Efficacy of cognitive behavioral therapy targeting severe fatigue following COVID-19: results of a randomized controlled trial.

BACKGROUND: Severe fatigue following COVID-19 is prevalent and debilitating. This study investigated the efficacy of cognitive behavioral therapy (CBT) for severe fatigue following COVID-19. METHODS: A multicenter, 2-arm randomized controlled trial was conducted in the Netherlands with patients being severely fatigued 3-12 months following COVID-19. Patients (n = 114) were randomly assigned (1:1) to CBT or care as usual (CAU). CBT, targeting perpetuating factors of fatigue, was provided for 17 weeks. The primary outcome was the overall mean difference between CBT and CAU on the fatigue severity subscale of the Checklist Individual Strength, directly post CBT or CAU (T1), and after six months (T2). Secondary outcomes were differences in proportions of patients meeting criteria for severe and/or chronic fatigue, differences in physical and social functioning, somatic symptoms and problems concentrating between CBT and CAU. RESULTS: Patients were mainly non-hospitalized and self-referred. Patients who received CBT were significantly less severely fatigued across follow-up assessments than patients receiving CAU (-8.8, (95% confidence interval (CI)) -11.9 to -5.8); P < 0.001), representing a medium Cohen's d effect size (0.69). The between-group difference in fatigue severity was present at T1 -9.3 (95% CI -13.3 to -5.3) and T2 -8.4 (95% CI -13.1 to -3.7). All secondary outcomes favored CBT. Eight adverse events were recorded during CBT, and 20 during CAU. No serious adverse events were recorded. CONCLUSIONS: Among patients, who were mainly non-hospitalized and self-referred, CBT was effective in reducing fatigue. The positive effect was sustained at six month follow-up.

Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19. METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort. RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively). CONCLUSIONS: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.

Mapping hematologists' HIV testing behavior among lymphoma patients-A mixed-methods study.

BACKGROUND: HIV testing among patients with malignant lymphoma (PWML) is variably implemented. We evaluated HIV testing among PWML, and mapped factors influencing hematologists' testing behavior. MATERIALS: We conducted a mixed-methods study assessing HIV testing among PWML, factors influencing HIV testing and opportunities for improvement in five hospitals in the region of Amsterdam, the Netherlands. The proportion of PWML tested for HIV within 3 months before or after lymphoma diagnosis and percentage positive were assessed from January 2015 through June 2020. Questionnaires on intention, behavior and psychosocial determinants for HIV testing were conducted among hematologists. Through twelve semi-structured interviews among hematologists and authors of hematology guidelines, we further explored influencing factors and opportunities for improvement. FINDINGS: Overall, 1,612 PWML were included for analysis, including 976 patients newly diagnosed and 636 patients who were referred or with progressive/relapsed lymphoma. Seventy percent (678/976) of patients newly diagnosed and 54% (343/636) of patients with known lymphoma were tested for HIV. Overall, 7/1,021 (0.7%) PWML tested HIV positive, exceeding the 0.1% cost-effectiveness threshold. Questionnaires were completed by 40/77 invited hematologists, and 85% reported intention to test PWML for HIV. In the interviews, hematologists reported varying HIV testing strategies, including testing all PWML or only when lymphoma treatment is required. Recommendations for improved HIV testing included guideline adaptations, providing electronic reminders and monitoring and increasing awareness. CONCLUSIONS: Missed opportunities for HIV testing among PWML occurred and HIV test strategies varied among hematologists. Efforts to improve HIV testing among PWML should include a combination of approaches.

