Prophylaxis with enoxaparin and antithrombin III in drug-induced coagulation alterations in childhood leukemia: a retrospective experience of 20 years.

BACKGROUND: Thromboembolic complications are well known in the treatment of childhood acute lymphoblastic leukemia. Over the years it has not been possible to reach a consensus on a possible prophylaxis of thromboembolic events during intensive therapy. Only the administration of enoxaparin was able to achieve evidence in the literature to date. METHODS: In this retrospective study, 173 childhood leukemia patients were treated over 20 years with a thromboembolic prophylaxis including enoxaparin and AT III during induction therapy with L-asparaginase and cortisone. RESULTS: We here report the effectiveness of administration of enoxaparin and AT III in childhood leukemia, showing a strikingly low prevalence of deep vein thrombosis (2.9%). Especially in adolescent patients, a particularly great need for AT III was demonstrated. CONCLUSIONS: We recommend thromboembolic prophylaxis with enoxaparin and AT III substitution during induction/reinduction therapy with L-asparaginase and glucocorticosteroids, especially from adolescence onwards.

Integration of Daily Patient-Reported Outcome Measures in Pediatric Stem Cell Transplantation.

Patients' reports of their health status are increasingly used in hematopoietic stem cell transplantation (SCT) to better understand the negative impact on symptom burden and quality of life. Little is known regarding the implementation in routine clinical care, particularly how it can be used to improve supportive care. We sought to the evaluate feasibility of capturing daily patient-reported outcomes (PROs) in the acute phase of SCT to measure physical and psychosocial symptom burden. In this single-center prospective observational study, we assessed daily PRO from conditioning to neutrophil engraftment in children (age 1 to 18 year) who underwent allogeneic or autologous SCT for malignant and nonmalignant disease. The most common acute adverse effects of chemotherapy (pain, nausea, loss of appetite, sleep disturbance, and physical performance impairment) were reported daily via ePROtect, a web-based program designed to integrate health responses. From February 2021 to March 2023, 20 children undergoing allogeneic (allo-) SCT (n = 11) or autologous (auto-) SCT (n = 9) and their proxies consented to participation, all of whom were included in this analysis. A total of 359 PRO questionnaires were completed, corresponding to a median daily completion rate of 72.7% (interquartile range, 60.4% to 83.6%). After conditioning, pain perception anticipated the rise of infectious parameters and the development of mucositis, thus initiating supportive treatment. Patients reported the strongest symptom burden at a median of 8.5 days post-transplantation. At 4 weeks post-transplantation, baseline values were restored for all symptoms. There were no significant differences between auto-SCT and allo-SCT, except for nausea and loss of appetite after administration of antithymocyte globulin in allo-SCT. This study empirically documents the daily health status of children undergoing SCT and proposes an attractive modus operandi on how continuous feedback on health-related symptoms can be integrated into daily clinical practice.

Recommendations for Nutritional Supplementation in Pediatric Oncology: A Compilation of the Facts.

BACKGROUND: As one of the few modifiable risk factors, the importance of dietary patterns for both disease prevention and treatment outcome in pediatric oncology has gained increasing popularity. Malnutrition is associated with lower survival rates, tolerance to treatment, and quality of life. Yet, especially in children with malignancies, nutritional deterioration is common, and pediatric cancer patients often present with inadequate intake of micro- and macronutrients alike. Despite the reported widespread use of dietary supplements, few empirical data provide a basis for clinical recommendations, and evidence for their efficacy is inconsistent. Current literature lacks a systematic approach as to how and which supplements should be recommended for specific patients, types of cancer, or during specific treatments. The aim of this review is to highlight the role of the most frequently used nutrients in pediatric malignant diseases and to give a practical guide based on current scientific evidence. METHODS: A comprehensive literature search was conducted on PubMed through April 2023 to select meta-analyses, systematic reviews, observational studies, and individual randomized controlled trials (RCTs) of macro- and micronutrient supplementation in pediatric oncology. The search strategy included the following medical subject headings (MeSH) and keywords: "childhood cancer", "pediatric oncology", "nutritional status", "dietary supplements", "vitamins", "micronutrients", "calcium", "magnesium", "vitamin D", "zinc" "glutamine", "selen", and "omega-3 fatty acids". The reference lists of all relevant articles were screened to include potentially pertinent studies. RESULTS: The present review provides a comprehensive and updated overview of the latest evidence about the role of nutrition and diet in pediatric oncology, also focusing on different nutritional interventions available for the management of the disease. We summarize evidence about the importance of adequate nutrition in childhood cancer and the role of several micronutrients and critically interpret the findings. Possible effects and benefits of supplementation during chemotherapy are discussed, as are strategies for primary and secondary prevention. CONCLUSIONS: We here describe the obvious benefits of dietary supplementation for childhood cancer. Further large-scale clinical trials are required to verify the impacts of deficiencies and the possible benefits of supplementation and optimal dosages. (337 words).

