Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel.

Background: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are syndromes commonly used as medical diagnoses. Since the existing literature has a mixture of diagnostic approaches, developing consensus-based recommendations would be helpful for clinicians, researchers, and patients. Methods: A modified Delphi process was performed from October 2022 to July 2023, involving 4 rounds of online surveys and 2 live video conferences. The panel comprised international experts recruited based on peer-reviewed published publications and studies. Results: Among 50 invited experts, 26 (52.0%) agreed to participate. Twenty-three panelists completed round 1 of the survey, 21 completed rounds 2 and 3, 20 completed round 4, and 7 participated in round 5 live video discussions. Of the participants, 18 (78.3%) were academic-based clinicians and researchers, 5 (21.7%) practiced in a community-based hospital, and 6 (26.1%) were female. Consensus was reached on 5 themes: (1) incorporating epidemiologic factors, such as geographic location and travel history; (2) updated criteria for classifying FUO or IUO; (3) initial evaluation approaches; (4) a classification system for diagnoses; and (5) recommendations for judicious limitation of empiric therapies. Experts strongly disagreed with using 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography as part of the diagnostic criteria for FUO. There were mixed opinions about the importance of the temperature measurement site, the 3-week minimum illness criterion, the need for a standard definition of relapsing fevers, and the use of similar evaluation strategies for FUO and IUO. Conclusions: These Delphi-generated consensus-based recommendations offer potential improvements compared with earlier definitions and a guide for clinical practice and future research.

ddPCR enables rapid detection of bloodstream infections in patients on home parenteral nutrition: A prospective cohort study.

INTRODUCTION: Chronic intestinal failure patients (CIF) require a central venous access device (CVAD) to administer parenteral nutrition. Most serious complication related to a CVAD is a central line-associated bloodstream infection (CLABSI). The golden standard to diagnose a CLABSI are blood cultures, however, they may require 1-5 days before getting a result. Droplet digital polymerase chain reaction (ddPCR) for the detection of pathogen 16S/28S rRNA is a novel culture-independent molecular technique that has been developed to enhance and expedite infection diagnostics within two and a half hours. In this study, we prospectively compared ddPCR with blood cultures to detect pathogens in whole blood. METHODS: We included adult CIF patients with a clinical suspicion of CLABSI in this prospective single-blinded clinical study. Blood cultures were routinely collected and subsequently two central samples from the CVAD and two peripheral samples from a peripheral venous access point. Primary outcome was the sensitivity and specificity of ddPCR. RESULTS: In total, 75 patients with 126 suspected CLABSI episodes were included, with 80 blood samples from the CVAD and 114 from peripheral veins. The central ddPCR samples showed a sensitivity of 91% (95%CI 77-98), and specificity of 96% (95%CI 85-99). Peripheral ddPCR samples had a sensitivity of 63% (95%CI 46-77) and specificity of 99% (95%CI 93-100). CONCLUSION: ddPCR showed a high sensitivity and specificity relative to blood cultures and enables rapid pathogen detection and characterization. Clinical studies should explore if integrated ddPCR and blood culture outcomes enables a more rapid pathogen guided CLABSI treatment and enhancing patient outcomes.

Perfectionism, self-esteem, and affective symptoms in anorexia nervosa subtypes: A network analysis of French inpatients.

OBJECTIVE: Previous studies have highlighted the relevance of perfectionism, self-esteem, and anxio-depressive symptoms in anorexia nervosa (AN). However, the relationships between these factors and cardinal eating disorders (ED) symptoms remain unclear, particularly in AN subtypes. This study aimed to examine their interconnections using network analysis. METHOD: The sample included n = 338 inpatients with AN who completed the Eating Disorder Examination Questionnaire, Frost Multidimensional Perfectionism Scale, Rosenberg Self-Esteem Scale, and Hospital Anxiety and Depression Scale. Using network analysis, we estimated three networks: full sample, AN-restrictive (AN-R) and AN-binge/purging (AN-BP) subtypes. We estimated central and bridge symptoms using expected influence and conducted an exploratory network comparison test to compare AN subtypes. RESULTS: Overvaluation of Weight and Shape, Concern over Mistakes, and Personal Standards were consistently central in all networks. The most central bridge symptoms across all networks were Concern over Mistakes and Self-Esteem. Concern over Mistakes bridged perfectionism and ED symptoms, while Self-Esteem was highly connected to all symptom clusters. Anxiety was significantly more central in the AN-R network compared to the AN-BP network. CONCLUSIONS: The present study contributes to a growing body of network studies suggesting that nodes related to perfectionism are just as central as cardinal ED symptoms, indicating the relevance of perfectionism in ED pathology. The high bridge centrality of self-esteem suggests that it may be an important link between perfectionism, mood, and ED symptoms. Future research should investigate the efficacy of targeting multiple psychological factors in the treatment of AN, as well as their potential transdiagnostic relevance.

