Two Gene Set Variation Index as Biomarker of Bacterial and Fungal Sepsis.

BACKGROUND: The incidence of sepsis has been increasing in recent years. The molecular mechanism of different pathogenic sepsis remains elusive, and biomarkers of sepsis against different pathogens are still lacking. METHODS: The microarray data of bacterial sepsis, fungal sepsis, and mock-treated samples were applied to perform differentially expressed gene (DEG) analysis to identify a bacterial sepsis-specific gene set and a fungal sepsis-specific gene set. Functional enrichment analysis was used to explore the body's response to bacterial sepsis and fungal sepsis. Gene set variation analysis (GSVA) was used to score individual samples against the two pathogen-specific gene sets, and each sample gets a GSVA index. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of sepsis. An independent data set was used to validate the bacterial sepsis-specific GSVA index. RESULTS: The genes differentially expressed only in bacterial sepsis and the genes differentially expressed only in fungal sepsis were significantly involved in different biological processes (BPs) and pathways. This indicated that the body's responses to fungal sepsis and bacterial sepsis are varied. Twenty-two genes were identified as bacterial sepsis-specific genes and upregulated in bacterial sepsis, and 23 genes were identified as fungal sepsis-specific genes and upregulated in fungal sepsis. ROC curve analysis showed that both of the two pathogen sepsis-specific GSVA indexes may be a reliable biomarker for corresponding pathogen-induced sepsis (AUC = 1.000), while the mRNA of CALCA (also known as PCT) have a poor diagnostic value with AUC = 0.512 in bacterial sepsis and AUC = 0.705 in fungi sepsis. In addition, the AUC of the bacterial sepsis-specific GSVA index in the independent data set was 0.762. CONCLUSION: We proposed a bacterial sepsis-specific gene set and a fungal sepsis-specific gene set; the bacterial sepsis GSVA index may be a reliable biomarker for bacterial sepsis.

Chemoport-related Fungemia Caused by Trichosporon asahii.

Trichosporon asahii is a rare opportunistic fungal pathogen that causes fatal systemic infection in immunocompromised patients. Neutropenia developing due to malignancies is an important risk factor for fungal infection. Invasive infections due to T. asahii can be divided into disseminated and localized forms. The disseminated form is more common and usually occurs in neutropenic patients. The patient typically has an acute febrile illness that progresses rapidly to multiorgan failure. Here, we are presenting a case of fungal sepsis by invasive T. asahii in a 1-year-old child with Wilms Tumor. To the best of our knowledge, this is the first time that fungal sepsis due to T. asahii has been reported in a Wilms tumor patient. The incidence of rare invasive fungal infections is increasing in immunocompromised patients in whom management becomes difficult due to their heterogenous antifungal susceptibility pattern and intrinsic resistance to the standard antifungal agents that are routinely given. The patient was admitted with high spiking fever, and his laboratory investigations suggested neutropenia. T. asahii was isolated from the blood culture, for which he was started on inj. voriconozole. After 14 days of treatment, the fungus was cleared out from the patient's blood.

Incidence, risk factors, and outcome of blood stream infections during the first 100 days post-pediatric allogeneic and autologous hematopoietic stem cell transplantations.

Bloodstream infections (BSI) are a frequently observed complication after hematopoietic stem cell transplant (HSCT). Retrospective analysis of clinical and microbiological data during the first 100 days from 302 consecutive pediatric patients who underwent HSCT for a malignant disease at our institute between January 2013 and June 2017. A total of 164 patients underwent autologous and 138 allogeneic HSCT. The overall incidence of BSI was 37% with 92% of infectious episodes occurring during the pre-engraftment phase. Gram-positive bacteria (GPB) accounted for 54.6% of the isolated pathogens, gram-negative bacteria (GNB) for 43.9%, and fungi for 1.4%. Coagulase-negative staphylococci and Escherichia coli were the most commonly isolated GPB and GNB, respectively. Forty-five percent of GNB were extended-spectrum beta-lactamase producers and 21% were multidrug-resistant organisms. Fluoroquinolone resistance was 92% and 68%, among GPB and GNB, respectively. Risk factors for BSI in univariate analysis were allogeneic HSCT, delayed time to engraftment more than 12 days, previous BSI before HSCT, and alternative donor. In multivariate analysis, only HSCT type (allogeneic vs autologous P = .03) and previous BSI within 6 months before HSCT (P = .016) were significant. Overall survival at day 100 was 98% and did not differ significantly between patients with and without BSI (P = .76). BSI is common in children undergoing HSCT for malignant diseases. Allogeneic HSCT recipients and previous BSI within 6 months before HSCT are associated with increased risk of post-transplant BSI. With current supportive measures, BSI does not seem to confer an increased risk for 100-day mortality.

