Cryptococcosis is a severe fungal infection primarily caused by two encapsulated yeasts: Cryptococcus neoformans and C. gattii. The most significant complication is cryptococcal meningitis, where the fungus crosses the blood-brain barrier, leading to a severe brain infection. Current treatments, which include amphotericin B and flucytosine or fluconazole, are often toxic and not very effective. Therefore, there is a pressing need for new antifungal agents. This study screened 30 thiazole derivatives for their antifungal activity against Cryptococcus and their toxicity to brain cells. Four compounds (RN86, RN88, RJ37, and RVJ42) showed particularly strong effects. These compounds reduced ergosterol levels in the fungal membrane and inhibited its ability to cross the blood-brain barrier. Notably, RN86 and RVJ42 improved survival rates in a mouse model of cryptococcosis by lowering the fungal load in the lungs and brain. These findings suggest that these derivatives could be promising treatments for pulmonary and neurocryptococcosis.

Cryptococcosis is an invasive fungal infection caused by yeasts of the genus Cryptococcus that causes a significant global burden of disease in both immunocompromised and immunocompetent individuals. Over the past several decades, diagnosis and management of cryptococcal disease have moved to focus on rapid, reliable, and cost-effective care delivery, with the advent of new antigen detection assays and novel antifungal treatment strategies.

Patients with liver disease in the intensive care unit (ICU) face a unique susceptibility to infection due to the complex immune dysfunction resulting from hepatic failure. Bacterial infections are commonly present in these patients upon arrival to the hospital, often being the primary reason for ICU admission. In contrast, invasive fungal infections (IFIs) afflict a smaller percentage of patients and are usually discovered in the course of the ICU stay. IFI diagnosis in the ICU, particularly in patients with liver disease, is often delayed or overlooked, contributing to the extremely high ICU mortality associated with IFI in these patients despite the availability of effective (and largely safe) antifungal therapy. Thus, to improve outcomes, it is crucial for intensive care clinicians to be vigilant for IFIs in patients with liver disease. This review aims to contribute to the intensive care literature in this regard. We begin with an overview of normal antifungal immunity followed by a summary of how it may become compromised in the setting of hepatic dysfunction. Next, a general discussion of IFIs in liver disease is presented and then the three most relevant fungal pathogens, namely Candida, Aspergillus, and Cryptococcus, are individually examined. This review concludes by highlighting key knowledge and practice gaps that require attention by the scientific and clinical communities in the coming years.

Cryptococcal meningitis is an important global health problem, resulting from infection with the yeast Cryptococcus, especially Cryptococcus neoformans and Cryptococcus gattii, which cause a spectrum of disease ranging from pulmonary and skin lesions to life-threatening central nervous system involvement. The diagnosis and management of cryptococcal meningitis have substantially changed in recent years. Cryptococcal meningitis often occurs in people living with advanced HIV infection, though in high-income countries with robust HIV detection and treatment programmes, it increasingly occurs in other groups, notably solid-organ transplant recipients, other immunosuppressed patients and even immunocompetent hosts. This review outlines the clinical presentation, management and prognosis of cryptococcal meningitis, including its salient differences in people living with HIV compared with HIV-negative patients. We discuss the importance of managing raised intracranial pressure and highlight the advantages of improved multidisciplinary team working involving neurologists, infectious disease specialists and neurosurgeons.

In immunocompromised patients, pneumonia presents a diagnostic challenge due to diverse etiologies, nonspecific symptoms, overlapping radiological presentation, frequent co-infections, and the potential for rapid progression to severe disease. Thus, timely and accurate diagnosis of all pathogens is crucial. This narrative review explores the latest advancements in microbiological diagnostic techniques for pneumonia in immunocompromised patients. It covers major available microbiological tools for diagnosing both community-acquired and hospital-acquired pneumonia, encompassing a wide spectrum of pathogens including bacterial, viral, fungal, and parasitic. While traditional culture methods remain pivotal in identifying many pneumonia-causing etiologies, their limitations in sensitivity and time to results have led to the rise of non-invasive antigen tests and molecular diagnostics. These are increasingly employed alongside cultures and microscopy for more efficient diagnosis, mainly in viral and fungal infections. Lastly, we report the future of pneumonia diagnostics, exploring the potential of metagenomics and CRISPR/Cas13a for more precise and rapid pathogen detection in immunocompromised populations.

Cryptococcal meningitis is mainly seen in immunocompromised patients, but in recent years, there has been an increase in cases involving patients with no known immunodeficiencies. These patients have symptomatic presentations that range from indolent and mild to typical and severe. We present a case of cryptococcal meningitis in an immunocompetent young patient with a chronic headache. The patient underwent imaging which showed diffuse leptomeningeal enhancement and a lumbar puncture which confirmed Cryptococcus neoformans. She underwent guideline-based treatment for cryptococcal meningitis and improved clinically. Cryptococcal meningitis should be considered in immunocompetent patients who present with typical signs of symptoms of meningitis, particularly chronic headaches and altered mental status.

Follow-up of previously healthy patients surviving cryptococcal meningitis found that cryptococcal antigen could be detected for >1 year in serum from 38 of 44 (86%) patients and in cerebrospinal fluid (CSF) from 20 of 31 patients (67%), far beyond the time of culture conversion. The speed of titer decline, measured as the number of days for a 2-fold drop in titer to occur, was slower in serum than in CSF. The speed of decline of antigen titers was much slower in serum and CSF for patients infected with Cryptococcus gattii than Cryptococcus neoformans. The speed of decline in CSF and serum titers was also much slower in patients who had received a ventriculoperitoneal shunt for increased intracranial pressure. The variable and extraordinarily slow rate of clearance in our patients did not appear to reflect differences in disease control but rather differences in species and shunting for increased intracranial pressure.

Cryptococcus is an opportunistic infection acquired through inhalation from the environment, primarily affecting individuals with compromised immune systems. It typically leads to pneumonia upon passing through lung tissue. The infection can disseminate to various organs via the bloodstream, resulting in meningitis or encephalitis in the central nervous system. Disseminated Cryptococcus has been reported to involve the skin, liver, eyes, lymph nodes, bone marrow, spleen, kidneys, and intestines, significantly increasing morbidity and mortality. However, pancreatic involvement in Cryptococcus is relatively rare, and a few case reports have highlighted severe organ damage and high mortality rates.