Development of a Consensus-Based List of Potential Quality Indicators for Fever and Inflammation of Unknown Origin.

With a growing emphasis on value-based reimbursement, developing quality indicators for infectious diseases has gained attention. Quality indicators for fever of unknown origin and inflammation of unknown origin are lacking. An assembled group of international experts developed 12 quality measures for these conditions, which could be validated with additional study.

Update on imaging in fever and inflammation of unknown origin: focus on infectious disorders.

BACKGROUND: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostic challenges that often require an extensive work-up. When first-line tests do not provide any or only misleading clues, second-line investigations such as specialized imaging techniques are often warranted. OBJECTIVES: To provide an overview of the diagnostic value of imaging techniques that are commonly used in patients with FUO/IUO. SOURCES: MEDLINE database was searched to identify the most relevant studies, trials, reviews, or meta-analyses until 31 March 2023. CONTENT: The most important types of second-line imaging tests for FUO and IUO are outlined, including [67Ga]-citrate single-photon emission computed tomography/computed tomography (CT), labelled leukocyte imaging, [18F]-fluorodeoxyglucose positron emission tomography CT ([18F]-FDG-PET), and whole-body magnetic resonance imaging. This review summarizes the diagnostic yield, extends on potential future imaging techniques (pathogen-specific bacterial imaging and [18F]-FDG-PET/magnetic resonance imaging), discusses cost-effectiveness, highlights practical implications and pitfalls, and addresses future perspectives. Where applicable, we provide additional data specifically for the infection subgroup. IMPLICATIONS: Although many imaging examinations are proven to be useful in FUO and IUO, [18F]-FDG-PET/CT is the preferred second-line test when available as it provides a high diagnostic yield in a presumably cost-effective way.

Genomic characterization of methicillin-susceptible Staphylococcus aureus carriage in patients on home parenteral nutrition and their caregivers.

In this prospective study, patients on home parenteral nutrition were twice as likely to be colonized with Staphylococcus aureus if their caregivers were also carriers. Among S. aureus-positive patients and their caregivers, molecular analysis showed 68% genetically related strains. Despite decolonization, genetically related strains reappeared in 70% of patients.

Oral antimicrobial agents in patients with short bowel syndrome: worth a try!

BACKGROUND: The use of oral antimicrobial agents in patients with short bowel syndrome (SBS) is challenging due to the changes in gastrointestinal anatomy that may result in diminished absorption and altered drug bioavailability. Prospective studies evaluating bioavailability of antimicrobial agents after oral administration in SBS patients are lacking. OBJECTIVES: To determine the bioavailability of orally administered antimicrobial agents commonly used for treatment in SBS patients to guide clinical decision making when faced with infections. METHODS: We performed an explorative, clinical study investigating the pharmacokinetics (PK) of clindamycin, ciprofloxacin, flucloxacillin and fluconazole in SBS patients with intestinal failure. Participants received a combination of two antimicrobial agents simultaneously. To determine the oral bioavailability, participants received a single oral and IV dose of both agents on two occasions, after which they underwent intensive PK sampling on six predefined time points up to 12 hours after administration. Primary outcome was the oral bioavailability of these antimicrobial agents. Secondary outcomes were intravenous PK characteristics following non-compartmental analysis. RESULTS: Eighteen SBS patients were included: the mean (SD) age was 59 (17) years and 61% of participants were female. The median observed (IQR) bioavailability of ciprofloxacin, clindamycin, flucloxacillin and fluconazole were 36% (24-50), 93% (56-106), 50% (32-76) and 98% (61-107), respectively. CONCLUSION: The bioavailability of selected antimicrobial agents in certain patients with SBS appeared to be better than expected, providing a feasible treatment option. Due to the large observed differences between patients, therapeutic drug monitoring should be part of the treatment to safeguard adequate exposure in all patients. TRIAL REGISTRATION: Registered in the Dutch Trial Register (NL7796) and EudraCT number 2019-002587-28.

Cognitive and Interpersonal Factors in Adolescent Inpatients with Anorexia Nervosa: A Network Analysis.

