Incidence of Secondary Sclerosing Cholangitis in Hospitalized Long COVID-19 Patients: A Retrospective Single Center Study.

BACKGROUND: SARS-CoV-2 infection and associated COVID-19 disease can lead to critical illness with a risk of developing a multiple organ failure. Subsequently, this may lead to various pathological sequelae, such as secondary sclerosing cholangitis after surviving COVID-19 (SSC-COVID). OBJECTIVE: The aim is to retrospectively analyze a cohort of hospitalized patients with first-wave (February 2020-June 2020) SARS-CoV-2 infection and persisting unclear cholangiopathy to determine the incidence of SSC-COVID and its risk factors. RESULTS: A total of 249 patients were hospitalized at the university hospital in Tübingen, Germany, with SARS-CoV-2 infection during the first wave of the pandemic. Of these, 35.3% (88/249) required intensive care treatment; 16.5% (41/249) of them died due to the complications of COVID-19; 30.8% (64/208) of surviving patients could be followed up und were retrospectively analyzed at our center. The incidence of confirmed SSC-COVID was 7.8% (5/64). All SSC-COVID patients had an ICU stay >20 days, for invasive ventilation, positioning treatment, vasopressor treatment, but possible risk factors for SSC were not significant due to the small number of patients. CONCLUSIONS: SSC-COVID is an emerging disease in post-COVID patients with a high incidence in our single-center cohort. SSC-COVID should be considered as a differential diagnosis, if unclear cholangiopathy or cholestasis persists after SARS-CoV-2 infection.

Modelling and Simulation of the Effect of Targeted Decolonisation on Incidence of Extended-Spectrum Beta-Lactamase-Producing Enterobacterales Bloodstream Infections in Haematological Patients.

INTRODUCTION: Haematological patients are at higher risk of bloodstream infections (BSI) after chemotherapy. The aim of this study was to develop a simulation model assessing the impact of selective digestive decontamination (SDD) of haematological patients colonised with extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) on the incidence of ESBL-E BSI after chemotherapy. METHODS: A patient population was created by a stochastic simulation model mimicking the patients' states of colonisation with ESBL-E during hospitalisation. A systematic literature search was performed to inform the model. All ESBL-E carriers were randomised (1:1) to either the intervention (targeted SDD) or the control group (placebo). ESBL-E BSI incidence was the outcome of the model. Sensitivity analyses were performed by prevalence of ESBL-E carriage at hospital admission (low: < 10%, medium: 10-25%, high: > 25%), duration of neutropenia after receiving chemotherapy, administration of antibiotic prophylaxis with quinolones, and time interval between SDD and chemotherapy. RESULTS: The model estimated that the administration of targeted SDD before chemotherapy reduces the incidence of ESBL-E BSI in the hospitalised haematological population up to 27%. The greatest benefit was estimated in high-prevalence settings, regardless of the duration of neutropenia, the time interval before chemotherapy, and the administration of antibiotic prophylaxis with quinolones (p < 0.05). In medium-prevalence settings, SDD was effective in patients receiving quinolone prophylaxis, with either 1-day time interval before chemotherapy and a neutropenia duration > 6 days (p < 0.05) or 7-day time interval before chemotherapy and a neutropenia duration > 9 days (p < 0.05). No benefit was observed in low-prevalence settings. CONCLUSIONS: Our model suggests that targeted SDD could decrease the rate of ESBL-E BSI in haematological carriers before chemotherapy in the setting of high ESBL-E prevalence at hospital admission. These estimates require confirmation by well-designed multicentre RCTs, including the assessment of the impact on resistance/disruption patterns of gut microbiome.

Simultaneous disseminated infections with intracellular pathogens: an intriguing case report of adult-onset immunodeficiency with anti-interferon-gamma autoantibodies.

BACKGROUND: Severe and disseminated non-tuberculous mycobacterial (NTM) infections are frequently linked to a genetic predisposition but acquired defects of the interferon gamma (IFNγ) / interleukin 12 (IL-12) pathway need to be considered in adult patients with persistent or recurrent infections. Neutralizing anti-IFNγ autoantibodies disrupting IFNγ signalling have been identified as the cause of a severe and unique acquired immunodeficiency syndrome with increased susceptibility to NTM and other intracellular pathogens. CASE PRESENTATION: An adult Asian female with a previous history of recurrent NTM infections presented with persistent diarrhea, abdominal pain, night sweats and weight loss. Severe colitis due to a simultaneous infection with cytomegalovirus (CMV) and Salmonella typhimurium was diagnosed, with both pathogens also detectable in blood samples. Imaging studies further revealed thoracic as well as abdominal lymphadenopathy and a disseminated Mycobacterium intracellulare infection was diagnosed after a lymph node biopsy. Further diagnostics revealed the presence of high-titer neutralizing anti-IFNγ autoantibodies, allowing for the diagnosis of adult-onset immunodeficiency with anti-IFNγ autoantibodies (AIIA). CONCLUSIONS: We here present a severe case of acquired immunodeficiency with anti-IFNγ autoantibodies with simultaneous, disseminated infections with both viral and microbial pathogens. The case illustrates how the diagnosis can cause considerable difficulties and is often delayed due to unusual presentations. Histological studies in our patient give further insight into the pathophysiological significance of impaired IFNγ signalling. B-cell-depleting therapy with rituximab offers a targeted treatment approach in AIIA.

