Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Autoantibodies neutralizing GM-CSF in HIV-negative Colombian patients infected with Cryptococcus gattii and C. neoformans.

Background: Cryptococcosis is a life-threatening disease caused by Cryptococcus neoformans or C. gattii. Autoantibodies (auto-Abs) neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) in otherwise healthy adults with cryptococcal meningitis have been described since 2013. We searched for neutralizing auto-Abs in sera from Colombian patients with non-HIV related cryptococcosis in a retrospective national cohort collected from 1997 to 2016. Methods: We reviewed clinical and laboratory records and assessed the presence of neutralizing auto-Abs in 30 HIV (-) adults presenting cryptococcosis (13 by C. gattii, and 17 by C. neoformans). Results: We detected auto-Abs neutralizing GM-CSF in the plasma of 9 out of 13 (69%) patients infected with C. gattii and 1 out of 17 (6%) patients with C. neoformans. Conclusions: We report ten Colombian patients with cryptococcosis due to auto-Abs neutralizing GM-CSF. Nine of the ten patients were infected with C. gattii, and only one with C. neoformans.

Indirect impact of PCV10 children vaccination on the serotype distribution and antimicrobial resistance of Streptococcus pneumoniae causing invasive disease in adults over 50 in Colombia, 2005-2019: Observational analysis.

INTRODUCTION: The introduction of pneumococcal conjugate vaccine (PCV) into childhood vaccination programmes has reduced the prevalence of vaccine serotypes (VTs) that cause invasive pneumococcal disease (IPD) in children. In the elderly population, an impact has also been seen through indirect protection (herd effect). The aim of this study was to estimate the changes in serotype distribution and antimicrobial susceptibility of Streptococcus pneumoniae isolates recovered from adult IPD and to evaluate the indirect effect of immunization with PCV10 based on laboratory records by analyzing the period from 2005 to 2019 for six years before and eight years after the universal PCV10 administration to Colombian children. METHODS: A total of 2204 S. pneumoniae isolates from adults (≥50 years) with IPD were analyzed. The analysis examined the percentage changes in proportions (prevalence) and percentage variations in population rates (annual reported rates - ARR) of VTs between the pre-PCV10 (2005-2009) and post-PCV10 (2015-2019) periods. RESULTS: The findings were (1) evidence of a significant percentage decrease of pneumococcal VT10 causing IPD in adults (50% pre-PCV10 and 16% post-PCV10); (2) significant increase of serotype 19A (from 1.6% to 14.8%) and less important increase of serotype 3 (from 10.5% to 14.5%) and non-vaccine serotypes (NVT) (from 21.4% to 38.4%) non-significant; and (3) meningitis and non-meningitis multidrug resistant isolates associated with serotype 19A. An improvement in the surveillance system is associated with the immunization of children, as noted by the increased ARRs across the analysis period. CONCLUSIONS: Our results show the indirect impact of PCV10 vaccination in children on the VT10 distribution and antimicrobial resistance of S. pneumoniae causing IPD in Colombian adults over 50 when comparing the pre-PCV10 (2005-2009) and post-PCV10 (2015-2019) periods.

Central Nervous System Cryptococcosis due to Cryptococcus gattii in the Tropics.

Purpose of Review: Cryptococcosis of the central nervous system due to Cryptococcus gattii species complex is a serious mycosis with worldwide distribution but of great importance in the tropics. This article aims to review the progress made in these regions in the knowledge of this disease and its etiological agent. Recent Findings: They can be summarized in the presence in apparently immunocompetent patients of autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), which is a hidden risk factor for acquiring C. gattii infection; this finding strengthens the concept that C. gattii is an opportunistic pathogen. A greater knowledge of the clinical and molecular epidemiology of C. gattii infection and of the different environmental niches of this fungus in the tropics. The discovery of a new lineage of C. gattii, VGV, in environmental samples from Africa. Until now, the COVID-19 pandemic has not meant an increase in cryptococcosis cases. Summary: Advances have been made in the identification of risk factors for cryptococcosis due to C. gattii as well as in the knowledge of its etiological agent and its relationship with the environment. Remarkably, there have been no significant achievements in diagnosis and treatment notwithstanding the documented importance.

