Tract Infections In Young Children Research Articles

Influence of Sex on Respiratory Syncytial Virus Genotype Infection Frequency and Nasopharyngeal Microbiome.

Respiratory syncytial virus (RSV) has a significant health burden in children, older adults, and the immunocompromised. However, limited effort has been made to identify emergence of new RSV genotypes' frequency of infection and how the combination of nasopharyngeal microbiome and viral genotypes impact RSV disease outcomes. In an observational cohort designed to capture the first infant RSV infection, we employed multi-omics approaches to sequence 349 RSV complete genomes and matched nasopharyngeal microbiomes, during which the 2012/2013 season was dominated by RSV-A, whereas 2013 and 2014 was dominated by RSV-B. We found non-G-72nt-duplicated RSV-A strains were more frequent in male infants (P = 0.02), whereas G-72nt-duplicated genotypes (which is ON1 lineage) were seen equally in both males and females. DESeq2 testing of the nasal microbiome showed Haemophilus was significantly more abundant in infants with RSV-A infection compared to infants with RSV-B infection (adjusted P = 0.002). In addition, the broad microbial clustering of the abundant genera was significantly associated with infant sex (P = 0.03). Overall, we show sex differences in infection by RSV genotype and host nasopharyngeal microbiome, suggesting an interaction between host genetics, virus genotype, and associated nasopharyngeal microbiome. IMPORTANCE Respiratory syncytial virus (RSV) is one of the leading causes of lower respiratory tract infections in young children and is responsible for high hospitalization rates and morbidity in infants and the elderly. To understand how the emergence of RSV viral genotypes and viral-respiratory microbiome interactions contribute to infection frequency and severity, we utilized an observational cohort designed to capture the first infant RSV infection we employed multi-omics approaches to sequence 349 RSV complete genomes and matched nasopharyngeal microbiomes. We found non-G-72nt-duplicated RSV-A genotypes were more frequent in male infants, whereas G-72nt-duplicated RSV-A strains (ON1 lineage) were seen equally in both males and females. Microbiome analysis show Haemophilus was significantly more abundant in infants with RSV-A compared to infants with RSV-B infection and the microbial clustering of the abundant genera was associated with infant sex. Overall, we show sex differences in RSV genotype-nasopharyngeal microbiome, suggesting an interaction host genetics-virus-microbiome interaction.

An outbreak of upper respiratory tract infections in young children during the COVID-19 pandemic: a lesson from Hong Kong

An outbreak of upper respiratory tract infections in young children during the COVID-19 pandemic: a lesson from Hong Kong

Severe Human Rhinovirus Lower Respiratory Tract Infections in Young Children

Severe Human Rhinovirus Lower Respiratory Tract Infections in Young Children

Profiles and predictive value of cytokines in children with human metapneumovirus pneumonia.

Human metapneumovirus (HMPV) is an important cause of respiratory tract infections in young children. Early innate immune response to HMPV is focused on induction of antiviral interferons (IFNs) and other pro-inflammatory cytokines that are critical for the formation of adaptive immune responses. To evaluate the predictive value of Th1/Th2 cytokines which include IL-2, IL-4, IL-6, IL-10, INF-γ and TNF-α in pneumonia caused by HMPV. A retrospective study was performed among 59 pneumonia pediatric patients with HMPV infection and 33 healthy children as the control cohort, which was detected by the immunofluorescence assay, and the Th1/Th2 cytokines were measured by flow cytometry. 131 children infected with Influenza virus A (IVA) and 41 children infected with influenza virus B (IVB) were detected by RT-PCR assay in throat swabs. When compared with the healthy children, children who were infected with HMPV pneumonia had a significantly lower level of IL-2 (p < 0.001) and higher levels of IL-4 (p < 0.001), IL-6 (p = 0.001), IL-10 (p < 0.001), and IFN-γ (p < 0.001). Compared with patients diagnosed with IVA or IVB infection, HMPV-positive patients had significantly higher levels of IL-4 (p < 0.001 and < 0.001), IFN-γ (p < 0.001 and < 0.001), and TNF-α (p < 0.001 and 0.016). Moreover, compared with IVA patients, HMPV-positive patients had a significantly lower level of IL-6 (p = 0.033). Finally, when comparing cytokine levels among the patients with HMPV pneumonia, IL-6 and TNF-α levels were found to be significantly higher in the severe group than the mild group (p = 0.027 and 0.049). The IL-6 and TNF-α were used to differentiate between mild symptoms and severe symptoms in children diagnosed with HMPV pneumonia with an AUC of 0.678 (95% CI 0.526-0.829) and 0.658 (95% CI 0.506-0.809), respectively. Our study indicated that difference in cytokine trends depending on the virus species. The levels of IL-4, TNF-α and IFN-γ were significantly distinguished in children infected with HMPV versus IVA and IVB. IL-6 and TNF-α may be helpful in assessing the severity and prognosis of HMPV infection.