Frozen Section as a Rapid and Accurate Method for Diagnosing Acute Invasive Fungal Rhinosinusitis.

Objective Identify methods to improve the frozen-section diagnosis of acute invasive fungal rhinosinusitis. Study Design Biopsies with frozen section for suspected acute invasive fungal rhinosinusitis were reviewed to identify causes for missed diagnoses and evaluate methods for potential improvement. Setting All aspects of the study were performed at the Penn State Milton S. Hershey Medical Center. Subjects and Methods All frozen sections performed for suspected acute invasive fungal rhinosinusitis between 2006 through 2017 were reviewed with their diagnoses compared to the final diagnoses. Sensitivity and specificity were determined for each biopsy specimen to evaluate the diagnostic method and for each patient for its effectiveness on outcome. Causes for frozen-section failures in diagnosis were identified. A periodic acid-Schiff stain for fungus (PASF) was modified for use on frozen tissue (PASF-fs) and applied both retrospectively and prospectively to frozen sections to determine its ability to identify undetected fungus and improve diagnostic sensitivity. Results Of 63 biopsies positive for acute invasive fungal rhinosinusitis, 51 were diagnosed on frozen section, while 61 were identified by including the novel PASF-fs stain, reducing the failure rate from 19% to 3%. Of 41 cases that were positive, 34 were diagnosed on frozen section. Of the 7 that were not, 5 were identified by including the PASF-fs, reducing the failure rate from 17% to 5%. Conclusions Frozen section interpretation of biopsies for suspected acute invasive fungal rhinosinusitis using a PASF-fs stain should enable a rapid and accurate diagnosis with improved outcomes by shortening the time to surgery.

Lomentospora prolificans fungemia in hematopoietic stem cell transplant patients: First report in South America and literature review.

Lomentospora prolificans is a filamentous fungus and an emerging pathogen in immunocompromised patients. It is encountered most commonly in Australia, Spain, and USA. We described the first case of Lomentospora prolificans fungemia in South America. The patient was a hematopoietic stem cell transplantation (HSCT) recipient who developed the infection 37 days after stem cells infusion. In addition, we performed a literature review of invasive lomentosporiosis in HSCT patients.

A saprophytic fungus ( Sepedonium) associated with fatal pneumonia in a patient undergoing stem cell transplantation.

Sepedonium sp . is a saprophytic fungus that inhabits soil and plant material. Few cases of infection with this fungus have been reported. We describe a case of a child who received haploidentical stem cell transplantation. The patient developed Sepedonium sp . infection after graft failure accompanied by cytomegalovirus infection. This was associated with two genotypes corresponding to a gB1 and gB3 mixture, which suggested involvement of two strains. Throughout the clinical course, immunosuppression and subsequent development of the fungal infection was observed. Our findings add to the available evidence regarding the potential for acquisition of fungal infection from the environment in patients at high risk because of immunosuppression. To the best of our knowledge, this is the first case of Sepedonium sp . infection following graft failure accompanied by previous cytomegalovirus infection in a patient with hematopoietic stem cell transplantation.

Cryptococcal cellulitis on the shin of an immunosuppressed patient.

Cryptococcus neoformans is a common fungus found throughout the environment that causes opportunistic disease in immunocompromised individuals. Infection of humans with C neoformans usually manifests as lung disease through inhalation of spores or meningoencephalitis by involvement of the central nervous system. Rarely, dissemination in the form of cutaneous lesions can occur in individuals with long term immunosuppression. We present a patient with C. neoformans manifesting as cellulitis with focal segmental glomerulosclerosis treated with corticosteroids. Because of the mortality associated with disseminated cryptococcosis, early identification, especially of atypical cutaneous presentations is critical from a dermatological perspective.