The cognitive-interpersonal model of anorexia nervosa (AN) posits that cognitive and interpersonal traits contribute to the development and maintenance of AN. We investigated cognitive and interpersonal factors put forward by the model in a sample of 145 adolescent inpatients with AN using network analysis. Our main outcomes included core eating disorder symptoms, cognitive style, socio-affective factors, and mood symptoms. We estimated a cross-sectional network using graphical LASSO. Core and bridge symptoms were identified using strength centrality. Goldbricker was used to reduce topological overlap. The node with the highest strength centrality was Concern over Mistakes, followed by Eating Preoccupation, Social Fear, and Overvaluation of Weight and Shape. The nodes with the highest bridge strength were Concern over Mistakes, Doubt about Actions, Overvaluation of Weight and Shape, and Depression. Notably, both performance on a cognitive flexibility task and BMI were not connected to any other nodes and were subsequently removed from the final network. We provide partial support for the cognitive-interpersonal model while also supporting certain premises put forward by the transdiagnostic cognitive-behavioral model. The high centrality of Concern over Mistakes and Social Fear supports the theory that both cognitive and interpersonal difficulties contribute to AN, particularly in adolescence.

Efficacy of Cognitive-Behavioral Therapy Targeting Severe Fatigue Following Coronavirus Disease 2019: Results of a Randomized Controlled Trial.

BACKGROUND: Severe fatigue following coronavirus disease 2019 (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 6 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 nonhospitalized 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 < .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 nonhospitalized and self-referred, CBT was effective in reducing fatigue. The positive effect was sustained at 6-month follow-up. CLINICAL TRIALS REGISTRATION: Netherlands Trial Register NL8947.

Randomized clinical trial: Long-term Staphylococcus aureus decolonization in patients on home parenteral nutrition.

BACKGROUND & AIMS: Staphylococcus aureus decolonization has proven successful in prevention of S. aureus infections and is a key strategy to maintain venous access and avoid hospitalization in patients receiving home parenteral nutrition (HPN). We aimed to determine the most effective and safe long-term S. aureus decolonization regimen. METHODS: A randomized, open-label, multicenter clinical trial was conducted. Adult intestinal failure patients with HPN support and carrying S. aureus were randomly assigned to a 'continuous suppression' (CS) strategy, a repeated chronic topical antibiotic treatment or a 'search and destroy' (SD) strategy, a short and systemic antibiotic treatment. Primary outcome was the proportion of patients in whom S. aureus was totally eradicated during a 1-year period. Secondary outcomes included risk factors for decolonization failure and S. aureus infections, antimicrobial resistance, adverse events, patient compliance and cost-effectivity. RESULTS: 63 participants were included (CS 31; SD 32). The mean 1-year S. aureus decolonization rate was 61% (95% CI 44, 75) for the CS group and 39% (95% CI 25, 56) for the SD group with an OR of 2.38 (95% CI 0.92, 6.11, P = 0.07). More adverse effects occurred in the SD group (P = 0.01). Predictors for eradication failure were a S. aureus positive caregiver and presence of a (gastro)enterostomy. CONCLUSION: We did not demonstrate an increased efficacy of a short and systemic S. aureus decolonization strategy over a continuous topical suppression treatment. The latter may be the best option for HPN patients as it achieved a higher long-term decolonization rate and was well-tolerated (NCT03173053).

Low SARS-CoV-2 Cq values in healthcare workers with symptomatic COVID-19 infections, regardless of symptom severity, The Netherlands, January to August 2022.

We analysed SARS-CoV-2 PCR Cq values from 3,183 healthcare workers who tested positive between January and August 2022. Median Cq values were lower in symptomatic than in asymptomatic HCW. The difference in Cq values between HCW with mild vs moderate/severe symptoms was statistically significant but negligibly small. To prevent nosocomial infections, all symptomatic HCW should be tested irrespective of symptom severity. This information can support decisions on testing and isolation, in the context of ongoing pressure on healthcare systems.

Success rates of MRSA decolonization and factors associated with failure.

BACKGROUND: We evaluated the success rate of MRSA decolonization directly after treatment and after one year in patients who were treated at the outpatient MRSA clinic of a large university medical centre to identify potential contributing factors to treatment success and failure. METHODS: Data from November 1, 2013 to August 1, 2020 were used. Only patients who had undergone complete MRSA decolonization were included. Risk factors for MRSA treatment failure were identified using a multivariable logistic regression model. RESULTS: In total, 127 MRSA carriers were included: 7 had uncomplicated carriage, 91 had complicated carriage, and 29 patients had complicated carriage in combination with an infection. In complicated carriers and complicated carriers with an infection final treatment was successful in 75.0%. Risk factors for initial treatment failure included having one or more comorbidities and not testing the household members. Risk factors for final treatment failure were living in a refugee centre, being of younger age (0-17 years), and having one or more comorbidities. CONCLUSIONS: The results of this study indicate that patients with a refugee status and children treated at the paediatric clinic have a higher risk of MRSA decolonisation treatment failure. For this reason, it might be useful to revise decolonization strategies for these subgroups and to refer these patients to specialized outpatient clinics in order to achieve higher treatment success rates.

