Five-year single-center analysis of cytomegalovirus viremia in kidney transplant recipients and possible implication for novel prophylactic therapy approaches.

BACKGROUND: Cytomegalovirus (CMV) infections are a common complication after kidney transplantation (KTx) and negatively affecting patient outcome. Valganciclovir (VGC) prophylaxis is often limited by drug-induced side effects and dose reduction due to decline in kidney function. METHOD: In the present study, episodes of CMV viremia in the first year after KTx in a cohort of 316 recipients were analyzed retrospectively to identify risk factors linked to persistent infections. RESULTS: In the studied cohort, 18.7% of patients showed a high-risk (HR) constellation (D+/R-) for CMV infections. CMV viremia affected 22% of our cohort, with HR patients being the most affected cohort (44.1%). Within this group, most viremic events (65.3%) occurred while patients were still on prophylactic therapy, showing significantly higher viral loads and a longer duration compared to seropositive recipients. CONCLUSION: The analysis at hand revealed that detection of viremia under ongoing antiviral prophylaxis bears an increased risk for sustained viral replication and antiviral drug resistance in HR patients. We identified low estimated glomerular filtration rate (eGFR) and lower dose VGC prophylaxis post-KTx as a risk factor for breakthrough infections in HR patients in our single center cohort. These patients might benefit from a closer CMV monitoring or novel prophylactic agents as letermovir.

Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway.

SIGNIFICANCE STATEMENT: AKI is a major clinical complication leading to high mortality, but intensive research over the past decades has not led to targeted preventive or therapeutic measures. In rodent models, caloric restriction (CR) and transient hypoxia significantly prevent AKI and a recent comparative transcriptome analysis of murine kidneys identified kynureninase (KYNU) as a shared downstream target. The present work shows that KYNU strongly contributes to CR-mediated protection as a key player in the de novo nicotinamide adenine dinucleotide biosynthesis pathway. Importantly, the link between CR and NAD+ biosynthesis could be recapitulated in a human cohort. BACKGROUND: Clinical practice lacks strategies to treat AKI. Interestingly, preconditioning by hypoxia and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. METHODS: Kynureninase (KYNU) knockout mice were generated by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and comparative transcriptome, proteome and metabolite analyses of murine kidneys pre- and post-ischemia-reperfusion injury in the context of CR or ad libitum diet were performed. In addition, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation. RESULTS: We identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the effect of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans. CONCLUSIONS: CR induces the de novo NAD+ synthesis pathway in the context of IRI and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.

SARS-CoV-2 infection in chronic kidney disease patients with pre-existing dialysis: description across different pandemic intervals and effect on disease course (mortality).

PURPOSE: Patients suffering from chronic kidney disease (CKD) are in general at high risk for severe coronavirus disease (COVID-19) but dialysis-dependency (CKD5D) is poorly understood. We aimed to describe CKD5D patients in the different intervals of the pandemic and to evaluate pre-existing dialysis dependency as a potential risk factor for mortality. METHODS: In this multicentre cohort study, data from German study sites of the Lean European Open Survey on SARS-CoV-2-infected patients (LEOSS) were used. We multiply imputed missing data, performed subsequent analyses in each of the imputed data sets and pooled the results. Cases (CKD5D) and controls (CKD not requiring dialysis) were matched 1:1 by propensity-scoring. Effects on fatal outcome were calculated by multivariable logistic regression. RESULTS: The cohort consisted of 207 patients suffering from CKD5D and 964 potential controls. Multivariable regression of the whole cohort identified age (> 85 years adjusted odds ratio (aOR) 7.34, 95% CI 2.45-21.99), chronic heart failure (aOR 1.67, 95% CI 1.25-2.23), coronary artery disease (aOR 1.41, 95% CI 1.05-1.89) and active oncological disease (aOR 1.73, 95% CI 1.07-2.80) as risk factors for fatal outcome. Dialysis-dependency was not associated with a fatal outcome-neither in this analysis (aOR 1.08, 95% CI 0.75-1.54) nor in the conditional multivariable regression after matching (aOR 1.34, 95% CI 0.70-2.59). CONCLUSIONS: In the present multicentre German cohort, dialysis dependency is not linked to fatal outcome in SARS-CoV-2-infected CKD patients. However, the mortality rate of 26% demonstrates that CKD patients are an extreme vulnerable population, irrespective of pre-existing dialysis-dependency.

