ABSTRACT
BackgroundMyocarditis is a rare but potentially serious complication of COVID-19 vaccination. Cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) imaging can identify cardiac scar, which may improve diagnostic accuracy and prognostication. ObjectivesTo define the incidence of long-term LGE post COVID-19 vaccine-associated myocarditis (C-VAM) and to establish the additive role of CMR in the diagnostic work-up. MethodsPatients with Brighton Collaboration Criteria Level 1 (definite) or Level 2 (probable) C-VAM were prospectively recruited from the Surveillance of Adverse Events Following Vaccination In the Community (SAEFVIC) database to undergo CMR at least 12 months after diagnosis. As there were limited patients with access to baseline CMR, prior CMR results were not included in the initial case definition. The presence of LGE on follow-up CMR was then integrated into the diagnostic algorithm and the reclassification rate (definite vs. probable) was calculated. ResultsSixty-seven patients with C-VAM (mean age 30 {+/-} 13 years, 72% male) underwent CMR evaluation. Median time from vaccination to CMR was 548 (range 398-603) days. Twenty patients (30%) had persistent LGE, most frequently found in the basal inferolateral segment (n = 11). At diagnosis, nine patients (13%) were classified as definite and 58 (87%) as probable myocarditis. With integration of CMR LGE data, 16 patients (28%) were reclassified from probable to definite myocarditis. ConclusionPersistent LGE on CMR occurs in one third of patients with C-VAM. Without CMR at diagnosis, almost one third of patients are misclassified as probable rather than definite myocarditis.
Subject(s)
COVID-19 , MyocarditisABSTRACT
Background: Following reduction of public health and social measures concurrent with SARS-CoV-2 Omicron emergence in late 2021 in Australia, COVID-19 case notification rates rose rapidly. As rates of direct viral testing and reporting dropped, true infection rates were most likely to be underestimated. Objective: To better understand infection rates and immunity in this population, we aimed to estimate SARS-CoV-2 seroprevalence in Australians aged 0-19 years. Methods: We conducted a national cross sectional serosurvey from June 1, 2022, to August 31, 2022, in children aged 0-19 years undergoing an anesthetic procedure at eight tertiary pediatric hospitals. Participant questionnaires were administered, and blood samples tested using the Roche Elecsys Anti-SARS-CoV-2 total spike and nucleocapsid antibody assays. S and N seroprevalence adjusted for geographic and socioeconomic imbalances in the participant sample compared to the Australian population was estimated using multilevel regression and poststratification within a Bayesian framework. Results: Blood was collected from 2,046 participants (median age: 6.6 years). Adjusted seroprevalence of spike-antibody was 92.1 % (95% credible interval (CrI) 91.0-93.3%) and nucleocapsid-antibody was 67.0% (95% CrI 64.6-69.3). In unvaccinated children spike and nucleocapsid antibody seroprevalences were 84.2% (95% CrI 81.9-86.5) and 67.1% (95%CrI 64.0-69.8), respectively. Seroprevalence increased with age but was similar across geographic distribution and socioeconomic quintiles. Conclusion: Most Australian children and adolescents aged 0-19 years, across all jurisdictions were infected with SARS-CoV-2 by August 2022, suggesting rapid and uniform spread across the population in a very short time period. High seropositivity in unvaccinated children informed COVID-19 vaccine recommendations in Australia. Funding: Australian Government Department of Health and Aged Care.
