Age-specific SARS-CoV-2 transmission differed from human rhinovirus in households during the early COVID-19 pandemic.

OBJECTIVES: Children are generally considered main drivers of transmission for respiratory viruses, but the emergence of SARS-CoV-2 challenged this paradigm. Human rhinovirus (RV) continued to co-circulate throughout the pandemic, allowing for direct comparison of age-specific infectivity and susceptibility within households between these viruses during a time of low SARS-CoV-2 population immunity. METHODS: Households with children were prospectively monitored for ≥23 weeks between August 2020 and July 2021. Upon onset of respiratory symptoms in a household, an outbreak study was initiated, including questionnaires and repeated nasal self-sampling in all household members. Swabs were tested by PCR. Age-stratified within-household secondary attack rates (SARs) were compared between SARS-CoV-2 and RV. RESULTS: 307 households participated including 582 children and 627 adults. Overall SAR was lower for SARS-CoV-2 than for RV (aOR 0.55) and age-distributions differed between both viruses (p<0.001). Following household exposure, children were significantly less likely to become infected with SARS-CoV-2 compared to RV (aOR 0.16), whereas this was opposite in adults (aOR 1.71). CONCLUSION: In households, age-specific susceptibility to SARS-CoV-2 and RV differs and drives differences in household transmission between these pathogens. This highlights the importance of characterizing age-specific transmission risks, particularly for emerging infections, to guide appropriate infection control interventions.

Diagnostic value of maternal, cord blood and neonatal biomarkers for early-onset sepsis: a systematic review and meta-analysis.

BACKGROUND: An accurate diagnosis of early-onset sepsis (EOS) is challenging because of subtle symptoms and the lack of a good diagnostic tool, resulting in considerable antibiotic overtreatment. A biomarker, discriminating between infected and non-infected newborns at an early stage of the disease, could improve EOS prediction. Numerous biomarkers have been tested, but have never been compared directly. OBJECTIVES: We aimed to provide a comprehensive overview of early biomarkers and their diagnostic value in maternal samples, umbilical cord blood, and neonatal serum. DATA SOURCES: PubMed-Medline, EMBASE, The Cochrane Library, and Web of Science were searched up to 1 March 2023, without restrictions on publication date, population, or language. STUDY ELIGIBILITY CRITERIA: Articles describing the diagnostic value of at least one biomarker in the detection of EOS in neonates, independent of gestational age, were included. ASSESSMENT OF RISK OF BIAS: The QUADAS-2 tool was used to assess study quality. METHODS OF DATA SYNTHESIS: Three independent researchers assessed the articles using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Meta-analysis was performed with all manuscripts describing diagnostic accuracy using a random-effects model. RESULTS: Of 2296 identified articles, 171 reports were included in the systematic review and 69 in the meta-analysis. Literature showed mixed and inconsistent evidence for most biomarkers and sample types, because of a lack of a uniform EOS case definition, small sample sizes, and large heterogeneity between studies. Interesting markers were procalcitonin (pooled sensitivity 79%, 95% CI 71-84%; specificity 91%, 95% CI 83-96%, n = 11) and interleukin (IL)-6 (pooled sensitivity 83%, 95% CI 71-90%; specificity 87%, 95% CI 78-93%, n = 8) in umbilical cord blood and presepsin (pooled sensitivity 82%, 95% CI 62-93%; specificity 86%, 95% CI 73-93%, n = 3) and serum amyloid A (pooled sensitivity 92%, 95% CI 75-98%; specificity 96%, 95% CI 78-99%, n = 4) in neonatal serum. Studies on the combination of biomarkers were scarce. CONCLUSIONS: A biomarker stand-alone test is currently not reliable for direct antibiotic stewardship in newborns, although several biomarkers show promising initial results. Further research into biomarker combinations could lead to an improved EOS diagnosis, reduce antibiotic overtreatment, and prevent associated health-related problems.

Estimation of introduction and transmission rates of SARS-CoV-2 in a prospective household study.

Household studies provide an efficient means to study transmission of infectious diseases, enabling estimation of susceptibility and infectivity by person-type. A main inclusion criterion in such studies is usually the presence of an infected person. This precludes estimation of the hazards of pathogen introduction into the household. Here we estimate age- and time-dependent household introduction hazards together with within household transmission rates using data from a prospective household-based study in the Netherlands. A total of 307 households containing 1,209 persons were included from August 2020 until March 2021. Follow-up of households took place between August 2020 and August 2021 with maximal follow-up per household mostly limited to 161 days. Almost 1 out of 5 households (59/307) had evidence of an introduction of SARS-CoV-2. We estimate introduction hazards and within-household transmission rates in our study population with penalized splines and stochastic epidemic models, respectively. The estimated hazard of introduction of SARS-CoV-2 in the households was lower for children (0-12 years) than for adults (relative hazard: 0.62; 95%CrI: 0.34-1.0). Estimated introduction hazards peaked in mid October 2020, mid December 2020, and mid April 2021, preceding peaks in hospital admissions by 1-2 weeks. Best fitting transmission models included increased infectivity of children relative to adults and adolescents, such that the estimated child-to-child transmission probability (0.62; 95%CrI: 0.40-0.81) was considerably higher than the adult-to-adult transmission probability (0.12; 95%CrI: 0.057-0.19). Scenario analyses indicate that vaccination of adults can strongly reduce household infection attack rates and that adding adolescent vaccination offers limited added benefit.

