Candida Albicans Sepsis Research Articles

Endothelial ADAM10 utilization defines a molecular pathway of vascular injury in mice with bacterial sepsis.

The endothelium plays a critical role in the host response to infection and has been a focus of investigation in sepsis. While it is appreciated that intravascular thrombus formation, severe inflammation, and loss of endothelial integrity impair tissue oxygenation during sepsis, the precise molecular mechanisms that lead to endothelial injury remain poorly understood. We demonstrate here that endothelial ADAM10 was essential for the pathogenesis of Staphylococcus aureus sepsis, contributing to α-toxin-mediated (Hla-mediated) microvascular thrombus formation and lethality. As ADAM10 is essential for endothelial development and homeostasis, we examined whether other major human sepsis pathogens also rely on ADAM10-dependent pathways in pathogenesis. Mice harboring an endothelium-specific knockout of ADAM10 were protected against lethal Pseudomonas aeruginosa and Streptococcus pneumoniae sepsis, yet remained fully susceptible to group B streptococci and Candida albicans sepsis. These studies illustrate a previously unknown role for ADAM10 in sepsis-associated endothelial injury and suggest that understanding pathogen-specific divergent host pathways in sepsis may enable more precise targeting of disease.

Targeted removal of macrophage-secreted interleukin-1 receptor antagonist protects against lethal Candida albicans sepsis

Invasive fungal infections are associated with high mortality rates, and the lack of efficient treatment options emphasizes an urgency to identify underlying disease mechanisms. We report that disseminated Candida albicans infection is facilitated by interleukin-1 receptor antagonist (IL-1Ra) secreted from macrophages in two temporally and spatially distinct waves. Splenic CD169+ macrophages release IL-1Ra into the bloodstream, impeding early neutrophil recruitment. IL-1Ra secreted by monocyte-derived tissue macrophages further impairs pathogen containment. Therapeutic IL-1Ra neutralization restored the functional competence of neutrophils, corrected maladapted hyper-inflammation, and eradicated the otherwise lethal infection. Conversely, augmentation of macrophage-secreted IL-1Ra by type I interferon severely aggravated disease mortality. Our study uncovers how a fundamental immunoregulatory mechanism mediates the high disease susceptibility to invasive candidiasis. Furthermore, interferon-stimulated IL-1Ra secretion may exacerbate fungal dissemination in human patients with secondary candidemia. Macrophage-secreted IL-1Ra should be considered as an additional biomarker and potential therapeutic target in severe systemic candidiasis.

Progranulin aggravates lethal Candida albicans sepsis by regulating inflammatory response and antifungal immunity.

Candida albicans is the most frequent pathogen of fungal sepsis associated with substantial mortality in critically ill patients and those who are immunocompromised. Identification of novel immune-based therapeutic targets from a better understanding of its molecular pathogenesis is required. Here, we reported that the production of progranulin (PGRN) levels was significantly increased in mice after invasive C.albicans infection. Mice that lacked PGRN exhibited attenuated kidney injury and increased survival upon a lethal systemic infection with C. albicans. In mice, PGRN deficiency protected against systemic candidiasis by decreasing aberrant inflammatory reactions that led to renal immune cell apoptosis and kidney injury, and by enhancing antifungal capacity of macrophages and neutrophils that limited fungal burden in the kidneys. PGRN in hematopoietic cell compartment was important for this effect. Moreover, anti-PGRN antibody treatment limited renal inflammation and fungal burden and prolonged survival after invasive C. albicans infection. In vitro, PGRN loss increased phagocytosis, phagosome formation, reactive oxygen species production, neutrophil extracellular traps release, and killing activity in macrophages or neutrophils. Mechanistic studies demonstrated that PGRN loss up-regulated Dectin-2 expression, and enhanced spleen tyrosine kinase phosphorylation and extracellular signal-regulated kinase activation in macrophages and neutrophils. In summary, we identified PGRN as a critical factor that contributes to the immunopathology of invasive C.albicans infection, suggesting that targeting PGRN might serve as a novel treatment for fungal infection.

Viral Delivery of IL-7 Is a Potent Immunotherapy Stimulating Innate and Adaptive Immunity and Confers Survival in Sepsis Models.