Subject(s)
COVID-19ABSTRACT
Reducing procedural discomfort for children requiring respiratory testing for SARS-CoV-2 is important in supporting testing strategies for case identification. Alternative sampling methods to nose and throat swabs, which can be self-collected, may reduce laboratory-based testing requirements and provide rapid results for clearance to attend school or hospital settings. The aim of this study was to compare preference and diagnostic sensitivity of a novel anterior nasal swab (ANS), and saliva, with a standard combined nose and throat (CTN) swab. The three samples were self-collected by children aged 5-18 years who had COVID-19 or were a household close contact. Samples were analysed by reverse transcription polymerase chain reaction (RT-PCR) on the Allplex SARS-CoV-2 Assay. Most children and parents preferred the ANS and saliva swab over the CTN swab for future testing. The ANS was highly sensitive (sensitivity 1.000 (95% Confidence Interval (CI) 0.920, 1.000)) for SARS-CoV-2 detection, compared to saliva (sensitivity 0.886, 95% CI 0.754, 0.962). We conclude the novel ANS is a highly sensitive and more comfortable method for SARS-CoV-2 detection when compared to CTN swab.
Subject(s)
COVID-19ABSTRACT
There is limited understanding of antibody responses in children across different SARS-CoV-2 variants. As part of an ongoing household cohort study, we assessed the antibody response among unvaccinated children infected with Wuhan, Delta or Omicron variants, as well as vaccinated children with breakthrough Omicron infection, using a SARS-CoV-2 S1-specific IgG assay and surrogate virus neutralisation test (sVNT). Most children infected with Delta (100%, 35/35) or Omicron (81.3%, 13/16) variants seroconverted by one month following infection. In contrast, 37.5% (21/56) children infected with Wuhan seroconverted, as previously reported. However, Omicron-infected children (GMC 46.4 BAU/ml; sVNT % inhibition: 16.3%) mounted a significantly lower antibody response than Delta (435.5 BAU/mL, sVNT=76.9%) or Wuhan (359.0 BAU/mL, sVNT=74.0%). Vaccinated children with breakthrough Omicron infection mounted the highest antibody response (2856 BAU/mL, sVNT=96.5%). Our findings suggest that despite a high seroconversion rate, Omicron infection in children results in lower antibody levels and function compared with Wuhan or Delta infection or with vaccinated children with breakthrough Omicron infection. Our data have important implications for public health measures and vaccination strategies to protect children.
Subject(s)
Hepatitis DABSTRACT
Background: Household studies are crucial for understanding the transmission of SARS-CoV-2 infection, which may be underestimated from PCR testing of respiratory samples alone. We aim to combine assessment of household mitigation measures; nasopharyngeal, saliva and stool PCR testing; along with mucosal and systemic SARS-CoV-2 specific antibodies, to comprehensively characterise SARS-CoV-2 infection and transmission in households. Methods: Between March and September 2020, we obtained samples from 92 participants in 26 households in Melbourne, Australia, in a 4-week period following onset of infection with ancestral SARS-CoV-2 variants. Results: The secondary attack rate was 36% (24/66) when using nasopharyngeal swab (NPS) PCR positivity alone. However, when respiratory and non-respiratory samples were combined with antibody responses in blood and saliva, the secondary attack rate was 76% (50/66). SARS-CoV-2 viral load of the index case and household isolation measures were key factors that determine secondary transmission. In 27% (7/26) of households, all family members tested positive by NPS for SARS-CoV-2 and were characterised by lower respiratory Ct-values than low transmission families (Median 22.62 vs 32.91; IQR 17.06 to 28.67 vs 30.37 to 34.24). High transmission families were associated with enhanced plasma antibody responses to multiple SARS-CoV-2 antigens and the presence of neutralising antibodies. Three distinguishing saliva SARS-CoV-2 antibody features were identified according to age (IgA1 to Spike 1, IgA1 to nucleocapsid protein (NP), suggesting that adults and children generate distinct mucosal antibody responses during the acute phase of infection. Conclusion: Utilising respiratory and non-respiratory PCR testing, along with measurement of SARS-CoV-2 specific local and systemic antibodies, provides a more accurate assessment of infection within households and highlights some of the immunological differences in response between children and adults.