Cryptococcus neoformans and Cryptococcus gattii Species Complexes in Latin America: A Map of Molecular Types, Genotypic Diversity, and Antifungal Susceptibility as Reported by the Latin American Cryptococcal Study Group.

Cryptococcosis, a potentially fatal mycosis, is caused by members of the Cryptococcus neoformans and Cryptococcus gattii species complexes. In Latin America, cryptococcal meningitis is still an important health threat with a significant clinical burden. Analysis of publicly available molecular data from 5686 clinical, environmental, and veterinary cryptococcal isolates from member countries of the Latin American Cryptococcal Study Group showed that, as worldwide, C. neoformans molecular type VNI is the most common cause of cryptococcosis (76.01%) in HIV-infected people, followed by C. gattii molecular type VGII (12.37%), affecting mostly otherwise healthy hosts. These two molecular types also predominate in the environment (68.60% for VNI and 20.70% for VGII). Among the scarce number of veterinary cases, VGII is the predominant molecular type (73.68%). Multilocus sequence typing analysis showed that, in Latin America, the C. neoformans population is less diverse than the C. gattii population (D of 0.7104 vs. 0.9755). Analysis of antifungal susceptibility data showed the presence of non-wild-type VNI, VGI, VGII, and VGIII isolates in the region. Overall, the data presented herein summarize the progress that has been made towards the molecular epidemiology of cryptococcal isolates in Latin America, contributing to the characterization of the genetic diversity and antifungal susceptibility of these globally spreading pathogenic yeasts.

The direct effect of pneumococcal conjugate vaccines on invasive pneumococcal disease in children in the Latin American and Caribbean region (SIREVA 2006-17): a multicentre, retrospective observational study.

BACKGROUND: Streptococcus pneumoniae isolated from patients with invasive pneumococcal disease has been subjected to laboratory-based surveillance in Latin American and Caribbean countries since 1993. Invasive pneumococcal diseases remain a major cause of death and disability worldwide, particularly in children. We therefore aimed to assess the direct effect of pneumococcal conjugate vaccines (PCVs) on the distribution of pneumococcal serotypes causing invasive pneumococcal disease in children younger than 5 years before and after PCV introduction. METHODS: We did a multicentre, retrospective observational study in eight countries that had introduced PCV (ie, PCV countries) in the Latin American and Caribbean region: Argentina, Brazil, Chile, Colombia, Dominican Republic, Mexico, Paraguay, and Uruguay. Cuba and Venezuela were also included as non-PCV countries. Isolate data for Streptococcus pneumoniae were obtained between 2006 and 2017 from children younger than 5 years with an invasive pneumococcal disease from local laboratories or hospitals. Species' confirmation and capsular serotyping were done by the respective national reference laboratories. Databases from the Sistema Regional de Vacunas (SIREVA) participating countries were managed and cleaned in a unified database using Microsoft Excel 2016 and the program R (version 3.6.1). Analysis involved percentage change in vaccine serotypes between pre-PCV and post-PCV periods and the annual reporting rate of invasive pneumococcal diseases per 100 000 children younger than 5 years, which was used as a population reference to calculate percentage vaccine type reduction. FINDINGS: Between 2006 and 2017, 12 269 isolates of invasive pneumococcal disease were collected from children younger than 5 years in the ten Latin American and Caribbean countries. The ten serotypes included in ten-valent pneumococcal conjugate vaccine (PCV10) decreased significantly (p<0·0001) after any PCV introduction, except for the Dominican Republic. The percentage change for the ten vaccine serotypes in PCV10 countries was -91·6% in Brazil (530 [72·9%] of 727 before, 27 [6·1%] of 441 after); -85·0% in Chile (613 [72·6%] of 844 before, 44 [10·9%] of 404] after); -84·7% in Colombia (231 [63·1%] of 366 before, 34 [9·7%] of 352 after); and -73·8% in Paraguay (127 [77·0%] of 165 before, 22 [20·2%] of 109 after). In the 13-valent pneumococcal conjugate vaccine (PCV13) countries, the percentage change for the 13 vaccine serotypes was -59·6% in Argentina (853 [85·0%] of 1003 before, 149 [34·3%] of 434 after); -16·5% in the Dominican Republic (95 [80·5%] of 118 before, 39 [67·2%] of 58 after); -43·7% in Mexico (202 [73·2%] of 276 before, 63 [41·2%] of 153 after); and -45·9% in Uruguay (138 [80·7%] of 171 before, 38 [43·7%] of 87 after). Annual reporting rates showed a reduction from -82·5% (6·21 before vs 1·09 after per 100 000, 95% CI -61·6 to -92·0) to -94·7% (1·15 vs 0·06 per 100 000, -89·7 to -97·3) for PCV10 countries, and -58·8% (2·98 vs 1·23 per 100 000, -21·4 to -78·4) to -82·9% (7·80 vs 1·33 per 100 000, -76·9 to -87·4) for PCV13 countries. An increase in the amount of non-vaccine types was observed in the eight countries after PCV introduction together with an increase in their percentage in relation to total invasive strains in the post-PCV period. INTERPRETATION: SIREVA laboratory surveillance was able to confirm the effect of PCV vaccine on serotypes causing invasive pneumococcal disease in the eight PCV countries. Improved monitoring of the effect and trends in vaccine type as well as in non-vaccine type isolates is needed, as this information will be relevant for future decisions associated with new PCVs. FUNDING: None. TRANSLATIONS: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.

