No association between disease severity and respiratory syncytial virus subtypes RSV-A and RSV-B in hospitalized young children in Norway.

OBJECTIVE: There is conflicting evidence whether subtypes of Respiratory syncytial virus have different seasonality or are differentially associated with clinical severity. We aimed to explore the associations between disease severity and RSV subtypes RSV-A and RSV-B and to describe the circulation of RSV subtypes pattern by season and age. METHODS: Active prospective hospital surveillance for RSV-A and RSV-B in children <59 months of age was conducted during 2015-2018. All febrile children 12-59 months of age were enrolled, whereas children <12 months were eligible if presenting with fever or respiratory symptoms. Risk factors and upper and lower respiratory tract infection was identified by linkage to national registry data and analyzed using penalized maximum likelihood logistic regression. RESULTS: Both RSV-A and B were found to co-circulate throughout all three study seasons, and no clear seasonal pattern was identified. Likewise, we found no association between sex or measures of severity with RSV-A or RSV-B. There was significantly more RSV-A than RSV-B among children with comorbidities. CONCLUSIONS: No association was found between disease severity or sex and RSV subtypes RSV-A and RSV-B in hospitalized young children in Norway.

Risk factors associated with severe disease in respiratory syncytial virus infected children under 5 years of age.

Objective: To evaluate risk factors for severe disease in children under 59 months of age hospitalized with respiratory syncytial virus (RSV) infection. Study design: We prospectively enrolled 1,096 cases of laboratory confirmed RSV infection during three consecutive RSV seasons in 2015-2018. Potential risk factors for severe disease were retrieved through patient questionnaires and linkage to national health registries. Need for respiratory support (invasive ventilation, bi-level positive airway pressure, or continuous positive airway pressure), and length of stay exceeding 72 h were used as measures of disease severity. Associations were investigated using multivariable logistic regression analyses. Multiple imputation was used to avoid bias and inference induced by missing data. Results: Risk factors associated with a need for respiratory support included age younger than 3 months of age [aOR: 6.73 (95% CI 2.71-16.7)], having siblings [aOR: 1.65 (95% CI 1.05-2.59)] and comorbidity [aOR: 2.40 (95% CI 1.35-4.24)]. The length of hospital stay >72 h was significantly associated with being younger than 3 months of age [aOR: 3.52 (95% CI 1.65-7.54)], having siblings [aOR: 1.45 (95% CI 1.01-2.08)], and comorbidity [aOR: 2.18 (95% CI 1.31-3.61)]. Sub-group analysis of children younger than 6 months of age confirmed the association between both young age and having siblings and the need for respiratory support. Conclusion: In a large cohort of children <59 months hospitalized with RSV infection, young age, comorbidity, and having siblings were associated with more severe disease.

The burden of respiratory syncytial virus in children under 5 years of age in Norway.

OBJECTIVES: To estimate age-specific incidence of medically attended respiratory syncytial virus (RSV) infections in hospitalised Norwegian children and describe disease epidemiology. METHODS: Active prospective hospital surveillance for RSV in children <59 months of age was conducted during 2015-2018. All febrile children 12-59 months of age were enrolled, whereas children <12 months were enrolled based on respiratory symptoms regardless of fever. Surveillance data were linked to national registry data to estimate the clinical burden of RSV. RESULTS: Of the children enrolled, 1096 (40%) were infected with RSV. The highest incidence rates were found in children 1 month of age, with a peak incidence of 43 per 1000 during the 2016-2017 season. In comparison, children 24-59 months of age had an infection rate of 1.4 per 1000 during the same winter season. The peak season was during the 2016-2017 winter, with an incidence rate of 6.0 per 1000 children 0-59 months of age. In the study population a total of 168 (15%) of the infected children had pre-existing medical conditions predisposing for more severe disease. High infection rates were found in this population. CONCLUSIONS: Children with comorbidities showed high hospital contact rates, but the majority of children in need of medical attention associated with RSV infection were previously healthy.

Viral lower respiratory tract infections-strict admission guidelines for young children can safely reduce admissions.

