Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex.

BACKGROUND: Myocarditis is more common after severe acute respiratory syndrome coronavirus 2 infection than after COVID-19 vaccination, but the risks in younger people and after sequential vaccine doses are less certain. METHODS: A self-controlled case series study of people ages 13 years or older vaccinated for COVID-19 in England between December 1, 2020, and December 15, 2021, evaluated the association between vaccination and myocarditis, stratified by age and sex. The incidence rate ratio and excess number of hospital admissions or deaths from myocarditis per million people were estimated for the 1 to 28 days after sequential doses of adenovirus (ChAdOx1) or mRNA-based (BNT162b2, mRNA-1273) vaccines, or after a positive SARS-CoV-2 test. RESULTS: In 42 842 345 people receiving at least 1 dose of vaccine, 21 242 629 received 3 doses, and 5 934 153 had SARS-CoV-2 infection before or after vaccination. Myocarditis occurred in 2861 (0.007%) people, with 617 events 1 to 28 days after vaccination. Risk of myocarditis was increased in the 1 to 28 days after a first dose of ChAdOx1 (incidence rate ratio, 1.33 [95% CI, 1.09-1.62]) and a first, second, and booster dose of BNT162b2 (1.52 [95% CI, 1.24-1.85]; 1.57 [95% CI, 1.28-1.92], and 1.72 [95% CI, 1.33-2.22], respectively) but was lower than the risks after a positive SARS-CoV-2 test before or after vaccination (11.14 [95% CI, 8.64-14.36] and 5.97 [95% CI, 4.54-7.87], respectively). The risk of myocarditis was higher 1 to 28 days after a second dose of mRNA-1273 (11.76 [95% CI, 7.25-19.08]) and persisted after a booster dose (2.64 [95% CI, 1.25-5.58]). Associations were stronger in men younger than 40 years for all vaccines. In men younger than 40 years old, the number of excess myocarditis events per million people was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (97 [95% CI, 91-99] versus 16 [95% CI, 12-18]). In women younger than 40 years, the number of excess events per million was similar after a second dose of mRNA-1273 and a positive test (7 [95% CI, 1-9] versus 8 [95% CI, 6-8]). CONCLUSIONS: Overall, the risk of myocarditis is greater after SARS-CoV-2 infection than after COVID-19 vaccination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly after a second dose of the mRNA-1273 vaccine.

Childhood, teenage and young adult cancer diagnosis during the first wave of the COVID-19 pandemic: a population-based observational cohort study in England.

OBJECTIVE: To investigate childhood, teenage and young adult cancer diagnostic pathways during the first wave of the COVID-19 pandemic in England. DESIGN: Population-based cohort study. SETTING AND PARTICIPANTS: QResearch, a nationally representative primary care database, linked to hospital admission, mortality and cancer registry data, was used to identify childhood, teenage and young adult cancers (0-24 years) diagnosed between 1 January 2017 and 15 August 2020. MAIN OUTCOMES: Main outcomes of interest were: (1) number of incident cancer diagnoses per month, (2) diagnostic, treatment time intervals and (3) cancer-related intensive care admissions. RESULTS: 2607 childhood, teenage and young adult cancers were diagnosed from 1 January 2017 to 15 August 2020; 380 were diagnosed during the pandemic period. Overall, 17% (95% CI -28.0% to -4.0%) reduction in the incidence rate ratio of cancers was observed during the pandemic. Specific decreases were seen for central nervous system tumour (-38% (95% CI -52% to -21%)) and lymphoma (-28% (95% CI -45% to -5%)) diagnoses. Additionally, childhood cancers diagnosed during the pandemic were significantly more likely to have intensive care admissions (adjusted OR 2.2 (95% CI 1.33 to 3.47)). Median time-to-diagnosis did not significantly differ across periods (+4.5 days (95% CI -20.5 to +29.5)), while median time-to-treatment was shorter during the pandemic (-0.7 days (95% CI -1.1 to -0.3)). CONCLUSIONS: Collectively, our findings of a significant reduction in cancer diagnoses and increase in intensive care admissions provide initial insight into the changes that occurred to childhood, teenage and young adult cancer diagnostic pathways during the first wave of the pandemic.

Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection.

Although myocarditis and pericarditis were not observed as adverse events in coronavirus disease 2019 (COVID-19) vaccine trials, there have been numerous reports of suspected cases following vaccination in the general population. We undertook a self-controlled case series study of people aged 16 or older vaccinated for COVID-19 in England between 1 December 2020 and 24 August 2021 to investigate hospital admission or death from myocarditis, pericarditis and cardiac arrhythmias in the 1-28 days following adenovirus (ChAdOx1, n = 20,615,911) or messenger RNA-based (BNT162b2, n = 16,993,389; mRNA-1273, n = 1,006,191) vaccines or a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (n = 3,028,867). We found increased risks of myocarditis associated with the first dose of ChAdOx1 and BNT162b2 vaccines and the first and second doses of the mRNA-1273 vaccine over the 1-28 days postvaccination period, and after a SARS-CoV-2 positive test. We estimated an extra two (95% confidence interval (CI) 0, 3), one (95% CI 0, 2) and six (95% CI 2, 8) myocarditis events per 1 million people vaccinated with ChAdOx1, BNT162b2 and mRNA-1273, respectively, in the 28 days following a first dose and an extra ten (95% CI 7, 11) myocarditis events per 1 million vaccinated in the 28 days after a second dose of mRNA-1273. This compares with an extra 40 (95% CI 38, 41) myocarditis events per 1 million patients in the 28 days following a SARS-CoV-2 positive test. We also observed increased risks of pericarditis and cardiac arrhythmias following a positive SARS-CoV-2 test. Similar associations were not observed with any of the COVID-19 vaccines, apart from an increased risk of arrhythmia following a second dose of mRNA-1273. Subgroup analyses by age showed the increased risk of myocarditis associated with the two mRNA vaccines was present only in those younger than 40.

Ethnic disparities in infectious disease hospitalisations in the first year of life in New Zealand.

AIM: Infectious disease (ID) hospitalisation rates are increasing in New Zealand (NZ), especially in pre-school children, and Maori and Pacific people. We aimed to identify risk factors for ID hospitalisation in infancy within a birth cohort of NZ children, and to identify differences in risk factors between ethnic groups. METHODS: We investigated an established cohort of 6846 NZ children, born in 2009-2010, with linkage to a national data set of hospitalisations. We used multivariable logistic regression to obtain odds ratios (OR) for factors associated with ID hospitalisation in the first year of life, firstly for all children, and then separately for Maori or Pacific children. RESULTS: In the whole cohort, factors associated with ID hospitalisation were Maori (OR: 1.49, 95% CI: 1.17-1.89) or Pacific (2.51; 2.00-3.15) versus European maternal ethnicity, male gender (1.32; 1.13-1.55), low birthweight (1.94, 1.39-2.66), exclusive breastfeeding for <4 months (1.22, 1.04-1.43), maternal experience of health-care racism (1.60, 1.19-2.12), household deprivation (most vs. least deprived quintile of households (1.50, 1.12-2.02)), day-care attendance (1.43, 1.12-1.81) and maternal smoking (1.55, 1.26-1.91). Factors associated with ID hospitalisation for Maori infants were high household deprivation (2.16, 1.06-5.02) and maternal smoking (1.48, 1.02-2.14); and for Pacific infants were delayed immunisation (1.72, 1.23-2.38), maternal experience of health-care racism (2.20, 1.29-3.70) and maternal smoking (1.59, 1.10-2.29). CONCLUSIONS: Maori and Pacific children in NZ experience a high burden of ID hospitalisation. Some risk factors, for example maternal smoking, are shared, while others are ethnic-specific. Interventions aimed at preventing ID hospitalisations should address both shared and ethnic-specific factors.

Can oral corticosteroids reduce the severity or duration of an acute cough, and the associated National Health Service and societal costs, in adults presenting to primary care? Study protocol for a randomised controlled trial.