[Regional System for Vaccines (SIREVA), laboratory surveillance and vaccine development for Streptococcus pneumoniae: bibliometric analysis, 1993-2019]. / Sistema Regional de Vacunas (SIREVA), vigilancia por laboratorio y desarrollo de vacunas para Streptococcus pneumoniae: análisis bibliométrico, 1993-2019.

OBJECTIVE: To measure through bibliometric analysis the productivity, visibility and impact of the Regional System for Vaccines (SIREVA, a project by the Pan American Health Organization), including its two components laboratory surveillance and vaccine development. METHODS: Publications about laboratory surveillance and vaccine development were recovered from Scopus, including their references and citations, and their bibliometric indicators were analyzed. VOSviewer 1.6.13® was used to visualize the co-authorship networks, by country and authors, and to perform a cooccurrence analysis of terms included in the titles and abstracts of the publications. RESULTS: The criteria for laboratory surveillance and vaccine development were met by 173 and 128 publications, respectively. Ten countries in the Region of the Americas were responsible for 90.8% of the publications on laboratory surveillance and 8 for all publications on vaccine development. The 10 most cited publications on laboratory surveillance and on vaccine development were included in 855 and 503 articles, respectively, the main authors being from Australia, Belgium, Brazil, China, Germany, the United Kingdom and the United States of America. Network building and visualization by author and country co-authors, and co-occurrence of terms showed networking and intraregional collaboration, and allowed for the follow-up of study areas and evolution over time. CONCLUSIONS: The bibliometric analysis allowed to objectively record the productivity and visibility of the Regional System for Vaccines for Streptococcus pneumoniae in the Region.

Sistema Regional de Vacunas (SIREVA), vigilancia por laboratorio y desarrollo de vacunas para Streptococcus pneumoniae: análisis bibliométrico, 1993-2019

