Research progress of Cryptococcus gattii meningitis with different immune status / 中华神经科杂志

Cryptococcus gattii is a kind of Cryptococcus that infects the lungs and central nervous system through the inhalation of infectious particles such as spores or Cryptococcus yeast cells. The development of clinical disease of Cryptococcus gattii may be determined by the sex, immunity and genetics of the host factors, in which immune system factors play an important role in host injury. Their defects will have serious clinical consequences. Cryptococcus gattii mainly infects the population with normal immune, and the infection of immunosuppressed population is rare. The infection mechanism, molecular types, clinical characteristics, treatment and prognosis of Cryptococcus gattii meningitis were different between the two populations. This article reviews the main differences in different immune status with Cryptococcus gattii meningitis.

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.

Clinical analysis of cryptococcosis neoformans infection in patients with connective tissue disease / 中华风湿病学杂志

Objective:To improve the level of clinical diagnosis and treatment by analyzing the clinical features and relevant factors of cryptococcosis neoformans in patients with connective tissue disease(CTD).Methods:Twelve patients with CTD and cryptococcosis neoformans infection in Peking University People's Hospital from January 2010 to April 2021 were retrospectively enrolled. Clinical and laboratory data, treatment and outcome were collected and analyzed. Independent sample t-test or Rank-sum test was used. Results:The age of the patients ranged from 18 to 85 years old(mean 51 years old), all of whom were female. None of them were exposed to pigeons and their feces. Of the 12 patients, 3 patients suffered from rheumatoid arthritis, 7 patients had systemic lupus erythematosus, 1 patient was diagnosed with primary Sj?gren 's syndrome, and 1 patient was diagnosed as undifferentiated connective tissue disease. Four cases were cryptococcal meningitis, 8 were pulmonary cryptococcosis. None of the 12 patients had immunodeficiency virus infection. All 12 patients were given glucocorticoid alone or combined with immunosuppressive or biological agents. All were detected with positive cryptococcus neoformans antigen in serum; 6 got lumbar puncture, 2 cases were positive for ink stain, cerebrospinal fluid (CSF) culture were positive in 2, in whom 3 had high intracranial pressure, in which the highest one was more than 600 mmH 2O (1 mmH 2O=0.009 8 kPa); 7 cases underwent lung biopsy. Among these patients, all were positive for cryptococcosis neoformans in lung tissue pathological examination; 6 had the number of peripheral lymphocytes less than 1.0×10 9/L, and 2 were detected for the number of CD4 + T cell, which was significantly decreased. As for the initial anti-fungal drug therapy, all cases were treated with fluconazole intravenously; 2 were treated with combined amphotericin, 1 was treated with combined fluorocytosine, 1 was treated with amphotericin and fluorocytosine. Then oral flu-conazole was prescribed as sequential therapy. The whole treatmentcourse ranged from 4 to 21 months. Eleven patients were cured, and 1 was relieved. Conclusion:Patients with connective tissue disease complicated with cryptococcus neoformans infection have atypical clinical symptoms. Treatment with immunosuppressive drugs and glucocorticoids are related causes. Patients with decreased peripheral blood lymphocytes, especially CD4 + T cell, are more susceptible to infection. Early diagnosis and timely treatment are the key to improve the prognosis and cure of the disease.

Co-infection with cryptococcal meningitis and Japanese encephalitis in an immunocompetent patient: A case report

@#Cryptococcal meningitis is a severe infection in both immunocompetent and immunosuppressed hosts. This report is an unusual case of co-infection with cryptococcal meningitis and Japanese encephalitis in a seronegative human immunodeficiency virus patient. A 51-year-old human immunodeficiency virus-negative patient presented with high-grade fever, nausea, vomiting, and later on, behavioral changes. A lumbar puncture was performed and cerebrospinal fluid revealed the presence of Cryptococcus and Japanese encephalitis virus. Treatment commenced with intravenous amphotericin B and flucytosine. Her condition initially improved but later on deteriorated due to bacteremia (MRSA-mecA gene positive) and septic shock which resulted in the patient’s demise. The occurrence of this co-infection in the absence of HIV infection is rare and there was no documented case up to this date.