Healthcare-associated infections in Dutch hospitals during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic hospitals reorganized their resources and delivery of care, which may have affected the number of healthcare-associated infections (HAIs). We aimed to quantify changes in trends in the number of HAIs in Dutch hospitals during the COVID-19 pandemic. METHODS: National surveillance data from 2016 to 2020 on the prevalence of HAIs measured by point prevalence surveys, and the incidence of surgical site infections (SSIs) and catheter-related bloodstream infections (CRBSIs) were used to compare rates between the pre-pandemic (2016-February 2020) and pandemic (March 2020-December 2020) period. RESULTS: The total HAI prevalence among hospitalised patients was higher during the pandemic period (7.4%) compared to pre-pandemic period (6.4%), mainly because of an increase in ventilator-associated pneumonia (VAP), gastro-intestinal infections (GIs) and central nervous system (CNS) infections. No differences in SSI rates were observed during the pandemic, except for a decrease after colorectal surgeries (6.3% (95%-CI 6.0-6.6%) pre-pandemic versus 4.4% (95%-CI 3.9-5.0%) pandemic). The observed CRBSI incidence in the pandemic period (4.0/1,000 CVC days (95%-CI 3.2-4.9)) was significantly higher than predicted based on pre-pandemic trends (1.4/1000 (95%-CI 1.0-2.1)), and was increased in both COVID-19 patients and non-COVID-19 patients at the intensive care unit (ICU). CONCLUSIONS: Rates of CRBSIs, VAPs, GIs and CNS infections among hospitalised patients increased during the first year of the pandemic. Higher CRBSI rates were observed in both COVID-19 and non-COVID-19 ICU population. The full scope and influencing factors of the pandemic on HAIs needs to be studied in further detail.

Predictors of Nonseroconversion to SARS-CoV-2 Vaccination in Kidney Transplant Recipients

Background. Kidney transplant recipients (KTRs) are still at risk of severe COVID-19 disease after SARS‑CoV‑2 vaccination, especially when they have limited antibody formation. Our aim was to understand the factors that may limit their humoral response. Methods. Our data are derived from KTRs who were enrolled in the Dutch Renal Patients COVID-19 Vaccination consortium, using a discovery cohort and 2 external validation cohorts. Included in the discovery (N = 1804) and first validation (N = 288) cohorts were participants who received 2 doses of the mRNA-1273 vaccine. The second validation cohort consisted of KTRs who subsequently received a third dose of any SARS-CoV-2 vaccine (N = 1401). All participants had no history of SARS-CoV-2 infection. A multivariable logistic prediction model was built using stepwise backward regression analysis with nonseroconversion as the outcome. Results. The discovery cohort comprised 836 (46.3%) KTRs, the first validation cohort 124 (43.1%) KTRs, and the second validation cohort 358 (25.6%) KTRs who did not seroconvert. In the final multivariable model‚ 12 factors remained predictive for nonseroconversion: use of mycophenolate mofetil/mycophenolic acid (MMF/MPA);chronic lung disease, heart failure, and diabetes;increased age;shorter time after transplantation;lower body mass index;lower kidney function;no alcohol consumption;≥2 transplantations;and no use of mammalian target of rapamycin inhibitors or calcineurin inhibitors. The area under the curve was 0.77 (95% confidence interval [CI], 0.74-0.79) in the discovery cohort after adjustment for optimism, 0.81 (95% CI, 0.76-0.86) in the first validation cohort, and 0.67 (95% CI, 0.64-0.71) in the second validation cohort. The strongest predictor was the use of MMF/MPA, with a dose-dependent unfavorable effect, which remained after 3 vaccinations. Conclusions. In a large sample of KTRs, we identify a selection of KTRs at high risk of nonseroconversion after SARS-CoV-2 vaccination. Modulation of MMF/MPA treatment before vaccination may help to optimize vaccine response in these KTRs. This model contributes to future considerations on alternative vaccination strategies.