Preoperative Short-Term Restriction of Sulfur-Containing Amino Acid Intake for Prevention of Acute Kidney Injury After Cardiac Surgery: A Randomized, Controlled, Double-Blind, Translational Trial.

Background Acute kidney injury (AKI) is a major risk factor for chronic kidney disease and increased mortality. Until now, no compelling preventive or therapeutic strategies have been identified. Dietary interventions have been proven highly effective in organ protection from ischemia reperfusion injury in mice and restricting dietary intake of sulfur-containing amino acids (SAA) seems to be instrumental in this regard. The UNICORN trial aimed to evaluate the protective impact of restricting SAA intake before cardiac surgery on incidence of AKI. Methods and Results In this single-center, randomized, controlled, double-blind trial, 115 patients were assigned to a SAA-reduced formula diet (LowS group) or a regular formula diet (control group) in a 1:1 ratio for 7 days before scheduled cardiac surgery. The primary end point was incidence of AKI within 72 hours after surgery, secondary end points included increase of serum creatinine at 24, 48, and 72 hours as well as safety parameters. Quantitative variables were analyzed with nonparametric methods, while categorical variables were evaluated by means of Chi-square or Fisher test. SAA intake in the group with SAA reduced formula diet was successfully reduced by 77% (group with SAA reduced formula diet, 7.37[6.40-7.80] mg/kg per day versus control group, 32.33 [28.92-33.60] mg/kg per day, P<0.001) leading to significantly lower serum levels of methionine. No beneficial effects of SAA restriction on the rate of AKI after surgery could be observed (group with SAA reduced formula diet, 23% versus control group, 16%; P=0.38). Likewise, no differences were recorded with respect to secondary end points (AKI during hospitalization, creatinine at 24, 48, 72 hours after surgery) as well as in subgroup analysis focusing on age, sex, body mass index and diabetes. Conclusions SAA restriction was feasible in the clinical setting but was not associated with protective properties in AKI upon cardiac surgery. Registration URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03715868.

Harmonized procedure coding system for surgical procedures and analysis of surgical site infections (SSI) of five European countries.

BACKGROUND: The use of routine data will be essential in future healthcare research. Therefore, harmonizing procedure codes is a first step to facilitate this approach as international research endeavour. An example for the use of routine data on a large scope is the investigation of surgical site infections (SSI). Ongoing surveillance programs evaluate the incidence of SSI on a national or regional basis in a limited number of procedures. For example, analyses by the European Centre for Disease Prevention (ECDC) nine procedures and provides a mapping table for two coding systems (ICD9, National Healthcare Safety Network [NHSN]). However, indicator procedures do not reliably depict overall SSI epidemiology. Thus, a broader analysis of all surgical procedures is desirable. The need for manual translation of country specific procedures codes, however, impedes the use of routine data for such an analysis on an international level. This project aimed to create an international surgical procedure coding systems allowing for automatic translation and categorization of procedures documented in country-specific codes. METHODS: We included the existing surgical procedure coding systems of five European countries (France, Germany, Italy, Spain, and the United Kingdom [UK]). In an iterative process, country specific codes were grouped in ever more categories until each group represented a coherent unit based on method of surgery, interventions performed, extent and site of the surgical procedure. Next two ID specialist (arbitrated by a third in case of disagreement) independently assigned country-specific codes to the resulting categories. Finally, specialist from each surgical discipline reviewed these assignments for their respective field. RESULTS: A total number of 153 SALT (Staphylococcus aureus Surgical Site Infection Multinational Epidemiology in Europe) codes from 10 specialties were assigned to 15,432 surgical procedures. Almost 4000 (26%) procedure codes from the SALT coding system were classified as orthopaedic and trauma surgeries, thus this medical field represents the most diverse group within the SALT coding system, followed by abdominal surgical procedures with 2390 (15%) procedure codes. CONCLUSION: Mapping country-specific codes procedure codes onto to a limited number of coherent, internally and externally validated codes proofed feasible. The resultant SALT procedure code gives the opportunity to harmonize big data sets containing surgical procedures from international centres, and may simplify comparability of future international trial findings. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov under NCT03353532 on November 27th, 2017.