Test and treat COVID 65 plus - Hydroxychloroquine versus placebo in early ambulatory diagnosis and treatment of older patients with COVID19: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The aim of this trial is to identify the effect of ambulatory treatment in early COVID-19 disease with hydroxychloroquine on the rate of hospitalization or death in older patients above the age of 64. TRIAL DESIGN: Parallel, 2:1 randomization, double blind, placebo-controlled, multi-center trial. PARTICIPANTS: Male and female patients above the age of 64 (i.e. ≥65 years of age) with COVID-19 diagnosis confirmed by SARS-CoV2 positive throat swab (PCR). Patients can only be included within 3 days of symptom onset in ambulatory care if they consent to the study procedure and are able to adhere to the study visit schedule and protocol requirements (including telephone visits concerning symptoms and side effects). Severity of disease at inclusion is mild to moderate defined as not requiring hospital admission: SpO2 >94%, respiratory rate <20, mental state alert, no signs of septic shock. Cardiac risk is minimised by requiring a Tisdale score ≤ 6. Patients are recruited in the two german cities of Ulm and Tübingen in various ambulatory care settings. INTERVENTION AND COMPARATOR: Each patient will be given a first dose of 600 mg Hydroxychloroquine or the equivalent number of placebo capsules (3 capsules) at the day of inclusion. From the 2nd day on, each patient will get 200 mg or the equivalent number of placebo capsules twice a day (400mg/day) until day 7 (6 more does of 400 mg); a cumulative dose of 3 g. MAIN OUTCOMES: Rate of hospitalization or death at day 7 after study inclusion RANDOMISATION: All consenting adult patients having confirmed COVID-19 are randomly and blindly allocated in a 2:1 ratio to either IMP or placebo. The biostatistical center produced a randomization list (block randomization) with varying block length and stratified for the study center. This list is provided for packaging to the pharmaceutical unit which is providing encapsulated placebo and IMP. Only the pharmaceutical unit is aware of group allocation according to the randomization list. BLINDING (MASKING): Patients and investigators, as well as treating physicians are blinded to the treatment- allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In the first stage of an adaptive design 120 patients in a 2:1 ration: 72 Verum and 36 Placebo, plus an increase for 10% drop outs. After interim analysis, the total sample size will be calculated based on the effect seen in the first stage. Total sample size is estimated approximately n = 300-400 patients. TRIAL STATUS: Protocol version number: V3, 19.05.2020 Recruitment not yet started but is anticipated to begin by June 2020 and be complete by December 2020 TRIAL REGISTRATION: ClinicalTrials.gov: NCT04351516 , date: 17 April 2020 EudraCT: 2020-001482-37, date: 30 March 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis.

BACKGROUND: Antibiotic stewardship programmes have been shown to reduce antibiotic use and hospital costs. We aimed to evaluate evidence of the effect of antibiotic stewardship on the incidence of infections and colonisation with antibiotic-resistant bacteria. METHODS: For this systematic review and meta-analysis, we searched PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Web of Science for studies published from Jan 1, 1960, to May 31, 2016, that analysed the effect of antibiotic stewardship programmes on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infections in hospital inpatients. Two authors independently assessed the eligibility of trials and extracted data. Studies involving long-term care facilities were excluded. The main outcomes were incidence ratios (IRs) of target infections and colonisation per 1000 patient-days before and after implementation of antibiotic stewardship. Meta-analyses were done with random-effect models and heterogeneity was calculated with the I2 method. FINDINGS: We included 32 studies in the meta-analysis, comprising 9 056 241 patient-days and 159 estimates of IRs. Antibiotic stewardship programmes reduced the incidence of infections and colonisation with multidrug-resistant Gram-negative bacteria (51% reduction; IR 0·49, 95% CI 0·35-0·68; p<0·0001), extended-spectrum ß-lactamase-producing Gram-negative bacteria (48%; 0·52, 0·27-0·98; p=0·0428), and meticillin-resistant Staphylococcus aureus (37%; 0·63, 0·45-0·88; p=0·0065), as well as the incidence of C difficile infections (32%; 0·68, 0·53-0·88; p=0·0029). Antibiotic stewardship programmes were more effective when implemented with infection control measures (IR 0·69, 0·54-0·88; p=0·0030), especially hand-hygiene interventions (0·34, 0·21-0·54; p<0·0001), than when implemented alone. Antibiotic stewardship did not affect the IRs of vancomycin-resistant enterococci and quinolone-resistant and aminoglycoside-resistant Gram-negative bacteria. Significant heterogeneity between studies was detected, which was partly explained by the type of interventions and co-resistance patterns of the target bacteria. INTERPRETATION: Antibiotic stewardship programmes significantly reduce the incidence of infections and colonisation with antibiotic-resistant bacteria and C difficile infections in hospital inpatients. These results provide stakeholders and policy makers with evidence for implementation of antibiotic stewardship interventions to reduce the burden of infections from antibiotic-resistant bacteria. FUNDING: German Center for Infection Research.