Pharmacokinetics, Safety, and Antiviral Effects of Multiple Doses of the Respiratory Syncytial Virus (RSV) Fusion Protein Inhibitor, JNJ-53718678, in Infants Hospitalized With RSV Infection: A Randomized Phase 1b Study

BACKGROUND: This phase 1b study evaluated the pharmacokinetics, safety, and antiviral effects of the respiratory syncytial virus (RSV)-specific fusion inhibitor JNJ-53718678 (JNJ-8678) in hospitalized RSV-infected patients aged > 1 to /=6 to /=3 to 1 to < 3 months) were randomized to oral JNJ-8678 or placebo once daily for 7 days. Dose increases followed data review committee recommendations (cohort 1: 2/6/8/9 mg/kg; cohort 2: 1.5/4.5/6 mg/kg; cohort 3: 1/3/5 mg/kg). Cohort 1 included a 9 mg/kg dose, as target exposures were not reached at lower doses. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modeling. Safety was assessed by adverse events (AEs), laboratory tests, and electrocardiograms. To assess antiviral effects, RSV RNA viral load from nasal swabs was quantified over time using reverse-transcription quantitative polymerase chain reaction. RESULTS: Patients received JNJ-8678 (n = 37) or placebo (n = 7). Pharmacokinetic parameters were similar at the highest doses for cohorts 1-3 (area under the plasma concentration-time curve from time of administration up to 24 hours postdosing at day 7: 35 840, 34 980, and 39 627 ng x hour/mL, respectively). Two grade 3 AEs were reported (both bronchiolitis; 1 JNJ-8678, 1 placebo), reported as serious AEs; all other AEs were grade 1 or 2. Two additional serious AEs were reported (rhinitis [JNJ-8678]; pneumonia [placebo]). No deaths, grade 4 AEs, or AEs leading to discontinuation were reported. Median RSV viral load change from baseline in JNJ-8678 vs placebo by day 3 was -1.98 vs -0.32 log10 copies/mL. CONCLUSIONS: In RSV-infected infants, JNJ-8678 was well tolerated. Target exposures were reached and antiviral activity was observed. CLINICAL TRIALS REGISTRATION: NCT02593851

Anti-group B Streptococcus antibody in infants born to mothers with human immunodeficiency virus (HIV) infection.

BACKGROUND: HIV-exposed uninfected infants have increased infection risk and mortality compared to HIV-unexposed infants. HIV-exposed infants may be at increased risk of invasive GBS disease due to reduced maternal antibody against GBS. METHODS: We quantified antibodies that bind to the surface of whole Group B Streptococcus (GBS) of serotypes Ia, Ib, II, III and V using novel flow cytometry assays in South African HIV-infected and non-infected mothers and their uninfected infants. Antibody-mediated complement C3b/iC3b deposition onto GBS of these serotypes was also quantified by a novel flow cytometry assay. RESULTS: Geometric mean concentration (GMC) of both surface-binding anti-GBS antibody and antibody-mediated complement deposition onto GBS were reduced in HIV-infected women (n=46) compared to HIV-uninfected women (n=58) for ST1a (surface-binding: 19.3 vs 29.3; p=0.003; complement deposition: 2.9 vs 5.3 SU/mL; p=0.003), STIb (24.9 vs 47.6; p=0.003; 2.6 vs 4.9 SU/mL; p=0.003), STII (19.8 vs 50.0; p=0.001; 3.1 vs 6.2 SU/mL; p=0.001), STIII (27.8 vs 60.1; p=0.001; 2.8 vs 5.3 SU/mL; p=0.001) and STV (121.9 vs 185.6 SU/mL; p<0.001) and in their infants for STIa (complement deposition 9.4 vs 27.0 SU/mL; p=0.02), STIb (13.4 vs 24.5 SU/mL; p=0.02), STII (14.6 vs 42.7 SU/mL; p=0.03), STIII (26.6 vs 62.7 SU/mL; p=0.03) and STV (90.4 vs 165.8 SU/mL; p=0.04). Median transplacental transfer of antibody from HIV-infected women to their infants was reduced compared to HIV-uninfected women for GBS serotypes II (0.42 [IQR 0.22-0.59] vs 1.0 SU/mL [0.42-1.66]; p<0.001), III (0.54 [0.31-1.03] vs 0.95 SU/mL [0.42-3.05], p=0.05) and V (0.51 [0.28-0.79] vs 0.75 SU/mL [0.26-2.9], p=0.04). The differences between infants remained significant at 16 weeks of age. CONCLUSIONS: Maternal HIV infection was associated with lower anti-GBS surface binding antibody concentration and antibody-mediated C3b/iC3b deposition onto GBS bacteria of serotypes Ia, Ib, II, III and V. This may render these infants more susceptible to early and late onset GBS disease