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.

A case of HIV negative cryptococcal meningitis with antiphospholipid syndrome / 中南大学学报(医学版)

Cryptococcal meningitis has become the largest cause for the death of infectious diseases in the central nervous system infectious disease worldwide. Most patients with cryptococcal meningitis have AIDS, autoimmune diseases, hematologic malignancies, and some other relevant diseases. It is mainly caused by infection with

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)

Visible DNA microarray and loop-mediated isothermal amplification (LAMP) for the identification of Cryptococcus species recovered from culture medium and cerebrospinal fluid of patients with meningitis

Cryptococcal meningitis affects normal hosts and immunocompromised patients exhibiting high mortality rates. The objective of this study was to design two molecular assays, visible microarray platforms and loop-mediated isothermal amplification (LAMP), to identify Cryptococcus spp. and the species neoformans and gattii from the cerebral spinal fluid (CSF). To identify Cryptococcus and the two species, we designed two microarrays DNA platforms based on the internal transcribed spacer (ITS) region and CAP59 gene and LAMP assays specific for Cryptococcus species. The assays were tested using CSF from patients with cryptococcal meningitis. CSF from patients with cryptococcal meningitis was cultured in Sabouraud culture medium, and the Cryptococcus spp. grown in the culture medium were also tested for LAMP and microarray platforms. The results were compared to DNA sequencing of the same genetic regions. A total of 133 CSF samples were studied. Eleven CSFs were positive for Cryptococcus (9 C. neoformans and 2 C. gattii), 15 were positive for bacteria, and 107 were negative. The CAP59 platform correctly identified 73% of the CSF samples, while the ITS platform identified 45.5%. CAP59 platform correctly identified 100% of the Cryptococcus isolates, and ITS platform identified 70%. The two sets of LAMP primers correctly identified 100% of the Cryptococcus isolates. However, for CSF samples, the amplification occurred only in 55.5% of C. neoformans. The methodologies were reliable in the identification of Cryptococcus species, mainly for isolates from culture medium, and they might be applied as adjunctive tests to identify Cryptococcus species.

Disseminated and cutaneous cryptococcosis by C. neoformans VNI in an immunocompetent patient / Criptococose disseminada e cutânea por C. neoformans VNI em paciente imunocompetente

ABSTRACT Cryptococcosis is caused by yeasts of the Cryptococcus neoformans/C. gattii complex, presenting cutaneous, respiratory and disseminated forms. A 44-year-old immunocompetent male with facial lesion and latent pneumonia was hospitalized and misdiagnosed with paracoccidioidomycosis. Computerized tomography scans showed pulmonary and neurological involvement, and cultures/China ink, cryptococcal antigen test and restriction fragment length polymorphism of urease gene (URA5-RFLP) confirmed C. neoformans genotype VNI. Hemoculture indicated ampicillin-resistant Klebsiella pneumoniae (healthcare-associated infection). Fluconazole was administered, but after resistance detection, amphotericin B was chosen (cumulative dose/1500 mg). The patient was discharged with clinical remission (75 days) and amphotericin for one year (maintenance phase).

RESUMEN La criptococosis es causada por levaduras del complejo Cryptococcus neoformans/C. gattii y se presenta en las formas cutánea, respiratoria y diseminada. Un hombre inmunocompetente de 44 años de edad con lesión facial y neumonía latente fue hospitalizado y erróneamente diagnosticado con paracoccidioidomicosis. Tomografías computarizadas mostraron afectación pulmonar y neurológica, y culturas/tinta china, prueba del antígeno criptocócico y URA5-polimorfismos en la longitud de los fragmentos de restricción (RFLP) confirmaron C. neoformans genotipo VNI. El hemocultivo indicó Klebsiella pneumoniae resistente a la ampicilina (infección asociada a la atención en salud). El fluconazol le fue administrado, pero tras detección de resistencia, se optó por anfotericina B (dosis acumulativa/1500 mg). Al paciente le dieron el alta en remisión clínica (75 días) y administración de anfotericina B durante un año (fase de mantenimiento).