The kidney in hantavirus infection-epidemiology, virology, pathophysiology, clinical presentation, diagnosis and management.

Hantavirus-induced diseases are emerging zoonoses with endemic appearances and frequent outbreaks in different parts of the world. In humans, hantaviral pathology is characterized by the disruption of the endothelial cell barrier followed by increased capillary permeability, thrombocytopenia due to platelet activation/depletion and an overactive immune response. Genetic vulnerability due to certain human leukocyte antigen haplotypes is associated with disease severity. Typically, two different hantavirus-caused clinical syndromes have been reported: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The primarily affected vascular beds differ in these two entities: renal medullary capillaries in HFRS caused by Old World hantaviruses and pulmonary capillaries in HCPS caused by New World hantaviruses. Disease severity in HFRS ranges from mild, e.g. Puumala virus-associated nephropathia epidemica, to moderate, e.g. Hantaan or Dobrava virus infections. HCPS leads to a severe acute respiratory distress syndrome with high mortality rates. Due to novel insights into organ tropism, hantavirus-associated pathophysiology and overlapping clinical features, HFRS and HCPS are believed to be interconnected syndromes frequently involving the kidneys. As there are no specific antiviral treatments or vaccines approved in Europe or the USA, only preventive measures and public awareness may minimize the risk of hantavirus infection. Treatment remains primarily supportive and, depending on disease severity, more invasive measures (e.g., renal replacement therapy, mechanical ventilation and extracorporeal membrane oxygenation) are needed.

Three-Dimensional Super-Resolved Imaging of Paraffin-Embedded Kidney Samples.

Background: Diseases of the glomeruli, the renal filtration units, are a leading cause of progressive kidney disease. Assessment of the ultrastructure of podocytes at the glomerular filtration barrier is essential for diagnosing diverse disease entities, providing insight into the disease pathogenesis, and monitoring treatment responses. Methods: Here we apply previously published sample preparation methods together with stimulated emission depletion and confocal microscopy for resolving nanoscale podocyte substructure. The protocols are modified and optimized in order to be applied to formalin-fixed paraffin-embedded (FFPE) samples. Results: We successfully modified our protocols to allow for deep three-dimensional stimulated emission depletion and confocal imaging of FFPE kidney tissue with similar staining and image quality compared with our previous approaches. We further show that quantitative analysis can be applied to extract morphometrics from healthy and diseased samples from both mice and humans. Conclusions: The results from this study could increase the feasibility of implementing optical kidney imaging protocols in clinical routines because FFPE is the gold-standard method for storage of patient samples.

A systematic analysis of diet-induced nephroprotection reveals overlapping changes in cysteine catabolism.

Caloric Restriction (CR) extends lifespan and augments cellular stress-resistance from yeast to primates, making CR an attractive strategy for organ protection in the clinic. Translation of CR to patients is complex, due to problems regarding adherence, feasibility, and safety concerns in frail patients. Novel tailored dietary regimens, which modulate the dietary composition of macro- and micronutrients rather than reducing calorie intake promise similar protective effects and increased translatability. However, a direct head-to-head comparison to identify the most potent approach for organ protection, as well as overlapping metabolic consequences have not been performed. We systematically analyzed six dietary preconditioning protocols - fasting mimicking diet (FMD), ketogenic diet (KD), dietary restriction of branched chained amino acids (BCAA), two dietary regimens restricting sulfur-containing amino acids (SR80/100) and CR - in a rodent model of renal ischemia-reperfusion injury (IRI) to quantify diet-induced resilience in kidneys. Of the administered diets, FMD, SR80/100 and CR efficiently protect from kidney damage after IRI. Interestingly, these approaches show overlapping changes in oxidative and hydrogen sulfide (H2S)-dependent cysteine catabolism as a potential common mechanism of organ protection.

