Epidemiological and clinical insights into the enterovirus D68 upsurge in Europe 2021/22 and the emergence of novel B3-derived lineages, ENPEN multicentre study.

Enterovirus D68 (EV-D68) infections are associated with severe respiratory disease and acute flaccid myelitis (AFM). The European Non-Polio Enterovirus Network (ENPEN) aimed to investigate the epidemiological and genetic characteristics of EV-D68 and its clinical impact during the fall-winter season of 2021/22. From 19 European countries, 58 institutes reported 10,481 (6.8%) EV-positive samples of which 1,004 (9.6%) were identified as EV-D68 (852 respiratory samples). Clinical data was reported for 969 cases. 78.9% of infections were reported in children (0-5 years); 37.9% of cases were hospitalised. Acute respiratory distress was commonly noted (93.1%) followed by fever (49.4%). Neurological problems were observed in 6.4% of cases with six reported with AFM. Phylodynamic/Nextstrain and phylogenetic analyses based on 694 sequences showed the emergence of two novel B3-derived lineages, with no regional clustering. In conclusion, we describe a large-scale EV-D68 European upsurge with severe clinical impact and the emergence of B3-derived lineages.

Tracing the adaptive evolution of SARS-CoV-2 during vaccine roll-out in Norway.

Vaccination against SARS-CoV-2 has greatly mitigated the impact of the COVID-19 pandemic. However, concerns have been raised about the degree to which vaccination might drive the emergence and selection of immune escape mutations that will hamper the efficacy of the vaccines. In this study, we investigate whether vaccination impacted the micro-scale adaptive evolution of SARS-CoV-2 in the Oslo region of Norway, during the first nine months of 2021, a period in which the population went from near-zero to almost 90 per cent vaccine coverage in the population over 50 years old. Weekly aggregated data stratified by age on vaccine uptake and number of SARS-CoV-2 cases in the area were obtained from the National Immunization Registry and the Norwegian Surveillance System for Communicable Diseases, respectively. A total of 6,438 virus sequences (7.5 per cent of the registered cases) along with metadata were available. We used a causal-driven approach to investigate the relationship between vaccination progress and changes in the frequency of 362 mutations present in at least ten samples, conditioned on the emergence of new lineages, time, and population vaccination coverage. After validating our approach, we identified 21 positive and 12 negative connections between vaccination progress and mutation prevalence, and most of them were outside the Spike protein. We observed a tendency for the mutations that we identified as positively connected with vaccination to decrease as the vaccinated population increased. After modelling the fitness of different competing mutations in a population, we found that our observations could be explained by a clonal interference phenomenon in which high fitness mutations would be outcompeted by the emergence or introduction of other high-fitness mutations.

Circulating markers of extracellular matrix remodelling in severe COVID-19 patients.

BACKGROUND: Abnormal remodelling of the extracellular matrix (ECM) has generally been linked to pulmonary inflammation and fibrosis and may also play a role in the pathogenesis of severe COVID-19. To further elucidate the role of ECM remodelling and excessive fibrogenesis in severe COVID-19, we examined circulating levels of mediators involved in various aspects of these processes in COVID-19 patients. METHODS: Serial blood samples were obtained from two cohorts of hospitalised COVID-19 patients (n = 414). Circulating levels of ECM remodelling mediators were quantified by enzyme immunoassays in samples collected during hospitalisation and at 3-month follow-up. Samples were related to disease severity (respiratory failure and/or treatment at the intensive care unit), 60-day total mortality and pulmonary pathology after 3-months. We also evaluated the direct effect of inactivated SARS-CoV-2 on the release of the different ECM mediators in relevant cell lines. RESULTS: Several of the measured markers were associated with adverse outcomes, notably osteopontin (OPN), S100 calcium-binding protein A12 and YKL-40 were associated with disease severity and mortality. High levels of ECM mediators during hospitalisation were associated with computed tomography thorax pathology after 3-months. Some markers (i.e. growth differential factor 15, galectin 3 and matrix metalloproteinase 9) were released from various relevant cell lines (i.e. macrophages and lung cell lines) in vitro after exposure to inactivated SARS-CoV-2 suggesting a direct link between these mediators and the causal agent of COVID-19. CONCLUSION: Our findings highlight changes to ECM remodelling and particularly a possible role of OPN, S100A12 and YKL-40 in the pathogenesis of severe COVID-19.