Clinical characteristics and molecular epidemiology of human metapneumovirus in children with acute lower respiratory tract infections in China, 2017 to 2019: A multicentre prospective observational study.

Human metapneumovirus (HMPV) infection is one of the leading causes of hospitalization in young children with acute respiratory illness. In this study, we prospectively collected respiratory tract samples from children who were hospitalized with acute lower respiratory tract infection in six hospitals in China from 2017 to 2019. HMPV was detected in 145 out of 2733 samples (5.3%) from the hospitalized children. The majority of HMPV-positive children were under the age of two (67.6%), with a median age of one year. HMPV can independently cause acute lower respiratory tract infection in young children, while all patients showed mild clinical symptoms. Of all the co-infected patients, HMPV was most commonly detected with enterovirus (EV) or rhinovirus (RhV) (38.0%, followed by respiratory syncytial virus (RSV) (32.0%). The highest detection rate occurred from March to May in both northern and southern China. Out of 145 HMPV positive samples, 48 were successfully typed, of which 36 strains were subgrouped into subtypes A2c (75%), eight strains were included in subtype B1 (16.7%), and four strains were included in subtype B2 (8.3%). Moreover, 16 A2c strains contained 111-nucleotide duplications in the G gene. Twenty-seven complete HMPV genomes were successfully obtained, and 25 (92.6%) strains belonged to subtype A2c, whereas one strain was included in subgroup B1 and another was included in subgroup B2. A total of 277 mutations were observed in the complete genomes of 25 A2c strains. All results presented here improve our understanding of clinical characteristics and molecular epidemiology of HMPV infection in children.

How did the covid-19 pandemic affect lower respiratory tract infections in young children in England?

Abstract Background Social distancing policies to reduce transmission of covid-19 also reduced children's exposures to endemic respiratory viruses. We aimed to examine the impact of the covid-19 pandemic on lower respiratory tract infections in under 5s presenting to primary care in England. Methods Longitudinal trends analysis using electronic health records from a nationally representative primary care database. Our target population was children aged &amp;lt;5 years registered with a primary care practice from January 2015 to March 2021. Our main outcome was total weekly contacts with primary care for a lower respiratory tract infection (LRTI). We defined three pandemic phases from March 2020 - March 2021: i) first national lockdown (late March to early June 2020), ii) childcare settings reopened and second national lockdown with schools open (mid-June to mid-December 2020) and iii) third national lockdown with schools closed (late December 2020 to end of March 2021). We compared outcomes during each of the three phases with corresponding calendar weeks during pre-pandemic years 2015 to 2019. Results Our study population included 843 020 children &amp;lt;5 years who had 1 076 181 contacts with primary care for LRTIs. During the first phase (first lockdown) there were falls of 79.3% (95% CI: 73.6 to 84.5) from an average of 28 547 primary care contacts for LRTI in 2015 - 2019 to 5915 in 2020; there was a 78.9% (95% CI: 73.7 to 83.9) fall in phase two (childcare settings reopened and second lockdown) from 107 873 to 22 792 contacts; and a 77.7% (95% CI: 73.5 to 81.4) fall in phase three (third lockdown) from 57 200 to 12 764 contacts. Conclusions Children under 5 in England had fewer contacts with primary care for LRTIs during the covid-19 pandemic. This change likely reflects lower prevalence of respiratory illness due to fewer social contacts. This may impact on future health service use as these children have had less exposure, and therefore may have less immunity, to respiratory diseases. Key messages • Children under 5 had fewer contacts with primary care for lower respiratory tract infections during the covid-19 pandemic in England likely due to the restrictions in place to reduce social contacts. • The falls in lower respiratory tract infections during the covid-19 pandemic in under 5s may mean they have less immunity to respiratory viruses which may impact upon their future health service use.