Diagnosis of multisystem inflammatory syndrome in children by a whole-blood transcriptional signature

BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C

Prognostic factors of a lower CD4/CD8 ratio in long term viral suppression HIV infected children

Background Combination antiretroviral therapy (cART) is associated with marked immune reconstitution. Although a long term viral suppression is achievable, not all children however, attain complete immunological recovery due to persistent immune activation. We use CD4/CD8 ratio like a marker of immune reconstitution. Methods Perinatal HIV-infected children who underwent a first-line cART, achieved viral suppression in the first year and maintained it for more than 5 years, with no viral rebound were included. Logistic models were applied to estimate the prognostic factors, clinical characteristics at cART start, of a lower CD4/CD8 ratio at the last visit. Results 146 HIV-infected children were included: 77% Caucasian, 45% male and 28% CDC C. Median age at cART initiation was 2.3 years (IQR: 0.5-6.2). 42 (30%) children received mono-dual therapy previously to cART. Time of undetectable viral load was 9.5 years (IQR: 7.8, 12.5). 33% of the children not achieved CD4/CD8 ratio >1. Univariate analysis showed an association between CD4/CD8 <1 with lower CD4 nadir and baseline CD4; older age at diagnosis and at cART initiation; and a previous exposure to mono-dual therapy. Multivariate analysis also revealed relationship between CD4/CD8 <1 and lower CD4 nadir (OR: 1.002, CI 95% 1.000-1.004) as well as previous exposure to mono-dual therapy (OR: 0.16, CI 95% 0.003-0.720). Conclusions CD4/CD8 > 1 was not achieved in 33% of the children. Lower CD4 nadir and previous exposure to suboptimal therapy, before initiating cART, are factors showing independently association with a worse immune recovery (CD4/CD8 < 1)

Group B Streptococcus vaccine development: present status and future considerations, with emphasis on perspectives for low and middle income countries.

Globally, group B Streptococcus (GBS) remains the leading cause of sepsis and meningitis in young infants, with its greatest burden in the first 90 days of life. Intrapartum antibiotic prophylaxis (IAP) for women at risk of transmitting GBS to their newborns has been effective in reducing, but not eliminating, the young infant GBS disease burden in many high income countries. However, identification of women at risk and administration of IAP is very difficult in many low and middle income country (LMIC) settings, and is not possible for home deliveries. Immunization of pregnant women with a GBS vaccine represents an alternate pathway to protecting newborns from GBS disease, through the transplacental antibody transfer to the fetus in utero. This approach to prevent GBS disease in young infants is currently under development, and is approaching late stage clinical evaluation. This manuscript includes a review of the natural history of the disease, global disease burden estimates, diagnosis and existing control options in different settings, the biological rationale for a vaccine including previous supportive studies, analysis of current candidates in development, possible correlates of protection and current status of immunogenicity assays. Future potential vaccine development pathways to licensure and use in LMICs, trial design and implementation options are discussed, with the objective to provide a basis for reflection, rather than recommendations

Aetiology of acute respiratory infection in preschool children requiring hospitalisation in Europe-results from the PED-MERMAIDS multicentre case-control study.