In this case report, we present the case of a 36-year-old Asian man who presented with a 2-week history of headaches and blurred vision in his right eye. Brain magnetic resonance imaging revealed multiple brain masses, along with a mass in the lower left lung field and a tumor in the pancreatic tail, as detected by chest computed tomography. Endoscopic ultrasound-guided fine needle biopsy and computed tomography-guided lung biopsy confirmed the diagnosis of disseminated cryptococcal infection involving the pancreas, lung, and brain. The patient's clinical condition improved following antifungal therapy. Additionally, we identified anti-granulocyte-macrophage colony-stimulating factor antibody as a risk factor for disseminated cryptococcal infection in this patient.

Disseminated cryptococcosis can be a potentially lethal condition, as highlighted by previous literature. However, early diagnosis using contrast-enhanced harmonic endoscopic ultrasound and endoscopic ultrasound-guided biopsies, as well as prompt treatment as demonstrated in our case, can improve outcomes and prevent mortality.

Cryptococcal meningitis (CM) is responsible for 15%-20% of human immunodeficiency virus (HIV)-associated mortalities. CM prevalence has also increased in other immunocompromised populations of transplant recipients, patients with cancer, and individuals on immunomodulatory medication.

This retrospective review included 51 definitive patients with CM hospitalized at a tertiary academic medical center in New York City between 2010 and 2023. We assessed clinical features and outcomes of CM, with additional analysis of factors related to antiretroviral therapy (ART) adherence in HIV-infected cases and immunomodulatory medication history of HIV-negative cases.

The cohort had a mean (standard deviation) age of 47.1 ± 15.1 years, and was predominantly male (37, 72.5%). Of 32 patients with HIV, 3 (9.4%) were newly diagnosed with HIV at the time of CM hospitalization, 5 (15.6%) had recurrent CM, and 2 (6.3%) had a CM relapse. The majority (30, 93.8%) of patients with HIV were ART nonadherent. Of 19 HIV-negative patients, 8 (42.1%) were solid-organ transplant recipients, 5 (26.3%) had autoimmune conditions of sarcoidosis or systemic lupus erythematosus, and 3 (15.8%) had chronic lymphocytic leukemia. Six (11.8%) patients died during hospitalization, 4 of whom had HIV.

The burden of CM in people with HIV and immunocompromised patients continues even in settings with accessible standard antifungal treatment though interventions of increased ART adherence for those with HIV and antifungal prophylaxis may improve morbidity and mortality.

Cryptococcal meningitis (CM) is a well-recognized fungal infection, with substantial mortality in individuals infected with the human immunodeficiency virus (HIV). However, the incidence, risk factors, and outcomes in non-HIV adults remain poorly understood. This study aims to investigate the characteristics and prognostic indicators of CM in non-HIV adult patients, integrating a novel predictive model to guide clinical decision-making. A retrospective cohort of 64 non-HIV adult CM patients, including 51 patients from previous studies and 13 from the First Hospital of Shanxi Medical University, was analyzed. We assessed demographic features, underlying diseases, intracranial pressure, cerebrospinal fluid characteristics, and brain imaging. Using the least absolute shrinkage and selection operator (LASSO) method, and multivariate logistic regression, we identified significant variables and constructed a Nomogram prediction model. The model's calibration, discrimination, and clinical value were evaluated using the Bootstrap method, calibration curve, C index, goodness-of-fit test, receiver operating characteristic (ROC) analysis, and decision curve analysis. Age, brain imaging showing parenchymal involvement, meningeal and ventricular involvement, and previous use of immunosuppressive agents were identified as significant variables. The Nomogram prediction model displayed satisfactory performance with an akaike information criterion (AIC) value of 72.326, C index of 0.723 (0.592-0.854), and area under the curve (AUC) of 0.723, goodness-of-fit test P = 0.995. This study summarizes the clinical and imaging features of adult non-HIV CM and introduces a tailored Nomogram prediction model to aid in patient management. The identification of predictive factors and the development of the nomogram enhance our understanding and capacity to treat this patient population. The insights derived have potential clinical implications, contributing to personalized care and improved patient outcomes.

Immunosenescence refers to the age-related progressive decline of immune function contributing to the increased susceptibility to infectious diseases in older people. Neurocryptococcosis, an infectious disease of central nervous system (CNS) caused by Cryptococcus neoformans (C. Neoformans) and C. gattii, has been observed with increased frequency in aged people, as result of the reactivation of a latent infection or community acquisition. These opportunistic microorganisms belonging to kingdom of fungi are capable of surviving and replicating within macrophages. Typically, cryptococcus is expelled by vomocytosis, a non-lytic expulsive mechanism also promoted by interferon (IFN)-I, or by cell lysis. However, whereas in a first phase cryptococcal vomocytosis leads to a latent asymptomatic infection confined to the lung, an enhancement in vomocytosis, promoted by IFN-I overproduction, can be deleterious, leading the fungus to reach the blood stream and invade the CNS. Cryptococcus may not be easy to diagnose in older individuals and, if not timely treated, could be potentially lethal. Therefore, this review aims to elucidate the putative causes of the increased incidence of cryptococcal CNS infection in older people discussing in depth the mechanisms of immunosenscence potentially able to predispose to neurocryptococcosis, laying the foundations for future research. A deepest understanding of this relationship could provide new ways to improve the prevention and recognition of neurocryptococcosis in aged frail people, in order to quickly manage pharmacological interventions and to adopt further preventive measures able to reduce the main risk factors.

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.