Antibiotic Consumption in a Cohort of Hospitalized Adults with Viral Respiratory Tract Infection.

Development of antibiotic resistance, a threat to global health, is driven by inappropriate antibiotic usage. Respiratory tract infections (RTIs) are frequently treated empirically with antibiotics, despite the fact that a majority of the infections are caused by viruses. The purpose of this study was to determine the prevalence of antibiotic treatment in hospitalized adults with viral RTIs, and to investigate factors influencing the antibiotic decision-making. We conducted a retrospective observational study of patients ≥ 18 years, hospitalized in 2015-2018 with viral RTIs. Microbiological data were taken from the laboratory information system and information on antibiotic treatment drawn from the hospital records. To investigate decisions for prescribing antibiotic treatment, we evaluated relevant factors such as laboratory and radiological results, in addition to clinical signs. In 951 cases without secondary bacterial RTIs (median age 73 years, 53% female), 720 (76%) were prescribed antibiotic treatment, most frequently beta-lactamase-sensitive penicillins, but cephalosporins were prescribed as first-line in 16% of the cases. The median length of treatment (LOT) in the patients treated with antibiotics was seven days. Patients treated with antibiotics had an average of two days longer hospital stay compared to patients with no such treatment, but no difference in mortality was found. Our study revealed that there is still a role for antimicrobial stewardship to further improve antibiotic use in patients admitted for viral RTIs in a country with relatively low antibiotic consumption.

Immunogenicity and safety of a two-dose regimen with hepatitis E virus vaccine in healthy adults in rural Bangladesh: A randomized, double-blind, controlled, phase 2/pilot trial.

BACKGROUND: Hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide and it contributes to considerable maternal and neonatal mortality and morbidity in many low-income countries like Bangladesh. A three-dose regimen of a vaccine against HEV (HEV 239) has shown promising results in China. The effects and safety of this vaccine in other populations and with different dosing regimens remains uncertain. OBJECTIVES: Investigate the immune response and safety of a two-dose regimen with the HEV 239 vaccine among healthy adults. Examine the feasibility of conducting a larger HEV 239 vaccine trial in rural Bangladesh. METHODS: One-hundred healthy men and non-pregnant women 16-39 years old were randomized in a 1:1 ratio to receive two doses of either the study (HEV) or control (Hepatitis B virus, HBV) vaccine (at 0, 1 month). Blood samples were collected at day 0, day 60 and 2 years after vaccination. The primary endpoints were the proportion and severity of adverse events up to 2 months after dose one and the longitudinal shift in anti-HEV IgG levels from day 0 to day 60 and 2 years after vaccination. RESULTS: Adverse events to HEV 239 were comparable to the control vaccine, mild in severity and resolved within one to nine days. All participants in the study group seroconverted and achieved high levels of HEV IgG antibodies that remained positive for two years in all but one. A T-cell response was detected one month after HEV 239 vaccination. CONCLUSION: Our results show that two doses of the HEV 239 vaccine produces broad and likely functional immune responses against HEV that remain for at least two years. The safety profile was acceptable and a phase four study of HEV 239 in rural Bangladesh is feasible. CLINICALTRIALS: gov Identifier: NCT02759991.

Maternal cytomegalovirus infection and delayed language development in children at 3 years of age-a nested case-control study in a large population-based pregnancy cohort.