Development and Validation of a Multivariable Prediction Model for Nonseroconversion after SARS-COV-2 Vaccination in Kidney Transplant Recipients

BACKGROUND AND AIMS Kidney transplant recipients (KTRs) are still at risk of fatal COVID-19 disease after SARS-CoV-2 vaccination, even after a third booster vaccination. With the spread of new SARS-CoV-2 variants, great urgency exists for a better understanding of the factors that impact the immune response in these patients. Our aim was to predict nonseroconversion after SARS-CoV-2 vaccination to understand the factors that may disrupt the humoral response in KTRs. METHOD A multivariable logistic regression model was developed and validated that uses routinely available clinical and laboratory information to predict nonseroconversion after two doses of SARS-CoV-2 mRNA vaccination in KTRs. KTRs were prospectively enrolled to the Dutch REnal patients COVID-19 VACcination (RECOVAC) consortium, specifically to the Immune Response (IR) study with four participating university medical centres in the Netherlands. The discovery cohort consisted of three participating centres (Amsterdam UMC, Radboud UMC Nijmegen and Erasmus MC Rotterdam), and the validation cohort of patients treated in UMC Groningen. A large second validation set from the RECOVAC consortium (LESS-CoV-2) was used to test a more simplified version of the model without lymphocyte counts. All participants received two doses of the mRNA-1273 COVID-19 vaccine (Moderna) and had no history of SARS-CoV-2 infection. Participants were classified as responder or non-responder based on seroconversion at day 28 following the second vaccination with a threshold for seropositivity based on receiver operator curve analysis set at S1-specific IgG antibody concentration ≥10 BAU/mL. RESULTS The discovery cohort included 215 KTRs of which 126 responders and 89 non-responders. After backward selection, 6 out of 19 factors remained predictive for nonseroconversion: increased age, lower lymphocyte count, lower estimated glomerular filtration rate (eGFR), shorter time after transplantation, not using steroids and the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) (Figure 1). The area under the curve (AUC) of the receiver operating characteristics was 0.83 (95% confidence interval 0.78–0.89) in the discovery cohort after adjustment for optimism and 0.84 (0.74–0.94) in external validation of the UMC Groningen cohort (n = 73), and 0.75 (0.72–0.77) in external validation of the LESS-CoV-2 dataset (n = 2484). In addition, MMF/MPA appeared to have a dose-dependent unfavourable association with the S1 IgG antibody titer (Figure 2).FIGURE 1: The effect of MMF/MPA dosing (mg/day) on the log S1 IgG antibody titer (BAU/mL).FIGURE 2: Nomogram for the prediction of nonseroconversion after SARS-CoV-2 vaccination in KTRs. CONCLUSION Six predictors allow for a better understanding of the process of the development of the humoral response in KTRs. These predictors could be applied to individualized patient counseling and treatment strategy during the COVID-19 pandemic and future innovative vaccine trial design for this complex patient group.

Fosfomycin Vs Ciprofloxacin as Oral Step-Down Treatment for Escherichia coli Febrile Urinary Tract Infections in Women: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial.

BACKGROUND: We aimed to determine the noninferiority of fosfomycin compared to ciprofloxacin as an oral step-down treatment for Escherichia coli febrile urinary tract infections (fUTIs) in women. METHODS: This was a double-blind, randomized, controlled trial in 15 Dutch hospitals. Adult women who were receiving 2-5 days of empirical intravenous antimicrobials for E. coli fUTI were assigned to step-down treatment with once-daily 3g fosfomycin or twice-daily 0.5g ciprofloxacin for 10 days of total antibiotic treatment. For the primary end point, clinical cure at days 6-10 post-end of treatment (PET), a noninferiority margin of 10% was chosen. The trial was registered on Trialregister.nl (NTR6449). RESULTS: After enrollment of 97 patients between 2017 and 2020, the trial ended prematurely because of the coronavirus disease 2019 pandemic. The primary end point was met in 36 of 48 patients (75.0%) assigned to fosfomycin and 30 of 46 patients (65.2%) assigned to ciprofloxacin (risk difference [RD], 9.6%; 95% confidence interval [CI]: -8.8% to 28.0%). In patients assigned to fosfomycin and ciprofloxacin, microbiological cure at days 6-10 PET occurred in 29 of 37 (78.4%) and 33 of 35 (94.3%; RD, -16.2%; 95% CI: -32.7 to -0.0%). Any gastrointestinal adverse event was reported in 25 of 48 (52.1%) and 14 of 46 (30.4%) patients (RD, 20.8%; 95% CI: 1.6% to 40.0%), respectively. CONCLUSIONS: Fosfomycin is noninferior to ciprofloxacin as oral step-down treatment for fUTI caused by E. coli in women. Fosfomycin use is associated with more gastrointestinal events. CLINICAL TRIAL REGISTRATION: Trial NL6275 (NTR6449).