A Candidate Therapeutic Monoclonal Antibody Inhibits Both HRSV and HMPV Replication in Mice.

Human metapneumovirus (HMPV) and human respiratory virus (HRSV) are two leading causes of acute respiratory tract infection in young children. While there is no licensed drug against HMPV, the monoclonal antibody (mAb) Palivizumab is approved against HRSV for prophylaxis use only. Novel therapeutics against both viruses are therefore needed. Here, we describe the identification of human mAbs targeting these viruses by using flow cytometry-based cell sorting. One hundred and two antibodies were initially identified from flow cytometry-based cell sorting as binding to the fusion protein from HRSV, HMPV or both. Of those, 95 were successfully produced in plants, purified and characterized for binding activity by ELISA and neutralization assays as well as by inhibition of virus replication in mice. Twenty-two highly reactive mAbs targeting either HRSV or HMPV were isolated. Of these, three mAbs inhibited replication in vivo of a single virus while one mAb could reduce both HRSV and HMPV titers in the lung. Overall, this study identifies several human mAbs with virus-specific therapeutic potential and a unique mAb with inhibitory activities against both HRSV and HMPV.

Non-hepatotropic viral hepatitis and its causative pathogens: The ongoing need for monitoring in children with severe acute hepatitis of unknown etiology.

Non-hepatotropic viral hepatitis and its causative pathogens: The ongoing need for monitoring in children with severe acute hepatitis of unknown etiology.

The small nonstructural protein NP1 of human bocavirus 1 directly interacts with Ku70 and RPA70 and facilitates viral DNA replication

Human bocavirus 1 (HBoV1), a member of the genus Bocaparvovirus of the family Parvoviridae, causes acute respiratory tract infections in young children. Well-differentiated pseudostratified human airway epithelium cultured at an air-liquid interface (HAE-ALI) is an ideal in vitro culture model to study HBoV1 infection. Unique to other parvoviruses, bocaparvoviruses express a small nonstructured protein NP1 of ~25 kDa from an open reading frame (ORF) in the center of the viral genome. NP1 plays an important role in viral DNA replication and pre-mRNA processing. In this study, we performed an affinity purification assay to identify HBoV1 NP1-inteacting proteins. We identified that Ku70 and RPA70 directly interact with the NP1 at a high binding affinity, characterized with an equilibrium dissociation constant (KD) of 95 nM and 122 nM, respectively. Furthermore, we mapped the key NP1-interacting domains of Ku70 at aa266-439 and of RPA70 at aa181-422. Following a dominant negative strategy, we revealed that the interactions of Ku70 and RPA70 with NP1 play a significant role in HBoV1 DNA replication not only in an in vitro viral DNA replication assay but also in HBoV1-infected HAE-ALI cultures. Collectively, our study revealed a novel mechanism by which HBoV1 NP1 enhances viral DNA replication through its direct interactions with Ku70 and RPA70.

Clinical Profile and Outcome of Respiratory Syncytial Virus-Infected Neonates—A Single Center Experience

Respiratory syncytial virus (RSV) has been identified as a leading cause of lower respiratory tract infections in young children and elderly. Limited data are available on the clinical profile and outcome in neonates from India. We describe clinical profile and outcome data of neonates infected with RSV. A total of 14 neonates with acute respiratory illness (ARI) requiring newborn intensive care unit (NICU) admission were tested for respiratory virus infection. All 14 (100%) tested positive for RSV-A infection. Of these positive cases, 11 (78.57%) were NICU graduates. Cough, cold, and respiratory distress was observed to be the chief complain in 13 (92.85%) neonates. All except 2 required respiratory support. Total duration of respiratory support and hospital stay was 7 (3-12) and 8 (5-14) days, respectively. All the RSV-infected patients showed complete recovery. We observed that predominantly NICU graduates were susceptible to RSV illness with a slight male preponderance. Amongst infected, majority presented with ARI requiring respiratory support. The severity was more in NICU graduates who were born very preterm.