Cryptococcus neoformans is a global invasive mycosis that is known to cause significant morbidity and mortality. It is commonly observed that individuals with compromised immune systems are more prone to developing cryptococcal meningitis. Although ocular involvement is rare, previous studies have indicated that ocular lesions precede symptomatic meningitis in only 27 % of patients with central nervous system involvement. Intraocular infections typically manifest as chorioretinopathy and vitreous inflammation, often leading to severe vision loss. In this case, we present the clinical details of a 57-year-old immunocompetent woman who visited the ophthalmology department of West China Hospital of Sichuan University with a progressive loss of vision in her right eye. After a thorough evaluation, she was diagnosed with fungal endophthalmitis, and subsequently initiated on appropriate induction anti-fungal therapy for cryptococcal meningoencephalitis. This case highlights the importance of early recognition and treatment, which can potentially improve the prognosis for patients.

Cryptococcus is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors-such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids-should also be taken into account during risk stratification.

The ventriculoperitoneal (VP) shunt is widely acknowledged as a treatment option for managing intracranial hypertension resulting from non-human immunodeficiency virus (HIV) cryptococcal meningitis (CM). Nonetheless, there is currently no consensus on the appropriate surgical indications for this procedure. Therefore, it is crucial to conduct a preoperative evaluation of patient characteristics and predict the outcome of the VP shunt to guide clinical treatment effectively.

A retrospective analysis was conducted on data from 85 patients with non-HIV CM who underwent VP shunt surgery at our hospital. The analysis involved studying demographic data, preoperative clinical manifestations, cerebrospinal fluid (CSF) characteristics, and surgical outcomes and comparisons between before and after surgery. A nomogram was developed and evaluated.

The therapy outcomes of 71 patients improved, whereas 14 cases had worse outcomes. Age, preoperative cryptococcus count, and preoperative CSF protein levels were found to influence the surgical outcome. The nomogram exhibited exceptional predictive performance (area under the curve = 0.896, 95% confidence interval: 0.8292-0.9635). Internal validation confirmed the nomogram's excellent predictive capabilities. Moreover, decision curve analysis demonstrated the nomogram's practical clinical utility.

The surgical outcome of VP shunt procedures patients with non-HIV CM was associated with age, preoperative cryptococcal count, and preoperative CSF protein levels. We developed a nomogram that can be used to predict surgical outcomes in patients with non-HIV CM.

Diagnosis and management of fungal infections are challenging in both animals and humans, especially in immunologically weakened hosts. Due to its broad spectrum and safety profile when compared to other antifungals, itraconazole (ITZ) has been widely used in the treatment and prophylaxis of fungal infections, both in human and veterinary medicine. The dose and duration of management depend on factors such as the type of fungal pathogen, the site of infection, sensitivity to ITZ, chronic stages of the disease, the health status of the hosts, pharmacological interactions with other medications and the therapeutic protocol used. In veterinary practice, ITZ doses generally vary between 3 mg/kg and 50 mg/kg, once or twice a day. In humans, doses usually vary between 100 and 400 mg/day. As human and veterinary fungal infections are increasingly associated, and ITZ is one of the main medications used, this review addresses relevant aspects related to the use of this drug in both clinics, including case reports and different clinical aspects available in the literature.

The most serious manifestation of pulmonary cryptococcosis is complicated with cryptococcal meningitis, while its clinical manifestations lack specificity with delayed diagnosis and high mortality. The early prediction of this complication can assist doctors to carry out clinical interventions in time, thus improving the cure rate. This study aimed to construct a nomogram to predict the risk of cryptococcal meningitis in patients with pulmonary cryptococcosis through a scoring system.

The clinical data of 525 patients with pulmonary cryptococcosis were retrospectively analyzed, including 317 cases (60.38 %) with cryptococcal meningitis and 208 cases (39.62 %) without cryptococcal meningitis. The risk factors of cryptococcal meningitis were screened by univariate analysis, LASSO regression analysis and multivariate logistic regression analysis. Then the risk factors were incorporated into the nomogram scoring system to establish a prediction model. The model was validated by receiver operating characteristic (ROC) curve, decision curve analysis (DCA) and clinical impact curve.

Fourteen risk factors for cryptococcal meningitis in patients with pulmonary cryptococcosis were screened out by statistical method, including 6 clinical manifestations (fever, headache, nausea, psychiatric symptoms, tuberculosis, hematologic malignancy) and 8 clinical indicators (neutrophils, lymphocytes, glutamic oxaloacetic transaminase, T cells, helper T cells, killer T cells, NK cells and B cells). The AUC value was 0.978 (CI 96.2 %∼98.9 %), indicating the nomogram was well verified.

The nomogram scoring system constructed in this study can accurately predict the risk of cryptococcal meningitis in patients with pulmonary cryptococcosis, which may provide a reference for clinical diagnosis and treatment of patients with cryptococcal meningitis.

We present an unusual case of an HIV-negative patient with postpartum pulmonary cryptococcosis and cryptococcemia.

The diagnostic methods and treatment of cryptococcosis in a postpartum patient are presented in this case report. Due to anaphylaxis to liposomal amphotericin B, desensitisation to the drug was performed.

We would like to raise awareness about rare infections such as cryptococcosis in pregnancy and the postpartum period. In addition, we were able to document a successful desensitisation to liposomal amphotericin B.

Cryptococcus neoformans is a fungal pathogen that can cause life-threatening brain infections in immunocompromised individuals. Unlike other fungal pathogens, it possesses a protective polysaccharide capsule that is crucial for its virulence. During infections, Cryptococcus cells release copious amounts of extracellular polysaccharides (exo-PS) that interfere with host immune responses. Both exo-PS and capsular-PS play pivotal roles in Cryptococcus infections and serve as essential targets for disease diagnosis and vaccine development strategies. However, understanding their structure is complicated by their polydispersity, complexity, sensitivity to sample isolation and processing, and scarcity of methods capable of isolating and analyzing them while preserving their native structure. In this study, we employ small-angle neutron scattering (SANS) and ultra-small-angle neutron scattering (USANS) for the first time to investigate both fungal cell suspensions and extracellular polysaccharides in solution. Our data suggests that exo-PS in solution exhibits collapsed chain-like behavior and demonstrates mass fractal properties that indicate a relatively condensed pore structure in aqueous environments. This observation is also supported by scanning electron microscopy (SEM). The local structure of the polysaccharide is characterized as a rigid rod, with a length scale corresponding to 3-4 repeating units. This research not only unveils insights into exo-PS and capsular-PS structures but also demonstrates the potential of USANS for studying changes in cell dimensions and the promise of contrast variation in future neutron scattering studies.