[University emergency departments in the corona pandemic-Results from the ReCovER registry]. / Universitäre Notaufnahmen in der Coronapandemie ­ Ergebnisse des ReCovER-Registers.

BACKGROUND: The current COVID-19 pandemic, despite the availability of rapid tests and the start of the vaccination campaign, continues to pose major challenges to emergency departments (ED). Structured collection of demographic, clinical, as well as treatment-related data provides the basis for establishing evidence-based processes and treatment concepts. AIM OF THE WORK: To present the systematic collection of clinical parameters in patients with suspected COVID-19 in the Registry for COVID-19 in the Emergency Room (ReCovER) and descriptive presentation of the first 1000 patients. MATERIALS AND METHODS: Data from patients with suspected COVID-19, regardless of evidence of SARS-CoV­2 infection, are continuously entered into a web-based, anonymized registry in ED at six university hospitals. RESULTS: Between 19 May 2020 and 13 January 2021, 1000 patients were entered into the registry, of whom 594 patients (59.4%) were in the SARS-CoV­2 positive group (PG) and 406 patients (40.6%) were in the negative group (NG). Patients of the PG had significantly fewer pre-existing conditions and a significantly longer latency between symptom onset and presentation to the ED (median 5 vs. 3 days), were more likely to suffer from cough, myalgia, fatigue, and loss of smell/taste and had significantly higher oxygen requirements than NG patients. The rate of severe disease progression was significantly higher in the PG, and persistent symptoms were more common after discharge (11.1 vs. 4.6%). CONCLUSIONS: The multicenter collection of comprehensive clinical data on COVID-19 suspected cases in the ED allows analysis of aspects specific to the situation in Germany in particular. This is essential for a targeted review and adaptation of internationally published strategies.

Mechanisms of Caloric Restriction-Mediated Stress-Resistance in Acute Kidney Injury.

Caloric restriction (CR)-mediated organ protection has been shown to be extremely efficient in rodent models of acute kidney injury (AKI). Limited understanding of the underlying mechanisms paired with a risk of malnourishment and feasibility problems has hindered the translation of this immense potential to the patient setting. In this mini-review, the current mechanistic concepts of CR-mediated stress-resistance as potential key targets for renal protection in AKI will be highlighted.

Development and design of the Hantavirus registry - HantaReg - for epidemiological studies, outbreaks and clinical studies on hantavirus disease.

BACKGROUND: Frequent outbreaks around the globe and endemic appearance in different parts of the world emphasize the substantial risk of hantavirus diseases. Increasing incidence rates, trends of changing distribution of hantavirus species and new insights into clinical courses of hantavirus diseases call for multinational surveillance. Furthermore, evidence-based guidelines for the management of hantavirus diseases and scoring systems, which allow stratification of patients into risk categories, are lacking. METHODS: Hantavirus registry (HantaReg) is a novel registry platform facilitating multinational research of hantavirus-caused diseases, such as haemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). HantaReg provides an electronic case report form and uses the General Data Protection Regulation compliant platform clinicalsurveys.net, which can be accessed from any internet browser in the world. Having a modular structure, the registry platform is designed to display or hide questions and items according to the documented case (e.g. patient with HFRS versus HCPS) to facilitate fast, but standardized, data entry. Information categories documented in HantaReg are demographics, pre-existing diseases, clinical presentation, diagnostic and therapeutic approaches, as well as outcome. CONCLUSIONS: HantaReg is a novel, ready-to-use platform for clinical and epidemiological studies on hantavirus diseases and facilitates the documentation of the disease course associated with hantavirus infections. HantaReg is expected to promote international collaboration and contributes to improving patient care through the analysis of diagnostic and treatment pathways for hantavirus diseases, providing evidence for robust treatment recommendations. Moreover, HantaReg enables the development of prognosis-indicating scoring systems for patients with hantavirus disease.