INTRODUCTION: Maternal cytomegalovirus (CMV) infection in pregnancy may result in vertical transmission of CMV to the child. Long-term effects of congenital CMV infection include visual, cognitive as well as neurological impairment. The aim of this study was to estimate the odds ratios for CMV seropositivity and seroconversion in mothers, with and without delayed language development in 3 year old children, nested within a large cohort. MATERIAL AND METHODS: The Norwegian Mother, Father and Child Cohort Study (MoBa) is a prospective population-based pregnancy cohort that includes 95 200 mothers and 114 500 children. Blood samples were obtained from mothers during pregnancy weeks 17 or 18 in pregnancy and after birth. We included 300 women from MoBa with children suffering from delayed language development at three years of age, based on validated questionnaires. Within the cohort, 1350 randomly selected women were included as controls to perform a nested case-control study. The cases and controls were tested for CMV IgG antibodies by an enzyme-linked immunosorbent assay. RESULTS: Among mothers of cases, 63.2% were CMV-IgG positive in the sample at birth, as compared to 55.9% among controls; OR 1.36, (95% CI; 1.05 to 1.76). Also, among case mothers, 8/118 (6.8%) initially seronegative cases, seroconverted. Among initially seronegative controls, seroconversion occurred in 23/618 (3.7%) mothers. The OR for seroconversion in cases as compared to control mothers was 1.88 (CI; 0.82 to 4.31), thus not statistically significant different. CONCLUSION: This study shows a higher risk of delayed language development at three years of age in children born by mothers seropositive for CMV, compared to children born from seronegative mothers.

Acute severe hepatitis outbreak in children: A perfect storm. What do we know, and what questions remain?

During the first half of 2022, the World Health Organization reported an outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children, following initial alerts from the United Kingdom (UK) where a cluster of cases was first observed in previously well children aged <6 years. Sporadic cases were then reported across Europe and worldwide, although in most countries incidence did not increase above the expected baseline. There were no consistent epidemiological links between cases, and microbiological investigations ruled out known infectious causes of hepatitis. In this review, we explore the evidence for the role of viral infection, superimposed on a specific host genetic background, as a trigger for liver pathology. This hypothesis is based on a high prevalence of Human Adenovirus (HAdV) 41F in affected children, together with metagenomic evidence of adeno-associated virus (Adeno-associated viruses)-2, which is a putative trigger for an immune-mediated liver injury. Roles for superantigen-mediated pathology have also been explored, with a focus on the potential contribution of SARS-CoV-2 infection. Affected children also had a high frequency of the MHC allele HLA-DRB1*04:01, supporting an immunological predisposition, and may have been vulnerable to viral coinfections due to disruption in normal patterns of exposure and immunity as a result of population lockdowns during the COVID-19 pandemic. We discuss areas of ongoing uncertainty, and highlight the need for ongoing scrutiny to inform clinical and public health interventions for this outbreak and for others that may evolve in future.

Stability and Feasibility of Dried Blood Spots for Hepatitis E Virus Serology in a Rural Setting.

Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide. In many low-income countries it causes large outbreaks and disproportionally affects pregnant women and their offspring. Surveillance studies to find effective preventive interventions are needed but are hampered by the lack of funding and infrastructure. Dried blood spots (DBS) offer an easier and more robust way to collect, transport, and store blood samples compared to plasma/serum samples, and could ease some of the barriers for such studies. In this study we optimize an HEV IgG ELISA for DBS samples and validate it on 300 paired DBS and plasma samples collected in rural areas of Bangladesh from participants in a HEV vaccine study. We demonstrate that HEV IgG in blood stored as DBS is stable for two months at up to 40 °C, and for five freeze-thaw cycles. The specificity was 97% and the overall sensitivity of the DBS assay was 81%. The sensitivity was higher in samples from vaccinated participants (100%) compared to previously infected participants (59%), reflecting a positive correlation between IgG titer and sensitivity. We found a strong correlation between DBS and plasma samples with an r2 of 0.90, but with a higher degree of difference between individual paired samples. Our study shows that DBS offers a stable alternative to plasma/serum for HEV IgG measurements and can facilitate serological studies, particularly in resource limited areas.

Omicron Variant Generates a Higher and More Sustained Viral Load in Nasopharynx and Saliva Than the Delta Variant of SARS-CoV-2.

The Omicron variant of SARS-CoV-2 spreads more easily than earlier variants, possibly as a result of a higher viral load in the upper respiratory tract and oral cavity. Hence, we investigated whether the Omicron variant generates a higher viral load than that of the Delta variant in saliva and nasopharynx. Both specimens were collected from 52 Omicron and 17 Delta cases at two time points one week apart and analyzed by qRT-PCR. Viral load was measured as 10 log RNA genome copies per 1000 human cells according to the WHO reference standard. We found that Omicron cases carried a higher viral load and had more sustained viral shedding compared to the Delta cases, especially in the nasopharynx.