Cryptococcal meningitis (CM) is an invasive fungal disease that currently poses a threat to human health worldwide, with high morbidity and mortality, particularly in immunocompromised patients. Although CM mainly occurs in HIV-positive patients and other immunocompromised patients, it is also increasingly seen in seemingly immunocompetent hosts. The clinical characteristics of CM between immunocompromised and immunocompetent populations are different. However, few studies have focussed on CM in immunocompetent individuals. This review summarizes the clinical characteristics of apparently immunocompetent CM patients in terms of aetiology, immune pathogenesis, clinical presentation, laboratory data, imaging findings, treatment strategies and prognosis. It is of great significance to further understand the disease characteristics of CM, explore new treatment strategies and improve the prognosis of CM in immunocompetent individuals.

Emerging risk factors highlight the need for an updated understanding of cryptococcosis in the United States.

Describe the epidemiological trends and clinical outcomes of cryptococcosis in three patient groups: people with HIV (PWH), non-HIV-infected and non-transplant (NHNT) patients, and patients with a history of solid organ transplantation.

We utilized data from the Merative Medicaid Database to identify individuals aged 18 and above with cryptococcosis based on the International Classification of Diseases, Tenth Revision diagnosis codes from January 2017 to December 2019. Patients were stratified into PWH, NHNT patients, and transplant recipients according to Infectious Diseases Society of America guidelines. Baseline characteristics, types of cryptococcosis, hospitalization details, and in-hospital mortality rates were compared across groups.

Among 703 patients, 59.7% were PWH, 35.6% were NHNT, and 4.7% were transplant recipients. PWH were more likely to be younger, male, identify as Black, and have fewer comorbidities than patients in the NHNT and transplant groups. Notably, 24% of NHNT patients lacked comorbidities. Central nervous system, pulmonary, and disseminated cryptococcosis were most common overall (60%, 14%, and 11%, respectively). The incidence of cryptococcosis fluctuated throughout the study period. PWH accounted for over 50% of cases from June 2017 to June 2019, but this proportion decreased to 47% from July to December 2019. Among the 52% of patients requiring hospitalization, 61% were PWH and 35% were NHNT patients. PWH had longer hospital stays. In-hospital mortality at 90 days was significantly higher in NHNT patients (22%) compared to PWH (7%) and transplant recipients (0%). One-year mortality remained lowest among PWH (8%) compared to NHNT patients (22%) and transplant recipients (13%).

In this study, most cases of cryptococcosis were PWH. Interestingly, while the incidence remained relatively stable in PWH, it slightly increased in those without HIV by the end of the study period. Mortality was highest in NHNT patients.

Cryptococcus neoformans is a fungal pathogen that can cause life-threatening brain infections in immunocompromised individuals. Unlike other fungal pathogens, it possesses a protective polysaccharide capsule that is crucial for its virulence. During infections, Cryptococcus cells release copious amounts of extracellular polysaccharides (exo-PS) that interfere with host immune responses. Both exo-PS and capsular-PS play pivotal roles in Cryptococcus infections and serve as essential targets for disease diagnosis and vaccine development strategies. However, understanding their structure is complicated by their polydispersity, complexity, sensitivity to sample isolation and processing, and scarcity of methods capable of isolating and analyzing them while preserving their native structure. In this study, we employ small-angle neutron scattering (SANS) and ultra-small angle neutron scattering (USANS) for the first time to investigate both fungal cell suspensions and extracellular polysaccharides in solution. Our data suggests that exo-PS in solution exhibits collapsed chain-like behavior and demonstrates mass fractal properties that indicate a relatively condensed pore structure in aqueous environments. This observation is also supported by scanning electron microscopy (SEM). The local structure of the polysaccharide is characterized as a rigid rod, with a length-scale corresponding to 3 to 4 repeating units. This research not only unveils insights into exo-PS and capsular-PS structures but also demonstrates the potential of USANS for studying changes in cell dimensions and the promise of contrast variation in future neutron scattering studies.

Cryptococcus neoformans and Cryptococcus gattii species complexes cause meningoencephalitis with high fatality rates and considerable morbidity, particularly in persons with deficient T cell-mediated immunity, most commonly affecting people living with HIV. Whereas the global incidence of HIV-associated cryptococcal meningitis (HIV-CM) has decreased over the past decade, cryptococcosis still accounts for one in five AIDS-related deaths globally due to the persistent burden of advanced HIV disease. Moreover, mortality remains high (~50%) in low-resource settings. The armamentarium to decrease cryptococcosis-associated mortality is expanding: cryptococcal antigen screening in the serum and pre-emptive azole therapy for cryptococcal antigenaemia are well established, whereas enhanced pre-emptive combination treatment regimens to improve survival of persons with cryptococcal antigenaemia are in clinical trials. Short courses (≤7 days) of amphotericin-based therapy combined with flucytosine are currently the preferred options for induction therapy of cryptococcal meningitis. Whether short-course induction regimens improve long-term morbidity such as depression, reduced neurocognitive performance and physical disability among survivors is the subject of further study. Here, we discuss underlying immunology, changing epidemiology, and updates on the management of cryptococcal meningitis with emphasis on HIV-associated disease.

Background: Cryptococcus neoformans is an opportunistic fungal pathogen that causes infections mainly in immunosuppressed individuals, such as transplant recipients. Aims: This study investigated the effects of rapamycin, an immunosuppressant drug, on the cellular organization, biophysical characteristics, and main virulence factors of C. neoformans. Methods: Morphological, structural, physicochemical and biophysical analyses of cells and secreted polysaccharides of the reference H99 C. neoformans strain were investigated under the effect of subinhibitory concentrations of rapamycin. Results: Rapamycin at a minimum inhibitory concentration of 2.5 μM reduced C. neoformans cell viability by 53%, decreased capsule, increased cell size, chitin and lipid body formation, and changed peptidase and urease activity. Conclusion: Further studies are needed to assess how rapamycin affects the virulence factors and pathogenicity of C. neoformans.