Clinical course and predictive risk factors for fatal outcome of SARS-CoV-2 infection in patients with chronic kidney disease.

PURPOSE: The ongoing pandemic caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) has stressed health systems worldwide. Patients with chronic kidney disease (CKD) seem to be more prone to a severe course of coronavirus disease (COVID-19) due to comorbidities and an altered immune system. The study's aim was to identify factors predicting mortality among SARS-CoV-2-infected patients with CKD. METHODS: We analyzed 2817 SARS-CoV-2-infected patients enrolled in the Lean European Open Survey on SARS-CoV-2-infected patients and identified 426 patients with pre-existing CKD. Group comparisons were performed via Chi-squared test. Using univariate and multivariable logistic regression, predictive factors for mortality were identified. RESULTS: Comparative analyses to patients without CKD revealed a higher mortality (140/426, 32.9% versus 354/2391, 14.8%). Higher age could be confirmed as a demographic predictor for mortality in CKD patients (> 85 years compared to 15-65 years, adjusted odds ratio (aOR) 6.49, 95% CI 1.27-33.20, p = 0.025). We further identified markedly elevated lactate dehydrogenase (> 2 × upper limit of normal, aOR 23.21, 95% CI 3.66-147.11, p < 0.001), thrombocytopenia (< 120,000/µl, aOR 11.66, 95% CI 2.49-54.70, p = 0.002), anemia (Hb < 10 g/dl, aOR 3.21, 95% CI 1.17-8.82, p = 0.024), and C-reactive protein (≥ 30 mg/l, aOR 3.44, 95% CI 1.13-10.45, p = 0.029) as predictors, while renal replacement therapy was not related to mortality (aOR 1.15, 95% CI 0.68-1.93, p = 0.611). CONCLUSION: The identified predictors include routinely measured and universally available parameters. Their assessment might facilitate risk stratification in this highly vulnerable cohort as early as at initial medical evaluation for SARS-CoV-2.

CALINCA-A Novel Pipeline for the Identification of lncRNAs in Podocyte Disease.

Diseases of the renal filtration unit-the glomerulus-are the most common cause of chronic kidney disease. Podocytes are the pivotal cell type for the function of this filter and focal-segmental glomerulosclerosis (FSGS) is a classic example of a podocytopathy leading to proteinuria and glomerular scarring. Currently, no targeted treatment of FSGS is available. This lack of therapeutic strategies is explained by a limited understanding of the defects in podocyte cell biology leading to FSGS. To date, most studies in the field have focused on protein-coding genes and their gene products. However, more than 80% of all transcripts produced by mammalian cells are actually non-coding. Here, long non-coding RNAs (lncRNAs) are a relatively novel class of transcripts and have not been systematically studied in FSGS to date. The appropriate tools to facilitate lncRNA research for the renal scientific community are urgently required due to a row of challenges compared to classical analysis pipelines optimized for coding RNA expression analysis. Here, we present the bioinformatic pipeline CALINCA as a solution for this problem. CALINCA automatically analyzes datasets from murine FSGS models and quantifies both annotated and de novo assembled lncRNAs. In addition, the tool provides in-depth information on podocyte specificity of these lncRNAs, as well as evolutionary conservation and expression in human datasets making this pipeline a crucial basis to lncRNA studies in FSGS.

Attributable mortality of candidemia after introduction of echinocandins.

