The applicability of the central line-associated bloodstream infection (CLABSI) criteria for the evaluation of bacteremia episodes in pediatric oncology patients.

BACKGROUND: The aim of this study was to investigate the applicability of the central line-associated bloodstream infection (CLABSI) criteria of the Centers for Disease Control and Prevention in pediatric oncology patients. METHODS: Bacteremia episodes from 2020 to 2022 from a prospective cohort of pediatric oncology patients with a central venous catheter were included. Episodes were classified by three medical experts following the CLABSI criteria as either a CLABSI or non-CLABSI (i.e., contamination, other infection source, or mucosal barrier injury-laboratory confirmed bloodstream infection (MBI-LCBI)). Subsequently, they were asked if and why they (dis)agreed with this diagnosis following the criteria. The primary outcome was the percentage of episodes where the experts clinically disagreed with the diagnosis given following the CLABSI criteria. RESULTS: Overall, 84 bacteremia episodes in 71 patients were evaluated. Following the CLABSI criteria, 34 (40%) episodes were classified as CLABSIs and 50 (60%) as non-CLABSIs. In 11 (13%) cases the experts clinically disagreed with the diagnosis following the CLABSI criteria. The discrepancy between the CLABSI criteria and clinical diagnosis was significant; McNemar's test p < .01. Disagreement by the experts with the CLABSI criteria mostly occurred when the experts found an MBI-LCBI a more plausible cause of the bacteremia than a CLABSI due to the presence of a gram negative bacteremia (Pseudomonas aeruginosa n = 3) and/or mucositis. CONCLUSIONS: A discrepancy between the CLABSI criteria and the evaluation of the experts was observed. Adding Pseudomonas aeruginosa as an MBI pathogen and incorporating the presence of mucositis in the MBI-LCBI criteria, might increase the applicability.

Appropriateness of empirical treatment and outcome in bacteremia caused by extended-spectrum-ß-lactamase-producing bacteria.

We studied clinical characteristics, appropriateness of initial antibiotic treatment, and other factors associated with day 30 mortality in patients with bacteremia caused by extended-spectrum-ß-lactamase (ESBL)-producing bacteria in eight Dutch hospitals. Retrospectively, information was collected from 232 consecutive patients with ESBL bacteremia (due to Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae) between 2008 and 2010. In this cohort (median age of 65 years; 24 patients were <18 years of age), many had comorbidities, such as malignancy (34%) or recurrent urinary tract infection (UTI) (15%). One hundred forty episodes (60%) were nosocomial, 54 (23%) were otherwise health care associated, and 38 (16%) were community acquired. The most frequent sources of infection were UTI (42%) and intra-abdominal infection (28%). Appropriate therapy within 24 h after bacteremia onset was prescribed to 37% of all patients and to 54% of known ESBL carriers. The day 30 mortality rate was 20%. In a multivariable analysis, a Charlson comorbidity index of ≥ 3, an age of ≥ 75 years, intensive care unit (ICU) stay at bacteremia onset, a non-UTI bacteremia source, and presentation with severe sepsis, but not inappropriate therapy within <24 h (adjusted odds ratio [OR], 1.53; 95% confidence interval [CI], 0.68 to 3.45), were associated with day 30 mortality. Further assessment of confounding and a stratified analysis for patients with UTI and non-UTI origins of infection did not reveal a statistically significant effect of inappropriate therapy on day 30 mortality, and these results were insensitive to the possible misclassification of patients who had received ß-lactam-ß-lactamase inhibitor combinations or ceftazidime as initial treatment. In conclusion, ESBL bacteremia occurs mostly in patients with comorbidities requiring frequent hospitalization, and 84% of episodes were health care associated. Factors other than inappropriate therapy within <24 h determined day 30 mortality.

CATERPILLAR-study protocol: an assessor-blinded randomised controlled trial comparing taurolidine-citrate-heparin to heparin-only lock solutions for the prevention of central line-associated bloodstream infections in paediatric oncology patients.