Breakthrough infections with the omicron and delta variants of SARS-CoV-2 result in similar re-activation of vaccine-induced immunity.

Background: Results showing that sera from double vaccinated individuals have minimal neutralizing activity against Omicron have been interpreted as indicating the need for a third vaccine dose for protection. However, there is little information about early immune responses to Omicron infection in double vaccinated individuals. Methods: We measured inflammatory mediators, antibodies to the SARS-CoV-2 spike and nucleocapsid proteins, and spike peptide-induced release of interferon gamma in whole blood in 51 double-vaccinated individuals infected with Omicron, in 14 infected with Delta, and in 18 healthy controls. The median time points for the first and second samples were 7 and 14 days after symptom onset, respectively. Findings: Infection with Omicron or Delta led to a rapid and similar increase in antibodies to the receptor-binding domain (RBD) of Omicron protein and spike peptide-induced interferon gamma in whole blood. Both the Omicron- and the Delta-infected patients had a mild and transient increase in inflammatory parameters. Interpretation: The results suggest that two vaccine doses are sufficient to mount a rapid and potent immune response upon infection in healthy individuals of with the Omicron variant. Funding: The study was funded by the Oslo University Hospital, and by grants from The Coalition for Epidemic Preparedness Innovations, Research Council of Norway (no 312780, 324272), South-Eastern Norway Regional Health Authority (no 2019067, 2021071, 10357, 2021047, 33612, 2021087, 2017092), EU Horizon 2020 grant no 848099, a philantropic donation from Vivaldi Invest A/S, and The European Virus Archive Global.

High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19.

BACKGROUND: Immune dysregulation is a major factor in the development of severe coronavirus disease 2019 (COVID-19). The homeostatic chemokines CCL19 and CCL21 have been implicated as mediators of tissue inflammation, but data on their regulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is limited. We thus investigated the levels of these chemokines in COVID-19 patients. METHODS: Serial blood samples were obtained from patients hospitalized with COVID-19 (n = 414). Circulating CCL19 and CCL21 levels during hospitalization and 3-month follow-up were analyzed. In vitro assays and analysis of RNAseq data from public repositories were performed to further explore possible regulatory mechanisms. RESULTS: A consistent increase in circulating levels of CCL19 and CCL21 was observed, with high levels correlating with disease severity measures, including respiratory failure, need for intensive care, and 60-day all-cause mortality. High levels of CCL21 at admission were associated with persisting impairment of pulmonary function at the 3-month follow-up. CONCLUSIONS: Our findings highlight CCL19 and CCL21 as markers of immune dysregulation in COVID-19. This may reflect aberrant regulation triggered by tissue inflammation, as observed in other chronic inflammatory and autoimmune conditions. Determination of the source and regulation of these chemokines and their effects on lung tissue is warranted to further clarify their role in COVID-19. CLINICAL TRIALS REGISTRATION: NCT04321616 and NCT04381819.

Clinical Outcome of Viral Respiratory Tract Infections in Hospitalized Adults in Norway: High Degree of Inflammation and Need of Emergency Care for Cases With Respiratory Syncytial Virus.