RESUMO A criptococose é causada por leveduras do complexo Cryptococcus neoformans/C. gattii e se apresenta nas formas cutânea, respiratória e disseminada. Um homem imunocompetente de 44 anos com lesão facial e pneumonia latente foi hospitalizado e erroneamente diagnosticado com paracoccidioidomicose. Tomografias computadorizadas mostraram envolvimento pulmonar e neurológico, e culturas/tinta da China, teste do antígeno criptocócico e técnica de polimorfismo de comprimento de fragmentos de restrição dogene urease (URA5-RFLP) confirmaram C. neoformans genótipo VNI. Hemocultura indicou Klebsiella pneumoniae resistente à ampicilina (infecção relacionada com a assistência à saúde). Fluconazol foi administrado, mas após detecção de resistência, optou-se por anfotericina B (dose cumulativa/1500 mg). O paciente recebeu alta com remissão clínica (75 dias) e administração de anfotericina B por um ano (fase de manutenção).

Minimum concentration of Amphotericin B in serum according to the formulation, dose, and daily or prolonged intermittent therapeutic regimen

Abstract INTRODUCTION: The therapeutic efficacy of daily amphotericin B infusion is related to its maximum concentration in blood; however, trough levels may be useful in intermittent regimens of this antifungal drug. METHODS : High performance liquid chromatography (HPLC) was used to determine the minimum concentration (Cmin) of amphotericin B in the serum of patients receiving deoxycholate (D-Amph) or liposomal amphotericin B (L-AmB) for the treatment of cryptococcal meningitis (n=28), histoplasmosis (n=8), paracoccidioidomycosis (n=1), and leishmaniasis (n=1). RESULTS: Daily use of D-Amph 30 to 50 mg or L-AmB 50 mg resulted in a similar Cmin, but a significant increase ocurred with L-AmB 100 mg/day. The geometric mean Cmin tended to decrease with a reduction in the dose and frequency of intermittent L-AmB infusions: 357 ng/mL (100 mg 4 to 5 times/week) > 263 ng/mL (50 mg 4 to 5 times/week) > 227 ng/mL (50 mg 1 to 3 times/week). The impact on Cmin was variable in patients whose dose or therapeutic scheme was changed, especially when administered the intermittent infusion of amphotericin B. The mean Cmin for each L-AmB schedule of intermittent therapy was equal or higher than the minimum inhibitory concentration of amphotericin B against Cryptococcus isolates from 10/12 patients. The Cmin of amphotericin B in patients with cryptococcal meningitis was comparable between those that survived or died. CONCLUSIONS: By evaluating the Cmin of amphotericin B, we demonstrated the therapeutic potential of its intermittent use including in the consolidation phase of neurocryptococcosis treatment, despite the great variability in serum levels among patients.

Meningitis Criptocócica. Diferentes Contextos Clínicos Y Complicaciones. Serie De 7 Casos / Cryptococal Meningitis. Different Clinical Context And Complications. Seven Cases