Can virtual care reduce treatment burden in pediatric leukemia? A retrospective cost analysis.

We conducted a retrospective analysis to determine the potential reduction in treatment burden through the expansion of virtual care among children with leukemia (n = 152). Patients living in urban areas traveled median distances of 1555 km compared with 7536 km for patients living in rural areas (p < .05). For the latter group, a median reduction in travel distance of 3560 km (interquartile range [IQR], 2136-5787 km), travel time of 51 h (IQR, 26-78 h), and CO2 emissions of 623 kg (IQR, 374-1013 kg) was estimated, if every second visit was replaced by video consultations.

Immature platelet fraction predicts early marrow recovery after severe chemotherapy associated neutropenia.

Febrile neutropenia secondary to chemotherapy is one of the most critical complications in cancer treatment. The aim of this study was to determine if an increase in the percentage of immature platelet fraction (IPF%) might predict early neutrophil recovery following cytostatic-dependent aplasia. A retrospective cohort study compared serial complete blood counts and the level of C-reactive protein (CRP) following induction chemotherapy for Ewing sarcoma and Non-Ewing sarcoma patients. The measurements were taken on a Sysmex XE-2100 instrument. A total of 287 paired samples from 28 children after the first cycle of chemotherapy were analyzed to test if an increase in the IPF% anticipated the CRP peak and recovery of neutrophil count. The chemotherapy associated nadir of neutrophils, reticulocytes and platelets was reached at 9.7 ± 1.5, 11.0 ± 1.7 and 11.9 ± 0.9 days (mean ± SD) respectively, in Ewing sarcoma patients. Still in severe neutropenia, IPF% was the first parameter that significantly increased and anticipated the CRP peak (11.9 ± 1.6 days, mean ± SD). The IPF% continuously increased (maximum = 6.56% ± 2.8%, mean ± SD) and peaked at 12.2 ± 1.4 days (mean ± SD) after commencement of chemotherapy. Compared to neutrophil recovery (14.6 ± 1.4 days, mean ± SD), the IPF% peak was anticipated by 2.4 days (p = 0.0085). Although variably treated, in non-Ewing sarcoma patients the effect was similar and the IPF% peak anticipated neutrophil recovery by 6.8 ± 4.7 days (p < 0.01). IPF% increased significantly at > 48 h before neutrophil recovery in patients treated with chemotherapy. IPF% is an inexpensive parameter and may be valuable in the management of febrile neutropenia.

Disagreement between mothers' and fathers' rating of health-related quality of life in children with cancer.

PURPOSE: Serial assessment of health condition based on self-report made by children and their proxies has consistently shown a lack of congruence. The study explored the discrepancies between mother's, father's, and children's reports on health-related quality of life (HRQOL) during the first two months of pediatric cancer treatment. METHODS: In this cohort study, children and parents completed the generic and cancer-specific Pediatric Quality-of-Life Inventory (PedsQL) questionnaires at initial diagnosis and in the subsequent months. Evaluation of discrepancies included intraclass correlations between mother-child and father-child dyads at different domain levels. RESULTS: Thirty-six children with a diagnosis of cancer between May 2020 and November 2021 and their parents were included in this study. At diagnosis, mother-child dyads showed better agreement on more domains of the PedsQL Generic Core Scale than father-child dyads; moderate agreement persisted for both parents at subsequent time points on the physical domain. The disease-specific PedsQL Cancer Module revealed moderate and better agreement for mother-child dyads during active cancer therapy. In particular, agreement of mother-child dyads was pronounced for domains such as worry (0.77 [95% CI 0.52-0.89, P < 0.001]), whereas fathers tended to overestimate the child's symptom burden for most of the remaining domains of the PedsQL Cancer Module. CONCLUSION: This cohort study shows that both parent proxy reports can provide valid information on child's HRQOL, but that fathers tend to overestimate, particularly for non-observable domains. Proxy reports derived from mothers more closely agreed with children's HRQOL and might be more weighted, if there is uncertainty between parents.