[RESUMEN]. Objetivo. Medir a través del análisis bibliométrico la productividad, la visibilidad y el impacto del Sistema Regional de Vacunas (SIREVA, un proyecto de la Organización Panamericana de la Salud) en sus dos componentes, la vigilancia por laboratorio y el desarrollo de vacunas. Métodos. Se recuperaron de Scopus las publicaciones correspondientes a vigilancia por laboratorio y desarrollo de vacunas con sus referencias y citas y se aplicó la herramienta para obtener los indicadores bibliométricos. Se utilizó VOSviewer® 1.6.13 para visualizar las redes de coautoría por país y autores, y para realizar un análisis de coocurrencia de términos incluidos en los títulos y resúmenes de las publicaciones. Resultados. Cumplieron los criterios establecidos para vigilancia por laboratorio y desarrollo de vacunas 173 y 128 publicaciones, respectivamente. Diez países de la Región fueron responsables de 90,8% de las publicaciones sobre vigilancia por laboratorio y 8 países de todas las publicaciones sobre desarrollo de vacunas. Las diez publicaciones más citadas sobre vigilancia por laboratorio y sobre desarrollo de vacunas estaban incluidas en 855 y 503 artículos, respectivamente; los principales autores se encontraban en Alemania, Australia, Bélgica, Brasil, China, Estados Unidos de América y el Reino Unido. La construcción y visualización de redes por coautorías de autores y países, y la coocurrencia de términos mostraron el trabajo en red y la colaboración intrarregional, así como permitieron hacer seguimiento a las diversas áreas de estudio y su evolución en el tiempo. Conclusiones. El análisis bibliométrico permitió documentar de manera objetiva la productividad y visibilidad del Sistema Regional de Vacunas para Streptococcus pneumoniae en la Región.

[ABSTRACT]. Objective. To measure through bibliometric analysis the productivity, visibility and impact of the Regional for Vaccines (SIREVA, a project by the Pan American Health Organization), including its two components laboratory surveillance and vaccine development. Methods. Publications about laboratory surveillance and vaccine development were recovered from Scopus, including their references and citations, and their bibliometric indicators were analyzed. VOSviewer 1.6.13® was used to visualize the co-authorship networks, by country and authors, and to perform a cooccurrence analysis of terms included in the titles and abstracts of the publications. Results. The criteria for laboratory surveillance and vaccine development were met by 173 and 128 publications, respectively. Ten countries in the Region of the Americas were responsible for 90.8% of the publications on laboratory surveillance and 8 for all publications on vaccine development. The 10 most cited publications on laboratory surveillance and on vaccine development were included in 855 and 503 articles, respectively, the main authors being from Australia, Belgium, Brazil, China, Germany, the United Kingdom and the United States of America. Network building and visualization by author and country co-authors, and co-occurrence of terms showed networking and intraregional collaboration, and allowed for the follow-up of study areas and evolution over time. Conclusions. The bibliometric analysis allowed to objectively record the productivity and visibility of the Regional System for Vaccines for Streptococcus pneumoniae in the Region.

Prevalence of cryptococcosis in Atlántico, department of Colombia assessed with an active epidemiological search.

INTRODUCTION: Cryptococcosis is the second most frequent cause of opportunistic infections in human immunodeficiency virus (HIV) patients in Colombia. We aimed to determine the prevalence of cryptococcosis in the Colombian department of Atlántico. METHODS: An active search for cryptococcosis cases was conducted between 2015 and 2017 in health institutions by distributing surveys to clinicians and characterizing samples phenotypically and genotypically. RESULTS: Thirty-eight cryptococcosis cases were identified (81.6% men, 76.3% HIV patients). The calculated annual prevalence was 5.08/1 million inhabitants. Cryptococcus neoformans var. grubii VNI was isolated in 34 cases. CONCLUSIONS: These results provide the basis for passive surveillance of cryptococcosis.

Fatal neurocryptococcosis in a Colombian underage patient.

Cryptococcosis is a life-threatening mycosis reported mainly in human adults with low frequency in children. High mortality rates may occur in cases with late diagnosis therefore, a timely suspicion of this pathology is important. Cryptococcus gattii is the less prevalent species complex predominantly isolated from apparently normal hosts. We report a fatal case of neurocryptococcosis in a Colombian minor without known risk factors, in Barranquilla, Colombia. The patient was hospitalized for neurological assessment with a recent history of intense headache, vomiting, anorexia, loss of consciousness, drowsiness, inability to recognize family members, disorientation, aphasia and anxiety. Despite initiating antifungal treatment after isolation of the fungus from cerebrospinal fluid (CSF), the patient died early due to his deteriorated condition.