Catheter-related bloodstream infection management in patients receiving home parenteral nutrition: An observational cohort study.

BACKGROUND AND AIMS: Patients with intestinal failure receiving home parenteral nutrition (HPN) are susceptible to central-line associated bloodstream infections (CLABSIs), with crucial roles for adequate (empiric) antimicrobial therapy and effective catheter management strategies. Our aim was to link recent epidemiologic CLABSI data with clinical outcomes and to identify risk factors for therapeutic failure to decide on the safest and most accurate CLABSI management in patients receiving HPN. METHODS: A retrospective observational cohort study was conducted. All data on CLABSIs (period 2010-2020) in adult patients receiving HPN were retrieved. The efficacy of attempted catheter salvage and empiric antimicrobial treatment (ß-lactam antibiotics) in our center, with a low prevalence of methicillin-resistant staphylococci, was investigated. Multivariate cox-regression analysis was performed to identify risk factors for recurrent CLABSI. RESULTS: 389 CLABSIs occurred in 149 patients. The overall infection rate was 0.64 per 1000 central venous catheter (CVC) days. Most CLABSIs were caused by Coagulase-negative staphylococci (37%). Attempted CVC salvage was successful in 70% of the cases. Empiric antimicrobial therapy was found to be adequate in only 47% of cases, mainly because of insufficient Coagulase-negative staphylococci coverage. According to the Cox model, patients with a replaced CVC had a 50% lower risk of a new CLABSI than patients with a retained (salvaged) CVC during follow-up (HR 0.50; 95% CI 0.35-0.72, P < 0.001). CONCLUSIONS: CVC salvage can be achieved in most CLABSI cases but seems associated with a shorter CLABSI-free survival. Importantly, based on our findings, a glycopeptide containing antibiotic treatment regimen will increase the likelihood of adequate empiric coverage.

Targeted Screening for Chronic Q Fever, the Netherlands.

Early detection of and treatment for chronic Q fever might prevent potentially life-threatening complications. We performed a chronic Q fever screening program in general practitioner practices in the Netherlands 10 years after a large Q fever outbreak. Thirteen general practitioner practices located in outbreak areas selected 3,419 patients who had specific underlying medical conditions, of whom 1,642 (48%) participated. Immunofluorescence assay of serum showed that 289 (18%) of 1,642 participants had a previous Coxiella burnetii infection (IgG II titer >1:64), and 9 patients were suspected of having chronic Q fever (IgG I y titer >1:512). After medical evaluation, 4 of those patients received a chronic Q fever diagnosis. The cost of screening was higher than estimated earlier, but the program was still cost-effective in certain high risk groups. Years after a large Q fever outbreak, targeted screening still detected patients with chronic Q fever and is estimated to be cost-effective.

Fluorescence in situ hybridization for detecting Coxiella burnetii in tissue samples from chronic Q fever patients.

OBJECTIVE: Detection of the intracellular bacterium Coxiella burnetii, causative agent of chronic Q fever, is notoriously difficult. Diagnosis of and duration of antibiotic treatment for chronic Q fever is partly determined by detection of the bacterium with polymerase chain reaction (PCR). Fluorescence in situ hybridization (FISH) might be a promising technique for detecting C. burnetii in tissue samples from chronic Q fever patients, but its value in comparison with PCR is uncertain. We aim to assess the value of FISH for detecting C. burnetii in tissue of chronic Q fever patients. METHODS: FISH and PCR were performed on tissue samples from Dutch chronic Q fever patients collected during surgery or autopsy. Sensitivity, specificity, and overall diagnostic accuracy were calculated. Additionally, data on patient and disease characteristics were collected from electronic medical records. RESULTS: In total, 49 tissue samples from mainly vascular walls, heart valves, or placentas, obtained from 39 chronic Q fever patients, were examined by FISH and PCR. The sensitivity and specificity of FISH compared to PCR for detecting C. burnetii in tissue samples from chronic Q fever patients was 45.2% (95% confidence interval (CI), 27.3% - 64.0%) and 84.6% (95% CI, 54.6% - 98.1%), respectively. The overall diagnostic accuracy was 56.8% (95% CI, 42.2% - 72.3%). Two C. burnetii PCR negative placentas were FISH positive. Four FISH results (8.2%) were deemed inconclusive because of autofluorescence. CONCLUSION: With an overall diagnostic accuracy of 57.8%, we conclude that FISH has limited value in the routine diagnostics of chronic Q fever.