Persistence of an immunosuppressive state plays a role in septic patient morbidity and late mortality. Both innate and adaptive pathways are impaired, pointing toward the need for immune interventions targeting both arms of the immune system. We developed a virotherapy using the nonpropagative modified vaccinia virus Ankara (MVA), which harbors the intrinsic capacity to stimulate innate immunity, to deliver IL-7, a potent activator of adaptive immunity. The rMVA-human IL-7 (hIL-7)-Fc encoding the hIL-7 fused to the human IgG2-Fc was engineered and shown to express a dimeric, glycosylated, and biologically active cytokine. Following a single i.v. injection in naive mice, the MVA-hIL-7-Fc increased the number of total and activated B, T, and NK cells but also myeloid subpopulations (Ly6Chigh, Ly6Cint, and Ly6Cneg cells) in both lung and spleen. It triggered differentiation of T cells in central memory, effector memory, and acute effector phenotypes and enhanced polyfunctionality of T cells, notably the number of IFN-γ-producing cells. The MVA vector contributed significantly to immune cell activation, particularly of NK cells. The MVA-hIL-7-Fc conferred a significant survival advantage in the cecal ligation and puncture (CLP) and Candida albicans sepsis models. It significantly increased cell numbers and activation in both spleen and lung of CLP mice. Comparatively, in naive and CLP mice, the rhIL-7-Fc soluble counterpart overall induced less vigorous, shorter lasting, and narrower immune activities than did the MVA-hIL-7-Fc and favored TNF-α-producing cells. The MVA-hIL-7-Fc represents a novel class of immunotherapeutic with clinical potential for treatment of septic patients.

INVASIVE FUNGAL INFECTIONS IN COVID-19 PATIENTS IN THE INTENSIVE CARE UNIT: ABOUT 5 CASES

Covid-19 is a serious pathology it is associated with a deep immunodepression which favors invasive fungal infections especially in patients in intensive care unit. We report in our work a series of five covid-19 patients with fungal co-infection. We conducted a retrospective study including all COVID-19 patients hospitalized in intensive care unit for acute respiratory distress syndrome. Patients who presented a clinical worsening during their hospitalization were sampled with mycological study (bronchoalveolar lavage, serum and fungal blood culture). The diagnosis of fungal superinfection was retained in five patients, two of whom had probable invasive pulmonary aspergillosis. Two other patients had a Cryptoccocusneoformans infection, one of which was disseminated. Candida albicans sepsis was found in only one patient. In the literature, invasive candidiasis and invasive pulmonary aspergillosis. in covid-19 patients are associated with a high morbidity and mortality rate, hence the importance of early diagnosis and management. It should be noted that the clinical presentation of invasive fungal infections is not very specific, especially at the beginning of the infection when antifungal treatment is more effective.

NLRP3炎性小体在白念珠菌脓毒症小鼠组织器官中的表达及作用

NLRP3炎性小体在白念珠菌脓毒症小鼠组织器官中的表达及作用

Inhibition of CBLB protects from lethal Candida albicans sepsis.

Fungal infections claim an estimated 1.5 million lives each year. Mechanisms that protect from fungal infections are still elusive. Recognition of fungal pathogens relies on C-type lectin receptors (CLRs) and their downstream signaling kinase SYK. Here we report that the E3 ubiquitin ligase CBLB controls proximal CLR signaling in macrophages and dendritic cells. We show that CBLB associates with SYK and ubiquitinates SYK, dectin-1, and dectin-2 after fungal recognition. Functionally, CBLB deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. Genetic deletion of Cblb protects mice from morbidity caused by cutaneous infection and markedly improves survival after a lethal systemic infection with Candida albicans. On the basis of these findings, we engineered a cell-permeable CBLB inhibitory peptide that protects mice from lethal C. albicans infections. We thus describe a key role for Cblb in the regulation of innate antifungal immunity and establish a novel paradigm for the treatment of fungal sepsis.

