SARS-CoV-2 incidence in secondary schools; the role of national and school-initiated COVID-19 measures.

INTRODUCTION: Our aim was to gain insight into the effect of COVID-19 measures on SARS-CoV-2 incidence in secondary schools and the association with classroom CO2 concentration and airborne contamination. METHODS: Between October 2020-June 2021, 18 schools weekly reported SARS-CoV-2 incidence and completed surveys on school-initiated COVID-19 measures (e.g. improving hygiene or minimizing contacts). CO2 was measured in occupied classrooms twice, and SARS-CoV-2 air contamination longitudinally using electrostatic dust collectors (EDC) and analyzed using RT-qPCR. National COVID-19 policy measures varied during pre-lockdown, lockdown and post-lockdown periods. During the entire study, schools were recommended to improve ventilation. SARS-CoV-2 incidence rate ratios (IRR) were estimated by Generalized Estimating Equation (GEE) models. RESULTS: During 18 weeks follow-up (range: 10-22) SARS-CoV-2 school-incidence decreased during national lockdown (adjusted IRR: 0.41, 95%CI: 0.21-0.80) and post-lockdown (IRR: 0.60, 0.39-0.93) compared to pre-lockdown. School-initiated COVID-19 measures had no additional effect. Pre-lockdown, IRRs per 10% increase in time CO2 exceeded 400, 550 and 800 ppm above outdoor level respectively, were 1.08 (1.00-1.16), 1.10 (1.02-1.19), and 1.08 (0.95-1.22). Post-lockdown, CO2-concentrations were considerably lower and not associated with SARS-CoV-2 incidence. No SARS-CoV-2 RNA was detected in any of the EDC samples. CONCLUSION: During a period with low SARS-CoV-2 population immunity and increased attention to ventilation, with CO2 levels most of the time below acceptable thresholds, only the national policy during and post-lockdown of reduced class-occupancy, stringent quarantine, and contact testing reduced SARS-CoV-2 incidence in Dutch secondary schools. Widespread SARS-CoV-2 air contamination could not be demonstrated in schools under the prevailing conditions during the study.

Virological and Social Outcomes of HIV-Infected Adolescents and Young Adults in The Netherlands Before and After Transition to Adult Care.

BACKGROUND: As a result of effective combination antiretroviral therapy (cART) and advanced supportive healthcare, a growing number of human immunodeficiency virus (HIV)-infected children survive into adulthood. The period of transition to adult care is often associated with impaired adherence to treatment and discontinuity of care. We aimed to evaluate virological and social outcomes of HIV-infected adolescents and young adults (AYAs) before and after transition, and explore which factors are associated with virological failure. METHODS: We included 59 HIV-infected AYAs from the Netherlands who had entered into pediatric care and transitioned from pediatric to adult healthcare. We used HIV RNA load and cART data from the Dutch Stichting HIV Monitoring database (1996-2014), and collected social and treatment data from patients' medical records from all Dutch pediatric HIV treatment centers and 14 Dutch adult treatment centers involved. We evaluated risk factors for virological failure (VF) in a logistic regression model adjusted for repeated measurements. RESULTS: HIV VF occurred frequently during the study period (14%-36%). During the transition period (from 18 to 19 years of age) there was a significant increase in VF compared with the reference group of children aged 12-13 years (odds ratio, 4.26 [95% confidence interval, 1.12-16.28]; P = .03). Characteristics significantly associated with VF were low educational attainment and lack of autonomy regarding medication adherence at transition. CONCLUSIONS: HIV-infected AYAs are vulnerable to VF, especially during the transition period. Identification of HIV-infected adolescents at high risk for VF might help to improve treatment success in this group.

Etiology of acute gastroenteritis in children requiring hospitalization in the Netherlands.

Infectious gastroenteritis causes a considerable burden of disease worldwide. Costs due to gastroenteritis are dominated by the hospitalized cases. Effective control of gastroenteritis should be targeted at the diseases with the highest burden and costs. For that, an accurate understanding of the relative importance of the different bacterial, viral, and parasitic pathogens is needed. The objective of the present study was to determine the incidence and etiology of gastroenteritis requiring hospital admission in the Netherlands. Six hospitals enrolled patients admitted with gastroenteritis for approximately one year over the period May 2008 to November 2009. Participants provided questionnaires and a fecal sample, and the hospital filled out a clinical questionnaire. In total, 143 children hospitalized for gastroenteritis and 64 matched controls were included in the study. Overall incidence of gastroenteritis requiring hospitalization was estimated at 2.92 per 1,000 children aged 0-17 years per year, with the highest incidence in children under the age of 5 years. The full diagnostic panel of pathogens could be studied in fecal samples of 96 cases. One or more pathogens were found in 98% of these cases. Co-infections were observed relatively often (40%). Viruses were detected in 82% of the samples, with rotavirus being most common (56%), bacteria in 32% and parasites in 10%. The present study emphasizes the importance of viral pathogens, especially rotavirus, in hospitalizations of children with gastroenteritis. Policies to reduce (costs of) hospitalizations due to gastroenteritis should therefore be first targeted at rotavirus.