Subject(s)
Mouth Diseases , Nasopharyngitis , COVID-19ABSTRACT
Objective(s): To describe the severity and clinical spectrum of SARS-CoV-2 infection in Australian children during the 2021 Delta outbreak. Design, Setting & Participants: A prospective cohort study of children <16 years with a positive SARS-CoV-2 nucleic acid test cared for by the Sydney Children's Hospital Network (SCHN) virtual and inpatient medical teams between 1 June-31 October 2021. Main outcome measures: Demographic and clinical data from all admitted patients and a random sample of outpatients managed under the SCHN virtual care team were analysed to identify risk factors for admission to hospital. Results: There were 17,474 SARS-CoV-2 infections in children <16 years in NSW during the study period, of whom 11,985 (68.6%) received care coordinated by SCHN. Twenty one percent of children infected with SARS-CoV-2 were asymptomatic. For every 100 SARS-CoV-2 infections in children <16 years, 1.26 (95% CI 1.06 to 1.46) required hospital admission for medical care; while 2.46 (95% CI 2.18 to 2.73) required admission for social reasons only. Risk factors for hospitalisation for medical care included age <6 months, a history of prematurity, age 12 to <16 years, and a history of medical comorbidities (aOR 7.23 [95% CI 2.92 to 19.4]). Of 17,474 infections, 15 children (median age 12.8years) required ICU admission; and 294 children required hospital admission due to social or welfare reasons. Conclusion: The majority of children with SARS-CoV-2 infection (Delta variant) had asymptomatic or mild disease. Hospitalisation was uncommon and occurred most frequently in young infants and adolescents with comorbidities. More children were hospitalised for social reasons than for medical care.
Subject(s)
COVID-19 , Severe Acute Respiratory SyndromeABSTRACT
Importance The immune response in children with SARS-CoV-2 infection is not well understood. Objective To compare seroconversion in children and adults with non-hospitalized (mild) SARS-CoV-2 infection and to understand the factors that influence this. Design Participants were part of a household cohort study of SARS-CoV-2 infection. Weekly nasopharyngeal/throat swabs and blood samples were collected during the acute and convalescent period following PCR diagnosis for analysis. Setting Participants were recruited at the Royal Children’s Hospital, Melbourne, Australia between May and October 2020. Participants Those who had a SARS-CoV-2 PCR-positive nasal/throat swab. Main outcomes and measures SARS-CoV-2 antibody and cellular responses in children and adults. Seroconversion was defined by seropositivity in all three serological assays. Results Among 108 SARS-CoV-2 PCR-positive participants, 57 were children (median age: 4, IQR 2-10) and 51 were adults (median age: 37, IQR 34-45). Using three established serological assays, a lower proportion of children seroconverted compared with adults [20/54 (37.0%) vs 32/42 (76.2%); (p<0.001)]. This was not related to viral load, which was similar in children and adults [mean Ct 28.58 (SD: 6.83) vs 24.14 (SD: 8.47)]. Age and sex also did not influence seroconversion or the magnitude of antibody response within children or adults. Notably, in adults (but not children) symptomatic adults had three-fold higher antibody levels than asymptomatic adults (median 227.5 IU/mL, IQR 133.7-521.6 vs median 75.3 IU/mL, IQR 36.9-113.6). Evidence of cellular immunity was observed in adults who seroconverted but not in children who seroconverted. Conclusion and Relevance In this non-hospitalized cohort with mild COVID-19, children were less likely to seroconvert than adults despite similar viral loads. This has implications for future protection following COVID-19 infection in children and for interpretation of serosurveys that involve children. Further research to understand why children are less likely to seroconvert and develop symptoms following SARS-CoV-2 infection, and comparison with vaccine responses may be of clinical and scientific importance. Key points Question What proportion of children with non-hospitalized (mild) SARS-CoV-2 infection seroconvert compared to adults? Findings In this cohort study conducted in 2020, we found the proportion of children who seroconverted to SARS-CoV-2 was half that in adults despite similar viral load. Meaning Serology is a less reliable marker of prior SARS-CoV-2 infection in children. SARS-CoV-2-infected children who do not seroconvert may be susceptible to reinfection. Our findings support strategies to protect children against COVID-19 including vaccination.