Supporting resident well-being on and outside the ICU during the COVID-19 pandemic: the use and value of institutional interventions and individual strategies.

During the COVID-19 pandemic, resident well-being has been shown to be at risk, which may interfere with residents' process of professional development during their educational trajectory. Therefore, we developed a well-being program for residents, aimed to help residents maintain their well-being during the COVID-19 pandemic. We explored residents' perceptions of their well-being as well as their perceived support of the well-being program during the COVID-19 pandemic. We invited all internal medicine residents and residents working in the ICU (N = 203) of one academic medical center to participate. The well-being program included a combination of (1) well-being measurements and (2) organizational support. The repeated well-being measurements involved a well-being survey on six measurement points from April to June 2020, and organizational support combined the provision of institutional interventions and promotion of individual strategies to help residents maintain their well-being during a pandemic. In total, 103 residents (50.1%) participated, showing that residents working in the ICU reported significantly lower levels of mental well-being than residents not working on the ICU. Furthermore, residents did not perceive the institutional interventions to benefit their well-being, while residents' reported engagement in individual strategies was significantly positively associated with their well-being. As ICU residents reported lower levels of mental well-being, well-being programs need to address ICU-specific stressors while enhancing supervision and peer support. Furthermore, the individual strategies of the well-being program should be tailored to residents' well-being needs as these were positively associated with resident well-being.

Deimplementation strategy to reduce overtreatment of asymptomatic bacteriuria: a study protocol for a stepped-wedge cluster randomised trial.

INTRODUCTION: Antimicrobial treatment of asymptomatic bacteriuria (ASB) is one of the most common unnecessary uses of antimicrobials. Earlier studies have shown that the prevalence of this inappropriate treatment ranges from 45% to 83%. Multifaceted interventions based on international guidelines and antimicrobial stewardship can decrease overtreatment of ASB. We have designed a study protocol with the main objective of reducing overtreatment of ASB by 50% through use of a deimplementation strategy. METHODS AND ANALYSIS: We will use a stepped-wedge cluster randomised design, comparing outcomes before and after introduction of our intervention in the emergency department (ED) of five hospitals (clusters) in the Netherlands. All patients (≥18 years old) who have a urine test performed in the ED will be screened for eligibility. The deimplementation strategy consists of a combination of interventions, including education, audit and feedback. The primary endpoint is overtreatment of ASB in patients without risk factors (eg, pregnancy, planned invasive urological procedures and neutropenia). Secondary endpoints are the duration of antimicrobial treatment for ASB, the number of urine cultures and urinalysis per 1000 patients, and overtreatment of positive urinalysis in asymptomatic patients. ETHICS AND DISSEMINATION: Ethical approval was obtained from the medical ethics research committee of the Academic Medical Centre (Amsterdam, the Netherlands) with a waiver for informed consent. Local feasibility was obtained by the local institutional review boards of all participating hospitals. Our study aims to reduce inappropriate screening and treatment of ASB in EDs, improve healthcare quality, lower the increase in antimicrobial resistance and save costs. If proven (cost)-effective, this study provides a well-suited strategy for a nationwide approach to reduce overtreatment of ASB. Relevant results of our study will be disseminated through publications in peer-reviewed journals and presentations at relevant (scientific) conferences. TRIAL REGISTRATION NUMBER: NL8242; Pre-results.