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In late 2019, SARS-CoV-2 emerged in the Wuhan province of China. Rapid global spread led to the Covid-19 pandemic. Rapid and accurate detection of SARS-CoV-2 has become a vitally important tool in controlling the spread of the virus. Lateral flow devices (LFDs) offer the potential advantage of speed and on-site testing. The sensitivity of these devices compared to the gold standard RT-PCR has been questioned. We compared the performance of the Innova lateral flow kit, recommended by the UK government, with our rapid in-house RT-PCR protocol using stored positive patient samples. The LFD device was found to be 6,000-10,000 times less sensitive than RT-PCR for the detection of SARS-CoV-2. Overall, the LFD detected 46.2% of the positives detected by RT-PCR. 50% of the LFD results were observed to be weak positives, only visible after careful examination by experienced laboratory staff. At lower viral loads, such as 10,000-100,000 RNA copies/ml, the LFD detected 22.2% of positives. In addition, two strong positives (3 and 1.5 million RNA copies/ml) were not detected by the LFD. The argument for use of LFD kits, despite their lack of sensitivity, is that they detect infectious virus and hence contagious individuals. At present, there is a lack of scientific evidence supporting this claim. The LFD used in the UK fails to identify individuals with considerable viral loads and has been subject to a class I recall by the US FDA but is still approved and recommended for use by the UK government. We believe that using LFD testing for assessing SARS-CoV-2 infection risk is a strategy which has risks that outweigh any benefits.

Background A critical window in infancy has been proposed, during which the microbiota may affect subsequent health. The longitudinal development of the oropharyngeal microbiota is under-studied and may be associated with early-life wheeze. We aimed to investigate the temporal association of the development of the oropharyngeal microbiota with early-life wheeze. Methods A population-based birth cohort based in London, UK was followed for 24 months. We collected oropharyngeal swabs at six time-points. Microbiota was determined using sequencing of the V3-V5 region of the 16S rRNA-encoding gene. Medical records were reviewed for the outcome of doctor diagnosed wheeze. We used a time-varying model to investigate the temporal association between the development of microbiota and doctor-diagnosed wheeze. Findings 159 participants completed the study to 24 months and for 98 there was complete sequencing data at all timepoints and outcome data. Of these, 26 had doctor-diagnosed wheeze. We observed significant increase in the abundance of Neisseria between 9 and 24 months in children who developed wheeze (p = 0∙003), while in those without wheezing there was a significant increment in the abundance of Granulicatella (p = 0∙012) between 9 and 12 months, and of Prevotella (p = 0∙018) after 18 months. Interpretation A temporal association between the respiratory commensal Granulicatella and also Prevotella with wheeze (negative), and between Neisseria and wheeze (positive) was identified in infants prior to one year of age. This adds to evidence for the proposed role of the microbiota in the development of wheeze. Fund Research funding from the Winnicott Foundation, Meningitis Now and Micropathology Ltd.

Neisseria meningitidis, the causative agent of meningococcal disease (MD), evades complement-mediated clearance upon infection by ‘hijacking’ the human complement regulator factor H (FH). The FH protein family also comprises the homologous FH-related (FHR) proteins, hypothesized to act as antagonists of FH, and FHR-3 has recently been implicated to play a major role in MD susceptibility. Here, we show that, next to FH and FHR-3, the circulating levels of all FH family proteins are equally decreased during pediatric MD. We did not observe a specific consumption of FH or FHR-3 by N. meningitidis during the first days of infection and the levels recovered over time. MD severity associated predominantly with a loss of FH. Strikingly, loss of FH and FHRs associated strongly with renal failure, suggesting insufficient protection of host tissue by the FH protein family. Retaining higher levels of FH family proteins may thus limit tissue injury during MD.

Background: Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication—the development of coronary artery aneurysms (CAA)—can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additional inflammatory parameters myeloid-related protein 8/14 (MRP8/14 or S100A8/9) and human neutrophil-derived elastase (HNE) could distinguish KD from infectious diseases. Methods and Results: The cross-sectional study included KD patients and children with proven infections as well as febrile controls. Patients were recruited between July 2006 and December 2018 in Europe and USA. MRP8/14, CRP, and HNE were assessed for their discriminatory ability by multiple logistic regression analysis with backward selection and receiver operator characteristic (ROC) curves. In the discovery cohort, the combination of MRP8/14+CRP discriminated KD patients (n = 48) from patients with infection (n = 105), with area under the ROC curve (AUC) of 0.88. The HNE values did not improve discrimination. The first validation cohort confirmed the predictive value of MRP8/14+CRP to discriminate acute KD patients (n = 26) from those with infections (n = 150), with an AUC of 0.78. The second validation cohort of acute KD patients (n = 25) and febrile controls (n = 50) showed an AUC of 0.72, which improved to 0.84 when HNE was included. Conclusion: When used in combination, the plasma markers MRP8/14, CRP, and HNE may assist in the discrimination of KD from both proven and suspected infection.

Fever is the most common reason that children present to Emergency Departments in the UK. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. As a result, many children are prescribed antibiotics often unnecessarily, while others with life-threatening bacterial infections can remain untreated. The ‘omics’ approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n=20) and confirmed viral infection (n=20). We show for the first time that bacterial and viral infection elicit distinct changes in the host lipidome. Glycerophosphoinositol, sphingomyelin, lysophosphotidylcholine and cholesterol sulfate were increased in the confirmed virus infected group, while fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were increased in cases with confirmed bacterial infection. A combination of three lipids achieved the area under the receiver operating characteristic (ROC) curve of 0.918 (95% CI 0.835 to 1). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.