Mortality of Hemato-Oncologic Patients Admitted to a Pediatric Intensive Care Unit: A Single-Center Experience.

Introduction: Mortality in children with hemato-oncologic disease admitted to a pediatric intensive care unit (PICU) is higher compared to the general population. The reasons for this fact remain unexplored. The aim of this study was to assess outcomes and trends in hemato-oncologic patients admitted to a PICU, with analytical emphasis on emergency admissions. Methods: Patients with a hemato-oncologic diagnosis admitted to a tertiary care university hospital PICU between 1 January 2009 and 31 December 2019 were retrospectively analyzed. Additionally, patient mortality 6 months after PICU admission and follow-up mortality until 31 December 2020 were recorded. Measurements and Main Results: We reviewed a total of 701 PICU admissions of 338 children with hemato-oncologic disease, of which 28.5% were emergency admissions with 200 admissions of 122 patients. Of these, 22 patients died, representing a patient mortality of 18.0% and an admission mortality of 11.0% in this group. Follow-up patient mortality was 25.4% in emergency-admitted children. Multivariable analysis revealed severe neutropenia at admission and invasive mechanical ventilation (IMV) as independent risk factors for PICU death (p = 0.029 and p = 0.002). The total number of PICU admissions of hemato-oncologic patients rose notably over time, from 44 in 2009 to 125 in 2019. Conclusion: Although a high proportion of emergency PICU admissions of hemato-oncologic patients required intensive organ support, mortality seemed to be lower than previously reported. Moreover, in this study, total PICU admissions of the respective children rose notably over time.

Use of Daily Patient-Reported Outcome Measurements in Pediatric Cancer Care.

Importance: Patient-reported outcome measurements (PROMs) are emerging as an important component of adult cancer care, but little has been done with regard to PROMs for pediatric cancer care. Objectives: To identify pediatric patients with cancer who are at risk of severe adverse effects of treatment and provide individualized supportive care using PROMs. Design, Setting, and Participants: This single-center cohort study with PROMs implemented in daily clinical routine was conducted from May 1, 2020, to November 15, 2021, among pediatric patients with a cancer diagnosis or their proxies. Inclusion criteria were treatment with chemotherapy and at least 30 days of active participation. Patients were followed up until completion of therapy or through ongoing therapy until November 15, 2021; data were analyzed from November 15, 2021, through January 31, 2022. Exposures: Cancer treatment, including chemotherapy, surgery, and radiotherapy. Main Outcomes and Measures: The primary outcome was occurrence and severity of ubiquitous complications of cancer treatment, such as nausea, appetite loss, pain, sleep disturbance, and deterioration of physical functioning. The secondary outcome was the identification of early and appropriate clinical interventions based on detection of cancer-related symptoms via PROMs. Results: A total of 4410 daily PROMs from 7082 therapy days for 40 children (35 children aged 5-18 years and 5 proxies for children aged 1-4 years) (median age, 9.1 [IQR, 6.3-12.2] years; 26 [65.0%] male) were analyzed during a median follow-up of 145.5 (IQR, 103.8-244.5) days. All participants were White. The overall median completion rate was 60.1% (IQR, 37.9%-81.0%); this rate was slightly lower during home care vs inpatient stay (57.5% [IQR, 30.7%-85.9%] vs 65.0% [IQR, 49.6%-92.5%], respectively; P = .01), with a decreasing trend over time (65.6% [IQR, 51.6%-85.9%] for the first 90 days vs 42.9% [IQR, 29.3%-82.3%] for beyond 90 days; P < .001). Severe symptoms were reported on 657 days (14.9%); most symptoms were associated with physical functioning, followed by pain, sleep disturbance, and nausea and appetite loss. In total, 321 adverse events (AEs) and cases of health deterioration were documented, and PROMs were completed for 251 (78.2%) of these events. Across all AEs, self-reported pain was the most useful marker, particularly when analyzed on the day before onset, and was associated with an odds ratio of 3.65 (95% CI, 1.54-8.62; P = .005) for the presence of mucositis. Conclusions and Relevance: The findings of this cohort study suggest that PROMs reflect daily symptoms in pediatric patients with cancer and assist in clinical management and intervention for AEs.

