Inappropriate prescribing contributes to high antibiotic exposure in young children in Australia.

BACKGROUND: Antibiotic exposure increases antimicrobial resistance and has also been associated with long-term harms, including allergies, inflammatory diseases and weight gain. We assessed antibiotic exposure in the first 2 years of life in Australian children, the factors influencing this and its appropriateness. METHODS: Data from 1201 participants in the MIS BAIR randomized controlled trial were used. Multivariable logistic regression was used to identify factors associated with antibiotic exposure. RESULTS: At 1 and 2 years of age, exposure to at least one course of antibiotics was 43% and 67%, with the highest first antibiotic prescription rate between 9 and 18 months. Amoxicillin was the most frequently used antibiotic (59%), followed by cefalexin (7%). The most common diagnoses for which antibiotics were prescribed were respiratory tract infections from 0 to 6 months of age and otitis media from 6 to 12 months. Factors associated with antibiotic exposure from 0 to 12 months of age were delivery by Caesarean section (adjusted odd-ratio (aOR) 1.5, 95%CI 1.1-1.9), birth in winter (aOR 1.7, 95%CI 1.2-2.4), maternal antibiotic exposure during the last trimester of pregnancy (aOR 1.6, 95%CI 1.1-2.3), cessation of breastfeeding by 6 months of age (aOR 1.5, 95%CI 1.1-2.0) and day-care attendance (aOR 1.4, 95%CI 1.1-1.8). Based on parent-reported questionnaires, 27% of infants were treated in the first year of life for conditions unlikely to need antibiotic treatment. CONCLUSION: At least two-thirds of children were prescribed antibiotics in the first 2 years of life, and more than a quarter of these exposures may have been unnecessary.

Long-term global longitudinal strain abnormalities in paediatric patients after multisystem inflammatory syndrome in children correlate with cardiac troponin T: a single-centre cohort study.

BACKGROUND: Multisystem inflammatory syndrome in children is an inflammatory syndrome related to severe acute respiratory syndrome coronavirus 2 with a high risk of cardiovascular complications (vasoplegia, cardiac shock). We investigated the cardiac outcomes in multisystem inflammatory syndrome in children, focusing on the identification of predictors for late cardiac function impairment. METHODS: Clinical characteristics, conventional echocardiography (left ventricle ejection fraction, fractional shortening), 4-chamber left ventricular global longitudinal strain, and cardiac MRI of multisystem inflammatory syndrome in children patients (n = 48) were collected during admission, 6 weeks, 6 months, >12-≤18 months, and >18-≤24 months post-onset. Paired over-time patterns were assessed and multivariable regression analyses were performed to identify predictors for late global longitudinal strain impairment. RESULTS: In total, 81.3% of patients had acute cardiac dysfunction (left ventricle ejection fraction <50% and/or fractional shortening <28%). The left ventricle ejection fraction and fractional shortening reached a plateau level ≤6 weeks, while the global longitudinal strain continued to decrease in the first 6 months post-onset (median -17.3%, P < 0.001 [versus acute]). At 6 months, 35.7% of the patients still had an abnormal global longitudinal strain, which persisted in 5/9 patients that underwent echocardiography >12-≤18 months post-onset and in 3/3 patients >18-≤24 months post-onset. In a multivariable analysis, soluble troponin T (>62.0 ng/L [median]) was associated with reduced global longitudinal strain at 6 months. Our cardiac MRI findings indicated acute myocardial involvement (increased T1/T2 value) in 77.8% (7/9), which recovered quickly without signs of fibrosis on convalescent cardiac MRIs. CONCLUSIONS: Late global longitudinal strain impairment is seen in some multisystem inflammatory syndrome in children patients up to one-year post-onset. Careful cardiac follow-up in patients with elevated troponin in the acute phase and patients with persistent abnormal global longitudinal strain is warranted until resolution of the global longitudinal strain since the long-term implications of such abnormalities are still unclear.

Acute and early-onset cardiotoxicity in children and adolescents with cancer: a systematic review.