Evaluation of the antiviral response to zanamivir administered intravenously for treatment of critically ill patients with pandemic influenza A (H1N1) infection.

A retrospective nationwide study on the use of intravenous (IV) zanamivir in patients receiving intensive care who were pretreated with oseltamivir in the Netherlands was performed. In 6 of 13 patients with a sustained reduction of the viral load, the median time to start IV zanamivir was 9 days (range, 4-11 days) compared with 14 days (range, 6-21 days) in 7 patients without viral load reduction (P = .052). Viral load response did not influence mortality. We conclude that IV zanamivir as late add-on therapy has limited effectiveness. The effect of an immediate start with IV zanamivir monotherapy or in combination with other drugs need to be evaluated.

Chronic norovirus infection among solid organ recipients in a tertiary care hospital, the Netherlands, 2006-2014.

OBJECTIVES: Immunocompromised patients can suffer prolonged norovirus symptoms and virus shedding for many years. Little is known about the prevalence of chronic norovirus infection among solid organ transplant (SOT) recipients. In this study, 2182 SOT recipients were retrospectively tested for chronic norovirus infection. METHODS: The first and last norovirus positive faecal samples of SOT recipients were sequenced to distinguish between persisting infection and re-infection. Patient charts were reviewed to obtain data on health status and treatments. RESULTS: In all, 101 of 2182 (4.6%) recipients were norovirus infected and 23 (22.8%) of these developed chronic norovirus infection. Chronic norovirus infection was found among allogeneic heart, kidney and lung transplant recipients. The median shedding period at the end of the study period was 218 days (range 32-1164 days). CONCLUSIONS: This study shows that chronic norovirus infection is not a rare phenomenon among SOT recipients in a tertiary-care hospital. Further research is needed to study the risk of norovirus transmission to other immunocompromised patients in the hospital and to the general population.

Performance evaluation of a rapid molecular diagnostic, MultiCode based, sample-to-answer assay for the simultaneous detection of Influenza A, B and respiratory syncytial viruses.

BACKGROUND: Clinical signs and symptoms of different airway pathogens are generally indistinguishable, making laboratory tests essential for clinical decisions regarding isolation and antiviral therapy. Immunochromatographic tests (ICT) and direct immunofluorescence assays (DFA) have lower sensitivities and specificities than molecular assays, but have the advantage of quick turnaround times and ease-of-use. OBJECTIVE: To evaluate the performance of a rapid molecular assay, ARIES FluA/B & RSV, using laboratory developed RT-PCR assays (LDA), ICT (BinaxNOW) and DFA. METHODS: Analytical and clinical performance were evaluated in a retrospective study arm (stored respiratory samples obtained between 2006-2015) and a prospective study arm (unselected fresh clinical samples obtained between December 2015 and March 2016 tested in parallel with LDAs). RESULTS: Genotype inclusivity and analytical specificity was 100%. However, ARIES was 0.5 log, 1-2logs and 2.5logs less sensitive for fluA, RSV and fluB respectively, compared to LDA. In total, 447 clinical samples were included, of which 15.4% tested positive for fluA, 9.2% for fluB and 26.0% for RSV, in both LDA and ARIES. ARIES clinical sensitivity compared to LDA was 98.6% (fluA), 93.3% (fluB) and 95.1% (RSV). Clinical specificity was 100% for all targets. ARIES detected 10.6% (4 fluA, 8 fluB, 11 RSV) and 26.9% (7 fluA, 3 fluB, 22 RSV) more samples compared to DFA and ICT, all confirmed by LDA. CONCLUSION: Although analytically ARIES is less sensitive than LDA, the clinical performance of the assay in our tertiary care setting was comparable, and significantly better than that of the established rapid assays.

Diagnostic performance of influenza viruses and RSV rapid antigen detection tests in children in tertiary care.

BACKGROUND: Rapid antigen detection tests (RADTs) are increasingly used to detect influenza viruses and respiratory syncytial virus (RSV). However, their sensitivity and specificity are a matter of debate, challenging their clinical usefulness. OBJECTIVES: Comparing diagnostic performances of BinaxNow Influenza AB(®) (BNI) and BinaxNow RSV(®) (BNR), to those of real-time reverse transcriptase PCR (RT-PCR), virus isolation and direct immunofluorescence (D-IF) in paediatric patients. STUDY DESIGN: Between November 2005 and September 2013, 521 nasal washings from symptomatic children (age <5 years) attending our tertiary care centre were tested, with a combination of the respective assays using RT-PCR as gold standard. RESULTS: Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of BNI were 69% (confidence interval [CI] [51-83]), 96% [94-97], 55% [39-70] and 98% [96-99] respectively. Of eleven false-negative samples, RT-PCR Ct-values were higher than all RT-PCR positive test results (27 vs 22, p=0.012). Of twenty false-positive samples, none were culture positive and two tested positive in D-IF. Sensitivity, specificity, PPV and NPV for BNR were 79% [73-85], 98% [96-99], 97% [93-99] and 88% [84-91]. Of the 42 false-negative samples the median Ct-value was higher than that of all RT-PCR positive samples (31 vs 23, p<0.0001). Five false-positive samples were detected. Three of these tested positive for RSV in virus isolation and D-IF. CONCLUSIONS: RADTs have a high specificity with BNR being superior to BNI. However, their relative low sensitivity limits their usefulness for clinical decision making in a tertiary care paediatric hospital.