Viral lower respiratory tract infection (VLRTI) is the most common cause of hospital admission among small children in high-income countries. Guidelines to identify children in need of admission are lacking in the literature. In December 2012, our hospital introduced strict guidelines for admission. This study aims to retrospectively evaluate the safety and efficacy of the guidelines. We performed a single-center retrospective administrative database search and medical record review. ICD-10 codes identified children < 24 months assessed at the emergency department for VLRTI for a 10-year period. To identify adverse events related to admission guidelines implementation, we reviewed patient records for all those discharged on primary contact followed by readmission within 14 days. During the study period, 3227 children younger than 24 months old were assessed in the ED for VLRTI. The proportion of severe adverse events among children who were discharged on their initial emergency department contact was low both before (0.3%) and after the intervention (0.5%) (p=1.0). Admission rates before vs. after the intervention were for previously healthy children > 90 days 65.3% vs. 53.3% (p<0.001); for healthy children ≤ 90 days 85% vs. 68% (p<0.001); and for high-risk comorbidities 74% vs. 71% (p=0.5).Conclusion: After implementation of admission guidelines for VLRTI, there were few adverse events and a significant reduction in admissions to the hospital from the emergency department. Our admission guidelines may be a safe and helpful tool in the assessment of children with VLRTI. What is Known: • Viral lower respiratory tract infection, including bronchiolitis, is the most common cause of hospitalization for young children in the developed world. Treatment is mainly supportive, and hospitalization should be limited to the cases in need of therapeutic intervention. • Many countries have guidelines for the management of the disease, but the decision on whom to admit for inpatient treatment is often subjective and may vary even between physicians in the same hospital. What is New: • Implementation of admission criteria for viral lower respiratory tract infection may reduce the rate of hospital admissions without increasing adverse events.

Assessing Severity in Pediatric Pneumonia: Predictors of the Need for Major Medical Interventions.

OBJECTIVE: The aim of this study was to determine potential predictors of the need for major medical interventions in the context of assessing severity in pediatric pneumonia. METHODS: This was a prospective, cohort study of previously healthy children and adolescents younger than 18 years presenting to the pediatric emergency room with clinically suspected pneumonia and examining both the full cohort and those with radiologically confirmed pneumonia. The presence of hypoxemia (peripheral oxygen saturation ≤92%), age-specific tachypnea, high temperature (≥38.5°C), chest retraction score, modified Pediatric Early Warning Score, age, C-reactive protein, white blood cell (WBC) count, and chest radiograph findings at first assessment were analyzed by univariate and multivariate analyses to examine their predictive ability for the need for major medical interventions: supplemental oxygen, supplemental fluid, respiratory support, intensive care, or treatment for complications during admission. RESULTS: Fifty percent of the 394 cases of suspected pneumonia and 60% of the 265 cases of proven pneumonia were in need of 1 or more medical interventions. In multivariate logistic regression, only the presence of hypoxemia (odds ratios, 3.66 and 3.83 in suspected and proven pneumonia, respectively) and chest retraction score (odds ratios, 1.21 and 1.31, respectively for each 1-point increase in the score) significantly predicted the need for major medical interventions in both suspected and proven pneumonia. Specificity of 94% or greater, positive likelihood ratio of 6.4 or greater, and sensitivity of less than 40% were found for both hypoxemia and chest retraction score in predicting major medical interventions. C-reactive protein and white blood cell count were not associated with the need for these interventions, whereas multifocal radiographic changes were. CONCLUSIONS: Hypoxemia and an assessment of chest retractions were the predictors significantly able to rule in more severe pneumonia, but with a limited clinical utility given their poor ability to rule out the need for major medical interventions. Future validation of these findings is needed.

Mycoplasma Pneumoniae: A Cross-sectional Population-based Comparison of Disease Severity in Preschool and School-age Children.

BACKGROUND: Mycoplasma pneumoniae causes epidemics of upper respiratory disease and pneumonia. It is thought that M. pneumoniae usually causes milder upper respiratory disease in preschool children, with a greater chance of pneumonia in school-age children. In this population-based cross-sectional study, we present evidence that severe M. pneumoniae infection is more common in preschool children than previously thought. METHODS: During an M. pneumoniae epidemic in our area, widespread health service and public awareness lead to extensive testing for M. pneumoniae. Medical records of hospital-referred M. pneumoniae-positive children were assessed retrospectively for respiratory disease and chest radiographic results. Severe disease was defined as supplementary oxygen or fluid requirement, mechanical ventilatory support or neurologic disease. Age-specific population figures were used to calculate incidence during the study period. Those who were 0-5-year-olds were considered preschool, whereas 6-17-year-olds were considered school-aged. RESULTS: Thirty-seven preschool and 55 school-age children were referred to the hospital and tested positive for M. pneumoniae. Twenty-two (60%) preschool and 23 (42%) school-age children had severe disease [incidence 56 vs. 29 per 100,000; relative risk: 1.9; 95% confidence interval (CI): 1.06-3.4; P = 0.03]. Twenty (54%) preschool and 19 (35%) school-age children had severe pneumonia (incidence 51 vs. 24 per 100,000; relative risk: 2.1; 95% CI: 1.1-3.9; P = 0.03). CONCLUSIONS: During an M. pneumoniae epidemic in Akershus and North Oslo in 2011-2012, preschool children infected with M. pneumoniae had significantly higher risk of severe disease, particularly severe pneumonia, when compared with school-age children. M. pneumoniae should be considered a potential pathogen in younger children with respiratory distress, particularly during an epidemic period.