Nasal discharge: A unique enhanced alternative for the detection of respiratory pathogens in adults.

Upper respiratory tract infections are a significant cause of social- and disease burden worldwide. Currently, invasive and uncomfortable molecular detection methods are used for respiratory pathogen detection. We aimed to assess the ability and bearability of a rhinorrhea swab (RS) to detect respiratory pathogens in comparison to the combined nasopharyngeal and oropharyngeal swab (NP/OP). This study was performed at a Public Health Service severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) testing facility between November and December 2022 in the Netherlands. Adults aged 16 years and older, being subjected to a standard of care NP/OP swab with nasal discharge, were included and received an additional RS. Respiratory pathogen detection was evaluated using SARS-CoV-2 polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification (MLPA) PCR. Bearability was evaluated using visual analog scale (VAS) scores and a questionnaire. A total of 100 adults with a mean age ± SD of 46 ± 16 years were included. The NP/OP swab detected 104 pathogens, the RS 83 pathogens (p < 0.001), and in total 108 respiratory pathogens were identified in 89 adults (89%). The ability to detect respiratory pathogens compared between the RS and the combined NP/OP swab revealed a sensitivity of 82% (95% CI 73%-89%) and specificity of 100% (95% CI 72%-100%). RS were significantly more bearable than the combined NP/OP swab (p value < 0.001). Therefore, nasal discharge found in adults can be used as an adequate reliable medium for respiratory pathogen detection using SARS-CoV-2 PCR and MLPA PCR.

Long term sequelae after SARS-CoV-2 infection in children: a household study.

BACKGROUND: In children persistent symptoms after SARS-CoV-2 infection have been reported, however, duration and characteristics of symptoms in previously healthy children remain unclear. Therefore this study aimed to evaluate persisting symptoms in children at 6 and 12 months after a SARS-CoV-2 infection. METHODS: In this prospective cohort study households with a confirmed SARS-CoV-2 positive outbreak were matched 1:1 to household controls from SARS-CoV-2 negative outbreaks. These households completed questionnaires at 6 and 12 months on the presence and severity of SARS-CoV-2 related symptoms, general well-being/functioning, cognition, persisting symptoms and quality of life. FINDINGS: None of the children who had a SARS-CoV-2 infection during the study reported persistent symptoms at 6 and 12 months after infection, whereas almost 8% of the children with a negative RT-PCR test during the study reported symptoms such as coughing and mild fever, however, no significant differences were found. In addition, for all other outcomes, no differences were observed between the two groups. TAKE HOME MESSAGE: Post-acute sequelae of mild SARS-CoV-2 infections appears to be uncommon in previously healthy children.

Estimation of introduction and transmission rates of SARS-CoV-2 in a prospective household study.

Household studies provide an efficient means to study transmission of infectious diseases, enabling estimation of individual susceptibility and infectivity. A main inclusion criterion in such studies is often the presence of an infected person. This precludes estimation of the hazards of pathogen introduction into the household. Here we use data from a prospective household-based study to estimate SARS-CoV-2 age- and time-dependent household introduction hazards together with within household transmission rates in the Netherlands from August 2020 to August 2021. Introduction hazards and within-household transmission rates are estimated with penalized splines and stochastic epidemic models, respectively. The estimated hazard of introduction of SARS-CoV-2 in the households was lower for children (0-12 years) than for adults (relative hazard: 0.62; 95%CrI: 0.34-1.0). Estimated introduction hazards peaked in mid October 2020, mid December 2020, and mid April 2021, preceding peaks in hospital admissions by 1-2 weeks. The best fitting transmission models include increased infectivity of children relative to adults and adolescents, such that the estimated child-to-child transmission probability (0.62; 95%CrI: 0.40-0.81) was considerably higher than the adult-to-adult transmission probability (0.12; 95%CrI: 0.057-0.19). Scenario analyses show that vaccination of adults could have strongly reduced infection attack rates in households and that adding adolescent vaccination would have offered limited added benefit.

High detection rate of viral pathogens in nasal discharge in children aged 0 till 5 years.

