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Background Plasma metagenomic next-generation sequencing (mNGS) is an emerging diagnostic tool. As the clinical use of mNGS increases, efforts to better understand the role of mNGS in diagnosis and management of infectious diseases are essential. Current literature is limited to small retrospective reviewers and a prospective study therefore subject to institutional variability. Here, we aim to describe the use, sensitivity, time to diagnosis, clinical impact, and cost effectiveness of mNGS in the largest patient cohort to date. Methods We included pediatric and adult patients who had plasma mNGS testing as part of care from December 2017 through December 2021 at University of Minnesota (UMN). Patients were identified using the Karius database. Electronic medical records were reviewed for every mNGS test, recording patient demographics, underlying conditions, indications, and results within 30 days of mNGS. All cases were assessed by 2 reviewers including one board-certified infectious diseases doctor. Sensitivity of mNGS was determined relative to conventional tests. The primary end point was change in clinical management. Secondary end points included accuracy, time to diagnosis, and infectious disease consultation. UMN IRB approved this study as non human subjects research. Results 584 mNGS tests were ordered in the study period, with 203 reviews completed to date. Solid organ transplantation (SOT) (32%) was the most common underlying condition, followed by hemopoietic stem cell transplantation (HSCT) (28%). Fever (45.8%), then pulmonary findings (26%) were the most common indications for ordering mNGS. Conventional and mNGS tests identified an infectious cause of the clinical syndrome in 49% of cases, while a contaminant was found in 52% of cases. The sensitivity of mNGS in identification of infectious cause was 47%, approximately 7% more sensitive than conventional testing. Despite this increased sensitivity, mNGS changed clinical management in 20% of cases. Conclusion mNGS demonstrated superiority in accurate detection of infectious causes of clinical syndromes, however, changed clinical management in a minority of cases, suggesting timing of the mNGS test is critical. This study identified SOT and HSCT as high yield patient groups for implementation of a prospective study. Disclosures Beth K. Thielen, MD, PhD, Horizon: Advisor/Consultant|Horizon: Honoraria|Merck: Grant/Research Support.

Angeborene Immundefekte sind einerseits selten, anderseits zeigen sie eine sehr variable initiale Symptomatik und stellen deshalb eine diagnostische Herausforderung dar. Prinzipiell können bei angeborenen Immundefekten drei Hauptprobleme auftreten: Beeinträchtigung der Infektabwehr, erhöhtes Malignomrisiko und Immundysregulation (z.B. Autoimmunerkrankungen und autoinflammatorische Syndrome).

Les déficits immunitaires congénitaux sont d’une part rares, d’autre part la symptomatologie initiale est très variable, leur diagnostic représente donc un défi. En principe un déficit immunitaire congénital peut se manifester par trois problèmes principaux: une perturbation de la défense immunitaire, un risque élevé de tumeurs malignes et une dysrégulation immunitaire (p.ex. maladies auto-immunes et syndromes auto-inflammatoires).

Background The palliation of patients with single ventricle (SV) undergoing Fontan procedure led to improved long-term survival but is still limited due to cardiovascular complications. The aim of this study was to describe the somatic and cardiovascular development of Fontan patients until adolescence and to identify determining factors. Methods We retrospectively assessed somatic growth, vascular growth of pulmonary arteries, and cardiac growth of the SV and systemic semilunar valve from 0 to 16 years of age using transthoracic echocardiography. The Doppler inflow pattern of the atrioventricular valve was quantified by E-, A-wave and E/A ratio. All data were converted to z-scores and analyzed using linear mixed effect models to identify associations with age at Fontan procedure, gender, and ventricular morphology. Results 134 patients undergoing Fontan procedure at a median age of 2.4 (IQR 2.12 to 2.8) years were analyzed. A catch-up of somatic growth after Fontan procedure until school age was found, with lower body height and weight z-scores in male patients and patients with systemic right ventricles. An early time of Fontan procedure was favorable for somatic growth, but not for vascular growth. Cardiac development indicated a decrease of SV end-diastolic diameter z-score until adolescence. Despite a trend towards normalization, E-wave and E/A ratio z-scores were diminished over the entire period. Conclusions There is a catch-up growth of somatic, vascular and cardiac parameters after Fontan procedure, which in our cohort depends on the time of Fontan procedure, ventricular morphology, and gender. Beside other factors, diastolic function of the SV remains altered.