Clinical features and inflammatory markers in pediatric pneumonia: a prospective study.

In this prospective, observational study on previously healthy children <18 years, we aimed to study the diagnostic ability of clinical features and inflammatory markers to (i) predict pathologic chest radiography in suspected pneumonia and (ii) differentiate etiology in radiological proven pneumonia. In 394 cases of suspected pneumonia, 265 (67%) had radiographs consistent with pneumonia; 34/265 had proof of bacterial etiology. Of the cases, 86.5% had received pneumococcal conjugate vaccine. In suspected pneumonia, positive chest radiography was significantly associated with increasing C-reactive protein (CRP) values, higher age, and SpO2 ≤92% in multivariate logistic regression, OR 1.06 (95% CI 1.03 to 1.09), OR 1.09 (95% CI 1.00 to1.18), and OR 2.71 (95% CI 1.42 to 5.18), respectively. In proven pneumonia, bacterial pneumonia was significantly differentiated from viral/atypical pneumonia by increasing CRP values and SpO2 >92% in multivariate logistic regression, OR 1.09 (95% CI 1.05 to 1.14) and OR 0.23 (95% CI 0.06 to 0.82), respectively. Combining high CRP values (>80 mg/L) and elevated white blood cell (WBC) count provided specificity >85%, positive likelihood ratios >3, but sensitivity <46% for both radiographic proven and bacterial pneumonia. CONCLUSION: With relatively high specificity and likelihood ratio CRP, WBC count and hypoxemia may be beneficial in ruling in a positive chest radiograph in suspected pneumonia and bacterial etiology in proven pneumonia, but with low sensitivity, the clinical utility is limited. What is Known: • Pneumonia is recommended to be a clinical diagnosis, and neither clinical features nor inflammatory markers can reliably distinguish etiology. • The etiology of pneumonia has changed after routine pneumococcal conjugate vaccine. What is New: • High CRP and WBC counts were associated with infiltrates in children with suspected pneumonia and with bacterial infection in proven pneumonia. • In the post-pneumococcal vaccination era, viral etiology is expected, and in cases of pneumonia with low CRP and WBC counts, a watch-and-wait strategy for antibiotic treatment may be applied.

Thymus activity measured by T-cell receptor excision circles in patients with different severities of respiratory syncytial virus infection.

BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of hospitalization in previously healthy infants. Immunological mechanisms predisposing infants to severe disease are poorly understood. Early biomarkers for disease severity may assist clinical decisions. We investigated T-cell receptor excision circles (TREC), episomal DNA made during thymic T-cell receptor rearrangement, and a marker for thymus activity, both during disease and in neonatal screening cards as a risk factor for RSV disease severity. METHODS: One hundred thirteen patients hospitalized with RSV infection <12 months of age, grouped by disease severity, were available for this investigation, in which we conducted both a prospective and a case-control study. The prospective study included 47 RSV positive infants (mild n = 13, moderate n = 10, severe n = 24). TREC counts were determined by PCR of DNA extracted from EDTA-blood collected on hospitalization, and corrected for lymphocytes using ANCOVA. The case-control study included 85 newborns who later in infancy became RSV positive (mild n = 32, moderate n = 24, severe n = 29) and 47 newborns who never developed RSV disease as healthy controls included from health centres in the same catchment area. TRECs were measured using DNA extracted from dry blood spots from stored neonatal screening cards, followed by PCR. Student's T-test compared patients with controls, ANOVA compared disease severity groups. RESULTS: During RSV infection patients in the severe disease group had significantly lower (p = 0.017) TREC/200 µL blood compared to the other two disease groups, after correction for lymphocyte count. Newborn TREC levels, were significantly higher in RSV patients compared to controls (p < 0.0001). No significant differences in TREC copies at birth were found between disease severities. CONCLUSION: During acute RSV infection a lower number of TREC is found in the severe disease group. TREC has potential as an immunological marker for severe RSV infection. Higher neonatal TREC counts indicate that infants later presenting with severe RSV do not have reduced thymic activity at birth and probably no congenital T-cell defect.