Respiratory tract infections (RTI) in children remain a cause of disease burden worldwide. Nasopharyngeal (NP) & oropharyngeal (OP) swabs are used for respiratory pathogen detection, but hold disadvantages particularly for children, highlighting the importance and preference for a child friendly detection method. We aimed to evaluate the performance and tolerability of a rhinorrhea swab (RS) in detecting viral pathogens when compared to a combined OP(/NP) or mid-turbinate (MT) nasal swab. This study was conducted between September 2021 and July 2022 in the Netherlands. Children aged 0-5 years, with an upper RTI and nasal discharge, were included and received a combined swab and a RS. Multiplex polymerase chain reaction (PCR) and severe acute respiratory syndrome coronavirus-2 PCR were used for viral pathogen detection. Tolerability was evaluated with a questionnaire and visual analog scale (VAS) scores. During 11 months 88 children were included, with a median age of 1.00 year [interquartile range 0.00-3.00]. In total 122 viral pathogens were detected in 81 children (92%). Sensitivity and specificity of the RS compared to a combined swab were respectively 97% (95% confidence interval [CI] 91%-100%) and 78% (95% CI 45%-94%). Rhinorrhea samples detected more pathogens than the (combined) nasal samples, 112 versus 108 respectively. Median VAS scores were significantly lower for the RS in both children (2 vs. 6) and their parents (0 vs. 5). A RS can therefore just as effectively/reliably detect viral pathogens as the combined swab in young children and is better tolerated by both children and their parents/caregivers.

Longitudinal Household Assessment of Respiratory Illness in Children and Parents During the COVID-19 Pandemic.

Importance: In the early COVID-19 pandemic, SARS-CoV-2 testing was only accessible and recommended for symptomatic persons or adults. This restriction hampered assessment of the true incidence of SARS-CoV-2 infection in children as well as detailed characterization of the SARS-CoV-2 disease spectrum and how this spectrum compared with that of other common respiratory illnesses. Objective: To estimate the community incidence of SARS-CoV-2 infection in children and parents and to assess the symptoms and symptom severity of respiratory illness episodes involving SARS-CoV-2-positive test results relative to those with SARS-CoV-2-negative test results. Design, Setting, and Participants: This cohort study randomly selected Dutch households with at least 1 child younger than 18 years. A total of 1209 children and adults from 307 households were prospectively followed up between August 25, 2020, and July 29, 2021, covering the second and third waves of the COVID-19 pandemic. Participation included SARS-CoV-2 screening at 4- to 6-week intervals during the first 23 weeks of participation (core study period; August 25, 2020, to July 29, 2021). Participants in all households finishing the core study before July 1, 2021, were invited to participate in the extended follow-up and to actively report respiratory symptoms using an interactive app until July 1, 2021. At new onset of respiratory symptoms or a SARS-CoV-2 positive test result, a household outbreak study was initiated, which included daily symptom recording, repeated polymerase chain reaction testing (nose-throat swabs and saliva and fecal samples), and SARS-CoV-2 antibody measurement (paired dried blood spots) in all household members. Outbreaks, households, and episodes of respiratory illness were described as positive or negative depending on SARS-CoV-2 test results. Data on participant race and ethnicity were not reported because they were not uniformly collected in the original cohorts and were therefore not representative or informative. Exposures: SARS-CoV-2-positive and SARS-CoV-2-negative respiratory illness episodes. Main Outcomes and Measures: Age-stratified incidence rates, symptoms, and symptom severity for SARS-CoV-2-positive and SARS-CoV-2-negative respiratory illness episodes. Results: Among 307 households including 1209 participants (638 female [52.8%]; 403 [33.3%] aged <12 years, 179 [14.8%] aged 12-17 years, and 627 [51.9%] aged ≥18 years), 183 household outbreaks of respiratory illness were observed during the core study and extended follow-up period, of which 63 (34.4%) were SARS-CoV-2 positive (59 outbreaks [32.2%] during the core study and 4 outbreaks [2.2%] during follow-up). SARS-CoV-2 incidence was similar across all ages (0.24/person-year [PY]; 95% CI, 0.21-0.28/PY). Overall, 33 of 134 confirmed SARS-CoV-2 episodes (24.6%) were asymptomatic. The incidence of SARS-CoV-2-negative respiratory illness episodes was highest in children younger than 12 years (0.94/PY; 95% CI, 0.89-0.97/PY). When comparing SARS-CoV-2-positive vs SARS-CoV-2-negative respiratory illness episodes in children younger than 12 years, no differences were observed in number of symptoms (median [IQR], 2 [2-4] for both groups), symptom severity (median [IQR] maximum symptom severity score, 6 [4-9] vs 7 [6-13]), or symptom duration (median [IQR], 6 [5-12] days vs 8 [4-13] days). However, among adults, SARS-CoV-2-positive episodes had a significantly higher number (median [IQR], 6 [4-8] vs 3 [2-4]), severity (median [IQR] maximum symptom severity score, 15 [9-19] vs 7 [6-11]), and duration (median [IQR] 13 [8-29] days vs 5 [3-11] days; P < .001 for all comparisons) of symptoms vs SARS-CoV-2-negative episodes. Conclusions and Relevance: In this cohort study, during the first pandemic year when mostly partial or full in-person learning occurred, the SARS-CoV-2 incidence rate in children was substantially higher than estimated from routine testing or seroprevalence data and was similar to that of adult household members. Unlike in unvaccinated adults, SARS-CoV-2 symptoms and symptom severity in children were similar to other common respiratory illnesses. These findings may prove useful when developing pediatric COVID-19 vaccine recommendations.