Cryptococcus neoformans is an encapsulated yeast. It is a significant pathogen among immunocompromised people with HIV & Non-HIV vulnerable populations. These conditions include cancer, corticosteroid usage, immunosuppression following sarcoidosis, organ transplantation, immunosuppressive medication, and liver cirrhosis. In cirrhotic, it accounts for 6-21% of systemic infections.

The retrospective study was conducted in tertiary care hepatobiliary center in New Delhi, India. Samples of blood, cerebrospinal fluid (CSF), urine, body fluids, and serum were processed for gram stain, India ink, fungal culture and identification, and cryptococcal antigen. Antifungal susceptibility was assessed using the micro-broth dilution technique.

30 patients with cryptococcal infection were analysed, and 40 isolates from various samples were recovered. Out of 40 samples, C. neoformans was isolated from blood (62.5%), urine (15%), ascitic fluid (10%), MiniBAL (5%), bone marrow, CSF, and pleural fluid in one sample each. India ink positivity was 56% and all samples were positive for Cryptococcal antigen. Alcoholic liver disease & Hepatitis B & C associated chronic liver disease were seen in 43% & 20% of patients. Other underlying conditions were diabetes mellitus (20%), TB (10%), autoimmune hepatitis (6.6%), autoimmune disease (autoimmune hemolytic anemia, Sjogren syndrome) (6.6%), sarcoidosis (3.3%), hepatocellular carcinoma (3.3%). 7.5%, 5%, 2.5%, 7.5%, and 2.5% of C. neoformans strains were the non-wild type to fluconazole, 5-fluorocytosine, amphotericin B, posaconazole, and itraconazole respectively, but all strains were wildtype to voriconazole.

According to the study liver conditions are a significant risk factor for cryptococcal infection. Therefore, cryptococcal isolation and antifungal susceptibility testing, as well as appropriate antifungal drug use, should be studied and paid attention too.

Cryptococcosis is an invasive fungal infection found worldwide that causes significant morbidity and mortality among a broad range of hosts. There are approximately 223,000 new cases of cryptococcosis annually throughout the world, and at least 180,000 deaths are attributed to this infection each year. Most of these are due to complications of cryptococcal meningoencephalitis among HIV-infected patients in resource-limited environments. The majority of individuals diagnosed with cryptococcosis have underlying conditions associated with immune dysfunction such as HIV, solid organ transplant, hematologic malignancy, organ failure syndromes, and/or the use of immunosuppressive agents such as glucocorticosteroids and biologic agents. In most clinical series, there is a small proportion of patients with cryptococcosis who are phenotypically normal; that is, they have no clinically obvious predisposition to disease. Cryptococcal meningoencephalitis (CME) presentation and management differ substantially between these normal individuals and their immunocompromised counterparts. In this review, we will focus on CME in the phenotypically normal host and underscore differences in the clinical presentation, management, outcome, and potential risk factors for these patients compared to immunocompromised persons who develop this potential devastating invasive fungal infection.

To present three case reports of cryptococcal laryngitis managed with potassium-titanyl-phosphate (KTP) laser, where only one case managed with KTP laser has previously been published to date to our knowledge. Further, to systematically review the medical literature and describe the epidemiology, clinical assessment, treatment, and prognosis of laryngeal cryptococcosis.

The PubMed, Embase, and OVID MEDLINE databases were searched using the terms "cryptococcal laryngitis" or "cryptococcus" and "larynx or laryngeal."

Thirty-eight cases were identified. The median age was 65 years with a 1 male:1.2 female ratio. Thirty-six cases (95%) presented with hoarseness. Twenty-one cases (55%) were systemically immunosuppressed and 19 (50%) were taking an inhaled corticosteroid. This paper lists the five clinical features (i. white exudate or lesion; ii. exophytic, verrucous or tumor-like mass; iii. diffuse erythema; iv. mucosal irregularity; v. thickened vocal fold) and four pathologic features or tests (i. Grocott Gomori Methenamine stain; ii. Mucicarmine stain; iii. fungal or yeast organisms; iv. fungal culture) that encompass 97% of cases of cryptococcal laryngitis reported in the medical literature. In 34 cases (89%), antifungal therapy was given. Four cases (11%) had excisional biopsy and 11 (29%) received combined surgery and medical therapy. There was uncomplicated resolution in 24 cases (63%).

Cryptococcal laryngitis is a rare cause of hoarseness that may be mistaken for malignancy or may be a manifestation of disseminated cryptococcal infection or underlying immunosuppression. Clinicians should be aware of the diagnostic features of cryptococcal laryngitis to facilitate diagnosis and treatment to prevent complicated disease and overly aggressive treatment.

Cryptococcal meningoencephalitis is a systemic fungal infection in immunocompromised and immunocompetent individuals. This study investigated the clinical characteristics and factors associated with mortality in HIV-associated and non-HIV-associated cryptococcal meningoencephalitis in a resource-limited setting. This was a retrospective cohort study of patients with cryptococcal meningoencephalitis between January 2009 and December 2019 at a tertiary teaching hospital in Thailand. Overall, 1019 patients with cryptococcal meningoencephalitis were enrolled, and 923 (90.6%) were HIV-positive. The patients with HIV-associated cryptococcal meningoencephalitis were younger than the HIV-negative patients (37 versus 56 years, p < 0.01). The HIV-negative patients were more likely to have underlying conditions (52.1% versus 7.5%; p < 0.01), had a longer median duration of headaches prior to admission (14 days versus 6 days, p < 0.01), and were more likely to have an altered mental status at presentation (36.5% versus 18.6%, p < 0.01) and pulmonary involvement (15.6% versus 0.8%, p < 0.01). The HIV-positive patients had lower cerebrospinal fluid (CSF) white blood cell counts (4 versus 94 cells/mm3; p < 0.01), lower CSF protein (69 versus 157 mg/dL; p < 0.01), higher CSF glucose (38.8 versus 21 mg/dL; p < 0.01), and more frequent cryptococcemia (44.1% versus 20.5%; p < 0.01). The mortality rate was high but not significantly different between the two groups (30.2% versus 33.2%; p = 0.53). The HIV-positive patients with comorbidities, fever, an altered mental status at presentation, a CSF white blood cell count below 20 cell/mm3, fungemia, and positive CSF India ink were independently associated with 30-day mortality. In comparison, an altered mental status at presentation and fungemia were associated with 30-day mortality in HIV-negative patients. In conclusion, HIV-negative patients with cryptococcal meningoencephalitis had more extensive central nervous system inflammation, although the two groups' mortality rates were similar. Unfavorable prognostic factors included comorbidities, fever, an altered mental status at presentation, a low CSF white blood cell count, fungemia, and positive CSF India ink.