Subject(s)
COVID-19ABSTRACT
Human respiratory syncytial virus (RSV) is an important cause of acute respiratory infection (ARI) with the most severe disease in the young and elderly. Non-pharmaceutical interventions (NPIs) and travel restrictions for controlling COVID-19 have impacted the circulation of most respiratory viruses including RSV globally, particularly in Australia, where during 2020 the normal winter epidemics were notably absent. However, in late 2020, unprecedented widespread RSV outbreaks occurred, beginning in spring, and extending into summer across two widely separated states of Australia, Western Australia (WA) and New South Wales (NSW) including the Australian Capital Territory (ACT). Genome sequencing revealed a significant reduction in RSV genetic diversity following COVID-19 emergence except for two genetically distinct RSV-A clades. These clades circulated cryptically, likely localized for several months prior to an epidemic surge in cases upon relaxation of COVID-19 control measures. The NSW/ACT clade subsequently spread to the neighbouring state of Victoria (VIC) and caused extensive outbreaks and hospitalisations in early 2021. These findings highlight the need for continued surveillance and sequencing of RSV and other respiratory viruses during and after the COVID-19 pandemic as mitigation measures introduced may result in unusual seasonality, along with larger or more severe outbreaks in the future.
Subject(s)
COVID-19 , Respiratory Syncytial Virus Infections , Respiratory Tract InfectionsABSTRACT
Encephalitis is most often caused by a variety of infectious agents, the identity of which is commonly determined through diagnostic tests utilising cerebrospinal fluid (CSF). Immune-mediated disorders are also a differential in encephalitis cases. We investigated the clinical characteristics and potential aetiological agents of unexplained encephalitis through metagenomic next-generation sequencing of residual clinical samples of multiple tissue types and independent clinical review. A total of 43 specimens, from both sterile and non-sterile sites, were collected from 18 encephalitis cases with no cause identified by the Australian Childhood Encephalitis study. Samples were subjected to total RNA sequencing to determine the presence and abundance of potential pathogens, to reveal mixed infections, pathogen genotypes, and epidemiological origins, and to describe the possible aetiologies of unexplained encephalitis. From this, we identified five RNA and two DNA viruses associated with human infection from both non-sterile (nasopharyngeal aspirates, nose/throat swabs, urine, stool rectal swab) and sterile (cerebrospinal fluid, blood) sites. These comprised two human rhinoviruses, two human seasonal coronaviruses, two polyomaviruses and one picobirnavirus. With the exception of picobirnavirus all have been previously associated with respiratory disease. Human rhinovirus and seasonal coronaviruses may be responsible for five of the encephalitis cases reported here. Immune-mediated encephalitis was considered clinically likely in six cases and RNA sequencing did not identify a possible pathogen in these cases. The aetiology remained unknown in nine cases. Our study emphasises the importance of respiratory viruses in the aetiology of unexplained child encephalitis and suggests that the routine inclusion of non-CNS sampling in encephalitis clinical guidelines/protocols could improve the diagnostic yield. Author Summary Encephalitis is caused by both infectious agents and auto-immune disorders. However, the aetiological agents, including viruses, remain unknown in around half the cases of encephalitis in many cohorts. Importantly, diagnostic tests are usually based on the analysis of cerebrospinal fluid which may limit their utility. We used a combination of meta-transcriptomic sequencing and independent clinical review to identify the potential causative pathogens in cases of unexplained childhood encephalitis. Accordingly, we identified seven viruses associated with both sterile and non-sterile sampling sites. Human rhinovirus and seasonal coronaviruses were considered as most likely responsible for five of the 18 encephalitis cases studied, while immune-mediated encephalitis was considered the cause in six cases, and we were unable to determine the aetiology in nine cases. Overall, we demonstrate the role of respiratory viruses as a cause of unexplained encephalitis and that sampling sites other than cerebrospinal fluid is of diagnostic value.