OBJECTIVES: Candidemia is among the most frequent nosocomial bloodstream infections. Landmark case-control studies on amphotericin B and fluconazole estimated attributable mortality rates of 38% and 49%, respectively. After introduction of echinocandins, these may have decreased. METHODS: In a case-control design, 100 consecutive, hospitalised patients with candidemia were enrolled at the University Hospital of Cologne, Germany between 2014 and 2017. Controls were patients without candidemia matched for age, sex, year and duration of hospitalisation, main admission diagnosis and Patient Clinical Complexity Level (PCCL). Main data captured were risk factors for candidemia, attributable mortality rates and diagnostic and therapeutic adherence according to the EQUAL Candida score. RESULTS: Overall mortality rates for cases and controls were 43% and 17% (P < .001), respectively; day 30 mortality rates were 38% and 11% (P = .03), accounting for an attributable mortality of 26% and 27%. Guideline adherence was higher in surviving vs non-surviving patients: while survivors reached a median of 17 (IQR: 16-19) points, non-surviving cases reached a median 16 (IQR: 14-18) points out of 22 maximum achievable points (P = .028). Risk factors for candidemia were more frequent in cases compared to control patients, especially chronic pulmonary disease (25% vs 16%; P = n.s.), chronic liver disease (21% vs 6%; P = .002), stay on intensive care unit (70% vs 64%; P = n.s.), respiratory failure (56% vs 50%; P = n.s.) and central venous catheter (97% vs 35%; P < .001). CONCLUSIONS: Attributable mortality of nosocomial candidemia is still substantial but has decreased compared to previous studies with similar design.

ECMM CandiReg-A ready to use platform for outbreaks and epidemiological studies.

BACKGROUND: Recent outbreaks of Candida auris further exemplify that invasive Candida infections are a substantial threat to patients and healthcare systems. Even short treatment delays are associated with higher mortality rates. Epidemiological shifts towards more resistant Candida spp. require careful surveillance. OBJECTIVES: Triggered by the emergence of C auris and by increasing antifungal resistance rates the European Confederation of Medical Mycology developed an international Candida Registry (FungiScope™ CandiReg) to allow contemporary multinational surveillance. METHODS: CandiReg serves as platform for international cooperation to enhance research regarding invasive Candida infections. CandiReg uses the General Data Protection Regulation compliant data platform ClinicalSurveys.net that holds the electronic case report forms (eCRF). Data entry is supported via an interactive macro created by the software that can be accessed via any Internet browser. RESULTS: CandiReg provides an eCRF for invasive Candida infections that can be used for a variety of studies from cohort studies on attributable mortality to evaluations of guideline adherence, offering to the investigators of the 28 ECMM member countries the opportunity to document their cases of invasive Candida infection. CandiReg allows the monitoring of epidemiology of invasive Candida infections, including monitoring of multinational outbreaks. Here, we describe the structure and management of the CandiReg platform. CONCLUSION: CandiReg supports the collection of clinical information and isolates to improve the knowledge on epidemiology and eventually to improve management of invasive Candida infections. CandiReg promotes international collaboration, improving the availability and quality of evidence on invasive Candida infection and contributes to improved patient management.

Baseline predictors influencing the prognosis of invasive aspergillosis in adults.

Invasive aspergillosis (IA) is a serious hazard to haematological and critical care patients. Impactful risk factors for developing IA have been characterised; however, systematic analysis of baseline prognostic factors for treatment course of IA is missing. To understand prognostic variables, we analysed original articles identifying baseline factors that predict treatment outcome in patients with IA. PubMed database was searched for publications since database inception until May 2018. Inclusion criteria were published baseline prognostic factors present at the diagnosis of IA. In total, 58 studies from 267 centres reported 7320 patients with IA and 40 different predictors. Unfavourable predictors in medical history were kidney (7.4%, 10/136) and liver failure (3.7%, 5/136), ICU admission (3.7%, 5/136) and uncontrolled underlying disease (3.7%, 5/136). Regarding state of immunosuppression, negative outcome predictors were prolonged neutropenia (12.5%, 17/136), corticosteroid treatment (8.1%, 11/136) and graft-vs-host disease (3.7%, 5/136). On the pathogen side, relevant predictors were galactomannan positivity (8.1%, 11/136), Aspergillus terreus infection (2.2%, 3/136) and lack of amphotericin B susceptibility (1.5%, 2/136). IA-specific predictors were disseminated disease (5.1%, 7/136) and CNS involvement (2.9%, 4/136). Imaging results associated with negative outcome were multiple consolidations (2.9%, 4/136), bipulmonary lesions (2.2%, 3/136) and pleural effusion (2.2%, 3/136). At diagnosis of IA, most frequently identified predictors of outcome were neutropenia, corticosteroid use, elevated galactomannan, renal failure and disseminated disease. The predictors may be used to identify patients at high risk for treatment failure and to stratify neglected patient groups for clinical trials.