IntroductionA high proportion of survivors of childhood and adolescent cancer experience chronic medical conditions — late effects. Most studies on late effects have a retrospective or questionnaire-based design, which leads to unavoidable limitations such as missing data or different severity coding and grading of late effects. We, therefore, need prospective data, including standardised severity coding and grading. ‘Young Survivors at KSA’ aims to close this gap by assessing frequency, severity, risk factors and longitudinal changes of late effects in childhood cancer survivors prospectively and in a standardised way.Methods and analysisWithin the ‘Young Survivors at KSA’ registry, we collect data from regular follow-up visits in a comprehensive database prospectively and repeatedly from start of the study and retrospectively at most until January 2016. We classify and grade the severity of late effects according to the Common Terminology Criteria for Adverse Events version 4.0 modified by Hudsonet al. The outcome variables correspond to results from risk-stratified organ examinations, performed according to the Children’s Oncology Group guidelines version 5.0 and the recommendations by the International Guideline Harmonization Group. We collect the exposure variables from the patients’ medical history, including detailed information on cancer diagnosis and treatment. We analyse the data in an exposure-driven and organ system-driven approach. We start recruitment with patients treated at the Kantonsspital Aarau, Switzerland. However, our design allows the inclusion of additional national centres later.Ethics and dissemination‘Young Survivors at KSA’ is approved by the Ethikkommission Nordwest- und Zentralschweiz, reference number AO_2020–00012. The results of this study will be presented at scientific meetings, including meetings with childhood cancer survivors and published in peer-reviewed and if possible open access journals. New insights gained from the study will be used directly in clinical practice.Trial registration numberClinicalTrials.govNCT04811794;https://clinicaltrials.gov/ct2/show/study/NCT04811794

After allogeneic hematopoietic stem cell transplantation (allo-HSCT), the recurrence of recent thymic emigrants (RTE) and self-tolerant T cells indicate normalized thymic function. From 2008 to 2019, we retrospectively analyzed the RTE-reconstitution rate and the minimal time to reach normal age-specific first percentiles for CD31

Hematopoietic cell transplantation (HCT) has become standard-of-care for an increasing number of inborn errors of immunity (IEI). This report is the first to compare transplant outcomes according to T-cell–replete (ie, T-replete) HLA-matched grafts using alemtuzumab (n = 117) and T-cell–depleted (ie, T-depleted) HLA-mismatched grafts using T-cell receptor-αβ (TCRαβ)/CD19 depletion (n = 47) in children with IEI who underwent first HCT between 2014 and 2019. All patients received treosulfan-based conditioning except patients with DNA repair disorders. For T-replete grafts, the stem cell source was marrow in 25 (21%) patients, peripheral blood stem cell (PBSC) in 85 (73%), and cord blood in 7 (6%). TCRαβ/CD19 depletion was performed on PBSCs from 45 haploidentical parental donors and 2 mismatched unrelated donors. The 3-year overall survival (OS) and event-free survival for the entire cohort were 85% (77%-90%) and 79% (69%-86%), respectively. Analysis according to age at transplant revealed a comparable 3-year OS between T-replete grafts (88%; 76%-94%) and T-depleted grafts (87%; 64%-96%) in younger patients (aged 5 years), the OS was significantly lower in T-depleted grafts (55%; 23%-78%) compared with T-replete grafts (87%; 68%-95%) (P = .03). Grade III to IV acute graft-versus-host disease was observed in 8% of T-replete marrow, 7% of T-replete PBSC, 14% of T-replete cord blood, and 2% of T-depleted PBSC (P = .73). Higher incidence of viremia (P < .001) and delayed CD3 reconstitution (P = .003) were observed after T-depleted graft HCT. These data indicate that mismatched donor transplant after TCRαβ/CD19 depletion represents an excellent alternative for younger children with IEI in need of an allograft.