Background: The clinical features and outcomes of viral respiratory tract infections (RTIs) in adults have not been thoroughly studied, especially the respiratory syncytial virus (RSV) disease burden. It has become apparent that outbreaks of RSV in the elderly are associated with increased hospitalization rates. However, little data exists on the severity of such viral RTIs in adults, particularly the need for hospitalization, respiratory support and intensive care. Methods: We conducted a retrospective observational single-center study at Østfold Hospital Trust, Norway, during three winter seasons 2015-2018. Patients ≥18 years with either influenza A, influenza B, RSV A/B, human metapneumovirus, parainfluenza virus 1-4 or adenovirus detected in respiratory specimens were included, if they were hospitalized 14 days prior or following the detection date, with signs of RTI. Hospital records on treatment and outcome were investigated, as well as mortality of all causes up to 30 days from discharge. Results: Of the 1222 infection events that were included, influenza A was the most frequent virus detected (39%), while 179 infection events (14.6%) were due to RSV. Influenza B counted for 24% of the infection events, human metapneumovirus 13%, parainfluenza virus 9% and adenovirus 1%. Patients admitted with RSV more often suffered from COPD and congestive heart failure than patients with influenza A. In addition, RSV patients were overrepresented in the urgent response NEWS score (National Early Warning Score) category ≥5. RSV patients also showed signs of more severe inflammation, with WBC ≥11.1 × 109/L and CRP >100 mg/L, and they were more often treated with antibiotic agents during their hospital stay. However, we found no differences in the need for ICU admission or mortality. Conclusion: Patients with RSV had more often high values for markers of inflammation and elevated NEWS score when compared to patients hospitalized with other common respiratory viruses. Taken into account that they suffered more frequently from comorbidities like COPD, these patients needed hospitalization more urgently. These findings highlight the need for further investigations on RSV disease in adults and the elderly.

The incidence of infectious diseases and viruses other than SARS-CoV-2 amongst hospitalised children in Oslo, Norway during the Covid-19 pandemic 2020-2021.

Background: Measures to reduce spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during the Covid-19 pandemic 2020-2021 may impact other microbiological agents. We aimed to investigate the incidence of infectious diseases and the incidence of viruses other than SARS-CoV-2 amongst children at The Department of Paediatric and Adolescent Medicine, Oslo University Hospital, Norway during 2020-2021 compared to previous years. Methods: Data from April 1st 2020 - March 31st 2021 were compared to data from corresponding 12-months periods 2017-2020. ICD-10 infectious disease diagnoses were collected from the Hospital Diagnosis and Procedure Registry and results of virus PCR analyses of different specimens (mainly nasopharyngeal (NF) and faecal samples) were collected from the Laboratory System at the Department of Microbiology. Results: The number of hospital contacts with acute bronchiolitis, viral pneumonia, gastroenteritis and viral central nervous system infections were reduced by 90% (p<0.0001), 89% (p<0.0001), 74% (p<0.0001) and 78% (p<0.01), respectively. Respiratory syncytial virus (RSV), influenza virus A and B and Human metapneumovirus (HMPV) were almost completely absent during the pandemic period. The proportions of rhinovirus positive NF samples were 31.7% vs. 34.9% (p<0.05), but not significantly different for adenovirus. The proportions of positive faecal samples were 1% vs. 10% for adenovirus (p<0.00001) and 3.3% vs. 12% for norovirus (p<0.00001), but not significantly different for rotavirus. The proportions of enterovirus positive samples were 3.5% vs. 21.6% (p<0.00001). Conclusion: The incidence of several paediatric infectious diseases mainly of viral aetiology declined significantly during the Covid-19 pandemic. Some common respiratory viruses were almost completely absent.

Hepatitis E Virus (HEV) Synopsis: General Aspects and Focus on Bangladesh.

HEV is the most common cause of acute hepatitis globally. This review summarizes the latest knowledge on the epidemiology, clinical characteristics, testing, and treatment of HEV infection. We also focused on Bangladesh to highlight the distinct challenges and the possible remedies. In low-income settings, the virus is mainly transmitted between people by fecal contamination of drinking water causing large outbreaks, and sporadic cases. The disease is usually mild and self-limiting acute hepatitis. Still, pregnant women and their offspring in low-income countries are at particular risk for severe disease, with up to 20% maternal mortality. Despite the high burden of the disease, HEV remains a relatively neglected virus, with detection hampered by costly tests and a lack of suitable treatments. Molecular PCR diagnostics, together with ELISA antibody tests, remain the preferred methods for diagnosis of HEV; however, rapid bedside diagnostics are available and could offer a practical alternative, especially in low-income countries. One vaccine (HEV 239) is only available in China and Pakistan, as efficacy against the other genotypes remains uncertain. The effectiveness trial conducted in Bangladesh might lead the way in gathering more efficacy data and could, together with improved surveillance and raised awareness, dramatically reduce the global burden of HEV.

Genetic diversity of rotavirus strains circulating in Norway before and after the introduction of rotavirus vaccination in children.