Resumen Introducción: La meningitis Criptocócica (MC) es una infección grave del Sistema Nervioso Central. El diagnóstico y tratamiento de estos pacientes suele ser complejo, tanto por la severidad de las manifestaciones clínicas, como por sus complicaciones. El objetivo de este trabajo es describir los diferentes contextos clínicos, las características neuroradiológicas y las complicaciones en estos pacientes. Pacientes: Se realizó una revisión retrospectiva de los factores clínicos y radiológicos de 7 pacientes atendidos con MC durante el periodo octubre 2016 y septiembre del 2017, en el hospital Eugenio Espejo. Resultados: Predominó el sexo masculino (6/7), con una edad promedio 31,6 años (rango 19-44). El tiempo promedio que tardó el diagnóstico fue de 8,1 semanas. Se evidenciaron causas de inmunosupresión en 5 pacientes, dos VIH positivos, un caso de Leucemia Linfoblástica Aguda, linfopenia idiopática CD4 y Linfagectasia Intestinal Primaria respectivamente. La disminución de la agudeza visual, auditiva y la criptococosis diseminada se presentaron en 3 de los enfermos, con una mortalidad del 26,8%. La hipoglucorraquia fue una característica relevante de los enfermos, el promedio fue de 12,7mmg/dl. En la IRM la lesión más común fue la dilatación de los espacios de Virchow Robins (5/7), seguido de las lesiones isquémicas (2/7). Conclusiones: La MC presenta una elevada morbimortalidad, con síntomas iniciales que pueden ser inespecíficos lo que retarda el diagnóstico e inicio de los antifúngicos. Las condiciones inmunosupresoras predisponentes pueden ser múltiples y en ocasiones todo un reto diagnóstico.

Abstract Introduction: Cryptococcal meningitis (CM) is a serious infection of the Central Nervous System. The diagnosis and treatment of these patients is often complex, due to the severity of the clinical manifestations and their complications. The aim of this study is to describe the different clinical contexts, the neuroradiological characteristics and the complications of patients with CM. Patients: We performed a retrospective review of clinical and radiological factors of 7 patient's diagnosis and treated with CM during the period October 2016 and September 2017, at the Eugenio Espejo Hospital. Results: Male sex was predominant (6/7), with an average age of 31.6 years (Range 19-44). The average time for the diagnosis was 8.1 weeks. Immunosuppression causes were evidenced in 5 patients, two HIV positive, one case with Acute Lymphoblastic Leukemia, CD4 idiopathic lymphopenia and Primary Intestinal Linfagectasia respectively. Three patients developed complications as disseminated cryptococcosis, visual acuity and hearing loss, mortality rate reach 26.8% of patients. Hypoglycorrhachia was a relevant feature with average 12.7mmg / dl. In MRI, the most common lesion was dilatation of Virchow Robins spaces (5/7), followed by ischemic lesions. Conclusions: CM is characterized for high morbidity and mortality, initial symptoms may be nonspecific and delays the diagnosis as well as initiation of antifungal agents. Several predisposing immunosuppressive conditions can be found and sometimes a diagnostic challenge.

A Study on Pattern of Neurological Complications in Human Immunodeficiency Virus Infected Patients Attending a Tertiary Care Center in South Tamil Nadu, India

background: Highly active antiretroviral therapy and adequate chemoprophylaxis for opportunistic infections for humanimmunodeficiency virus (HIV) infected patients have led to increasing survival in people living with HIV/AIDS. The nervous systemis among the most frequent and serious targets of HIV infection. 40–70% of all persons infected with HIV develop symptomaticneurological disorders. This study was undertaken to study the diverse clinical presentations of neurologic abnormalities in HIVpatients admitted in a tertiary care center in South Tamil Nadu.Materials and Methods: A prospective study was conducted for 2 years in HIV-infected patients who were admitted at a tertiarycare hospital were subjected to thorough neurological evaluation and those with symptoms referring to neurological illnesswere enrolled, and clinical signs and symptoms were noted. CD4 counts of all the cases were performed by FACS counter,and neuroimaging study was performed on necessary cases.Results: A total of 71 cases with 74.6% males and 25.4% females were enrolled. Mean age for males 34.6 years; for females31.1 years. Headache was the most common symptom (67.3%) followed by altered sensorium (40.8%). Central nervous system(CNS) tuberculosis (TB) is the most common disease in patients presenting with neurological abnormalities (42.25%). Thereis a significant correlation between the levels of CD4 counts and the type of neurological manifestations.Conclusions: Incidence of neurological illness in HIV infection was 41.7%. Opportunistic infections are the leading cause ofneurological disorders in our population. Meningitis was the most common neurological presentation (57.7%). TB is the singlemost common organism affecting CNS (42.2%).

