Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.We performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.Data were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.We found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).
Abstract Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK 1 . Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.
Introduction: Previous retrospective evaluation of the use of an age-adjusted d-dimer (INNOVACE semi-quantitative, latex agglutination assay) suggested it was safe and applicable to patients over 50 with a low probability of venous thromboembolism (VTE). Subsequently this has been implemented in our institution. Aim: To evaluate the safety and effectiveness of the new reference ranges for d-dimer. Methods: All d-dimer blood tests sent during the first year of implementation (2013-14) were reviewed. The electronic notes for all those which were negative under the new age-adjusted system (< age x 10 ug/L or < 750u/L in the over 609s) that would have previously been positive ( >420 ug/L) were reviewed to see if there had been any instances of VTE. Results: 2008 d-dimer tests were sent in the over 509s. 365 were normal using the age-adjusted stystem but > 420ug/L. 62 out of 365 were investigated suspected for VTE. 5 patients had VTE found - 1 was 7 months after the d-dimer test for an unrelated presenting complaint; 2 were intermediate/high probability patients; 1 had a positive d-dimer prior to diagnosis and the d-dimer sent was during treatment for previously diagnosed VTE; 1 patient had a negative d-dimer but represented 1 month later, had a positive d-dimer and was found to have below knee DVT. Conclusion: Using this new reference range is safe and did not miss any clinically important VTE when used appropriately in low probability patients.
Background: The neonatal mortality rate in Uganda has been 24-27/1000 live births for the last 14 years. Aim: To determine the impact on neonatal mortality of the introduction of infection prevention and treatment guidelines in a resource-poor setting. Methods: A prospective study was undertaken in Kagando Hospital, a rural hospital in Western Uganda of infants live-born in hospital and those admitted from the community or other hospitals between 2013 and 2017. Guidelines were developed from a literature review and informed by local doctors and nurses and a visiting paediatrician. The guidelines highlighted that unwell infants should be admitted to the neonatal unit which was a section of the paediatric ward, emphasised hand hygiene, the separation of infants with and without sepsis and that unwell infants should be treated with evidence-based antibiotic regimens and enteral feeds withheld from unwell infants. Mortality within 28 days of birth was audited for 3 months before and after the intervention; the audit was repeated 3 and 5 years later. Results: Pre-intervention, there were 137 neonatal admissions and 79 neonatal deaths in 3 months (0.58 deaths per admission). Post-intervention there were 187 admissions and the death rate was lower (0.26 deaths per admission, p < 0.001). Three years after the intervention, there were 60 deaths among 233 admissions (0.26 deaths per admission, p < 0.001) and, at 5 years, 53 deaths among 315 admissions (0.17 deaths per admission, p < 0.001). Conclusion: These data suggest that the introduction of infection, prevention and treatment guidelines can reduce neonatal mortality in a resource-poor setting.
Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13.
Abstract Severe febrile illnesses in children, such as multi-system inflammatory syndrome in children (MIS-C), severe bacterial infection (SBI), severe viral infection (SVI), and Kawasaki disease (KD), have shared clinical features. We used immunophenotyping with mass cytometry and cell stimulation experiments to illustrate shared and distinct mechanisms of immune dysfunction in 74 children with MIS-C, 30 with SBI, 16 with SVI, 8 with KD, and 42 controls. We then used targeted gene expression analysis to explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. Immunophenotyping and clustering analysis revealed neutrophil activation and apoptosis and T cell activation to be prominent in MIS-C and SBI. Cell stimulation experiments showed T cells from patients with acute MIS-C were exhausted. SVI was characterized by phosphorylated STAT signaling but lower gene expression for interferon receptors. Improved understanding of immune dysfunction may improve immunomodulator therapy in severe childhood febrile illnesses.
High quality paediatric training is essential to the provision of excellent child health care both now and in the future. To ensure a high standard of training is maintained within The London School of Paediatrics, an annual trainee survey has taken place since 2012. The COVID-19 pandemic brought new challenges to paediatric training (and meant that many of the usual metrics to assess training across the region became obsolete) and in September 2020, The School conducted an abbreviated, tailored survey to capture experiences of trainees, and challenges faced in training during a pandemic.
Objectives
To ascertain the ways in which London paediatric trainees were impacted by the emergency operational response to the first wave of the COVID-19 pandemic. To provide rapid feedback to training centres to inform the response to any subsequent surges.
Methods
950 (769 in programme) London Paediatric trainees were surveyed about their March-September 2020 training placement. Online survey was emailed directly, with reminders, and promoted via social media. Five closed questions addressed overall placement satisfaction (excellent to poor), performance areas (morale, educational supervision, teaching and rest/catering facilities), and specific impact of covid-19. Three free text questions addressed the impact of covid-19, positive practices and initiatives, and areas of improvement.
Results
There were 638 responses, with 566 from in-programme trainees (74% of in-programme trainees). 83.4% trainees rated their placement excellent/good (2019, 84%) and 5.8% rated it poor/below average (2019, 4%). There was inter-sector variability, with higher number of poor/below average ratings in the sector with most disruption to service. 147 (23%) trainees were seconded from their placement, 102 (16%) to another paediatric department and 45 (7%) to an adult department. 102 (16%) trainees worked additional antisocial hours to cover for seconded colleagues, and 165 (26%) worked additional antisocial hours for other reasons. 38 (6%) trainees had no direct patient contact. Only 125 trainees (20%) reported that their work was not impacted by COVID. Other ways in which work was impacted included: cancelled OOP (11), PICU taken over for adult patients (13), department closed without redeployment (5). The performance area most impacted by the pandemic was the provision of educational supervision. There was improvement in provisions for rest, food and drink. Thematic analysis of the free text identified that good team relationships, senior support and a supportive work environment were key to a positive training experience. Challenges faced were around teaching, lack of learning opportunities and poor communication. 8% of trainees highlighted that lack of communication worsened their training experience.
Conclusions
The survey shows that overall, the excellent standards of training were maintained during the first wave, despite evidence of significant disruption to services. The highlighted challenges can be used to guide training provision during the ongoing pandemic, and ensure that trainees continue to receive the highest standard of training.
The National Institute for Health and Care Excellence (NICE) guidelines recommend intravenous antibiotics to be discontinued at 36 hours in asymptomatic, low-risk babies with negative blood cultures and reassuring inflammatory markers.1 Despite this, national practice remains varied.
On contacting all 155 neonatal units in England, 91 units reported using a 36-hour blood culture threshold. Fifty-nine (38%) units reported awaiting 48-hour cultures, with 235 972 babies born in these units in 2016–2017.2 A further five units awaited 24-hour cultures (table 1).
View this table:
Table 1
National variation in time to stop antibiotics in low-risk, asymptomatic babies with reassuring inflammatory markers and negative culture results
The barriers to 36-hour culture results may be varied, often involving transport to central laboratories and access to reporting/analysing systems.3 However, stopping antibiotics at 36 hours could …
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