Ethnic differences in cellular and humoral immune responses to SARS-CoV-2 vaccination in UK healthcare workers: a cross-sectional analysis.

Background: Few studies have compared SARS-CoV-2 vaccine immunogenicity by ethnic group. We sought to establish whether cellular and humoral immune responses to SARS-CoV-2 vaccination differ according to ethnicity in UK Healthcare workers (HCWs). Methods: In this cross-sectional analysis, we used baseline data from two immunological cohort studies conducted in HCWs in Leicester, UK. Blood samples were collected between March 3, and September 16, 2021. We excluded HCW who had not received two doses of SARS-CoV-2 vaccine at the time of sampling and those who had serological evidence of previous SARS-CoV-2 infection. Outcome measures were SARS-CoV-2 spike-specific total antibody titre, neutralising antibody titre and ELISpot count. We compared our outcome measures by ethnic group using univariable (t tests and rank-sum tests depending on distribution) and multivariable (linear regression for antibody titres and negative binomial regression for ELISpot counts) tests. Multivariable analyses were adjusted for age, sex, vaccine type, length of interval between vaccine doses and time between vaccine administration and sample collection and expressed as adjusted geometric mean ratios (aGMRs) or adjusted incidence rate ratios (aIRRs). To assess differences in the early immune response to vaccination we also conducted analyses in a subcohort who provided samples between 14 and 50 days after their second dose of vaccine. Findings: The total number of HCWs in each analysis were 401 for anti-spike antibody titres, 345 for neutralising antibody titres and 191 for ELISpot. Overall, 25.4% (19.7% South Asian and 5.7% Black/Mixed/Other) were from ethnic minority groups. In analyses including the whole cohort, neutralising antibody titres were higher in South Asian HCWs than White HCWs (aGMR 1.47, 95% CI [1.06-2.06], P = 0.02) as were T cell responses to SARS-CoV-2 S1 peptides (aIRR 1.75, 95% CI [1.05-2.89], P = 0.03). In a subcohort sampled between 14 and 50 days after second vaccine dose, SARS-CoV-2 spike-specific antibody and neutralising antibody geometric mean titre (GMT) was higher in South Asian HCWs compared to White HCWs (9616 binding antibody units (BAU)/ml, 95% CI [7178-12,852] vs 5888 BAU/ml [5023-6902], P = 0.008 and 2851 95% CI [1811-4487] vs 1199 [984-1462], P < 0.001 respectively), increments which persisted after adjustment (aGMR 1.26, 95% CI [1.01-1.58], P = 0.04 and aGMR 2.01, 95% CI [1.34-3.01], P = 0.001). SARS-CoV-2 ELISpot responses to S1 and whole spike peptides (S1 + S2 response) were higher in HCWs from South Asian ethnic groups than those from White groups (S1: aIRR 2.33, 95% CI [1.09-4.94], P = 0.03; spike: aIRR, 2.04, 95% CI [1.02-4.08]). Interpretation: This study provides evidence that, in an infection naïve cohort, humoral and cellular immune responses to SARS-CoV-2 vaccination are stronger in South Asian HCWs than White HCWs. These differences are most clearly seen in the early period following vaccination. Further research is required to understand the underlying mechanisms, whether differences persist with further exposure to vaccine or virus, and the potential impact on vaccine effectiveness. Funding: DIRECT and BELIEVE have received funding from UK Research and Innovation (UKRI) through the COVID-19 National Core Studies Immunity (NCSi) programme (MC_PC_20060).

Respiratory virus transmission using a novel viral challenge model: An observational cohort study.

OBJECTIVES: Knowledge of Acute Respiratory virus Infection (ARI) is limited in relation to their substantial global burden. We completed a feasibility study of a novel method to study the natural transmission of respiratory viruses from young children to adults in hospital. METHODS: Between September 2012 and May 2015, we recruited healthy adults (contacts) and paediatric inpatients with ARIs (index) presenting to the University Hospitals Leicester NHS Trust, Leicester, UK. We took nose and throat swabs from all participants prior to controlled, 30 minute interactions between the children with ARIs and adult contacts. Contacts recorded symptoms and provided four nose and throat swabs over ten days post-interaction, which were tested for a panel of respiratory viruses to assess transmission. RESULTS: 111 interactions occurred between children with ARIs and adult contacts. Respiratory viruses were detected in 103 of 111 children (93%), most commonly rhinoviruses (RVs) (67 of 103, 65%). Transmission to an adult contact occurred in 15 (14·6%) of 103 interactions and was inversely associated with the contact being male (adjusted OR 0·12; 95% CI 0·02-0·72). CONCLUSION: Using a novel methodology, we found that natural transmission of ARIs occurred in 15% of an infected child's contacts following a 30 minute interaction, primarily by RVs and when the contact was female. Our model has key advantages in comparison with human challenge studies making it well-suited for further studies of respiratory virus transmission, disease pathogenesis, and clinical and public health interventions to interrupt transmission.