BACKGROUND: Acute lower respiratory tract infection (LRTI) is one of the most common conditions managed internationally and is costly to health services and patients. Despite good evidence that antibiotics are not effective for improving the symptoms of uncomplicated LRTI, they are widely prescribed, contributing to antimicrobial resistance. Many of the symptoms observed in LRTI are mediated by inflammatory processes also observed in exacerbations of asthma, for which there is strong evidence of corticosteroid effectiveness. The primary aim of the OSAC (Oral Steroids for Acute Cough) Trial is to determine whether oral prednisolone (40 mg daily for 5 days) can reduce the duration of moderately bad (or worse) cough and the severity of all its associated symptoms on days 2 to 4 post-randomisation (day 1 is trial entry) by at least 20% in adults ≥18 years with acute LRTI presenting to primary care. METHODS/DESIGN: OSAC is a two-arm, multi-centre, placebo-controlled, randomised superiority trial. The target sample size is 436 patients, which allows for a 20% dropout rate. Patients will be recruited from primary care sites (General Practitioner surgeries) across England and followed up until symptom resolution. The two primary clinical outcomes are the duration of moderately bad (or worse) cough, and the severity of all its associated symptoms on days 2 to 4 post-randomisation. Secondary outcomes include: antibiotic consumption; symptom burden; adverse events; participant satisfaction with treatment and intention to consult for future similar illnesses. A parallel economic evaluation will investigate the cost-effectiveness of the intervention. DISCUSSION: Results from the OSAC trial will increase knowledge regarding the clinical and cost-effectiveness of corticosteroids for LRTI, and will establish the potential of a new treatment option that could substantially improve patient health. We have chosen a relatively high 'efficacy dose' as this will enable us to decide on the potential for further research into lower dose oral and/or inhaled corticosteroids. This trial will also contribute to a growing body of research investigating the natural course of this very common illness, as well as the effects of steroids on the undesirable inflammatory symptoms associated with infection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN57309858 (31 January 2013).

Montelukast for postinfectious cough in adults: a double-blind randomised placebo-controlled trial.

BACKGROUND: Postinfectious cough is common in primary care, but has no proven effective treatments. Cysteinyl leukotrienes are involved in the pathogenesis of postinfectious cough and whooping cough (pertussis). We investigated the effectiveness of montelukast, a cysteinyl leukotriene receptor antagonist, in the treatment of postinfectious cough. METHODS: In this randomised, placebo-controlled trial, non-smoking adults aged 16-49 years with postinfectious cough of 2-8 weeks' duration were recruited from 25 general practices in England. Patients were tested for pertussis (oral fluid anti-pertussis toxin IgG) and randomly assigned (1:1) to montelukast 10 mg daily or image-matched placebo for 2 weeks. Patients chose whether to continue study drug for another 2 weeks. The randomisation sequence was computer-generated and stratified by general practice. Patients, health-care professionals, and researchers were masked to treatment allocation. Effectiveness was assessed with the Leicester Cough Questionnaire to measure changes in cough-specific quality of life; the primary outcomes were changes in total score between baseline and two follow-up stages (2 weeks and 4 weeks). The primary analysis was by intention to treat with imputation by last observation carried forward. Recruitment closed on Sept 21, 2012, and follow-up has been completed. This trial is registered with EudraCT (2010-019647-19), UKCRN Portfolio (ID 8360), and ClinicalTrials.gov (NCT01279668). FINDINGS: From April 13, 2011, to Sept 21, 2012, we randomly assigned 276 patients to montelukast (n=137) or placebo (n=139). 70 (25%) patients had laboratory-confirmed pertussis. Improvements in cough-specific quality of life occurred in both groups after 2 weeks (montelukast: mean 2·7, 95% CI 2·2-3·3; placebo: 3·6, 2·9-4·3), but the difference between groups did not meet the minimum clinically important difference of 1·3 (mean difference -0·9, -1·7 to -0·04, p=0·04). This difference was not statistically significant in any sensitivity analyses. After 2 weeks, 192 of 259 participants from whom data were available elected to continue study drug (99 [77%] of 129 participants on montelukast; 93 [72%] of 130 on placebo). After 4 weeks, there were no significant between-group differences in cough-specific quality of life improvement (montelukast: 5·2, 4·5-5·9; placebo: 5·9, 5·1-6·7; mean difference -0·5, -1·5 to 0·6, p=0·38) or adverse event rates (21 (15%) of 137 patients on montelukast reported one or more adverse events; 31 (22%) of 139 on placebo; p=0·14). The most common adverse events reported were increased mucus production (montelukast, n=6; placebo, n=2), gastrointestinal disturbance (montelukast, n=3; placebo, n=5), and headache (montelukast, n=2; placebo, n=6). One serious adverse event was reported (placebo, n=1), which was unrelated to study drug (shortness of breath and throat tightness after severe coughing bouts). INTERPRETATION: Montelukast is not an effective treatment for postinfectious cough. However, the burden of postinfectious cough in primary care is high, making it an ideal setting for future antitussive treatment trials. FUNDING: National Institute for Health Research School for Primary Care Research, UK.