Fungal Endocarditis: Update on Diagnosis and Management.

Fungal endocarditis is an extremely debilitating disease associated with high morbidity and mortality. Candida spp. are the most common isolated organisms in fungal endocarditis. It is most prevalent in patients who are immunosuppressed and intravenous drug users. Most patients present with constitutional symptoms, which are indistinguishable from bacterial endocarditis, hence a high index of suspicion is required for pursuing diagnosis. Diagnosis of fungal endocarditis can be very challenging: most of the time, blood cultures are negative or take a long time to yield growth. Fungal endocarditis mandates an aggressive treatment strategy. A medical and surgical combined approach is the cornerstone of therapy.

Resistance Mechanisms and Clinical Features of Fluconazole-Nonsusceptible Candida tropicalis Isolates Compared with Fluconazole-Less-Susceptible Isolates.

We investigated the azole resistance mechanisms and clinical features of fluconazole-nonsusceptible (FNS) isolates of Candida tropicalis recovered from Korean surveillance cultures in comparison with fluconazole-less-susceptible (FLS) isolates. Thirty-five clinical isolates of C. tropicalis, comprising 9 FNS (fluconazole MIC, 4 to 64 µg/ml), 12 FLS (MIC, 1 to 2 µg/ml), and 14 control (MIC, 0.125 to 0.5 µg/ml) isolates, were assessed. CDR1, MDR1, and ERG11 expression was quantified, and the ERG11 and UPC2 genes were sequenced. Clinical features of 16 patients with FNS or FLS bloodstream isolates were analyzed. Both FNS and FLS isolates had >10-fold higher mean expression levels of CDR1, MDR1, and ERG11 genes than control isolates (P values of <0.02 for all). When FNS and FLS isolates were compared, FNS isolates had 3.4-fold higher mean ERG11 expression levels than FLS isolates (P = 0.004), but there were no differences in those of CDR1 or MDR1 Of all 35 isolates, 4 (2 FNS and 2 FLS) and 28 (8 FNS, 11 FLS, and 9 control) isolates exhibited amino acid substitutions in Erg11p and Upc2p, respectively. Both FNS and FLS bloodstream isolates were associated with azole therapeutic failure (3/4 versus 4/7) or uncleared fungemia (4/6 versus 4/10), but FNS isolates were identified more frequently from patients with previous azole exposure (6/6 versus 3/10; P = 0.011) and immunosuppression (6/6 versus 3/10; P = 0.011). These results reveal that the majority of FNS C. tropicalis isolates show overexpression of CDR1, MDR1, and ERG11 genes, and fungemia develops after azole exposure in patients with immunosuppression.

The bone marrow represents an enrichment site of specific T lymphocytes against filamentous fungi.

Bone marrow has already been described as an enrichment site for several antigen-specific T lymphocytes, but the presence of mould-specific T cells has never been investigated in the bone marrow. We have previously demonstrated that mould-specific T cells emerge in the peripheral blood of patients with invasive fungal infections (IFI) but tend to become undetectable after disease resolution. In seven patients with a history of IFI, we investigated the presence of mould-specific T cells secreting different cytokines in bone marrow and peripheral blood paired samples. The results showed that the frequencies of mould-specific T cells secreting the protective cytokine IFNγ are significantly higher in bone marrow (BM) and are mainly represented by CD8+ T lymphocytes with effector phenotype. A putative disappearance of such protective BM responses after myeloablative therapy could contribute to the increased risk of IFI in hematologic patients.

Folliculocentric cutaneous presentation of disseminated Candida krusei infection in a patient with acute myeloid leukemia.