INTRODUCTION: The efficacy of taurolidine containing lock solutions for the prevention of central line-associated bloodstream infections (CLABSI) in paediatric oncology patients is still unknown. If the taurolidine-citrate-heparin lock appears to decrease the incidence of CLABSIs, we hope to increase the quality of life of children with cancer by subsequently reducing the central venous access device (CVAD)-removal rates, dispense of antibiotics, hospital admissions and incidence of severe sepsis resulting in intensive care unit admission. METHODS AND ANALYSIS: This assessor-blinded randomised controlled trial including 462 patients was designed to compare the taurolidine-citrate-heparin lock to the heparin-only lock for the prevention of CLABSIs in paediatric oncology patients. Patients receiving their first CVAD at the Princess Máxima Centre for Paediatric Oncology, Utrecht, the Netherlands, are eligible for inclusion. The primary outcome of this study is the incidence of first CLABSIs from CVAD insertion until the end of the study, maximum follow-up of 90 days. An intention-to-treat and a per-protocol analysis will be performed. An interim analysis will be performed after the inclusion of 50% of the patients. The results of the interim analysis and overall conduct of the trial will be discussed by a data safety monitoring board. ETHICS AND DISSEMINATION: The medical ethics committee NedMec, Utrecht, the Netherlands, has approved this research (number 20/370). Written informed consent for participation in this trial and publication of the trial data is obtained from all patients and/or their parents/guardians. The results of this trial will be published in a peer-reviewed journal and the data will be made available on reasonable request after publication of the main results manuscript. TRIAL REGISTRATION NUMBERS: NTR6688; NCT05740150.

Mannose-binding lectin (MBL) substitution: recovery of opsonic function in vivo lags behind MBL serum levels.

Mannose-binding lectin (MBL) deficiency is often associated with an increased risk of infection or worse prognosis in immunocompromised patients. MBL substitution in these patients might diminish these risks. We therefore performed an open, uncontrolled safety and pharmacokinetic MBL-substitution study in 12 pediatric oncology patients with chemotherapy-induced neutropenia. Twice weekly MBL infusions with plasma-derived MBL yielded MBL trough levels >1.0 microg/ml. We tested whether MBL substitution in vivo increased MBL-dependent complement activation and opsonophagocytosis of zymosan in vitro. Upon MBL substitution, opsonophagocytosis by control neutrophils increased significantly (p < 0.001) but remained suboptimal, although repeated MBL infusions resulted in improvement over time. The MBL-dependent MBL-associated serine protease (MASP)-mediated complement C3 and C4 activation also showed a suboptimal increase. To explain these results, complement activation was studied in detail. We found that in the presence of normal MASP-2 blood levels, MASP-2 activity (p < 0.0001) was reduced as well as the alternative pathway of complement activation (p < 0.05). This MBL-substitution study demonstrates that plasma-derived MBL infusions increase MBL/MASP-mediated C3 and C4 activation and opsonophagocytosis, but that higher circulating levels of plasma-derived MBL are required to achieve MBL-mediated complement activation comparable to healthy controls. Other patient cohorts should be considered to demonstrate clinical efficacy in phase II/III MBL-substitution studies, because we found a suboptimal recovery of (in vitro) biological activity upon MBL substitution in our neutropenic pediatric oncology cohort.

Incidence, severity and outcome of central line related complications in pediatric oncology patients; A single center study.

BACKGROUND: Central venous access device (CVAD)-related complications are associated with high morbidity rates. This study was performed to underline the importance of CVAD-complication prevention and treatment. METHODS: An audit of practice of CVAD-related complications in pediatric oncology patients receiving a CVAD between January 2015 and June 2017 was performed. CVADs included were totally implantable venous access ports (TIVAPs), Hickman-Broviac® (HB), nontunneled, and peripherally inserted CVADs. RESULTS: A total of 201 children, with 307 CVADs, were analyzed. The incidence rates per 1000 CVAD-days for the most common complications were 1.66 for malfunctions, and 1.51 for central line-associated bloodstream infections (CLABSIs). Of all CVADs inserted, 37.1% were removed owing to complications, of which 45.6% were owing to CLABSIs. In 42% of the CLABSIs, the CLABSI could be successfully cured with systemic antibiotic treatment only. Of all included patients, 5.0% were admitted to the intensive care unit owing to CLABSI. The HB-CVAD compared to the TIVAP was a risk factor for CVAD-related complications, CLABSIs and dislocations in particular. CONCLUSIONS: The incidence of CVAD-related complications is high. Research on the prevention and treatment of CVAD-related complications in pediatric oncology patients should be a high priority for all health care professionals. TYPE OF STUDY: Prognosis study (retrospective). LEVEL OF EVIDENCE: Level II.