Race and Urinary Tract Infections in Young Children With Fever

Race and Urinary Tract Infections in Young Children With Fever

The 2018 annual cost burden for children under five years of age hospitalised with respiratory syncytial virus in Australia.

Respiratory syncytial virus (RSV) is one of the principal causes of acute bronchiolitis and respiratory tract infections in young children. Routine RSV surveillance in Australian children is limited; vaccines are in late stage development; prophylactic monoclonal antibody (mAb) treatment is available but expensive; and there has been uncertainty around the cost burden. The objective of this study was to determine the annual cost burden for children under five years of age hospitalised with RSV in a single health service in 2018, with national extrapolation based on published Australian prevalence data. The methods utilised individual patient-level cost data prospectively collected for hospitalised children under five years of age in a tertiary Melbourne paediatric hospital. Results were extrapolated to all Australian children under five years of age to determine the national annual health cost burden, from a healthcare sector perspective over a 12 month time horizon. The results included 363 children with a mean age of 9.2 months (standard deviation, SD: 8.5 months). The mean cost per child was $17,120 (SD: $37,562), with a combined health service cost of $6,214,439. The reported Australian hospitalisation rate for RSV in the target age group ranged from 2.2 to 4.5 per 1,000 children under five years of age, resulting in a 2018 extrapolated cost range of $59,218,844-$121,129,453 for the estimated 3,459-7,075 children affected (combined index and all-cause six-month readmissions). This study concluded that RSV represents a significant cost burden to Australia's health care system. These data are important for future health economic assessments of preventative therapies, such as new RSV mAb treatments and maternal/childhood RSV vaccines, and provides valuable insights to inform health care planning and health policy.

Clinical prediction rules for childhood urinary tract infections: a cross-sectional study in ambulatory care.

BackgroundDiagnosing childhood urinary tract infections (UTIs) is challenging. Clinical prediction rules may help to identify children that require urine sampling. However, there is a lack of research to determine the accuracy of the scores in general practice.AimTo validate clinical prediction rules (UTI Calculator [UTICalc], A Diagnosis of Urinary Tract Infection in Young Children [DUTY], and Gorelick score) for paediatric UTIs in primary care.Design & settingPost-hoc analysis of a cross-sectional study in 39 general practices and two emergency departments (EDs). The study took place in Belgium from March 2019–March 2020.MethodPhysicians recruited acutely ill children aged ≤18 years and sampled urine systematically for culture. Per rule, an apparent validation was performed, and sensitivities and specificities were calculated with 95% confidence intervals (CIs) per threshold in the target group. For the DUTY coefficient-based algorithm, a logistic calibration was performed and the area under the receiver operating characteristic curve (AUC) was calculated with 95% CI.ResultsOf 834 children aged ≤18 years recruited, there were 297 children aged <5 years. The UTICalc and Gorelick score had high-to-moderate sensitivity and low specificity: UTICalc (≥2%) 75% and 16%, respectively; Gorelick (≥2 variables) 91% and 8%, respectively. In contrast, the DUTY score ≥5 points had low sensitivity (8%) but high specificity (99%). Urine samples would be obtained in 72% versus 38% (UTICalc), 92% versus 38% (Gorelick) or 1% versus 32% (DUTY) of children, compared with routine care. The number of missed infections per score was 1/4 (UTICalc), 2/23 (Gorelick), and 24/26 (DUTY). The UTICalc + dipstick model had high sensitivity and specificity (100% and 91%), resulting in no missed cases and 59% (95% CI = 49% to 68%) of antibiotics prescribed inappropriately.ConclusionIn this study, the UTICalc and Gorelick score were useful for ruling out UTI, but resulted in high urine sampling rates. The DUTY score had low sensitivity, meaning that 92% of UTIs would be missed.