Subject(s)
Encephalitis , Respiratory Tract InfectionsABSTRACT
Background: There are limited data in paediatric populations evaluating whether chronic cardiorespiratory conditions are associated with increased risk of COVID-19. We aimed to compare the rates of chronic cardiac and respiratory disease in children testing positive (SARS-CoV-2[+]) compared to those testing negative (SARS-CoV-2[-]) at our institution. Method Prospective cohort with nested case-control study of all children tested by PCR for SARS-CoV-2 by nasopharyngeal/oropharyngeal sampling between March and October 2020. Children were identified prospectively via laboratory notification with age and sex-matching of SARS-CoV-2[+] to SARS-CoV-2[-] (1:2). Clinical data were extracted from the electronic medical record. Results In total, 179 SARS-CoV-2[+] children (44% female, median age 3.5 yrs, range 0.1 to 19.0 yrs) were matched to 391 SARS-CoV-2[-] children (42% female, median age 3.7 yrs, range 0.1 to 18.3 yrs). The commonest co-morbidities showed similar frequencies in the SARS-CoV-2[+] and [-] groups: asthma (n = 9, 5% vs n = 17, 4.4%, p = 0.71), congenital heart disease (n = 6, 3.4% vs n = 7, 1.8%, p = 0.25) and obstructive sleep apnoea (n = 4, 2.2% vs n = 10, 2.3%, p = 0.82). In the SARS-CoV-2 group, the prevalence of symptomatic disease was similar amongst children with and without cardiorespiratory comorbidities (n = 12, 75% vs n = 103, 57%, p = 0.35) who tested positive. A high proportion of children hospitalised with SARS-CoV-2 infection had cardiac comorbidities (23.8%). Conclusions In this single site dataset, rates of pre-existing cardiorespiratory disease were similar in SARS-CoV-2[+] and SARS-CoV-2[-] children. High rates of comorbid cardiac disease were observed amongst hospitalised children with COVID-19, warranting further research to inform public health measures and vaccine prioritisation.
Subject(s)
COVID-19 , Heart DiseasesABSTRACT
Children have lower hospitalisation and mortality rates for coronavirus disease-2019 (COVID-19) than adults; however, younger children (<4 years of age)1 may develop more severe disease than older children. To date, the immune correlates of severe COVID-19 in young children have been poorly characterized. We report the kinetics of immune responses in relation to clinical and virological features in an infant with acute severe COVID-19. Systemic cellular and cytokine profiling showed initial increase in neutrophils and monocytes with depletion of lymphoid cell populations (particularly CD8+ T and NK cells) and elevated inflammatory cytokines. Expansion of memory CD4+T (but not CD8+T) cells occurred over time, with predominant Th2 bias. Marked activation of T cell populations observed during the acute infection gradually resolved as the child recovered. Significant in vitro activation of T-cell populations and robust cytokine production, in response to inactivated SARS-CoV-2 stimulation, was observed 3 months after infection indicating durable, long-lived cellular immune memory.
Subject(s)
COVID-19ABSTRACT
Compared to adults, children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have mild or asymptomatic infection, but the underlying immunological differences remain unclear. We describe clinical features, virology, longitudinal cellular and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who were repeatedly SARS-CoV-2 PCR negative. Cellular immune profiles and cytokine responses of all children were similar to their parents at all timepoints. All family members had salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA, that coincided with symptom resolution in 3 of 4 symptomatic members. Plasma from both parents and one child had IgG antibody detected against the S1 protein and virus neutralising activity ranging from just detectable to robust titers. Using a systems serology approach, we show that all family members demonstrated higher levels of SARS-CoV-2-specific antibody features than healthy controls. These data indicate that children can mount an immune response to SARS-CoV-2 without virological evidence of infection. This raises the possibility that despite chronic exposure, immunity in children prevents establishment of SARS-CoV-2 infection. Relying on routine virological and serological testing may therefore not identify exposed children, with implications for epidemiological and clinical studies across the life-span.