Prevalence of cryptococcosis in Atlántico, department of Colombia assessed with an active epidemiological search

Abstract INTRODUCTION Cryptococcosis is the second most frequent cause of opportunistic infections in human immunodeficiency virus (HIV) patients in Colombia. We aimed to determine the prevalence of cryptococcosis in the Colombian department of Atlántico. METHODS An active search for cryptococcosis cases was conducted between 2015 and 2017 in health institutions by distributing surveys to clinicians and characterizing samples phenotypically and genotypically. RESULTS Thirty-eight cryptococcosis cases were identified (81.6% men, 76.3% HIV patients). The calculated annual prevalence was 5.08/1 million inhabitants. Cryptococcus neoformans var. grubii VNI was isolated in 34 cases. CONCLUSIONS These results provide the basis for passive surveillance of cryptococcosis.

Genotypic Diversity Is Independent of Pathogenicity in Colombian Strains of Cryptococcus neoformans and Cryptococcus gattii in Galleria mellonella.

Cryptococcosis is a potentially fatal opportunistic mycosis that affects the lungs and central nervous system. It has been suggested that certain strains of C. neoformans/C. gattii may have the potential to be more virulent according to the molecular type. This study aims to investigate the association between virulence in the G. mellonella model and genotypic diversity of Colombian clinical and environmental isolates of C. neoformans/C. gattii. A total of 33 clinical and 12 environmental isolates were selected according to their geographical origin and sequence types (STs). Pathogenicity was determined using the G. mellonella model, and the cell and capsular size before and after inoculation was determined. For C. neoformans, virulence in G. mellonella revealed that death occurred on average on day 6 (p < 0.05) and that ST5C, 6C, 25C and 71C were the most virulent. In C. gattii, death occurred at 7.3 days (p < 0.05), and ST47C, 58C, 75A and 106C were the most virulent. Capsular size increased for both species after passage in G. mellonella. In conclusion, the pathogenicity of Cryptococcus strains in the G. mellonella invertebrate model is independent of molecular type or pathogenicity factor, even within the same ST, but it is possible to find variable degrees of pathogenicity.

Streptococcus pneumoniae serotype 19A in Latin America and the Caribbean 2010-2015: A systematic review and a time series analysis.

BACKGROUND: This systematic review aims to describe the prevalence, trends, and antibiotic resistance of Streptococcus pneumoniae serotype 19A (Spn19A) that causes invasive and non-invasive diseases in children <5 years in Latin-American and Caribbean countries. METHODS: We searched for published (between January 2010 and February 2016) observational and clinical studies within the region including effectiveness and impact on Spn19A after pneumococcal conjugate vaccine (PCV) introduction. We calculated prevalence estimates by country and standardized the frequency of isolates to conduct an interrupted time series analysis for selected countries and to assess the potential changes in disease trends, overall and for Spn19A. RESULTS: We identified and reviewed full-text of 89 publications and included 59 in the analysis. Data from the laboratory surveillance network, SIREVA, were included in 43 (74%) of the invasive pneumococcal disease reports. There are differences in the sensitivity, representativeness, and heterogeneity of laboratory surveillance. There has been and overall reduction in the trend and number of invasive S. pneumoniae isolates in children <5 years after PCVs introduction. To date, the prevalence of Spn19A has increased, however, there has been no observed change in the trend. CONCLUSIONS: This updated systematic review provides evidence of a reduction in the total number of invasive pneumococcal disease isolates after the introduction of PCVs in the region but cannot yet conclude a change in the trend of Spn19A disease.

The status of cryptococcosis in Latin America.