Background: An intervention trial found a trend for shorter length of stay (LOS) in patients with community-acquired pneumonia (CAP) when the CURB65 score was combined with the prognostic biomarker proadrenomedullin (ProADM) (CURB65-A). However, the efficacy and safety of CURB65-A in real life situations remains unclear. Methods: From September, 2011, until April, 2012, we performed a post-study prospective observational quality control survey at the cantonal Hospital of Aarau, Switzerland of consecutive adults with CAP. The primary endpoint was length of stay (LOS) during the index hospitalization and within 30 days. We compared the results with two well-defined historic cohorts of CAP patients hospitalized in the same hospital with the use of multivariate regression, namely 83 patients in the observation study without ProADM (OPTIMA I) and the 169 patients in the intervention study (OPTIMA II RCT). Results: A total of 89 patients with confirmed CAP were included. As compared to patients with CURB65 only observed in the OPTIMA I study, adjusted regression analysis showed a significant shorter initial LOS (7.5 vs. 10.4 days; −2.32; 95% CI, −4.51 to −0.13; p = 0.04) when CURB65-A was used in clinical routine. No significant differences were found for LOS within 30 days. There were no significant differences in safety outcomes in regard to mortality and ICU admission between the cohorts. Conclusion: This post-study survey provides evidence that the use of ProADM in combination with CURB65 (CURB65-A) in “real life” situations reduces initial LOS compared to the CURB65 score alone without apparent negative effects on patient safety.

Background: In 14 randomized controlled studies to date, a procalcitonin (PCT)-based algorithm has been proven to markedly reduce the use of antibiotics along with an unimpaired high safety and low complication rates in patients with lower respiratory tract infections (LRTIs). However, compliance with the algorithm and safety out of controlled study conditions has not yet been sufficiently investigated. Methods: We performed a prospective international multicenter observational post-study surveillance of consecutive adults with community-acquired LRTI in 14 centers (Switzerland (n = 10), France (n = 3) and the United States (n = 1)). Results: Between September 2009 and November 2010, 1,759 patients were enrolled (median age 71, female sex 44.4%). 1,520 (86.4%) patients had a final diagnosis of LRTI (community-acquired pneumonia (CAP), 53.7%, acute exacerbation of chronic obstructive pulmonary disease (AECOPD), 17.1%, and acute bronchitis, 14.4%). Compliance with the PCT-guided therapy (overall 68.2%) was highest in patients with bronchitis (81.0% vs. AECOPD, 70.1%, CAP, 63.7%, p &lt, 0.001), outpatients (86.1% vs. inpatients, 65.9%, 0.001) and algorithm-experienced centers (82.5% vs. algorithm-naive, 60.1%, 0.001) and showed significant geographical differences. The initial decision about the antibiotic therapy was based on PCT value in 72.4%. In another 8.6% of patients, antibiotics were administered despite low PCT values but according to predefined criteria. Thus, the algorithm was followed in 81.0% of patients. In a multivariable Cox hazard ratio model, longer antibiotic therapy duration was associated with algorithm-non-compliance, country, hospitalization, CAP vs. bronchitis, renal failure and algorithm-naïvety of the study center. In a multivariable logistic regression complications (death, empyema, ICU treatment, mechanical ventilation, relapse, and antibiotic-associated side effects) were significantly associated with increasing CURB65-Score, CAP vs. bronchitis, multilobar pneumonia, but not with algorithm-compliance. Discussion: Cultural and geographic differences in antibiotic prescribing affected the compliance with our PCT-guided algorithm. Efforts to reinforce compliance are needed. Antibiotic stewardship with PCT is possible, effective and safe without increasing the risk of complications in real-life conditions.

BACKGROUND: Survival probability in children, adolescents, and young adults with chronic myeloid leukemia (CML) has dramatically improved during recent years. Tyrosine kinase inhibitors (TKI), targeted drugs developed for patients with CML, were introduced in 2001 in England. We here quantify the trends in the "cure" proportion according to the year of diagnosis. METHODS: We included all children, adolescents, and young patients with CML (0 to 24 years) diagnosed in England during 1980 to 2005. We fitted mixture cure models to estimate the "cure" proportion and the median survival time among the "uncured" patients according to the year of diagnosis, adjusted for age at diagnosis. RESULTS: The "cure" proportion increased dramatically between 1980 and 2005, from under 10% to over 80%, while conversely, the median survival time of "uncured" patients decreased slightly between 1980 and 1999, with the trend from 2000 being uncertain. CONCLUSIONS: The striking improvement of the "cure" fraction in young patients with CML since the early 1980s is concomitant with improvement of treatment, especially the allogeneic hematopoietic stem-cell transplant and, later, the introduction of TKI. The trends over the last years (2000-2005) remain, however, uncertain and would benefit from further studies with more recent data and updated follow-up.