BACKGROUND: Both pathogenic bacteria and viruses are frequently detected in the nasopharynx (NP) of children in the absence of acute respiratory infection (ARI) symptoms. The aim of this study was to estimate the aetiological fractions for ARI hospitalisation in children for respiratory syncytial virus (RSV) and influenza virus and to determine whether detection of specific respiratory pathogens on NP samples was associated with ARI hospitalisation. METHODS: 349 children up to 5 years of age hospitalised for ARI (following a symptom-based case definition) and 306 hospital controls were prospectively enrolled in 16 centres across seven European Union countries between 2016 and 2019. Admission day NP swabs were analysed by multiplex PCR for 25 targets. RESULTS: RSV was the leading single cause of ARI hospitalisations, with an overall population attributable fraction (PAF) of 33.4% and high seasonality as well as preponderance in younger children. Detection of RSV on NP swabs was strongly associated with ARI hospitalisation (OR adjusted for age and season: 20.6, 95% CI: 9.4 to 45.3). Detection of three other viral pathogens showed strong associations with ARI hospitalisation: influenza viruses had an adjusted OR of 6.1 (95% CI: 2.5 to 14.9), parainfluenza viruses (PIVs) an adjusted OR of 4.6 (95% CI: 1.8 to 11.3) and metapneumoviruses an adjusted OR of 4.5 (95% CI: 1.3 to 16.1). Influenza viruses had a PAF of 7.9%, PIVs of 6.5% and metapneumoviruses of 3.0%. In contrast, most other pathogens were found in similar proportions in cases and controls, including Streptococcus pneumoniae, which was weakly associated with case status, and endemic coronaviruses. CONCLUSION: RSV is the predominant cause of ARI hospitalisations in young children in Europe and its detection, as well as detection of influenza virus, PIV or metapneumovirus, on NP swabs can establish aetiology with high probability. PAFs for RSV and influenza virus are highly seasonal and age dependent

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study

Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75–1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58–1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91–1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70–1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11–0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50–0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38–0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45–0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

Viruses and Mycoplasma pneumoniae are the main etiological agents of community-acquired pneumonia in hospitalized pediatric patients in Spain

[Objectives]: To describe the etiology of community-acquired pneumonia (CAP) in hospitalized children in Spain and analyze the predictors of the etiology.[Hypothesis]: The different etiological groups of pediatric CAP are associated with different clinical, radiographic, and analytical data.[Design]: Observational, multicenter, and prospective study.[Patient selection]: This study included children aged 1 month to 17 years with CAP, who were hospitalized between April 2012 and May 2019.[Methods]: An extensive microbiological workup was performed. The clinical, radiographic, and analytical parameters were analyzed for three etiological groups.[Results]: Among the 495 children included, at least one causative pathogen was identified in 262 (52.9%): pathogenic viruses in 155/262 (59.2%); atypical bacteria (AB), mainly Mycoplasma pneumonia, in 84/262 (32.1%); and typical bacteria (TyB) in 40/262 (15.3%). Consolidation was observed in 89/138 (64.5%) patients with viral CAP, 74/84 (88.1%) with CAP caused by AB, and 40/40 (100%) with CAP caused by TyB. Para-pneumonic pleural effusion (PPE) was observed in 112/495 (22.6%) patients, of which 61/112 (54.5%) presented a likely causative pathogen: viruses in 12/61 (19.7%); AB in 23/61 (37.7%); and TyB in 26/61 (42.6%). Viral etiology was significantly frequent in young patients and in those with low oxygen saturation, wheezing, no consolidation, and high lymphocyte counts. CAP patients with AB as the etiological agent had a significantly longer and less serious course as compared to those with other causative pathogens.[Conclusions]: Viruses and M. pneumoniae are the main causes of pediatric CAP in Spain. Wheezing, young age, and no consolidation on radiographs are indicative of viral etiology. Viruses and AB can also cause PPE. Since only a few cases can be directly attributed to TyB, the indications for antibiotics must be carefully considered in each patient.Instituto de Investigación Hospital 12 de Octubre (i+12), Grant/Award Number: AY191212‐1; Instituto de Salud Carlos III (Ministry of Economy, Industry and Competitiveness) and co‐funded by the European Regional Development Funds, Grant/Award Number: Project PI17/01458; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Grant/Award Number: PCAPE 2011_0025 Register 320/11; Research Project of Universidad Europea de Madrid, Grant/Award Number: 2017/UEM03Peer reviewe