Pattern of HIV infected meningitis patient investigated in a tertiary care institute of eastern India

Background: This study was started in the aim of determining the pattern of meningitis and their clinico-laboratorial presentation among HIV infected patients.Methods: This secondary data based cross-sectional study was conducted on 2010 in a tertiary care institute of eastern India among HIV infected meningitis patients. From June 2009 to May 2010, 92 patients were included in our study. Bed head tickets, laboratory reports and registers were used for data collection. Chi square test was applied for the test of significance.Results: 70.7% cryptococcal and 29.3% tubercular meningitis cases were found. Mean CD4 cell count, CSF protein, CSF glucose, WBC cell count of TB and cryptococcal meningitis patients were 143 cells/cumm, 546.1 mg/dl, 26.8 mg/dl, 550 cells/ cumm and 175 cells/ cumm, 189.1 mg/dl, 30.1 mg/dl, 36 cells/ cumm respectively. 29.2% patients of Cryptococcal meningitis were presented with mental change, confusion or psychological disorders, but these symptoms were not observed among TB meningitis patients.Conclusions: This study provided a baseline data about epidemiology and clino-laboratorial features of HIV meningitis patients of eastern India and will help for further investigation in this field.

Epidemiological and TNFα polymorphism evaluation in patients with cryptococcal meningitis treated at a referral hospital in North Brazil

Abstract INTRODUCTION: The present study evaluated the epidemiology of cryptococcal meningitis and TNFα gene polymorphisms in patients at a reference hospital in northern Brazil. METHODS: Samples from 25 patients infected with Cryptococcus spp. were collected to confirm the infection and to analyze the TNFα gene polymorphisms. RESULTS: Cryptococcus neoformans was detected as the predominant etiological agent (100%) in HIV-positive patients. No genetic polymorphic changes were found. CONCLUSIONS: No correlation was observed between the analyzed TNFα polymorphisms and cryptococcal meningitis.

Drug development for cryptococcosis treatment: what can patents tell us?

BACKGROUND Cryptococcosis is one of the most devastating fungal infections in humans. Despite the disease's clinical importance, current therapy is based on limited antifungals that are either toxic, inefficient, unavailable worldwide, or that quickly lead to resistance. OBJECTIVES The goal of this study was to provide insight into the future of cryptococcosis treatment by describing the patent scenario in this field. METHODS We identified and analysed patent documents revealing compounds with anti-cryptococcal activity supported by experimental evidence. FINDINGS Patenting in this field has been historically low, with an overall tendency of increase since 2012. Most applications are single filings, suggesting that they do not encompass strategic inventions requiring broad protection. Research and development essentially took place in China and the United States, which also represent the main countries of protection. Both academic and corporate institutions contributed to patenting in this field. Universities are the leading actors, with the highest patent family counts. CONCLUSION The low number of patents in this field indicates that efforts to mitigate the unmet needs for cryptococcosis treatment remain insufficient. Without investment to drive research and innovation, patients will likely continue to face inadequate assistance. Given the current scenario characterised by poor funding and low interest for technological development, drug repurposing may be the best alternative for cryptococcosis treatment.

A study on clinical profile of neurological manifestations among HIV infected patients attending a tertiary care hospital of south India