POSC127 Evolution of Direct Medical Costs Associated with Respiratory Syncytial Virus Disease in Children Younger Than 5 Years: A Retrospective Database Analysis from 2008 to 2017

Respiratory syncytial virus (RSV) can cause serious lower respiratory tract infections in young children, such as bronchiolitis and pneumonia. This study describes the evolution of RSV-related direct medical costs (DMCs) in children <5 years of age between 2008 and 2017 in the United States (US).

Respiratory syncytial virus infection induces the release of transglutaminase 2 from human airway epithelial cells.

Respiratory syncytial virus (RSV) is an important human pathogen that causes severe lower respiratory tract infections in young children, the elderly, and the immunocompromised, yet no effective treatments or vaccines are available. The precise mechanism underlying RSV-induced acute airway disease and associated sequelae are not fully understood; however, early lung inflammatory and immune events are thought to play a major role in the outcome of the disease. Moreover, oxidative stress responses in the airways play a key role in the pathogenesis of RSV. Oxidative stress has been shown to elevate cytosolic calcium (Ca2+) levels, which in turn activate Ca2+-dependent enzymes, including transglutaminase 2 (TG2). Transglutaminase 2 is a multifunctional cross-linking enzyme implicated in various physiological and pathological conditions; however, its involvement in respiratory virus-induced airway inflammation is largely unknown. In this study, we demonstrated that RSV-induced oxidative stress promotes enhanced activation and release of TG2 from human lung epithelial cells as a result of its translocation from the cytoplasm and subsequent release into the extracellular space, which was mediated by Toll-like receptor (TLR)-4 and NF-κB pathways. Antioxidant treatment significantly inhibited RSV-induced TG2 extracellular release and activation via blocking viral replication. Also, treatment of RSV-infected lung epithelial cells with TG2 inhibitor significantly reduced RSV-induced matrix metalloprotease activities. These results suggested that RSV-induced oxidative stress activates innate immune receptors in the airways, such as TLRs, that can activate TG2 via the NF-κB pathway to promote cross-linking of extracellular matrix proteins, resulting in enhanced inflammation.

Exchange Protein Directly Activated by cAMP 2 Enhances Respiratory Syncytial Virus-Induced Pulmonary Disease in Mice

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in young children. It is also a significant contributor to upper respiratory tract infections, therefore, a major cause for visits to the pediatrician. High morbidity and mortality are associated with high-risk populations including premature infants, the elderly, and the immunocompromised. However, no effective and specific treatment is available. Recently, we discovered that an exchange protein directly activated by cyclic AMP 2 (EPAC2) can serve as a potential therapeutic target for RSV. In both lower and upper epithelial cells, EPAC2 promotes RSV replication and pro-inflammatory cytokine/chemokine induction. However, the overall role of EPAC2 in the pulmonary responses to RSV has not been investigated. Herein, we found that EPAC2-deficient mice (KO) or mice treated with an EPAC2-specific inhibitor showed a significant decrease in body weight loss, airway hyperresponsiveness, and pulmonary inflammation, compared with wild-type (WT) or vehicle-treated mice. Overall, this study demonstrates the critical contribution of the EPAC2-mediated pathway to airway diseases in experimental RSV infection, suggesting the possibility to target EPAC2 as a promising treatment modality for RSV.

Obesity and febrile urinary tract infection in young children.