PS-220 Nosocomial Infections Due To Multidrug-resistant Microorganisms In Neonates

Aim We aimed to evaluate nosocomial infection (NI) rate and antimicrobial susceptibilities of microorganisms causing NI in our Neonatal Intensive Care Unit (NICU). Material and method NI afflicting infants admitted to NICU of Bahcesehir University Goztepe Medicalpark Hospital between January 2012 and December 2012 were assessed using Centre For Disease Control And Prevention (CDC) criteria. Only culture-positive infants were enrolled. Results Of 328 infants, 49.1% were preterm. Thirty-five nosocomial infections occurred in 19 (6.4%) patients. Incidence density was 6.8/1000 patient-days. Attact rate per patient was 1.84. Two infants (10.5%) succumbed to death, one with a liver abscess due to Staphylococcus epidermidis, other with Candida albicans sepsis. Ventilator associated-pneumonia (VAP) rate (n = 4) 2.3/1000, sepsis rate (n = 19) 5.7/1000, UTI rate (n = 10) 1.5/1000, wound infection rate (n = 1) 0.1/1000, catheter infection rate (n = 2) 4/1000 and meningitis rate were (n = 1) 0.1/1000. Of 35 nosocomial agents 22 (62.8%) were gram negative (10 Klebsiella spp, 4 Enterobacter, 3 Acinetobacter, 3 E. coli, 2 Peudomonas), 10 (28.5%) were gram positive and 3 (8.6%) were Candida spp. All gram negatives were resistant to cephalosporins. Thirty-one percent of gram negative bacteria were resistant to carbapenems. Carbapenem-resistant gram negative agents were namely Acinetobacter baumanii complex, Pseudomonas aeruginosa and Enterobacter cloacea complex, All bacteria were susceptible to colistine. Conclusion ESBL positive and carbapenem-resistant gram negative bacteria are threats for NICU. It is of vital importance to implement reasonable antibiotherapy strategies and to propagate standart infection control measures.

Pharmacological resolution of a multiloculated Candida spp. liver abscess in a preterm neonate

We report the case of a 31-week gestational age neonate with Candida albicans sepsis and a hepatic abscess. Diagnosis relied on clinical and radiological signs of sepsis, liver function impairment and culture isolation of Candida spp. from sterile sites. Liver ultrasound documented the presence of a multiloculated abscess. Treatment with micafungin (3 mg/kg/day) resulted in normalization of liver function and inflammatory laboratory values and improvement of clinical condition. After 30 days of treatment, the liver abscess resolved and at the 8-month follow up the infant is doing well. Prompt diagnosis and antifungal treatment avoided surgical drainage and liver surgery in this high-risk neonate.

Successful Treatment of Candida albicans Septicemia in a Preterm Infant with Severe Congenital Ichthyosis (Harlequin baby)

Candida infections are a major cause of fungal septicemia in neonates and are associated with marked morbidity and mortality. Despite the spectrum of antifungal drugs being dramatically extended during the last decade, invasive fungal infections remain a serious challenge for neonatologists. Amphotericin B and its lipid formulations are the drugs of choice for the treatment of systemic candidiasis in neonates. The combination of antifungal drugs with different sites of action, like caspofungin and amphotericin B, may improve antifungal efficacy. Severe congenital ichthyosis often leads to death within the neonatal period. Main causes of death are dehydration, electrolyte disturbances, and respiratory or systemic infections. We report the case of a preterm infant with severe congenital ichthyosis and sepsis caused by Candida albicans. The infection did not improve despite proper liposomal amphotericin B treatment. After addition of caspofungin, the baby recovered. To our best knowledge, a case of a preterm infant suffering from severe congenital ichthyosis and Candida albicans sepsis, who survived, has not been previously described.

Successful resolution of cardiac mycetomas by combined liposomal Amphotericin B with Fluconazole treatment in premature neonates

This manuscript reports on two very low birth weight premature infants with respiratory distress, receiving parenteral nutrition and broad-spectrum antibiotics for about 3 weeks, who developed Candida albicans sepsis associated with fungal mycoses and endocarditis, despite treatment with Amphotericin B and Caspofungin. On days 40 and 47, respectively, antifungal therapy was modified to liposomal Amphotericin B combined with Fluconazole 6 mg/kg/day for 4 weeks, resulting in complete resolution of the mycetomas. Our observations suggest that the combination of liposomal Amphotericin B with Fluconazole is able to result in complete resolution of cardiac mycetomas in preterm infants.