Cryptococcal meningitis (CM) is often associated with human immunodeficiency virus (HIV). Recently, this microorganism has been increasingly identified in HIV-negative patients. CM cases are encountered in HIV-negative individuals, especially secondary to liver disease, solid organ transplantation (SOT), tuberculosis, lymphoproliferative diseases with T-cell-mediated immunological disorders, long-term corticosteroid use, malignancies, diabetes mellitus, and sarcoidosis. Our patient is an HIV-negative, SOT case with CM. It should be considered that CM can also occur in HIV-negative patients. As in our case, patients receiving long-term immunosuppressive therapy should be evaluated for CM, and renal functions should be closely monitored during treatment. There is a need for more case reports on the subject, especially in CM detected HIV-negative patients, due to the different treatment protocols and challenging clinical conditions compared to HIV-positive cases.

Cryptococcal meningoencephalitis can occur in both previously healthy and immunocompromised hosts. Here, we describe a 55 year-old HIV-negative male with no known prior medical problems, who presented with three months of worsening headaches, confusion, and memory changes without fever. Magnetic resonance imaging of the brain demonstrated bilateral enlargement/enhancement of the choroid plexi, with hydrocephalus, temporal and occipital horn entrapments, as well as marked periventricular transependymal cerebrospinal fluid (CSF) seepage. CSF analysis yielded a lymphocytic pleocytosis and cryptococcal antigen titer of 1:160 but sterile fungal cultures. Despite standard antifungal therapy and CSF drainage, the patient had worsening confusion and persistently elevated intracranial pressures. External ventricular drainage led to improved mental status but only with valve settings at negative values. Ventriculoperitoneal shunt placement could thus not be considered due to a requirement for drainage into the positive pressure venous system. Due to this persistent CSF inflammation and cerebral circulation obstruction, the patient required transfer to the National Institute of Health. He was treated for cryptococcal post-infectious inflammatory response syndrome with pulse-taper corticosteroid therapy, with resultant reductions in CSF pressures along with decreased protein and obstructive material, allowing successful shunt placement. After tapering of corticosteroids, the patient recovered without sequelae. This case highlights (1) the necessity to consider cryptococcal meningitis as a rare cause of neurological deterioration in the absence of fever even in apparently immunocompetent individuals and (2) the potential for obstructive phenomena from inflammatory sequelae and the prompt response to corticosteroid therapy.

Herein, we review the current knowledge of donor-derived disease and current US Organ Procurement and Transplantation Network policies to minimize the risk. During the process, we also consider actions to further mitigate the risk of donor-derived disease. The overarching goal is to provide an infectious disease perspective on the complex decision of organ acceptance for transplant programs and candidates.

Patients with cryptococcal meningitis (CM) often have ocular manifestations; although data are describing these findings in nonimmunosuppressed, previously healthy individuals are scarce.

A retrospective chart review was performed for previously healthy patients with CM who underwent a complete ophthalmological examination within a 5-year period at the National Institutes of Health. Demographics, CSF parameters, findings on initial ophthalmological examination, and MRI abnormalities were analyzed.

Forty-four patients within a median of 12 weeks after CM diagnosis were included in our study; 27 patients (61%) reported abnormal vision on presentation. Seventy-one percent of patients were not shunted at the time of their initial eye examination. The most common ocular abnormalities were visual field defects in 21 (66%), decreased visual acuity in 14 (38%), and papilledema in 8 (26%) patients. Intraocular pressure was within normal range in all patients. Cranial nerve defects were identified in 5 patients and optic neuropathy in 2 patients. Patients who had hydrocephalus or did not receive a ventriculoperitoneal shunt were not noted to have worse ocular abnormalities.

The most common ocular findings in our cohort of nontransplant, non-HIV cryptococcal meningitis patients were visual field defects, decreased visual acuity, and papilledema. Our results emphasize the need for a comprehensive eye examination in patients with CM who may not always report a change in vision on presentation.

Cryptococcosis is one of the most significant systemic fungal infections worldwide. Epidemiological data for pediatric cryptococcosis is very limited. Therefore, we planned this study to determine the burden of cryptococcosis in the pediatric population at our tertiary care center and performed review of literature.

In this retrospective study, all the patients less than 18 years of age were diagnosed with cryptococcosis, from January 2015-June 2021 were included. Demographic, clinical, and laboratory details of all the patients were noted. Furthermore, PubMed and MedLine databases were comprehensively searched for cases of pediatric cryptococcosis till June 2021.

Of the total 5420 samples from suspected cryptococcosis cases processed at mycology laboratory, a total of 21 episodes of cryptococcosis (0.39%) were identified in 15 pediatric patients. The majority of the patients were apparently immunocompetent (10/15). Central nervous system (CNS) cryptococcosis was the most common presentation, followed by disseminated disease. All the isolates were identified as Cryptococcus neoformans (formerly referred to as C. neoformans var grubii), except one that was identified as Papiliotrema laurentii (formerly referred to as Cryptococcus laurentii). A standard treatment regimen inclusive of induction and maintenance therapy was provided in only five patients. The literature review revealed a total of 125 studies describing 1134 cases, of which 76.4% are reported from outside Asia, the majority (65.7%) restricted to CNS with C. neoformans as the commonest species. The management profile divulged a significantly higher use of standard drug regimen in Asia as compared to the rest of the world. Mortality of 13.32% was noted worldwide.