Sepsis in Pediatric Cancer: Does Gender Matter? A 20-Year Retrospective Study.

INTRODUCTION: Gender plays an active role in the incidence and outcome of many infectious and malignant diseases. However, there is still no study examining sex differences for developing bloodstream infections (BSIs) in pediatric patients with cancer. We sought to identify potential gender-specific risk factors for BSIs. METHODS: Data were retrospectively analyzed from 621 pediatric patients treated for childhood cancer in a tertiary single center between 1 January 2000 and 31 June 2018. After central venous access device (CVAD) placement, patients were followed up until CVAD was removed or at the most for 1 year. We calculated the gender-specific prevalence for BSIs and compared the causative bacterial strains. RESULTS: Of 621 pediatric patients with cancer (283 girls [45.6%] and 338 boys [54.4%]), 110 patients (41 girls [37.3%] and 69 boys [62.7%]) were identified with a total of 134 BSIs. Girls and boys had a similar incidence for BSI (13%) within the first 3 months of therapy, after which the risk for BSI increased significantly for boys (34% versus 21%, boys versus girls, P = 0.025). Moreover, BSI with gram-positive bacteria affected boys nearly twice as often as girls (29.8% versus 56.5%, girls versus boys). CONCLUSIONS: Future clinical awareness of hygiene-related BSIs in boys could be helpful in identifying areas for improvement.

Bridging the gap in outpatient care: Can a daily patient-reported outcome measure help?

BACKGROUND: Childhood patients have high risks for developing debilitating somatic and mental health side-effects as a consequence of the many different approaches employed in treating their cancer. Early recognition and close monitoring of clinical and psychological problems are essential in planning appropriate interventions and preventing further deterioration. CASE: ePROtect was established as an easy-to-use application for daily self-reporting of symptoms during cancer therapy. ePROtect includes six to eight questions pertaining to seven common symptoms: appetite loss, fatigue, nausea, pain, physical functioning, cognitive impairments and sleep quality. The case of a child diagnosed with Burkitt leukemia developing chemotherapy-induced oral mucositis in home care is presented to show the therapeutic impact of early symptom detection with a daily web-based tool. CONCLUSION: This case highlights how electronic patient-reported outcome measures (PROM) can directly facilitate patient care in real time and might be incorporated in future clinical routine.

What We Learn from Surveillance of Microbial Colonization in Recipients of Pediatric Hematopoietic Stem Cell Transplantation.

Infections in hematopoietic stem cell transplant (HSCT) remain one of the major causes for morbidity and mortality, and it is still unclear whether knowledge of microbial colonization is important. In this single-center study, we collected weekly surveillance cultures in pediatric recipients of allogenic HSCT from five different body regions and tested for bacteria and fungi. Between January 2010 and December 2021, we collected 1095 swabs from 57 recipients of allogeneic HSCTs (median age: 7.5 years, IQR 1−3: 2.5−11.9). The incidence of positive microbiological cultures (n = 220; 20.1%) differed according to the anatomic localization (p < 0.001) and was most frequent in the anal region (n = 98), followed by the genital, pharyngeal and nasal regions (n = 55, n = 37 and n = 16, respectively). Gram-positive bacteria (70.4%) were the most commonly isolated organisms, followed by fungi (18.6%), Gram-negative (5.5%), non-fermenting bacteria (1.4%), and other flora (4.1%). No association with increased risk of infection (n = 32) or septicemia (n = 7) was noted. Over time, we did not observe any increase in bacterial resistance. We conclude that there is no benefit to surveillance of microbial colonization by culture-based techniques in pediatric HSCT. Sequencing methods might enhance the detection of pathogens, but its role is still to be defined.

Implementation of daily patient-reported outcome measurements to support children with cancer.