Background: Sepsis is one of the main reasons for non-elective admission to pediatric intensive care units (PICUs), but little is known about determinants influencing outcome. We characterized children admitted with community-acquired sepsis to European PICUs and studied risk factors for mortality and disability.Methods: Data were collected within the collaborative Seventh Framework Programme (FP7)-funded EUCLIDS study, which is a prospective multicenter cohort study aiming to evaluate genetic determinants of susceptibility and/or severity in sepsis. This report includes 795 children admitted with community-acquired sepsis to 52 PICUs from seven European countries between July 2012 and January 2016. The primary outcome measure was in-hospital death. Secondary outcome measures were PICU-free days censured at day 28, hospital length of stay, and disability. Independent predictors were identified by multivariate regression analysis.Results: Patients most commonly presented clinically with sepsis without a source (n = 278, 35%), meningitis/encephalitis (n = 182, 23%), or pneumonia (n = 149, 19%). Of 428 (54%) patients with confirmed bacterial infection, Neisseria meningitidis (n = 131, 31%) and Streptococcus pneumoniae (n = 78, 18%) were the main pathogens. Mortality was 6% (51/795), increasing to 10% in the presence of septic shock (45/466). Of the survivors, 31% were discharged with disability, including 24% of previously healthy children who survived with disability. Mortality and disability were independently associated with S. pneumoniae infections (mortality OR 4.1, 95% CI 1.1–16.0, P = 0.04; disability OR 5.4, 95% CI 1.8–15.8, P P P Conclusions: Despite widespread immunization campaigns, invasive bacterial disease remains responsible for substantial morbidity and mortality in critically ill children in high-income countries. Almost one third of sepsis survivors admitted to the PICU were discharged with some disability. More research is required to delineate the long-term outcome of pediatric sepsis and to identify interventional targets. Our findings emphasize the importance of improved early sepsis-recognition programs to address the high burden of disease.

We report an HIV-positive patient who developed a unilateral retinitis and subsequent intracranial lesions. The finding of Epstein Barr virus (EBV) DNA at a > 1-log greater concentration in the vitreous compared to blood raised the possibility of a primary CNS non-Hodgkin's lymphoma, which was subsequently confirmed on brain biopsy. EBV DNA quantification acted as a diagnostic marker that led to a change in the management of our patient.

The Department of Defense (DoD) Space Test Program (STP) was created in 1965 to provide access to space for DoD research and development activities. STP provides spaceflight opportunities for payloads vetted through the DoD Space Experiments Review Board (SERB). Small spacecraft acquisition is one of STP's key areas of excellence; it is a key aspect to the program that enables the program to fly multi-payload missions for low costs and provides flexibility to fly on a variety of launch vehicles. To facilitate the space flight of these experiments, the Evolved Expendable Launch Vehicle (EELV) Secondary Payload Adaptor (ESPA) was developed and flown under the direction of STP. The same payload interface requirements and environments defined for ESPA are now being applied to other multi-payload adaptors (MPAs) for other launch vehicles. To fully utilize the capabilities and opportunities presented by ESPA opportunities, STP is looking to take advantage of the ESPA form factor and success of the Standard Interface Vehicle (SIV) Program through lessons learned and innovative acquisition approaches. STP's goal is to access capable, low cost spacecraft buses through partnering and utilizing the pre-existing industry base while encouraging standardized mechanical and data interfaces where appropriate to maximize responsive spaceflight opportunities. These principles are at the foundation of STP and are influencing the future of small spacecraft acquisition and access-to-space across the space community.

Background. Molecular techniques can often reveal a broader range of pathogens in respiratory infections. We aim to investigate the prevalence and age pattern of viral co-infection in children hospitalized with lower tract acute respiratory infection (LT-ARI), using molecular techniques. Methods. A nested polymerase chain reaction approach was used to detect Influenza (A, B), metapneumovirus, respiratory syncytial virus (RSV), parainfluenza (1-4), rhinovirus, adenovirus (A-F), bocavirus and coronaviruses (NL63, 229E, OC43) in respiratory samples of children with acute respiratory infection prospectively admitted to any of the GENDRES network hospitals between 2011-2013. The results were corroborated in an independent cohort collected in the UK. Results. A total of 204 and 97 nasopharyngeal samples were collected in the GENDRES and UK cohorts, respectively. In both cohorts, RSV was the most frequent pathogen (52.9% and 36.1% of the cohorts, respectively). Co-infection with multiple viruses was found in 92 samples (45.1%) and 29 samples (29.9%), respectively; this was most frequent in the 12-24 months age group. The most frequently observed co-infection patterns were RSV-Rhinovirus (23 patients, 11.3%, GENDRES cohort) and RSV-bocavirus / bocavirus-influenza (5 patients, 5.2%, UK cohort). Conclusion. The presence of more than one virus in pediatric patients admitted to hospital with LT-ARI is very frequent and seems to peak at 12-24 months of age. The clinical significance of these findings is unclear but should warrant further analysis.