To the best of our knowledge, this is the first clinico-epidemiological study of pediatric cryptococcosis from India and the largest retrospective study worldwide. The rising incidence among immunocompetent individuals, especially in Asia, is a matter of concern. Clinical suspicion and early diagnosis are the cornerstones for the management of cases.

Cryptococcus neoformans sequence type 5 (ST5) lineage could infect immunocompetent hosts and cause a significant medical burden. We sought to identify characteristics and prognostic risk factors of ST5 lineage-associated cryptococcosis.

Multilocus sequence typing and antifungal susceptibility testing were conducted for Cryptococcus isolates. The clinical and laboratory characteristics of cryptococcosis patients were investigated. The multivariable logistic regression identified variables independently associated with 30-day mortality in patients with ST5 lineage-associated cryptococcosis without HIV.

The infection rate of the ST5 isolates was 89.4% (370/414) in China. The proportion of ST5 isolates with nonwild-type minimum inhibitory concentrations to amphotericin B, 5-flucytosine, voriconazole, posaconazole, itraconazole, and fluconazole were 0%, 5.4%, 0.3%, 1.4%, 0.3%, and 8.1%, respectively. The ST5 lineage-infected group exhibited significantly higher blood platelet count, lower blood cryptococcal antigen (CrAg) titer, lower cerebrospinal fluid (CSF) CrAg titer than the non-ST5 lineage-infected group, and lower hemoglobin and lower CSF CrAg titer than the Cryptococcus gattii isolates-infected group. Seven baseline parameters, including underlying disease, dyskinesia, anemia, high peripheral blood neutrophils, low platelet count, high CSF fungal burden, and high CSF opening pressure, were associated independently with the 30-day mortality of patients with ST5 lineage-associated cryptococcosis without HIV.

Our study has provided an understanding of the ST5 lineage associated with cryptococcosis.

The relation between antifungal susceptibility and treatment outcomes is not well-characterized. There is paucity of surveillance data for cerebrospinal fluid (CSF) isolates of cryptococcus investigated with YEASTONE colorimetric broth microdilution susceptibility testing. A retrospective study of laboratory-confirmed cryptococcus meningitis (CM) patients was conducted. The antifungal susceptibility of CSF isolates was determined using YEASTONE colorimetric broth microdilution. Clinical parameters, CSF laboratory indices, and antifungal susceptibility results were analyzed to identify risk factors for mortality. High rates of resistance to fluconazole and flucytosine were observed in this cohort. Voriconazole had the lowest MIC (0.06 µg/mL) and lowest rate of resistance (3.8%). In a univariate analysis, hematological malignancy, concurrent cryptococcemia, high Sequential Organ Failure Assessment (SOFA) score, low Glasgow coma scale (GCS) score, low CSF glucose level, high CSF cryptococcal antigen titer, and high serum cryptococcal antigen burden were associated with mortality. In a multivariate analysis, meningitis with concurrent cryptococcemia, GCS score, and high CSF cryptococcus burden, were independent predictors of poor prognosis. Both early and late mortality rates were not significantly different between CM wild type and non-wild type species.

Cryptococcal meningitis (CM) is a not rare condition in HIV-negative patients. Here, we describe the clinical characteristics, possible risk factors, and outcomes of HIV-negative patients with CM.

Medical records from 99 HIV-negative patients with CM admitted to our hospital from 2010 to 2021 were reviewed systematically. We compared the clinical features and outcomes between patients with underlying diseases and otherwise healthy hosts.

The 99 HIV-negative CM patients had a mean age at presentation of 56.2 ± 16.2 years, and the female-to-male ratio was 77:22. A total of 52 (52.5%) CM patients had underlying conditions, and 47 patients (47.5%) had no underlying conditions. Kidney transplant represented the most frequent underlying condition (11.1%), followed by rheumatic disease (10.1%) and hematological diseases (9.1%). Compared to patients without underlying conditions, those with underlying conditions had significantly more fever, more steroid therapy, higher serum creatinine, and lower albumin, IgG, hemoglobin, and platelets (p < 0.05 for each). CM patients without underlying conditions had significantly more alcohol abuse than those with underlying conditions (31.9% vs. 9.6%, p = 0.011). By logistic regression analysis, male gender (OR = 3.16, p = 0.001), higher CSF WBC (OR = 2.88, p = 0.005), and protein (OR = 2.82, p = 0.002) were significantly associated with mortality.

Patients with underlying conditions had a similar mortality to patients without underlying conditions. Alcohol abuse was a probable risk factor for CM for previously healthy patients. Male gender, higher CSF WBC, and protein were significantly associated with mortality.

Cryptococcus is the causal agent of cryptococcosis, a disease with high mortality mainly related to HIV immunosuppression and usually manifests with pneumonia and/or meningoencephalitis. There are very few therapeutic options; thus, innovative approaches are required. Herein, We examined the interaction of everolimus (EVL) with amphotericin B (AmB) and azoles [fluconazole (FLU), posaconazole (POS), voriconazole (VOR), itraconazole (ITR)] against Cryptococcus. Eighteen Cryptococcus neoforman clinical isolates were analyzed. Following the guidelines of the Clinical and Laboratory Standards Institute (CLSI) M27-A4, we conducted a broth microdilution experiment to determine the minimum inhibitory concentrations (MICs) of azoles, EVL, and AmB for assessing antifungal susceptibility. A fractional inhibitory concentration index (FICI) of less than and equal to 0.5 indicated synergy, with a range of 0.5 to 4.0 indicated indifference and a value more than 4.0 indicated antagonism. These experiments revealed that EVL had antifungal activity against C. neoforman. Moreover, EVL, POS, AmB, FLU, ITR, and VOR exhibited MIC values ranging from 0.5-2 μg/mL, 0.03125-2 μg/mL, 0.25-4 μg/mL, 0.5-32μg/mL, 0.0625-4μg/mL and 0.03125-2μg/mL, respectively. The combination of EVL with AmB and azoles (POS, FLU, ITR, and VOR) exhibited synergistic antifungal effects against 16 (88.9%), 9 (50%), 11 (61.1%), 10 (55.6%) or 6 (33.3%) of analyzed Cryptococcus strains. In the presence of EVL, the MIC values of AmB and azoles were significantly lowered. No antagonism was observed. Subsequently, in vivo analyses conducted using the G. mellonella model further confirmed that combination EVL+ POS, EVL+ FLU, and EVL+ITR treatment were associated with significantly improved larval survival following Cryptococcus spp. infection. These findings provide the first published evidence suggesting that a combination of EVL and AmB or azoles exhibit a synergistic effect and may be an effective antifungal disease treatment strategy for infections caused by Cryptococcus spp.