BACKGROUND: Several stakeholders, including patients and health care providers, suggest symptom self-reporting measurements for a more patient-directed cancer control approach. However, services tailored to measure daily reporting and implementing it in clinical care are lacking. This study aimed to evaluate the feasibility and value of daily patient-reported outcome measures (PROMs) by children receiving chemotherapy for cancer. METHODS: Health status was recorded daily with a web-based child-friendly patient portal (ePROtect). Following aspects of feasibility and usability were assessed: (a) the completion rate and time, (b) user feedback on usability and satisfaction, and (c) the performed interventions if moderate to severe symptom deterioration was noted. RESULTS: Twelve children (median age: 7.2 years) were included. A total number of 891 daily reports were collected during the study period; the median percentage of ePROtect completion days was 85.3% (interquartile range [IQR] 64.2-100.0) and 55.9% (IQR 51.9-76.9) for inpatient and outpatient stay, respectively. Mean time to complete the questionnaire was 47.6 seconds. Severe symptoms were reported in 14.7% of measurement time points, which led to prompt health care interventions in 57 cases, including extension of supportive care (n = 37) and pre-emptive inpatient admissions (n = 5). Over 80% of the patients (10/12) and their proxies (16/18) provided feedback with high rating for satisfaction (>90%) and usefulness (>80%) of ePROtect. CONCLUSION: Our study shows that daily symptom monitoring is feasible for all children with newly diagnosed cancer aged 5-18 years. Monitoring offers the opportunity to identify symptoms early and trigger appropriate clinical action.

Omega-3 Fatty Acids and Their Role in Pediatric Cancer.

BACKGROUND: Malnutrition is common in children with cancer and is associated with adverse clinical outcomes. The need for supportive care is becoming ever more evident and the role of nutrition in oncology is still not sufficiently understood. In particular, the consequences of macro- and micronutrient deficiencies require further research. As epidemiological data suggest anti-tumoral properties of omega-3 (n-3) polyunsaturated fatty acids (PUFAs), we reviewed the role of nutrition and n-3 supplementation in pediatric oncology. METHODS: A comprehensive literature search was conducted on PubMed through 5 February 2021 to select meta-analyses, systematic reviews, observational studies, and individual randomized controlled trials (RCTs) on macro- and micronutrient supplementation in pediatric oncology. The search strategy included the following medical subject headings (MeSH) and keywords: "childhood cancer", "pediatric oncology", "nutritional status", "malnutrition", and "omega-3-fatty-acids". The reference lists of all relevant articles were screened to include potentially pertinent studies. RESULTS: We summarize evidence about the importance of adequate nutrition in childhood cancer and the role of n-3 PUFAs and critically interpret findings. Possible effects of supplementation on the nutritional status and benefits during chemotherapy are discussed as well as strategies for primary and secondary prevention. CONCLUSION: We here describe the obvious benefits of omega-3 supplementation in childhood cancer. Further large scale clinical trials are required to verify potential anti-cancer effects of n-3 fatty acids.

Which Type of Empiric Antibiotic Therapy is Appropriate? A 20-Year Retrospective Study of Bloodstream Infections in Childhood Cancer.

INTRODUCTION: Sufficient empirical antimicrobial therapy in febrile patients with cancer is challenging, owing to the limited arsenal of available antibiotics in an era of growing resistance. Because of the emergence of gram-negative bacteria resistant to ceftazidime and piperacillin, a combination antibiotic therapy was employed that uses meropenem combined with gentamicin and/or vancomycin if the patient further deteriorates. METHODS: A retrospective cohort analysis was performed including all patients with catheter-associated bloodstream infections (BSIs) and treated for childhood cancer in a tertiary single centre between 1 January 2000 and 31 June 2018. We calculated the prevalence and the risk for BSIs and compared the in vitro susceptibility to various antimicrobial agents. RESULTS: Of 653 patients with childhood cancer, 113 patients (17.3%) were identified with a total of 139 BSIs, most of them occurring in patients with leukaemia (n = 90, 64.7%) and were associated with gram-positive bacteria (60.5%). In our cohort, all BSIs with gram-negative bacteria exhibited in vitro susceptibility against meropenem alone without any signs of resistance development. The antibiotic coverage of our meropenem-based combination therapy was also highly effective for gram-positive and non-fermenting bacteria. Thus, BSI-related mortality in all 139 BSI episodes was 1.4%. Clostridium difficile infections (CDIs), as main adverse event of carbapenem usage, occurred in only 16 (2.5%) patients. CONCLUSION: Our meropenem-based combination therapy showed sufficient empirical antibiotic coverage in the majority of BSIs (96.4%) and did not result in an increased rate of unwanted side effects or development of antibiotic resistance.