Background: Current statistics show that 36.9 million (31.1-43.9 million) people were living with HIV globally at the end of 2017. 15-73% of people with HIV may develop neurological disorders with sometimes as a presenting illness. The aim of present study is to document the various neurological manifestations and presentations with relation to CD4 counts among the HIV/AIDS cases attending a tertiary care hospital of south India.Methods: A prospective study was conducted for two years at a tertiary care hospital among confirmed cases of HIV and the neurological manifestations were diagnosed and clinical signs and symptoms were noted. CD4 counts of all the cases were performed by FACS counter and Neuroimaging study was performed on necessary cases.Results: Total of 125 cases with 69.6% males and 30.4% females were enrolled. Mean age of cases was 35.14±3.8years. 86.4% were positive for HIV-1 type. Headache was the most common ailment (78.4%). Meningeal enhancement observed in 24.5% followed in order by ring enhancing lesion (18.37%), cerebral atrophy and infarction (12.24%). Tubercular meningitis was the commonest type (33.6%). In 12 cases of cryptococcal meningitis the CD4 counts were <100 cells/mm3.Conclusions: To conclude in present study, secondary neurological manifestations were more common than primary manifestations in present study. Tubercular meningitis being the most common and CD4 counts <100cells/mm3 were associated with cryptococcal meningitis. Cases with CD4 counts less than 100cells/mm3 had poor prognosis.

Meningoencefalitis criptocóccica refractaria en una mujer joven

RESUMEN Mujer de 23 años presenta hace 2 meses cefalea que se acompaña de visión borrosa, disartria y pérdida de la conciencia. Por líquido cefalorraquídeo se confirma meningitis a criptococo. A pesar del tratamiento con anfotericina B y fluconazol presenta empeoramiento general. Durante su evolución presentó paracoccidioidomicosis pulmonar y candidiasis vaginal. A pesar de la terapia dirigida, la paciente fallece con la tardía confirmación de una inmunodeficiencia variable común.

ABSTRACT A 23-year-old woman has been presenting headache for two months that is accompanied by blurred vision, dysarthria and loss of consciousness. Cerebrospinal fluid confirms meningitis to Cryptococcus. In spite of the treatment with amphotericin B and fluconazole she presents a general deterioration. During her evolution she presented pulmonary paracoccidiomycosis and vaginal candidiasis. Despite specific therapy, the patient dies with the late confirmation of a common variable immunodeficiency.

Comparison and Correlation of Magnetic Resonance Imaging and Clinical Severity in Nonhuman Immunodeficiency Virus Patients with Cryptococcal Infection of Central Nervous System / 中华医学杂志(英文版)

Background@#The incidence of cryptococcal meningitis among immunocompetent patients increases, especially in China and imaging plays an important role. The current study was to find the correlation between magnetic resonance imaging (MRI) manifestation and clinical severity in nonhuman immunodeficiency virus patients with cryptococcal infection of central nervous system (CNS).@*Methods@#A total of 65 patients with CNS cryptococcal infection from August 2014 to October 2016 were retrospectively included in this study. All the patients had MRI data and clinical data. The patients were divided into two groups according to whether the patients were confirmed with identifiable underlying disease. Comparison and correlation of MRI and clinical data in both groups were investigated using independent sample t- test, Chi-square test, Mann-Whitney test and Spearman rank correlation analysis.@*Results@#In all 65 patients, 41 cases (41/65, 63.1%; Group 1) had normal immunity and 24 cases (24/65, 36.9%; Group 2) had at least one identifiable underlying disease. Fever, higher percentage of neutrophil (NEUT) in white blood cell (WBC), and increased cell number of cerebral spinal fluid (CSF) were much common in patients with underlying disease (Group 1 vs. Group 2: Fever: 21/41 vs. 21/24, χ = 8.715, P = 0.003; NEUT in WBC: 73.15% vs. 79.60%, Z = -2.370, P = 0.018; cell number of CSF: 19 vs. 200, Z = -4.298, P < 0.001; respectively). Compared to the patients with normal immunity, the lesions are more common in the basal ganglia among patients with identifiable underlying disease (Group 1 vs. Group 2: 20/41 vs. 20/24, χ = 7.636, P = 0.006). The number of the involved brain areas in patients with identifiable underlying disease were well correlated with the number of cells and pressure of CSF (r = -0.472, P = 0.031; r = 0.779, P = 0.039; respectively).@*Conclusions@#With the increased number of the involved brain areas in patients with identifiable underlying disease, the body has lower immunity against the organism which might result in higher intracranial pressure and more severe clinical status.