A 52-year-old man was referred to our hospital with an abnormal chest radiography infiltrate. He presented with cough that persisted for 1 month without fever, chills, dyspnea, or sputum. He has been treated with clarithromycin 400 mg/d for 1 week with no improvement. He had a history of hypertension, hyperuricemia, and gastroesophageal reflux disease. He had no family history of respiratory disease. He smoked 10 cigarettes daily for 10 years, which he had quit 15 years ago. He denied a history of alcohol or illicit drug use, occupational exposure, recent travel, and exposure to TB. He reported being sexually active with one current partner.

The purpose of this study was to assess the short-term and long-term outcomes of ventriculoperitoneal shunt (VPS) placement in patients with cryptococcal meningitis (CM).

We performed a retrospective analysis of all patients with CM admitted to the Peking Union Medical College Hospital from September 1990 to January 2021. We collected related clinical features to analyze the short- and long-term outcomes of VPS at 1 month and 1 year at least the following therapy, respectively. Overall survival (OS) was compared with all patients and a subgroup of critically ill cases by the Kaplan-Meier method with the log-rank test. Univariable and multivariable analyses were also performed using the Cox proportional hazard model to identify statistically significant prognostic factors.

We enrolled 98 patients, fifteen of whom underwent VPS. Those who received VPS had a lower cerebrospinal fluid (CSF) Cryptococcus burden (1:1 vs. 1:16; p = 0.046), lower opening pressures (173.3 mmH2 O vs. 224 mmH2O; p = 0.009) at lumbar punctures, and a lower incidence of critical cases (6.7 vs. 31.3%; p = 0.049). According to our long-term follow-up, no significant difference was shown in the Barthel Index (BI) between the two groups. Two patients in the VPS group suffered postoperative complications and had to go through another revision surgery. According to survival analysis, overall survival (OS) between the VPS and non-VPS groups was not significantly different. However, the Kaplan-Meier plots showed that critical patients with VPS had better survival in OS (p < 0.009). Multivariable analyses for critical patients showed VPS was an independent prognostic factor.

A VPS could reduce the intracranial pressure (ICP), decrease the counts of Cryptococcus neoformans by a faster rate and reduce the number of critical cases. The VPS used in critical patients with CM has a significant impact on survival, but it showed no improvement in the long-term Barthel Index (BI) vs. the conservative treatment and could lead to postoperative complications.

Pulmonary cryptococcosis describes an invasive lung mycosis caused by Cryptococcus neoformans or Cryptococcus gattii complex. It is often a high-consequence disease in both immunocompromised and immunocompetent populations, and may be misdiagnosed as pulmonary malignancy, leading to a delay in therapy. Epidemiology follows that of cryptococcal meningoencephalitis, with C. gattii infection more common in certain geographic regions. Diagnostic tools include histopathology, microscopy and culture, and the detection of cryptococcal polysaccharide antigen or Cryptococcus-derived nucleic acids. All patients with lung cryptococcosis should have a lumbar puncture and cerebral imaging to exclude central nervous system disease. Radiology is key, both as an adjunct to laboratory testing and as the initial means of detection in asymptomatic patients or those with non-specific symptoms. Pulmonary cryptococcomas (single or multiple) may also be associated with disseminated disease and/or cryptococcal meningitis, requiring prolonged treatment regimens. Optimal management for severe disease requires extended induction (amphotericin B and flucytosine) and consolidation therapy (fluconazole) with close clinical monitoring. Susceptibility testing is of value for epidemiology and in regions where relatively high minimum inhibitory concentrations to azoles (particularly fluconazole) have been noted. Novel diagnostic tools and therapeutic agents promise to improve the detection and treatment of cryptococcosis, particularly in low-income settings where the disease burden is high.

Neuromeningeal cryptococcosis and pulmonary tuberculosis are respectively serious mycotic and bacterial infections occurring in a subject regardless of its HIV serological status. We report here a case of neuromeningeal cryptococcosis associated with pulmonary tuberculosis and malnutrition in an HIV-seronegative patient with a CD4 count of 750/mm³, to highlight some particularities opposed to certain literatures. This is an 18-year-old patient, housewife, from Bamako, admitted in the Infectious and tropical diseases department of the University teaching hospital Point G of Bamako on March 13, 2022 for fever and impaired consciousness. Her symptomatology appears to have gradually set in over a month, preceded by headache resistant to paracetamol, jet vomiting and irregular dry cough, initially treated with ceftriaxone, artesunate and paracetamol for confirmed malaria and suspicion of bacterial meningitis before admission. In whom no known medical-surgical history, no use of topical corticosteroids, no immunosuppressive therapy, no alcohol or tobacco, and no immunosuppressive pathology was found. The diagnoses of neuromeningeal cryptococcosis, pulmonary tuberculosis and undernutrition were retained in view of clinical and microbiological arguments. Diabetes, sickle cell disease, viral hepatitis B and C, kidney failure and cancer, which are immunosuppressive pathologies, were not found. She was successfully treated with first-line oral antituberculous drugs and fluconazole infusion. Three interests are drawn from this clinical case: neuromeningeal cryptococcosis is not only the prerogative of HIV-positive subjects, a high CD4 count does not always mean immunocompetence and fluconazole is an effective therapeutic alternative for neuromeningeal cryptococcosis.