Incidence of Sepsis in Central Venous Catheter-Bearing Patients with Hematologic Malignancies: Preliminary Results

Indwelling central venous catheters (CVCs) are essential devices in the management of patients with hematological disorders treated with chemotherapy. However, their nature predisposes patients to unwanted complications. CVC-related complications were retrospectively analyzed in 227 hematologic patients who were consecutively admitted to our hematology department between May 2002 and April 2004. Patients' diagnoses comprised acute myeloid leukemia (36.8%), acute lymphoid leukemia (7.3%), lymphoproliferative disorders (28.3%), multiple myeloma (19.5%), myeloproliferative syndromes (5%) and others (3.1%). The CVCs used were polyurethane three lumen 7-Fr (111 patients) for chemotherapy and 12-Fr (114 patients) for chemotherapy and peripheral blood stem cell apheresis, plus two tunneled catheters. The pathological events were: bacteriaemias (n=46); occlusions (n=10); exit tunnel infections (n=8); thrombosis (n=6); lung emboli (n=2). Among febrile patients the bacteriemia frequency was 20%, of which 13.6% were CVC-related (with a higher incidence in leukemia patients (p=0.027). Among the isolates, gram-positive bacteria were found in 29 cases (23 CVC-related cases), and gram-negative bacteria in 16 cases (8 CVC-related cases). Only one patient had Candida albicans sepsis. At univariate and multivariate analysis significant risk factors for infection (p<0.0001) were only the number of days/catheters and neutropenia duration. In our hematologic patients, the CVC complications were mainly septic, with only 10.1% of CVC-related bacteriemias, despite prolonged catheterization duration. Acute leukemia patients were at major risk for sepsis, probably due to a more severe neutropenia and prolonged catheterization duration.

口底癌術後に発生した多発性カンジダ骨髄炎の１例

We describe a 46-year-old man with T 4 N 2 bM 0 squamous cell cancer of the floor of the mouth. After concomitant radiotherapy (51.2Gy) and chemotherapy (CBDCA 480mg), he underwent total glossolaryngectomy, bilateral neck dissection, and reconstruction using a free rectus abdominis flap. Postoperatively, an IVH catheter was placed, and antibiotics (CEZ) were given prophylactically. Candida albicans sepsis developed 3 weeks after the operation. Administration of FCZ 200 mg daily for 17 days improved sepsis; however, candida osteomyelitis developed in the ribs and lumbar vertebrae 4 months after the operation. Persistent osteomyelitis of the ribs required partial costectomy. Postoperatively, the patient received FCZ 200 mg daily for 1 month, followed by FCZ 100mg daily. Osteomyelitis of the ribs completely healed, but the lesions of the lumbar vertebrae were not controlled.

Management of candida septicaemia in a regional burn unit

Sepsis due to candida infection is a major cause of mortality and morbidity on our unit. Over a period of 3 years and 4 months, 29 cases of candida septicaemia, diagnosed by blood cultures, were encountered at the burn unit at Augusta Regional Medical Center. Factors known to predispose to fungal sepsis were present in all cases. All patients had large burns (14–98 per cent total body surface (TBSA) with a mean of 48.3 per cent). All but one patient had at least one central venous line. Respiratory problems requiring ventilator support were present in 24 patients. Sixteen patients had Candida albicans sepsis, two in association with another fungal sepsis. Candida parapsilosis was encountered in nine patients, one in combination with another species. Four patients had Candida tropicalis. Amphotericin B was prescribed therapeutically in 25 patients, in seven together with fluconazole. Two patients received fluconazole only and two received no antifungal therapy. There were eight deaths all attributed to sepsis and all of whom had multiple organ failure. Five of those who died had completed a course of amphotericin B therapy, two were receiving treatment at the time of death, and one patient died before culture data became available. Early and aggressive therapy is advised and amphotericin B appears to be the drug of choice.