Comparison of pediatric scoring systems for mortality in septic patients and the impact of missing information on their predictive power: a retrospective analysis.

BACKGROUND: Scores can assess the severity and course of disease and predict outcome in an objective manner. This information is needed for proper risk assessment and stratification. Furthermore, scoring systems support optimal patient care, resource management and are gaining in importance in terms of artificial intelligence. OBJECTIVE: This study evaluated and compared the prognostic ability of various common pediatric scoring systems (PRISM, PRISM III, PRISM IV, PIM, PIM2, PIM3, PELOD, PELOD 2) in order to determine which is the most applicable score for pediatric sepsis patients in terms of timing of disease survey and insensitivity to missing data. METHODS: We retrospectively examined data from 398 patients under 18 years of age, who were diagnosed with sepsis. Scores were assessed at ICU admission and re-evaluated on the day of peak C-reactive protein. The scores were compared for their ability to predict mortality in this specific patient population and for their impairment due to missing data. RESULTS: PIM (AUC 0.76 (0.68-0.76)), PIM2 (AUC 0.78 (0.72-0.78)) and PIM3 (AUC 0.76 (0.68-0.76)) scores together with PRSIM III (AUC 0.75 (0.68-0.75)) and PELOD 2 (AUC 0.75 (0.66-0.75)) are the most suitable scores for determining patient prognosis at ICU admission. Once sepsis is pronounced, PELOD 2 (AUC 0.84 (0.77-0.91)) and PRISM IV (AUC 0.8 (0.72-0.88)) become significantly better in their performance and count among the best prognostic scores for use at this time together with PRISM III (AUC 0.81 (0.73-0.89)). PELOD 2 is good for monitoring and, like the PIM scores, is also largely insensitive to missing values. CONCLUSION: Overall, PIM scores show comparatively good performance, are stable as far as timing of the disease survey is concerned, and they are also relatively stable in terms of missing parameters. PELOD 2 is best suitable for monitoring clinical course.

Stereotactic radiofrequency ablation of a variety of liver masses in children.

BACKGROUND AND AIMS: Surgical resection is currently the cornerstone of liver tumor treatment in children. In adults radiofrequency ablation (RFA) is an established minimally invasive treatment option for small focal liver tumors. Multiprobe stereotactic RFA (SRFA) with intraoperative image fusion to confirm ablation margins allows treatment for large lesions. We describe our experience with SRFA in children with liver masses. METHODS: SRFA was performed in 10 patients with a median age of 14 years (range 0.5-17.0 years) suffering from liver adenoma (n = 3), hepatocellular carcinoma (n = 1), hepatoblastoma (n = 2), myofibroblastic tumor (n = 1), hepatic metastases of extrahepatic tumors (n = 2) and infiltrative hepatic cysts associated with alveolar echinococcosis (n = 1). Overall, 15 lesions with a mean lesion size of 2.6 cm (range 0.7-9.5 cm) were treated in 11 sessions. RESULTS: The technical success rate was 100%, as was the survival rate. No transient adverse effects higher than grade II (Clavien and Dindo) were encountered after interventions. The median hospital stay was 5 d (range 2-33 d). In two patients who subsequently underwent transplant hepatectomy complete ablation was histologically confirmed. Follow-up imaging studies (median 55 months, range 18-129 months) revealed no local or distant recurrence of disease in any patient. CONCLUSIONS: SRFA is an effective minimal-invasive treatment option in pediatric patients with liver tumors of different etiologies.

"Enhanced acquisition of antibiotic-resistant intestinal E. coli during the first year of life assessed in a prospective cohort study".