Priorities for child health research across the UK and Ireland.

BACKGROUND: The General and Adolescent Paediatric Research Network in the UK and Ireland (GAPRUKI) was established in 2016. The aims of GAPRUKI are to unite general paediatricians around the UK and Ireland, to develop research ideas and protocols, and facilitate delivery of multicentre research. OBJECTIVES: To undertake a research prioritisation exercise among UK and Ireland general paediatricians. METHODS: This was a four-phase study using a modified Delphi survey. The first phase asked for suggested research priorities. The second phase developed ideas and ranked them in priority. In the third phase, priorities were refined; and the final stage used the Hanlon Prioritisation Process to agree on the highest priorities. RESULTS: In phase one, there were 250 questions submitted by 61 GAPRUKI members (66% of the whole membership). For phase two, 92 priorities were scored by 62 members and the mean Likert scale (1-7) scores ranged from 3.13 to 5.77. In a face-to-face meeting (phases three and four), 17 research questions were identified and ultimately 14 priorities were identified and ranked. The four priorities with the highest ranking focused on these three respiratory conditions: asthma, bronchiolitis and acute wheeze. Other priorities were in the diagnosis or management of constipation, urinary tract infection, fever, gastro-oesophageal reflux and also new models of care for scheduled general paediatric clinics. CONCLUSION: Research priorities for child health in the UK and Ireland have been identified using a robust methodology. The next steps are for studies to be designed and funded to address these priorities.

Neonates With SARS-CoV-2 Infection and Pulmonary Disease Safely Treated With Remdesivir.

We describe 2 expremature infants presenting with SARS-CoV-2-related pulmonary disease in their second and fifth week of life needing support with mechanical ventilation. Both infants' initial presentation was with repeated apneas. These cases highlight that SARS-CoV-2 infection could present with apneas and has the potential to progress to more severe pulmonary disease in this high-risk age group of patients. Both patients were treated with remdesivir (RDV). We provide the data of 2 high-risk neonates successfully treated with RDV without observation of any described side effects. A recognition that these high-risk neonates could deteriorate and early multidisciplinary team discussion is the mainstay to the compassionate access to RDV. Our experience led us to develop a guideline on the use of RDV below 12 years of age, with particular focus on infants and young children.

Group A Streptococcal Infections in Children.

BACKGROUND: Invasive group A streptococcal disease (iGAS) can have varied clinical presentations in children, are responsible for prolonged hospital stays and can cause mortality and long-term morbidity in children. Over the last decade, there has been an increase in the incidence of iGAS infections in the UK and worldwide. This has renewed the focus on early diagnosis, management and prevention of this disease. AIMS AND OBJECTIVES: The aim of this study was to review the varied clinical presentations and management of children with iGAS infections. METHODS: We reviewed the data of children admitted to our tertiary Children's Hospital who had positive isolation of Group A Streptococcus( GAS) from sterile site cultures over the last 8 years. We reviewed their clinical presentations and management including treatment given (antibiotics and duration), outcome and follow up. RESULTS: A total of 57 children had iGAS during the study period. The incidence of iGAS was 6-7 cases per year during the study period, except for 2015 when we had 11 cases. The mean length of stay of children admitted with iGAS was 11 days (range 2- 35 days). 21.1% children were admitted to intensive care during their hospital stay. Fever was the most common presenting symptom. Pneumonia with or without empyema was the most common Diagnosis. Initial antibiotic management was varied with ceftriaxone the most commonly used antibiotic in 30% of the cases. 50% of children had their antimicrobial therapy optimised to IV benzylpenicillin after the confirmed isolation of GAS. 7 Children were re-admitted for further treatment and needed a further course of antibiotics. 4 children (7%) died due to iGAS infection. CONCLUSION: Our study highlighted the varied symptomatology and management practices in children with iGAS and showed that early diagnosis and prompt initiation of appropriate antibiotics for iGAS can help in the resolution of symptoms and good outcomes.

COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.