BACKGROUND: Cardiotoxicity is among the most important adverse effects of childhood cancer treatment. Anthracyclines, mitoxantrone and radiotherapy involving the heart are its main causes. Subclinical cardiac dysfunction may over time progress to clinical heart failure. The majority of previous studies have focused on late-onset cardiotoxicity. In this systematic review, we discuss the prevalence and risk factors for acute and early-onset cardiotoxicity in children and adolescents with cancer treated with anthracyclines, mitoxantrone or radiotherapy involving the heart. METHODS: A literature search was performed within PubMed and reference lists of relevant studies. Studies were eligible if they reported on cardiotoxicity measured by clinical, echocardiographic and biochemical parameters routinely used in clinical practice during or within one year after the start of cancer treatment in ≥ 25 children and adolescents with cancer. Information about study population, treatment, outcomes of diagnostic tests used for cardiotoxicity assessment and risk factors was extracted and risk of bias was assessed. RESULTS: Our PubMed search yielded 3649 unique publications, 44 of which fulfilled the inclusion criteria. One additional study was identified by scanning the reference lists of relevant studies. In these 45 studies, acute and early-onset cardiotoxicity was studied in 7797 children and adolescents. Definitions of acute and early-onset cardiotoxicity prove to be highly heterogeneous. Prevalence rates varied for different cardiotoxicity definitions: systolic dysfunction (0.0-56.4%), diastolic dysfunction (30.0-100%), combinations of echocardiography and/or clinical parameters (0.0-38.1%), clinical symptoms (0.0-25.5%) and biomarker levels (0.0-37.5%). Shortening fraction and ejection fraction significantly decreased during treatment. Cumulative anthracycline dose proves to be an important risk factor. CONCLUSIONS: Various definitions have been used to describe acute and early-onset cardiotoxicity due to childhood cancer treatment, complicating the establishment of its exact prevalence. Our findings underscore the importance of uniform international guidelines for the monitoring of cardiac function during and shortly after childhood cancer treatment.

Treatment and Coronary Artery Aneurysm Formation in Kawasaki Disease: A Per-Day Risk Analysis.

OBJECTIVE: To assess whether 'treatment day' is a significant predicting factor in Kawasaki disease and imposes a risk for coronary artery aneurysms (CAAs) in a per-day analysis. CAA formation can be reduced from 25% to 10% when treated with intravenous immunoglobulin (IVIG). STUDY DESIGN: Patient data from (n = 1016) a single center were collected for an observational cohort study. After exclusions, we retrospectively analyzed 776 patients in total. A multivariate analysis was performed with treatment day as a continuous variable (n = 691). Patients were categorized as no enlargement, small CAA, medium CAA, and giant CAA. RESULTS: Late treatment per-day was a significant predicting factor for the development of larger CAAs. ORs for medium and giant CAAs per delayed day were 1.1 (95% CI 1.1-1.2) P < .05 and 1.2 (95% CI 1.1-1.2) P < .05, respectively. CONCLUSION: We showed that every day of delay in treatment of patients with Kawasaki disease inherently carries a risk of medium and giant aneurysm formation. There was no cut-off point for treatment day that could mark a safe zone.

An anti-inflammatory property of Candida albicans ß-glucan: Induction of high levels of interleukin-1 receptor antagonist via a Dectin-1/CR3 independent mechanism.

BACKGROUND: Candida albicans is an opportunistic fungal pathogen that induces strong proinflammatory responses, such as IL-1ß production. Much less is known about the induction of immune modulatory cytokines, such as the IL-1 receptor antagonist (IL-1Ra) that is the main natural antagonist of IL-1, by C. albicans. METHODS: Peripheral blood mononuclear cells (PBMC) of healthy individuals were stimulated with C. albicans and different components of the fungal cell wall. The role of pathogen recognition receptors (PRRs) for the induction of IL-1ß and IL-1Ra was investigated by using specific blockers or in PBMC from Dectin-1 deficient patients. RESULTS: C. albicans induced a strong IL-1Ra response, and this induction was primarily induced by the cell-wall component ß-glucan. Blocking IL-1Ra significantly increased C. albicans ß-glucan hyphae induced IL-1ß and IL-6 production. Surprisingly, blocking the ß-glucan receptor Dectin-1 or the downstream Syk or Raf-1 pathways only marginally reduced C. albicans-induced IL-1Ra production, while blocking of the complement receptor 3 (CR3), TLR2 or TLR4 had no effect. In line with this, blocking MAP kinases had little effect on Candida-induced IL-1Ra production. PBMC isolated from Dectin-1 deficient patients produced normal IL-1Ra amounts in response to C. albicans stimulation. Interestingly, the IL-1Ra synthesis induced by ß-glucan was blocked by inhibitors of the Akt/PI3K pathway. CONCLUSIONS: ß-glucan of C. albicans induces a strong IL-1Ra response, which is independent of the ß-glucan receptors dectin-1 and CR3. These data strongly argue for the existence of an unknown ß-glucan receptor that specifically induces an Akt/PI3K-dependent anti-inflammatory IL-1Ra response upon recognition of C. albicans.