Cryptococcosis is a life-threatening fungal infection caused by the encapsulated yeasts Cryptococcus neoformans and C. gattii, acquired from the environment. In Latin America, as occurring worldwide, C. neoformans causes more than 90% of the cases of cryptococcosis, affecting predominantly patients with HIV, while C. gattii generally affects otherwise healthy individuals. In this region, cryptococcal meningitis is the most common presentation, with amphotericin B and fluconazole being the antifungal drugs of choice. Avian droppings are the predominant environmental reservoir of C. neoformans, while C. gattii is associated with several arboreal species. Importantly, C. gattii has a high prevalence in Latin America and has been proposed to be the likely origin of some C. gattii populations in North America. Thus, in the recent years, significant progress has been made with the study of the basic biology and laboratory identification of cryptococcal strains, in understanding their ecology, population genetics, host-pathogen interactions, and the clinical epidemiology of this important mycosis in Latin America.

Cryptococcosis in Colombia: Compilation and Analysis of Data from Laboratory-Based Surveillance.

The passive and voluntary surveillance of cryptococcosis in Colombia since 1997 has seen an increasing participating rate, revealing its importance to both in immunosuppressed and immunocompetent people. The present work details the national data gathered in 1997-2016, through a retrospective analysis of the information collected in the survey. From a total of 1974 cases reported, an overall incidence of 0.23 cases per 100,000 people was found. This incidence rose to 1.1 cases per 1000 people in the Acquired Immunodeficiency Syndrome (AIDS) population. Cryptococcosis was most common in male young adults (26-40 years), with a male:female ratio of 3.9:1 in the general population and 5.4:1 in Human Immunodeficiency Virus (HIV) patients. Culture was the most common form of diagnosis in 96.3% of cases, recovering C. neoformans species in 87.5% and C. gattii in 3.1% of samples. VNI was the most prevalent (96.1%) molecular type, while VGII predominated in C. gattii isolates (54.3%). Early mortality was reported as the outcome in 47.5% of patients. Cryptococcosis remains an important opportunistic disease in Colombia and is gaining status as a primary pathogen in apparently immunocompetent patients. Our findings show the importance of including cryptococcosis as a notifiable disease, which will allow for improving opportune diagnosis and treatment, resulting in better patient outcomes.

Fatal Cryptococcus gattii genotype VGI infection in an HIV-positive patient in Barranquilla, Colombia.

Cryptococcosis is a major invasive fungal disease related worldwide with the AIDS population. New reports of HIV/AIDS cases to the national public health surveillance system (SIVIGILA) in Colombia have shown that there is a growing community at risk of contracting cryptococcosis throughout the country who do not have access to ART. Even though the most prevalent species Cryptococcus neoformans is mainly associated with the HIV population, we report a fatal case of cryptococcosis in an AIDS patient in Barranquilla, associated with Cryptococcus gattii VGI, isolated from blood culture.

The Case for Adopting the "Species Complex" Nomenclature for the Etiologic Agents of Cryptococcosis.

Cryptococcosis is a potentially lethal disease of humans/animals caused by Cryptococcus neoformans and Cryptococcus gattii. Distinction between the two species is based on phenotypic and genotypic characteristics. Recently, it was proposed that C. neoformans be divided into two species and C. gattii into five species based on a phylogenetic analysis of 115 isolates. While this proposal adds to the knowledge about the genetic diversity and population structure of cryptococcosis agents, the published genotypes of 2,606 strains have already revealed more genetic diversity than is encompassed by seven species. Naming every clade as a separate species at this juncture will lead to continuing nomenclatural instability. In the absence of biological differences between clades and no consensus about how DNA sequence alone can delineate a species, we recommend using "Cryptococcus neoformans species complex" and "C. gattii species complex" as a practical intermediate step, rather than creating more species. This strategy recognizes genetic diversity without creating confusion.

Fatal Cryptococcus gattii genotype VGI infection in an HIV-positive patient in Barranquilla, Colombia

ABSTRACT Cryptococcosis is a major invasive fungal disease related worldwide with the AIDS population. New reports of HIV/AIDS cases to the national public health surveillance system (SIVIGILA) in Colombia have shown that there is a growing community at risk of contracting cryptococcosis throughout the country who do not have access to ART. Even though the most prevalent species Cryptococcus neoformans is mainly associated with the HIV population, we report a fatal case of cryptococcosis in an AIDS patient in Barranquilla, associated with Cryptococcus gattii VGI, isolated from blood culture.