Globally, rotavirus (RV) is the leading cause of acute gastroenteritis (AGE) in young children under 5 years of age. Implementation of RV vaccination is expected to result in fewer cases of RV in the target population, but it is unknown if this also results in vaccine-induced virus strain replacement. Rotarix, a monovalent vaccine based on G1P[8] RV, was introduced in Norway in the children's immunization program in September 2014. The main aim of this study was to describe the diversity of RV circulating pre and post introduction of the RV vaccine in Norway and investigate changes in genotype distribution during the first 4 years after implementation. A total of 1108 samples were collected from children under 5 years enrolled with AGE from five large hospitals in Norway and were analyzed for RV by enzyme immunoassay (EIA). All positive results were genotyped by multiplex semi-nested reverse transcription PCR for identification of G and P types. In total, 487 of the 1108 (44%) samples, collected from the enrolled children, were positive for RV by EIA method which were further genotyped. G1P[8] was found to be the most common type of RV pre and post RV vaccine implementation followed by G9P[8]. There were neither geographical nor temporal differences in genotype dominance. Also, no apparent changes were shown in the genotype distribution in the postvaccine era for years from 2015 to 2018. In 21.4% of the cases, vaccine strains were detected. Continuous RV genotype surveillance is vital for assessing the effectiveness of a vaccine program and monitoring for any emergence of vaccine-escape strains. Genotyping is also necessary to detect vaccine strains to avoid reporting false-positive cases of active RV infection in newly vaccinated cases.

Tick-transmitted co-infections among erythema migrans patients in a general practice setting in Norway: a clinical and laboratory follow-up study.

BACKGROUND: Erythema migrans (EM) is the most common manifestation of Lyme borreliosis. Here, we examined EM patients in Norwegian general practice to find the proportion exposed to tick-transmitted microorganisms other than Borrelia, and the impact of co-infection on the clinical manifestations and disease duration. METHODS: Skin biopsies from 139/188 EM patients were analyzed using PCR for Neoehrlichia mikurensis, Rickettsia spp., Anaplasma phagocytophilum and Babesia spp. Follow-up sera from 135/188 patients were analyzed for spotted fever group (SFG) Rickettsia, A. phagocytophilum and Babesia microti antibodies, and tested with PCR if positive. Day 0 sera from patients with fever (8/188) or EM duration of ≥ 21 days (69/188) were analyzed, using PCR, for A. phagocytophilum, Rickettsia spp., Babesia spp. and N. mikurensis. Day 14 sera were tested for TBEV IgG. RESULTS: We detected no microorganisms in the skin biopsies nor in the sera of patients with fever or prolonged EM duration. Serological signs of exposure against SFG Rickettsia and A. phagocytophilum were detected in 11/135 and 8/135, respectively. Three patients exhibited both SFG Rickettsia and A. phagocytophilum antibodies, albeit negative PCR. No antibodies were detected against B. microti. 2/187 had TBEV antibodies without prior immunization. There was no significant increase in clinical symptoms or disease duration in patients with possible co-infection. CONCLUSIONS: Co-infection with N. mikurensis, A. phagocytophilum, SFG Rickettsia, Babesia spp. and TBEV is uncommon in Norwegian EM patients. Despite detecting antibodies against SFG Rickettsia and A. phagocytophilum in some patients, no clinical implications could be demonstrated.

Etiology of viral respiratory tract infections in hospitalized adults, and evidence of the high frequency of prehospitalization antibiotic treatment in Norway.