Incidence of Candida parapsilosis colonization in an intensive care nursery population and its association with invasive fungal disease

We have studied 82 consecutive intensive care nursery admissions to determine rates of colonization and incidence of fungal sepsis. Cultures were obtained from stool, gastric aspirate and skin at three different times. Infants studied ranged in gestational age from 23 to 38 weeks (mean +/- SEM 29 +/- 0.4 weeks). Nineteen percent of all infants were colonized with Candida sp.; stools were more frequently culture-positive than skin or gastric aspirates. Colonized infants began enteral feeds at a later time compared with noncolonized neonates. Five of the study infants developed fungal sepsis. One had congenital Candida albicans sepsis and died at 10 days of age; the other four had Candida parapsilosis sepsis and survived. The development of C. parapsilosis sepsis was significantly associated with gastrointestinal colonization. Our results suggest that early initiation of enteral feeds decreases gastrointestinal colonization with C. parapsilosis. Gastrointestinal colonization was strongly associated with the subsequent development of C. parapsilosis sepsis in this group of high risk neonates.

Protein-calorie malnutrition impairs host defense against Candida albicans

Protein-calorie malnutrition (PCM) impairs immune responsiveness predisposing to Candida albicans sepsis, but mechanisms are unclear. This study examined the effect of PCM on enteric-derived C. albicans intestinal translocation and the ability of in vivo interferon-γ (IFN-γ) to upregulate macrophage (MØ) candidacidal mechanisms in PCM mice. Control (24% casein) and low protein (2.5%) diets were given for 4 weeks. Mice ( n = 160) were fed C. albicans in their drinking water for 3 days and C. albicans translocation (mean colony-forming units (CFU)/g tissue ± SEM) to the GI tract, liver, spleen, and kidney was assessed at 1 and 5 days following endotoxin challenge of 1, 5, and 10 mg/kg body wt. In a separate study ( n = 100 mice), IFN-γ (1000–10,000 U/day ip) vs saline was given for 3 days prior to harvesting peritoneal macrophages for assay of superoxide anion (O 2 −, percentage macrophage phagocytosis of C. albicans, and percentage killing of C. albicans. On Day 1, fungal translocation to the intestinal wall and systemic organs in the PCM group was significantly higher. On Day 5, mean CFU were significantly higher in the PCM group, indicating impaired organ clearance. Mean O 2, phagocytosis, and killing were significantly impaired in the PCM group ( P < 0.05), but IFN-γ improved all functions. PCM significantly depressed host responses to C. albicans. IFN-γ treatment enhanced candidacidal mechanisms, suggesting a therapeutic role in the malnourished host predisposed to C. albicans sepsis.

Immunotherapeutic modification of experimental infections by Indian medicinal plants

AbstractSecondary infections are the most common cause of mortality in the immunocompromised host. A recent therapeutic approach has aimed at bolstering the host's defence mechanism to assist in eradication of infection, using naturally occurring and synthetic substances like BCG, C. parvum, muramyl dipeptide and glucans. Tinospora cordifolia (TC), Asparagus racemosus (AR) and Withania somnifera (WS) are plants prescribed in Ayurveda, the Indian traditional system of medicine, as agents to strengthen host defence mechanisms. The present article reviews the effects of TC, AR and WS in diverse experimental infections. TC, AR and WS protected rats against caecal ligation induced abdominal sepsis and mice against Escherichia coli peritonitis. This was associated with a faster bacteremia clearance. Myelosuppression induced by single and multiple doses of cyclophosphamide was reversed. Mortality due to Staphylococcus aureus sepsis in neutropenic and hemisplenectomized mice was reduced in treated animals. Candida albicans sepsis induced mortality was also reduced by the plants. The plants induced leucocytosis with predominant neutrophilia associated with stimulation of phagocytic and bactericidal capacity of neutrophils and macrophages. In view of their oral efficacy and relative lack of adverse effects, AR, TC and WS show promise as useful immunomodulators.

The effects of protein hydrolysate-monosaccharide infusion on low-birth-weight infants

Four neonates who weighed between 940 and 1,200 Gm. at birth were studied for themetabolic effects of the infusion of a solution of 4.5 per cent protein hydrolysate with 13.5 per cent monosaccharide. Infusion for 48 hours resulted in increased serum and urine osmolality, positive potassium balance, negative sodium balance, increased serum urea nitrogen, increased blood glucose and total hexose, and decreased aortic arterial pH. One infant developed Candida albicans sepsis. From these limited data it is concluded that before prolonged parenteral alimentation is applied clinically to the care of low-birth-weight neonates, the relationship of benefit to risk must be evaluated by controlled studies.