Obesity is a risk factor for infectious diseases. However, the relationship between obesity and febrile urinary tract infection (fUTI) is controversial. This study aimed to determine the relationship between obesity and fUTI in young children. We analyzed the medical records of children aged <2 years who were admitted to our hospital because of fever between April 2013 to March 2018. The children were categorized into three groups of non-obese, overweight, and obese according to the World Health Organization weight-for-length curves for children aged <2 years. A total of 600 patients were enrolled in this study, of whom 118 were diagnosed with first fUTI. Patients in the fUTI group were younger than those in the control group (patients who were diagnosed with other febrile diseases) (5 ± 5.11 vs 11 ± 6.53 months; P < 0.001). There were no significant differences in the populations of overweight and obese children between the fUTI and control groups. In the fUTI group, the duration of fever, types of pathogen, recurrent rate, the grades of vesicoureteral reflux, and renal scarring were not associated with obesity. The white blood cell count and C-reactive protein levels were not significantly different among the three weight-for-length categories. The same results were obtained when the fUTI group was compared with an age-matched control group (n = 192, 4 ± 2.55 months old; P = 0.261). Obesity is not a significant risk factor for fUTI in febrile hospitalized young children. Our study suggests that conducting urinalysis for febrile young children without obvious sources, irrespective of obesity, should be considered.

Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017–2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.

Small quantities of respiratory syncytial virus RNA only in large droplets around infants hospitalized with acute respiratory infections

BackgroundRespiratory syncytial virus (RSV) is a major cause of respiratory tract infections in young children. The predominant transmission routes for RSV are still a matter of debate. Specifically, it remains unclear if RSV can be transmitted through the air and what the correlation is between the amount of RSV in nasopharynx samples and in the air.MethodsThe amount of RSV in the air around hospitalized RSV infected infants in single-patient rooms was quantified using a six-stage Andersen cascade impactor that collects and fractionates aerosols and droplets according to size. RSV shedding in the nasopharynx of patients was followed longitudinally by quantifying RSV RNA levels and infectious virus in nasopharyngeal aspirates. Nose and throat swabs of parents and swabs of the patient’s bedrail and a datalogger were also collected.ResultsPatients remained RSV positive during the air sampling period and infectious virus was isolated up to 9 days post onset of symptoms. In three out of six patients, low levels of RSV RNA, but no infectious virus, were recovered from impactor collection plates that capture large droplets > 7 μm. For four of these patients, one or both parents were also positive for RSV. All surface swabs were RSV-negative.ConclusionsDespite the prolonged detection of infectious RSV in the nasopharynx of patients, only small amounts of RSV RNA were collected from the air around three out of six patients, which were primarily contained in large droplets which do not remain suspended in the air for long periods of time.

Recent Advances in Molecular Biology of Human Bocavirus 1 and Its Applications.

Human bocavirus 1 (HBoV1) was discovered in human nasopharyngeal specimens in 2005. It is an autonomous human parvovirus and causes acute respiratory tract infections in young children. HBoV1 infects well differentiated or polarized human airway epithelial cells in vitro. Unique among all parvoviruses, HBoV1 expresses 6 non-structural proteins, NS1, NS1-70, NS2, NS3, NS4, and NP1, and a viral non-coding RNA (BocaSR), and three structural proteins VP1, VP2, and VP3. The BocaSR is the first identified RNA polymerase III (Pol III) transcribed viral non-coding RNA in small DNA viruses. It plays an important role in regulation of viral gene expression and a direct role in viral DNA replication in the nucleus. HBoV1 genome replication in the polarized/non-dividing airway epithelial cells depends on the DNA damage and DNA repair pathways and involves error-free Y-family DNA repair DNA polymerase (Pol) η and Pol κ. Importantly, HBoV1 is a helper virus for the replication of dependoparvovirus, adeno-associated virus (AAV), in polarized human airway epithelial cells, and HBoV1 gene products support wild-type AAV replication and recombinant AAV (rAAV) production in human embryonic kidney (HEK) 293 cells. More importantly, the HBoV1 capsid is able to pseudopackage an rAAV2 or rHBoV1 genome, producing the rAAV2/HBoV1 or rHBoV1 vector. The HBoV1 capsid based rAAV vector has a high tropism for human airway epithelia. A deeper understanding in HBoV1 replication and gene expression will help find a better way to produce the rAAV vector and to increase the efficacy of gene delivery using the rAAV2/HBoV1 or rHBoV1 vector, in particular, to human airways. This review summarizes the recent advances in gene expression and replication of HBoV1, as well as the use of HBoV1 as a parvoviral vector for gene delivery.