Human bocavirus infection as a cause of severe acute respiratory tract infection in children.

In 2005 human bocavirus (HBoV) was discovered in respiratory tract samples of children. The role of HBoV as the single causative agent for respiratory tract infections remains unclear. Detection of HBoV in children with respiratory disease is frequently in combination with other viruses or bacteria. We set up an algorithm to study whether HBoV alone can cause severe acute respiratory tract infection (SARI) in children. The algorithm was developed to exclude cases with no other likely cause than HBoV for the need for admission to the paediatric intensive care unit (PICU) with SARI. We searched for other viruses by next-generation sequencing (NGS) in these cases and studied their HBoV viral loads. To benchmark our algorithm, the same was applied to respiratory syncytial virus (RSV)-positive patients. From our total group of 990 patients who tested positive for a respiratory virus by means of RT-PCR, HBoV and RSV were detected in 178 and 366 children admitted to our hospital. Forty-nine HBoV-positive patients and 72 RSV-positive patients were admitted to the PICU. We found seven single HBoV-infected cases with SARI admitted to PICU (7/49, 14%). They had no other detectable virus by NGS. They had much higher HBoV loads than other patients positive for HBoV. We identified 14 RSV-infected SARI patients with a single RSV infection (14/72, 19%). We conclude that our study provides strong support that HBoV can cause SARI in children in the absence of viral and bacterial co-infections.

Indinavir/low-dose ritonavir containing HAART in HIV-1 infected children has potent antiretroviral activity, but is associated with side effects and frequent discontinuation of treatment.

We here present the study results of 21 HIV-1 infected children who were treated with indinavir plus low-dose ritonavir and two nucleoside reverse transcriptase inhibitors (NRTIs) for 48 weeks. Although this q12h HAART regimen had potent antiretroviral activity, it was frequently associated with side effects and discontinuation of therapy.

Changes in indinavir exposure over time: a case study in six HIV-1-infected children.

OBJECTIVE: To study changes in indinavir exposure over time in HIV-1-infected children. MATERIALS AND METHODS: Protease inhibitor (PI)-naive HIV-1-infected children were treated with indinavir, zidovudine and lamivudine. Steady-state plasma pharmacokinetic (PK) sampling was carried out as standard of care. The AUC(0-8) was targeted between 15 and 30 mg h/L. PK sampling was repeated after dosage adjustment until the AUC(0-8) reached target values. Patients were included when the time interval between PK samplings was > or =2 years and differences in dosage/m2 <10% between PK samplings 1 and 2. Corrections of dose for changes in body size were carried out. RESULTS: Six children were enrolled with a median age of 5.2 years (range 1.7-13.6 years). All had a viral load below 500 copies/mL. The geometric mean (GM) of the AUC(0-8) decreased from 25.3 mg h/L at the first PK-day to 19.1 mg h/L at the second PK-day [geometric mean ratio (GMR): 0.76 (95% C.I.: 0.48-1.20)]. The GM of Cmax decreased from 11.8 to 10.4 mg/L [GMR: 0.88 (95% C.I.: 0.59-1.32)]. The GM of Cmin decreased from 0.08 to 0.07 mg/L [GMR: 0.86 (95% C.I.: 0.62-1.18)]. All children had an AUC(0-8) above 15 mg h/L on the first PK-day; three had an AUC(0-8) below 15 mg h/L on the second PK-day. In two of these three children, the plasma viral load was >500 copies/mL. CONCLUSION: Changes in indinavir exposure were observed over time. In two patients, decreased indinavir exposure was associated with virological failure. Therapeutic drug monitoring should be carried out over time since this may prevent subtherapeutic dosing in children.

Pharmacokinetics of indinavir combined with low-dose ritonavir in human immunodeficiency virus type 1-infected children.

So far, no pediatric doses for indinavir combined with ritonavir have been defined. This study evaluated the pharmacokinetics of 400 mg of indinavir/m(2) combined with 125 mg of ritonavir/m(2) every 12 h (q12h) in 14 human immunodeficiency virus type 1-infected children. The area under the concentration-time curve from 0 to 24 h and the minimum concentration of drug in serum for indinavir were similar to those for 800 mg of indinavir-100 mg of ritonavir q12h in adults, while the maximum concentration of drug in serum was slightly decreased, with geometric mean ratios (90% confidence intervals in parentheses) of 1.1 (0.87 to 1.3), 0.96 (0.60 to 1.5), and 0.80 (0.68 to 0.94), respectively.