who received care in a public hospital in Joinville, Santa Catarina, Brazil, between 2018 and 2019. Patients with a clinical diagnosis confirmed by the presence of the fungus Cryptococcus spp. in cerebrospinal fluid by means of the Chinese ink staining were evaluated regarding clinical aspects, treatment, and complications during hospitalization. Results: The diagnosis of the disease was confirmed for two patients in 2018 and six patients in 2019. All of them showed no apparent factors for immunodeficiency and no evident environmental risk factors. Most were men with an average age of 39 years. Fever and mental confusion were the most common symptoms at admission. The variant C. neoformans was found in 75% of the cases. All patients received amphotericin B for at least 13 days with or without combined fluconazole. Six patients had nephrotoxicity due to amphotericin B, two evolved to in-hospital death, and two had neurological sequelae. Conclusion: Mortality and complications related to the treatment of neurocryptococcosis in immunocompetent people showed high rates in the studied sample. The recent inclusion of this disease as a mandatory reporting pathology can improve epidemiological data, which will be used to achieve better understanding and prevention of this problem.(AU)

Justificación y Objetivos: La neurocriptococosis es una enfermedad fúngica que afecta especialmente a pacientes inmunocomprometidos. Fueron citados casos en pacientes inmunocompetentes en algunos relatos. Por no considerársela de notificación obligatoria en Brasil hasta 2020, poco se sabe aún sobre su epidemiología en el sur del país. El estudio objetivó describir aspectos epidemiológicos relativos a la enfermedad en pacientes supuestamente inmunocompetentes. Métodos: Estudio retrospectivo, observacional, en base a una serie de casos atendidos entre 2018 y 2019 en un hospital público de Joinville, Santa Catarina. Pacientes con diagnóstico clínico confirmado por presencia de Cryptococcus spp., utilizándose el método de tinta china en líquido cefalorraquídeo fueron evaluados respecto de aspectos clínicos, tratamiento y complicaciones durante su internación. Resultados: Hubo 2 pacientes en 2018 y 6 en 2019 con diagnóstico confirmado, todos sin factores aparentes de inmunocompromiso y sin factor de riesgo ambiental evidente. Mayoría de hombre, media etaria de 39 años. Fueron hallazgos comunes en su presentación la fiebre y confusión mental. La variante C. neoformans fue hallada en 75% de los casos. Todos recibieron anfotericina B como mínimo durante 13 días, en asociación o no con fluconazol. Seis pacientes presentaron nefrotoxicidad por anfotericina B, dos sufrieron fallecimiento intrahospitalario, y dos resultaron con secuelas neurológicas. Conclusión: La mortalidad y las complicaciones relativas al tratamiento de la neurocriptococosis en inmunocompetentes fueron altas en la muestra estudiada. La inclusión de la enfermedad como patología de notificación obligatoria podrá mejorar los datos epidemiológicos para entender mejor y prevenir la enfermedad.(AU)