Child deaths: confidential enquiry into the role and quality of UK primary care.

BACKGROUND: In 2006 the Confidential Enquiry into Maternal and Perinatal Deaths was extended to pilot a collection of child deaths. This helped optimise data collection for local safeguarding children's boards, which, since April 2008, have a statutory responsibility to review all child deaths. Reviewing primary care records may highlight areas in which systems, skills, and care could be improved. AIM: To review the role and quality of primary care in child deaths. DESIGN OF STUDY: Confidential enquiry into child deaths. SETTING: Five regions of the UK: North-East, South-West and West Midlands, Wales, and Northern Ireland. METHOD: The confidential enquiry collected core data for all child deaths (age range 28 days to 17 years) and an age-stratified sample was assessed by multidisciplinary panels for avoidable factors. An independent detailed review was conducted of the primary care records on all children in the North-East region and all children who were reviewed by panel in the other four regions. RESULTS: Primary care records were reviewed for 168 child deaths. There were 25 (15%) deaths from acute infection, 22 (13%) from cancer, and 11 (7%) from asthma or epilepsy. Fifty-nine (35%) deaths were sudden: sudden unexplained death in infancy, suicides, and assaults. Of 149 with immunisation records, only 88 (59%) had been fully vaccinated on time. One or more primary care professionals were involved in the management of 90 (54%) children. Avoidable primary care factors were identified in 18 (20%) of these deaths. Avoidable primary care factors included failure in the recognition and management of serious infection, failure to vaccinate, and inadequate management of asthma and epilepsy. CONCLUSION: Decisions made about diagnosis and management in primary care may affect the cause, time, and circumstances of a child's death. Maintaining skills in assessing the acutely ill child remains an essential part of good clinical practice.

Effect of antibiotic prescribing on antibiotic resistance in individual children in primary care: prospective cohort study.

OBJECTIVE: To assess the effect of community prescribing of an antibiotic for acute respiratory infection on the prevalence of antibiotic resistant bacteria in an individual child. STUDY DESIGN: Observational cohort study with follow-up at two and 12 weeks. SETTING: General practices in Oxfordshire. PARTICIPANTS: 119 children with acute respiratory tract infection, of whom 71 received a beta lactam antibiotic. MAIN OUTCOME MEASURES: Antibiotic resistance was assessed by the geometric mean minimum inhibitory concentration (MIC) for ampicillin and presence of the ICEHin1056 resistance element in up to four isolates of Haemophilus species recovered from throat swabs at recruitment, two weeks, and 12 weeks. RESULTS: Prescribing amoxicillin to a child in general practice more than triples the mean minimum inhibitory concentration for ampicillin (9.2 microg/ml v 2.7 microg/ml, P=0.005) and doubles the risk of isolation of Haemophilus isolates possessing homologues of ICEHin1056 (67% v 36%; relative risk 1.9, 95% confidence interval 1.2 to 2.9) two weeks later. Although this increase is transient (by 12 weeks ampicillin resistance had fallen close to baseline), it is in the context of recovery of the element from 35% of children with Haemophilus isolates at recruitment and from 83% (76% to 89%) at some point in the study. CONCLUSION: The short term effect of amoxicillin prescribed in primary care is transitory in the individual child but sufficient to sustain a high level of antibiotic resistance in the population.