Candida krusei (C. krusei) is a multidrug-resistant opportunistic fungal pathogen that may cause disseminated infections in immunocompromised hosts. However, its clinical and histologic features are not well-characterized. We present a unique case to contribute to the growing knowledge base associated with this organism. During hospitalization for neutropenic fever, a 19-year-old man with acute myeloid leukemia, who underwent hematopoietic stem cell transplantation, developed a generalized folliculocentric eruption following initiation of antifungal therapy for newly diagnosed C. krusei fungemia. Despite adequate antifungal coverage and negative blood cultures, the follicular-based erythematous papules persisted. Biopsies demonstrated yeast within ruptured follicles, without angiotropism or involvement of the interfollicular dermis, subcutaneous tissue, or stratum corneum. Concurrent skin tissue cultures confirmed C. krusei. The patient remained febrile despite aggressive antifungal therapy, with relapse of leukemia and subsequent death. Our case is unusual given the development of cutaneous lesions following clearance of fungemia, with yeast limited to ruptured follicular lumina, possibly indicating a primary cutaneous source or early transfollicular/transepidermal elimination. Given the limited available descriptions of cutaneous histopathology for C. krusei, we seek to add to the understanding of its pathophysiology and aid in the diagnosis and treatment of this often fatal infection.

Cryptococcus laurentii fungaemia in a cervical cancer patient

ABSTRACT Infections caused by emerging Cryptococcus non-neoformans species are being reported with increasingly frequency. Here, we present a case of fungaemia byCryptococcus laurentii in a woman receiving aggressive immunosuppressive therapy for cervical neoplasia. Three venous blood samples were aseptically collected on consecutive days and C. laurentiiwas isolated and identified through phenotypic and molecular methods. After central venous catheter removal and appropriate antifungal therapy, the patient showed significant improvement and blood culture became negative. Thus, patients following immunosuppressive therapies and using invasive medical devices are at risk of C. laurentii blood infections.

Cryptococcus laurentii fungaemia in a cervical cancer patient.

Infections caused by emerging Cryptococcus non-neoformans species are being reported with increasingly frequency. Here, we present a case of fungaemia by Cryptococcus laurentii in a woman receiving aggressive immunosuppressive therapy for cervical neoplasia. Three venous blood samples were aseptically collected on consecutive days and C. laurentii was isolated and identified through phenotypic and molecular methods. After central venous catheter removal and appropriate antifungal therapy, the patient showed significant improvement and blood culture became negative. Thus, patients following immunosuppressive therapies and using invasive medical devices are at risk of C. laurentii blood infections.

Host response to Candida albicans bloodstream infection and sepsis.

Candida albicans is a major cause of bloodstream infection which may present as sepsis and septic shock - major causes of morbidity and mortality world-wide. After invasion of the pathogen, innate mechanisms govern the early response. Here, we outline the models used to study these mechanisms and summarize our current understanding of innate immune responses during Candida bloodstream infection. This includes protective immunity as well as harmful responses resulting in Candida induced sepsis. Neutrophilic granulocytes are considered principal effector cells conferring protection and recognize C. albicans mainly via complement receptor 3. They possess a range of effector mechanisms, contributing to elimination of the pathogen. Neutrophil activation is closely linked to complement and modulated by activated mononuclear cells. A thorough understanding of these mechanisms will help in creating an individualized approach to patients suffering from systemic candidiasis and aid in optimizing clinical management.

[Disseminated mucormycosis in immunocompetent patients: A disease that also exists]. / Mucormicosis diseminadas en pacientes sin inmunodeficiencias: una enfermedad que también existe.

Mucormycosis is usually an acute angioinvasive infections, which leads to non-suppurative necrosis and significant tissue damage. It represents 1.6% of all the invasive fungal infections and predominates in immunosuppressed patients with risk factors. Incidence has been significantly increased even in immunocompetent patients. Due to finding a case of disseminated mucormycosis caused by Rhizomucor pusillus in a young immunocompetent patient, a systematic review was carried out of reported cases in PubMed of mucormycosis in immunocompetent adults according to the main anatomic locations, and especially in disseminated cases. A review of the main risk factors and pathogenicity, clinical manifestations, techniques of early diagnosis, current treatment options, and prognosis is presented. Taxonomy and classification of the genus Mucor has also been reviewed.

[Immunopathogenesis of invasive mould infections]. / Inmunopatología de las micosis invasivas por hongos filamentosos.