Chocolate consumption modulates cytokine production in healthy individuals.

Epidemiological studies suggest that chocolate increases the incidence and severity of acne. Here we demonstrate that chocolate consumption primes human blood mononuclear cells from volunteers to release more interleukin-1ß (IL-1ß) and IL-10 upon stimulation with Propionibacterium acne or Staphylcoccus aureus, the two microorganisms involved in the pathogenesis of acne. In contrast, production of the Th17-derived cytokine IL-22 was inhibited by chocolate. Modulation of inflammation could represent an important mechanism through which chocolate consumption influences acne.

[Kawasaki disease or SARS-CoV-2 related MIS-C? How to discriminate between these hyperinflammatory syndromes in children?] / Ziekte van Kawasaki of SARS-CoV-2-gerelateerde MIS-C?

Increasing waiting lists and a structural staff shortage are putting pressure on the health system. Because care production is lower than care demand, there is no longer competition. Competition is over and we are beginning to see the contours of the new health system. The new system takes health instead of care as its starting point by legally embedding health goals in addition to the duty of care. The new system is based on health regions, but does not require a regional health authority. It is based on health manifestos that include agreements about cooperation in good and bad times.

Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease.

BACKGROUND: Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease severity in adult COVID-19 is associated to the presence of anti-cytokine autoantibodies (ACAAs) against type I interferons. Similarly, ACAAs may be implicated in KD and MIS-C. Therefore, we explored the immunological response, presence of ACAAs and disease correlates in both disorders. METHODS: Eighteen inflammatory plasma protein levels and seven ACAAs were measured in KD (n = 216) and MIS-C (n = 56) longitudinally by Luminex and/or ELISA. Levels (up to 1 year post-onset) of these proteins were related to clinical data and compared with healthy paediatric controls. FINDINGS: ACAAs were found in both patient groups. The presence of ACAAs lagged behind the inflammatory plasma proteins and peaked in the subacute phase. ACAAs were mostly directed against IFN-γ (>80%) and were partially neutralising at best. KD presented with a higher variety of ACAAs than MIS-C. Increased levels of anti-IL-17A (P = 0·02) and anti-IL-22 (P = 0·01) were inversely associated with ICU admission in MIS-C. Except for CXCL10 in MIS-C (P = 0·002), inflammatory plasma proteins were elevated in both KD and MIS-C. Endothelial angiopoietin-2 levels were associated with coronary artery aneurysms in KD (P = 0·02); and sCD25 (P = 0·009), angiopoietin-2 (P = 0·001), soluble IL-33-receptor (ST2, P = 0·01) and CXCL10 (P = 0·02) with ICU admission in MIS-C. INTERPRETATION: Markers of endothelial activation (E-selectin, angiopoietin-2), and innate and adaptive immune responses (macrophages [CD163, G-CSF], neutrophils [lipocalin-2], and T cells [IFN-γ, CXCL10, IL-6, IL-17]), are upregulated in KD and MIS-C. ACAAs were detected in both diseases and, although only partly neutralising, their transient presence and increased levels in non-ICU patients may suggest a dampening role on inflammation. FUNDING: The Kawasaki study is funded by the Dutch foundation Fonds Kind & Handicap and an anonymous donor. The sponsors had no role in the study design, analysis, or decision for publication.