[Nosocomial outbreaks and resistant microorganisms]. / Ziekenhuisuitbraken en resistente micro-organismen.

OBJECTIVE: To determine the number and duration of nosocomial outbreaks caused by highly resistant microorganisms (HRMO) posing a potential threat to public health, in order to undertake a risk assessment. DESIGN: Descriptive study. METHOD: Data on nosocomial outbreaks were collected from April 2012 to June 2014. The following characteristics were recorded at the start and end of each outbreak: type of microorganism, reason for reporting, phase of outbreak, number of patients colonised and infected, and infection prevention measures implemented. RESULTS: 47 medical institutions reported 87 outbreaks (mean: 3 outbreaks per month). 20 outbreaks were reported in 2012 (2.2/month), 39 in 2013 (3.3/month), and 28 in the first six months of 2014 (4.7/month). Outbreaks of vancomycin-resistant enterococci (n = 26), methicillin-resistant Staphylococcus aureus (MRSA; n = 23) and resistant or highly resistant Enterobacteriaceae (n = 17) were reported most frequently. 65 outbreaks (75%) were controlled within two months of reporting. CONCLUSION: Transparent reporting of HRMO outbreaks is important for correct public perceptions of the safety of hospitals and nursing homes in the Netherlands. Reports to the Hospital-acquired Infection and Antimicrobial Resistance Monitoring Group show that HRMO outbreaks are an almost daily occurrence in Dutch hospitals. However, most outbreaks are quickly controlled without posing a threat to public health.

[Clinical manifestations and hazards of brucellosis in the Netherlands]. / Klinisch beeld en gevaren van brucellose in Nederland.

Brucellosis, a zoonotic infection characterised by undulant fever, has a low incidence in the Netherlands and is therefore rarely considered. We describe 3 patients aged 26, 47 and 56 years old; each presented with long-standing fever as predominant symptom after having travelled to an endemic area, Iraq or Turkey, 1 week to 4 months prior to manifestation of illness. They had similar symptoms: fever, weight loss, chills, night sweats and dry cough. Blood cultures of all patients became positive for gram-negative rods after 3-4 days of incubation. One patient had imported and consumed sheep-milk cheese from which a genetically indistinguishable Brucella strain was cultured. In another patient, identification of the bacterium proved difficult, resulting in delayed prescription of adequate antibiotic treatment. Serologic testing confirmed the diagnosis in this case. In the laboratory, there is a considerable risk of airborne transmission of the disease necessitating clear notification of the suspicion of brucellosis when material for culturing is submitted.

Mannose-binding lectin and the risk of HIV transmission and disease progression in children: a systematic review.

BACKGROUND: Mannose-binding lectin (MBL) can activate the complement system by binding to carbohydrates, such as those presented on the HIV virion surface. It is unclear whether genetically determined MBL deficiency is related to vertical HIV transmission and disease progression in HIV-infected children. METHODS: A literature search of Medline, Embase and Cochrane Central Register identified all relevant studies on MBL and HIV infection in children. We extracted information on the characteristics of the study group, method of MBL analysis, outcome definitions, follow-up and the risk estimates. The validity of each study was assessed. RESULTS: Nine studies were retrieved. Most were of good validity, but risk adjustment for confounders was missing in 6 studies. Age, treatment and outcome definitions differed between the study groups. In most of the studies, MBL deficiency was associated with an increased frequency of vertical HIV transmission and an increased speed of disease progression. In the 2 most valid studies, carriers of variant genes had an increased odds ratio for transmission and an increased relative hazard for disease progression and central nervous system impairment, especially in children <2 years of age. CONCLUSIONS: MBL deficiency is associated with an increased risk of vertical HIV transmission. How this risk relates to other factors that influence transmission is unclear. The association between HIV disease progression and MBL deficiency is most pronounced in children <2 years of age, probably due to immaturity of their adaptive immunity.

Safety and pharmacokinetics of plasma-derived mannose-binding lectin (MBL) substitution in children with chemotherapy-induced neutropaenia.