BACKGROUND AND AIMS: Respiratory tract infections (RTIs) cause considerable morbidity and mortality in all age groups, but the epidemiology and role of several of the viral RTIs in the adult and elderly patients are still unclear, as is the extent of prehospitalization antibacterial drug use in this population. METHODS: We conducted a three-year (2015-2018) observational study of viral RTIs in hospitalized patients in a 500-bed hospital in Southeastern Norway, including all patients ≥18 years with RTI symptoms where one of the following viral agents was detected in a respiratory specimen (Seegene Allplex): Influenza A/B, RSV A/B, human metapneumovirus (hMPV), adenovirus and parainfluenza virus 1-4. Viral findings, demographical data, and information on prehospital antibiotic prescriptions were recorded. RESULTS: In 1182 patients 1222 viral infection events occurred. The mean patient age was 69.6 years, and 53% were females. Influenza virus A/B (63%), RSV A/B (15%) and hMPV (13%) were the most common agents detected. The proportional burden of influenza A H1 was found to be relatively high (65%) in the age groups <69 years, compared to older patients (P = .001, chi-square).As many as 20% of the patients had been treated with antibiotics prior to admission, with the lowest rate for influenza A H3 group at 17% (P = .036, chi-square), and highest for the RSV group at 28% (P = .004, chi-square).Oseltamivir was prescribed prior to hospitalization in only 3 cases (0.2%). CONCLUSIONS: We found a high rate of prehospital antibiotic prescription in adults hospitalized with viral RTIs, warranting better stewardship programs to tackle the increasing antibiotic resistance problem.

Diversity of Rotavirus Strains in Children; Results From a Community-Based Study in Nepal.

Objective: The objectives of this study were to describe the incidence and genetic diversity of Rotavirus (RV) infection among children up to 3 years of age in a community in Nepal. Methods: We investigated community-acquired cases of asymptomatic and symptomatic RV infections in children from birth to 36 months of age in a community-based birth cohort in Bhaktapur, Nepal. Monthly surveillance and diarrheal stool samples were collected from 240 children enrolled at birth, of which 238 completed the 3 years of follow-up. Samples were screened for rotavirus by Enzyme Immuno Assay (EIA). All RV screened positives were further genotyped by reverse transcription-polymerase chain reaction for the capsid genes VP7 and VP4. Results: In total, 5,224 stool samples were collected from 238 children, followed from birth to 36 months of age. Diarrhea occurred in 92.4% (230/238) of all children in the cohort. During the 3 years study period, RV was more frequently seen in children with symptoms (7.6%) than in non-symptomatic children (0.8%). The highest RV detection rate was found in younger children between 3 and 21 months of age. Although rotavirus is known as winter diarrhea, it was detected throughout the year except in August. The highest positivity rate was observed in the months between December and March, with a peak in January. Four common G types were seen: G2 (30%), G1 (29%), G12 (19%), and G9 (16%). The most predominant genotypes seen were G2P[4] (30%), followed by G1P[8] (27.0%), G12P[6] (14.0%), G9P[8] (10%), and remaining were mixed, partial, and untyped. Conclusion: Our study confirms that rotavirus is a common cause of gastroenteritis in young children in the community. The prevalence and pathogenicity of rotavirus infection differed by age. There was substantial variability in circulating strains in the community samples compared to samples collected from hospitals. This shows the importance of including community-based surveillance systems to monitor the diversity of circulating rotavirus strains in Nepal.

Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial.

BACKGROUND: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. OBJECTIVE: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. DESIGN: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). SETTING: 23 hospitals in Norway. PATIENTS: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. INTERVENTION: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). MEASUREMENTS: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. RESULTS: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. LIMITATION: The trial had no placebo group. CONCLUSION: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19. PRIMARY FUNDING SOURCE: National Clinical Therapy Research in the Specialist Health Services, Norway.

Molecular Epidemiology and Evolutionary Trajectory of Emerging Echovirus 30, Europe.

In 2018, an upsurge in echovirus 30 (E30) infections was reported in Europe. We conducted a large-scale epidemiologic and evolutionary study of 1,329 E30 strains collected in 22 countries in Europe during 2016-2018. Most E30 cases affected persons 0-4 years of age (29%) and 25-34 years of age (27%). Sequences were divided into 6 genetic clades (G1-G6). Most (53%) sequences belonged to G1, followed by G6 (23%), G2 (17%), G4 (4%), G3 (0.3%), and G5 (0.2%). Each clade encompassed unique individual recombinant forms; G1 and G4 displayed >2 unique recombinant forms. Rapid turnover of new clades and recombinant forms occurred over time. Clades G1 and G6 dominated in 2018, suggesting the E30 upsurge was caused by emergence of 2 distinct clades circulating in Europe. Investigation into the mechanisms behind the rapid turnover of E30 is crucial for clarifying the epidemiology and evolution of these enterovirus infections.