Invasive fungal infections caused by filamentous fungi are devastating diseases that occur in patients with a variety of immunosuppressive conditions. This review focuses on the pathogenesis of the most important invasive mycosis in the human being caused by the filamentous fungi Aspergillus, Fusarium, Scedosporium and mucorales. The first contact between the mould and the patient, the host defense to different fungi, including the role of mucosa in the innate immune system, the whole innate immune recognition receptors, and the pathways connecting innate and adaptive immunity, as well as the virulence factors of fungi, are discussed in this paper.

Chronic granulomatous disease presenting as hemophagocytic lymphohistiocytosis: a case report.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent infections and a dysregulated inflammatory response. Infection-triggered hemophagocytic lymphohistiocytosis (HLH), which manifests itself as pathologic hyperactive inflammation, has been observed in subjects with CGD. However, there have been no reports of HLH as the initial presentation with subsequent diagnosis of CGD. Furthermore, the primary therapeutic strategy for HLH focuses on immunosuppressive therapies, which limits immune-mediated tissue damage. With immunodeficiency, this therapeutic strategy may worsen the outcome. This article discusses an 8-week-old Hispanic male who presented with fever of unknown origin. The initial diagnostic evaluation demonstrated pathologic hyperactive inflammation, meeting the HLH-2004 diagnostic criteria without an identified infectious etiology. Immunosuppressive therapy was initiated, with subsequent disseminated candida septic shock and sepsis-induced multisystem organ failure. Additional evaluations ultimately established the diagnosis of CGD. We transitioned to an immune-enhancing strategy with granulocyte and immunoglobulin infusions, and intensified antifungal therapies. These interventions ultimately led to the clearance of the fungal infection and the resolution of the hyperactive inflammatory state. This case represents the first reported case of HLH as the presenting finding leading to the subsequent diagnosis of CGD. It serves as a reminder that both immunodeficiency and inflammatory disorders may share features of pathologic hyperactive inflammation and highlights the conundrum that clinicians face when treating HLH in the setting of an unresolved infection. In this case report, we demonstrate that immune-enhancing therapies may aid in the control and the clearance of the infection, thus paradoxically decreasing the pathologic hyperactive inflammatory response.

Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis.

INTRODUCTION: Fungal sepsis is an increasingly common problem in intensive care unit patients.Mortality from fungal sepsis remains high despite antimicrobial therapy that is highly active against most fungal pathogens, a finding consistent with defective host immunity that is present in many patients with disseminated fungemia.One recently recognized immunologic defect that occurs in patients with sepsis is T cell "exhaustion" due to increased expression of programmed cell death -1 (PD-1).This study tested the ability of anti-PD-1 and anti-programmed cell death ligand -1 (anti-PD-L1) antagonistic antibodies to improve survival and reverse sepsis-induced immunosuppression in two mouse models of fungal sepsis. METHODS: Fungal sepsis was induced in mice using two different models of infection, that is, primary fungal sepsis and secondary fungal sepsis occurring after sub-lethal cecal ligation and puncture (CLP).Anti-PD-1 and anti-PD-L1 were administered 24 to 48 h after fungal infection and effects on survival, interferon gamma production, and MHC II expression were examined. RESULTS: Anti-PD-1 and anti-PD-L1 antibodies were highly effective at improving survival in primary and secondary fungal sepsis.Both antibodies reversed sepsis-induced suppression of interferon gamma and increased expression of MHC II on antigen presenting cells.Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a second negative co-stimulatory molecule that is up-regulated in sepsis and acts like PD-1 to suppress T cell function, also improved survival in fungal sepsis. CONCLUSIONS: Immuno-adjuvant therapy with anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies reverse sepsis-induced immunosuppression and improve survival in fungal sepsis.The present results are consistent with previous studies showing that blockade of PD-1 and CTLA-4 improves survival in bacterial sepsis.Thus, immuno-adjuvant therapy represents a novel approach to sepsis and may have broad applicability in the disorder.Given the relative safety of anti-PD-1 antibody in cancer clinical trials to date, therapy with anti-PD-1 in patients with life-threatening sepsis who have demonstrable immunosuppression should be strongly considered.