BACKGROUND: To date, few data on paediatric COVID-19 have been published, and most reports originate from China. This study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across Europe to inform physicians and health-care service planning during the ongoing pandemic. METHODS: This multicentre cohort study involved 82 participating health-care institutions across 25 European countries, using a well established research network-the Paediatric Tuberculosis Network European Trials Group (ptbnet)-that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. We included all individuals aged 18 years or younger with confirmed SARS-CoV-2 infection, detected at any anatomical site by RT-PCR, between April 1 and April 24, 2020, during the initial peak of the European COVID-19 pandemic. We explored factors associated with need for intensive care unit (ICU) admission and initiation of drug treatment for COVID-19 using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with ICU admission. FINDINGS: 582 individuals with PCR-confirmed SARS-CoV-2 infection were included, with a median age of 5·0 years (IQR 0·5-12·0) and a sex ratio of 1·15 males per female. 145 (25%) had pre-existing medical conditions. 363 (62%) individuals were admitted to hospital. 48 (8%) individuals required ICU admission, 25 (4%) mechanical ventilation (median duration 7 days, IQR 2-11, range 1-34), 19 (3%) inotropic support, and one (<1%) extracorporeal membrane oxygenation. Significant risk factors for requiring ICU admission in multivariable analyses were being younger than 1 month (odds ratio 5·06, 95% CI 1·72-14·87; p=0·0035), male sex (2·12, 1·06-4·21; p=0·033), pre-existing medical conditions (3·27, 1·67-6·42; p=0·0015), and presence of lower respiratory tract infection signs or symptoms at presentation (10·46, 5·16-21·23; p<0·0001). The most frequently used drug with antiviral activity was hydroxychloroquine (40 [7%] patients), followed by remdesivir (17 [3%] patients), lopinavir-ritonavir (six [1%] patients), and oseltamivir (three [1%] patients). Immunomodulatory medication used included corticosteroids (22 [4%] patients), intravenous immunoglobulin (seven [1%] patients), tocilizumab (four [1%] patients), anakinra (three [1%] patients), and siltuximab (one [<1%] patient). Four children died (case-fatality rate 0·69%, 95% CI 0·20-1·82); at study end, the remaining 578 were alive and only 25 (4%) were still symptomatic or requiring respiratory support. INTERPRETATION: COVID-19 is generally a mild disease in children, including infants. However, a small proportion develop severe disease requiring ICU admission and prolonged ventilation, although fatal outcome is overall rare. The data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed. FUNDING: ptbnet is supported by Deutsche Gesellschaft für Internationale Zusammenarbeit.

COVID-19 multisystem inflammatory syndrome in three teenagers with confirmed SARS-CoV-2 infection.

Coronavirus disease 2019 (COVID-19) is generally a relatively mild illness in children. An emerging disease entity coined as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) has been reported recently, but is very rare and only affects a very small minority of children. Here we describe the clinical presentations and outcomes of three teenagers with serologically-confirmed SARS-CoV-2 infection admitted to a pediatric intensive care unit for PIMS-TS. Although their initial presentations were very similar, their COVID-19-related disease varied in severity.

COVID-19 in Neonates and Infants: Progression and Recovery.

Between March 10, 2020 and April 17, 2020, of 8/70 (11.4%) SARS-CoV-2 positive infants that presented, 5/8 (63%) developed fever, 4/8 (50%) had lower respiratory tract involvement, 2/8 (25%) had neutropenia and thrombocytosis, and 4/8 infants (50%) were treated for suspected sepsis with broad-spectrum antibiotics. Only 1/8 (13%) required pediatric intensive care. All patients were eventually discharged home well.

A rare case of osteomyelitis of the clavicle in a child due to Group A streptococcal infection.

Acute osteomyelitis of the clavicle is rare in the paediatric age group. We treated a 5-year-old boy who presented initially with fever and left shoulder pain, and subsequently developed swelling in the region of the left clavicle. Group A Streptococcus (GAS) was isolated in blood culture. MRI of the clavicle showed osteomyelitis of the medial clavicle. The child had incision and drainage of his clavicular collection. The child received intravenous benzylpenicillin and oral cephalexin in the initial presentation; he was treated with 2 weeks of intravenous ceftriaxone and 4 weeks of oral penicillin thereafter with the resolution of his symptoms. There are no previous case reports of osteomyelitis of the clavicle in children caused by GAS. This case highlights the importance of identifying the microbial aetiology in these children to ensure early initiation of treatment with appropriate antibiotics.

Comparing the Clinical Severity of Disease Caused by Enteroviruses and Human Parechoviruses in Neonates and Infants.

Comparison of children hospitalized with enterovirus or human parechovirus (HPeV) detected in their cerebrospinal fluid revealed that HPeV infections presented with more persistent fever, irritability and feeding problems, more frequent leukopenia and lymphopenia and higher admission rates to high dependency or intensive care units. Few HPeV cases were followed up, further studies on long-term outcomes are needed.

Cluster of human parechovirus infections as the predominant cause of sepsis in neonates and infants, Leicester, United Kingdom, 8 May to 2 August 2016.

We report an unusually high number of cases (n = 26) of parechovirus infections in the cerebrospinal fluid (CSF) of neonates and infants admitted with sepsis in the United Kingdom during 8 May to 2 August 2016. Although such infections in neonates and infants are well-documented, parechovirus has not been routinely included in many in-house and commercial PCR assays for CSF testing. Clinicians should consider routine parechovirus testing in young children presenting with sepsis.