Background Urinary tract infections (UTIs) are common drivers of antibiotic use. The minimal effective duration of antibiotic therapy for UTIs is unknown, but any reduction is important to diminish selection pressure for antibiotic resistance, costs, and drug-related side-effects. The aim of this study was to investigate whether an algorithm based on procalcitonin (PCT) and quantitative pyuria reduces antibiotic exposure. Methods From April 2012 to March 2014, we conducted a factorial design randomized controlled open-label trial. Immunocompetent adults with community-acquired non-catheter-related UTI were enrolled in the emergency department of a tertiary-care 600-bed hospital in northwestern Switzerland. Clinical presentation was used to guide initiation and duration of antibiotic therapy according to current guidelines (control group) or with a PCT-pyuria-based algorithm (PCT-pyuria group). The primary endpoint was overall antibiotic exposure within 90 days. Secondary endpoints included duration of the initial antibiotic therapy, persistent infection 7 days after end of therapy and 30 days after enrollment, recurrence and rehospitalizations within 90 days. Results Overall, 394 patients were screened, 228 met predefined exclusion criteria, 30 declined to participate, and 11 were not eligible. Of these, 125 (76% women) were enrolled in the intention-to-treat (ITT) analysis and 96 patients with microbiologically confirmed UTI constituted the per protocol group; 84 of 125 (67%) patients had a febrile UTI, 28 (22%) had bacteremia, 5 (4%) died, and 3 (2%) were lost to follow-up. Overall antibiotic exposure within 90 days was shorter in the PCT-pyuria group than in the control group (median 7.0 [IQR, 5.0–14.0] vs. 10.0 [IQR, 7.0–16.0] days, P = 0.011) in the ITT analysis. Mortality, rates of persistent infections, recurrences, and rehospitalizations were not different. Conclusions A PCT-pyuria-based algorithm reduced antibiotic exposure by 30% when compared to current guidelines without apparent negative effects on clinical outcomes. Trial registration Current controlled trials ISRCTN13663741, date applied: 22/05/2012, date assigned: 03/07/2012, last edited: 28/01/2014. Electronic supplementary material The online version of this article (doi:10.1186/s12916-015-0347-y) contains supplementary material, which is available to authorized users.

Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia.In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154.From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group (4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups.Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency.Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung.

Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for community-acquired pneumonia (CAP). We evaluated whether short-term corticosteroid treatment reduces time to clinical stability in patients hospitalized for CAP.

Background Urinary tract infections (UTIs) are among the most common infectious diseases and drivers of antibiotic use and in-hospital days. A reduction of antibiotic use potentially lowers the risk of antibiotic resistance. An early and adequate risk assessment combining medical, biopsychosocial and functional risk scores has the potential to optimize site-of-care decisions and thus allocation of limited health-care resources. The aim of this factorial design study is twofold: first, for Intervention A, it investigates antibiotic exposure of patients treated with a protocol based on the type of UTI, procalcitonin (PCT) and pyuria. Second, for Intervention B, it investigates the usefulness of the prognostic biomarker proadrenomedullin (ProADM) integrated into an interdisciplinary assessment bundle for site-of-care decisions. Methods and design This randomized controlled open-label trial has a factorial design (2 × 2). Randomization of patients will be based on a pre-specified computer-generated randomization list and independent for the two interventions. Adults with UTI presenting to the emergency department (ED) will be screened and enrolled after providing informed consent. For our first Intervention (A), we developed a protocol based on previous observational research to recommend initiation and duration of antibiotic use based on the clinical presentation of UTI, pyuria and PCT levels. For our second intervention (B), an algorithm was developed to support site-of care decisions based on the prognostic marker ProADM and distinct nursing factors on days 1 and 3. Both interventions will be compared with a control group conforming to the guidelines. The primary endpoints for the two interventions will be: (A) overall exposure to antibiotics and (B) length of physician-led hospitalization within a follow-up of 30 days. Endpoints are assessed at discharge from hospital, and 30 and 90 days after admission. We plan to screen 300 patients and enroll 250 for an anticipated estimated loss of follow-up of 20%. This will provide adequate power for the two interventions. Discussion This trial investigates two strategies for improved individualized medical care in patients with UTI. The minimally effective duration of antibiotic therapy is not known for UTIs, which is important for reducing the selection pressure for antibiotic resistance, costs and drug-related side effects. Triage decisions must be improved to reflect the true medical, biopsychosocial and functional risks in order to allocate patients to the most appropriate care setting and reduce hospital-acquired disability. Trial registration Trial registration number:ISRCTN13663741