Development and validation of the European QUALity (EQUAL) score for mucormycosis management in haematology.

BACKGROUND: Mucormycosis is a life-threatening infection in immunocompromised patients and in haematological malignancy patients in particular. OBJECTIVES: Our aim was to develop and evaluate a scoring tool to measure adherence to current guidelines for mucormycosis. METHODS: Current guidelines of scientific societies on mucormycosis management were reviewed. We assembled diagnostic, treatment and follow-up milestones and designed the EQUAL Mucormycosis Score. The EQUAL Mucormycosis Score was evaluated in the ECMM Excellence Centres. RESULTS: An 18-item tool with one to three points per item resulted in a maximum achievable score depending on disease complexity and ranging from 25 to 32 points. Given variable patient disease course, the diagnostic score is higher in patients with positive fungal culture and biopsy, thus reflecting more decision points and higher management complexity. Eleven patients from two centres were included during the study period. A total of 200 EQUAL Mucormycosis Score points were achieved, which is 62.7% of the maximum EQUAL Mucormycosis Score of 319 points achievable in that cohort (median 18 points, range 7-27). The total score accomplished for diagnostic procedures was 112 of 165 points (67.9%), for first-line treatment 54 of 88 (61.4%) and for follow-up management 34 of 66 points (51.5%). CONCLUSIONS: The EQUAL Mucormycosis Score quantitates adherence to current guideline recommendations for mucormycosis management. With 62.7% of maximum achievable score points, a first result is obtained that may serve as a reference for future evaluations. It remains to be shown whether guideline adherence and mortality rates correlate.

Candida-Reactive T Cells for the Diagnosis of Invasive Candida Infection-A Prospective Pilot Study.

Background: Blood or tissue culture or histology prove invasive Candida infection, but long time to result, limited feasibility and sensitivity call for new approaches. In this pilot project, we describe the diagnostic potential of quantitating Candida-reactive, CD4/CD69/CD154 positive lymphocytes in blood of patients with invasive Candida infection. Methods: We used flow cytometry quantitating Candida-reactive, CD4/CD69/CD154 positive lymphocytes from peripheral blood of patients with invasive Candida infection, from patients at risk and healthy volunteers as controls. Results: Elevated levels of Candida-reactive lymphocytes were measured in 13 patients with proven invasive Candida infection and in one patient with probable hepatosplenic candidiasis. Results of three candidemia patients were uninterpretable due to autofluorescence of samples. Twelve of 13 patients had Candida identified to species level by conventional methods, and T cell reactivity correctly identified Candida species in 10 of 12 patients. Nine hematological high-risk patients and 14 healthy donors had no elevated Candida-reactive T cell counts. Conclusions: This Candida-reactive lymphocyte assay correctly identified the majority of patients with invasive Candida infection and the respective species. Our assay has the potential to support diagnosis of invasive Candida infection to species level and to facilitate tailored treatment even when biopsies are contraindicated or cultures remain negative.

Candida-reactive T cells for the diagnosis of invasive Candida infection of the lumbar vertebral spine.

Invasive Candida infection is the fourth most common bloodstream infection. Blood cultures are the current gold standard diagnostic method, however, false negatives remain a clinical challenge. We developed a new technique measuring Candida-reactive T cells as diagnostic read-out for invasive Candida infection. In a pilot study, we followed the treatment course of a patient with an invasive Candida infection of the lumbar vertebral spine. We present the case of a 56-year-old patient with HIV-associated Burkitt lymphoma who developed septic shock during chemotherapy-induced neutropenia. For the first time, we provide flow cytometry-based diagnostics with Candida-reactive T cells for invasive candidiasis with comprehensive MRI imaging. The Candida-reactive T cell assay has potential to complement current diagnostic assays for invasive Candida infection and thus to support targeted treatment.