Background: Increasing bacterial resistance to antibiotics is a serious problem worldwide. We sought to record the acquisition of antibiotic-resistant Escherichia coli (E. coli) in healthy infants in Northern Thailand and investigated potential determinants. Methods: Stool samples from 142 infants after birth, at ages 2wk, 2mo, 4 to 6mo, and 1y, and parent stool samples were screened for E. coli resistance to tetracycline, ampicillin, co-trimoxazole, and cefazoline by culture, and isolates were further investigated for multiresistance by disc diffusion method. Pulsed-field gel electrophoresis was performed to identify persistent and transmitted strains. Genetic comparison of resistant and transmitted strains was done by multilocus sequence typing (MLST) and strains were further investigated for extra- and intra-intestinal virulence factors by multiplex PCR. Results: Forty-seven (33%) neonatal meconium samples contained resistant E. coli. Prevalence increased continuously: After 1y, resistance proportion (tetracycline 80%, ampicillin 72%, co-trimoxazole 66%, cefazoline 35%) almost matched those in parents. In 8 infants (6%), identical E. coli strains were found in at least 3 sampling time points (suggesting persistence). Transmission of resistant E. coli from parents to child was observed in only 8 families. MLST showed high diversity. We could not identify any virulence genes or factors associated with persistence, or transmission of resistant E. coli. Full-term, vaginal birth and birth in rural hospital were identified as risk factors for early childhood colonization with resistant E. coli. Conclusion: One third of healthy Thai neonates harboured antibiotic-resistant E. coli in meconium. The proportion of resistant E. coli increased during the first year of life almost reaching the value in adults. We hypothesize that enhancement of infection control measures and cautious use of antibiotics may help to control further increase of resistance.

SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase.

The syndromic form of congenital sodium diarrhea (SCSD) is caused by bi-allelic mutations in SPINT2, which encodes a Kunitz-type serine protease inhibitor (HAI-2). We report three novel SCSD patients, two novel SPINT2 mutations and review published cases. The most common findings in SCSD patients were choanal atresia (20/34) and keratitis of infantile onset (26/34). Characteristic epithelial tufts on intestinal histology were reported in 13/34 patients. Of 13 different SPINT2 variants identified in SCSD, 4 are missense variants and localize to the second Kunitz domain (KD2) of HAI-2. HAI-2 has been implicated in the regulation of the activities of several serine proteases including prostasin and matriptase, which are both important for epithelial barrier formation. No patient with bi-allelic stop mutations was identified, suggesting that at least one SPINT2 allele encoding a protein with residual HAI-2 function is necessary for survival. We show that the SCSD-associated HAI-2 variants p.Phe161Val, p.Tyr163Cys and p.Gly168Ser all display decreased ability to inhibit prostasin-catalyzed cleavage. However, the SCSD-associated HAI-2 variants inhibited matriptase as efficiently as the wild-type HAI-2. Homology modeling indicated limited solvent exposure of the mutated amino acids, suggesting that they induce misfolding of KD2. This suggests that prostasin needs to engage with an exosite motif located on KD2 in addition to the binding loop (Cys47/Arg48) located on the first Kunitz domain in order to inhibit prostasin. In conclusion our data suggests that SCSD is caused by lack of inhibition of prostasin or a similar protease in the secretory pathway or on the plasma membrane.

Vedolizumab use after failure of TNF-α antagonists in children and adolescents with inflammatory bowel disease.

BACKGROUND: Vedolizumab is safe and effective in adult patients with Crohn's disease (CD) and ulcerative colitis (UC); however, data in children with inflammatory bowel disease (IBD) are scarce. Therefore, we evaluated vedolizumab use in a cohort of Austrian paediatric patients with IBD. METHODS: Twelve patients (7 female; 7 CD; 5 UC), aged 8-17 years (median, 15 years), with severe IBD who received vedolizumab after tumour necrosis factor α antagonist treatment were retrospectively analysed. Clinical activity scores, relevant laboratory parameters, and auxological measures were obtained at infusion visits. RESULTS: In the CD group, 1/7 patient discontinued therapy due to a severe systemic allergic reaction; 1/7 and 2/7 patients achieved complete and partial response, respectively, at week 14; and 3/7 patients discontinued therapy due to a primary non-response or loss of response. In the UC group, complete clinical remission was achieved at weeks 2, 6, and 14 in 2/5, 1/5 and 1/5 patients respectively; partial response was observed in one patient at week 2. CD activity scores did not significantly change from baseline to week 38 (median 47.5 vs. 40 points, p = 1,0), while median UC activity scores changed from 70 to 5 points (p < 0,001). Substantial weight gain and increased albumin and haemoglobin levels were observed in both groups. CONCLUSION: These results demonstrate that vedolizumab can be an effective treatment for individual paediatric patients with IBD who are unresponsive, intolerant, or experience a loss of efficacy in other therapies. However, vedolizumab appears to be more effective in paediatric UC than in paediatric CD.