Mannose-binding lectin (MBL)-deficient children with cancer may benefit from substitution of the innate immune protein MBL during chemotherapy-induced neutropaenia. We determined the safety and pharmacokinetics of MBL substitution in a phase II study in MBL-deficient children. Twelve MBL-deficient children with cancer (aged 0-12 years) received infusions of plasma-derived MBL once, or twice weekly during a chemotherapy-induced neutropaenic episode (range: 1-4 weeks). Four patients participated multiple times. Target levels of 1.0 microg/ml were considered therapeutic. In total, 65 MBL infusions were given. No MBL-related adverse reactions were observed, and the observed trough level was 1.06 microg/ml (range: 0.66-2.05 microg/ml). Pharmacokinetics were not related to age after correction for body weight. The half-life of MBL, for a child of 25 kg, was 36.4h (range: 23.7-66.6h). No anti-MBL antibodies were measured 4 weeks after each MBL course. Substitution therapy with MBL-SSI twice weekly was safe and resulted in trough levels considered protective.

Mannose-binding lectin deficiency is associated with early onset of polyarticular juvenile rheumatoid arthritis: a cohort study.

BACKGROUND: Mannose-binding lectin (MBL) is an innate immune protein. The aim of our study was to determine whether genetically determined MBL deficiency is associated with susceptibility to juvenile rheumatoid arthritis (JRA) and whether MBL2 genotypes are associated with JRA severity. METHODS: In a retrospective cohort study of 218 patients with polyarthritis (n = 67) and oligoarthritis (n = 151), clinical and laboratory disease variables were obtained by clinical examination and chart reviews. Healthy Caucasian adults (n = 194) served as control individuals. MBL2 gene mutations were determined by Taqman analysis to identify genotypes with high, medium and low expression of MBL. Functional MBL plasma concentrations were measured using enzyme-linked immunosorbent assay. Associations between clinical and laboratory variables and MBL2 genotypes were determined by Kruskal-Wallis and chi2 tests. RESULTS: MBL2 genotype frequencies were similar in polyarthritis and oligoarthritis patients as compared with control individuals. MBL plasma concentrations were associated with the high, medium and low MBL genotype expression groups (P < 0.01). In polyarthritis patients, the presence of low-expressing (deficient) MBL2 genotypes was associated with early age at onset of disease (P = 0.03). In oligoarthritis patients, patients with low-expressing MBL2 genotypes were more often in remission (81%) than patients in the medium (54%) and high (56%) genotype groups (P = 0.02). The remaining clinical and laboratory variables, such as arthritis severity index, presence of radiographic erosions and antinuclear antibody positivity, were not associated with MBL2 genotypes. CONCLUSION: Genetically determined MBL deficiency does not increase susceptibility to JRA, but MBL deficiency is associated with a younger age at onset of juvenile polyarthritis. On the other hand, MBL-deficient children with juvenile oligoarthritis are more often in remission. Therefore, MBL appears to play a dual role in JRA.

Expansion of CMV-specific CD8+CD45RA+CD27- T cells in B-cell chronic lymphocytic leukemia.

In patients with B-cell chronic lymphocytic leukemia (B-CLL), the absolute number of T cells is increased. Although it has been suggested that these T cells might be tumor specific, concrete evidence for this hypothesis is lacking. We performed a detailed immunophenotypic analysis of the T-cell compartment in the peripheral blood of 28 patients with B-CLL (Rai 0, n = 12; Rai I-II, n = 10; Rai III-IV, n = 6) and 12 healthy age-matched controls and measured the ability of these patients to mount specific immune responses. In all Rai stages a significant increase in the absolute numbers of CD3+ cells was observed. Whereas the number of CD4+ cells was not different from controls, patients with B-CLL showed significantly increased relative and absolute numbers of CD8+ cells, which exhibited a CD45RA+CD27- cytotoxic phenotype. Analysis of specific immune responses with tetrameric cytomegalovirus (CMV)-peptide complexes showed that patients with B-CLL had significantly increased numbers of tetramer-binding CMV-specific CD8+ T cells. The rise in the total number of CD8+ cytotoxic T cells was evident only in CMV-seropositive B-CLL patients. Thus, our data suggest that in patients with B-CLL the composition of T cells is shifted toward a CD8+ cytotoxic cell type in an effort to control infections with persistent viruses such as CMV. Moreover, they offer an explanation for the high incidence of CMV reactivation in CLL patients treated with T cell-depleting agents, such as the monoclonal antibody (mAb) alemtuzumab (Campath; alpha-CD52 mAb). Furthermore, because in CMV-seronegative patients no increase in cytotoxic CD8+ T cells is found, our studies do not support the hypothesis that tumor-specific T cells account for T-cell expansion in B-CLL.