The role of microRNAs in respiratory viral infection: friend or foe?

MicroRNAs (miRNAs) have emerged as a class of regulatory RNAs in host-pathogen interactions. Aberrant miRNA expression seems to play a central role in the pathology of several respiratory viruses, promoting development and progression of infection. miRNAs may thus serve as therapeutic and prognostic factors for respiratory viral infectious disease caused by a variety of agents. We present a comprehensive review of recent findings related to the role of miRNAs in different respiratory viral infections and discuss possible therapeutic opportunities aiming to attenuate the burden of viral infections. Our review supports the emerging concept that cellular and viral-encoded miRNAs might be broadly implicated in human respiratory viral infections, with either positive or negative effects on virus life cycle. Copyright © 2016 John Wiley & Sons, Ltd.

Etiology of Pneumonia in a Pediatric Population with High Pneumococcal Vaccine Coverage: A Prospective Study.

BACKGROUND: Improved Childhood Immunizations Programs, especially the introduction of pneumococcal vaccination, better diagnostic methods and the importance of reduced antibiotic misuse, make this a critical time to increase knowledge on the etiology of pediatric pneumonia. Our main objective was to identify the contribution of various microbiological species that causes pneumonia in previously healthy children and adolescents in a population with high pneumococcal conjugate vaccine coverage. METHODS: This prospective, observational study enrolled patients with clinical and radiological signs of pneumonia over a 2-year period. Both inpatients and outpatients were included. Paired sera, nasopharyngeal polymerase chain reaction and bacterial cultures from blood and pleura were analyzed to detect potential viral and bacterial causative pathogens. RESULTS: TWO HUNDRED AND SIXTY-FIVE: cases of clinical and radiological verified pneumonia were identified. The pneumococcal vaccine coverage was 85%. We identified a causative pathogen in 84.2% of all cases; 63.4% with single viral etiology, 11.3% with pneumococcus and 7.5% with mycoplasma infection. Respiratory syncytial virus was the most common pathogen in children younger than 5 years, whereas mycoplasma was the most common in older children. CONCLUSIONS: We identified the majority of 265 cases with radiology proven pneumonia as single viral infections, predominantly respiratory syncytial virus and a much lower proportion of bacterial causes. These findings may impact pneumonia management guidelines in areas where widespread pneumococcal vaccination is provided and contribute to reduced antibiotic overuse in pediatric pneumonia.

Comparison of nasopharyngeal aspirate with flocked swab for PCR-detection of respiratory viruses in children.

Fast- and high-throughput molecular workflows require sample matrices to be suitable for automation. Respiratory swabs are better suited for this purpose compared to the more viscous nasopharyngeal aspirates. Samples collected by nasopharyngeal aspiration and nasopharyngeal flocked swab from 81 children were compared for detection and recovery of respiratory viruses. Using real-time RT-PCR, no statistically significant differences in virus detection between the two sample types were found, supporting the use of flocked swabs in children aged one month to two years.

Nasal mucosal microRNA expression in children with respiratory syncytial virus infection.

BACKGROUND: Respiratory syncytial virus (RSV) infection is a common cause of pediatric hospitalization. microRNA, key regulators of the immune system, have not previously been investigated in respiratory specimens during viral infection. We investigated microRNA expression in the nasal mucosa of 42 RSV-positive infants, also comparing microRNA expression between disease severity subgroups. METHODS: Nasal mucosa cytology specimens were collected from RSV-positive infants and healthy controls. 32 microRNA were selected by microarray for qPCR verification in 19 control, 16 mild, 7 moderate and 19 severe disease samples. RESULTS: Compared to healthy controls, RSV-positive infants downregulated miR-34b, miR-34c, miR-125b, miR-29c, mir125a, miR-429 and miR-27b and upregulated miR-155, miR-31, miR-203a, miR-16 and let-7d. On disease subgroups analysis, miR-125a and miR-429 were downregulated in mild disease (p=0.03 and 0.02, respectively), but not in severe disease (p=0.3 and 0.3). CONCLUSION: microRNA expression in nasal epithelium cytology brushings of RSV-positive infants shows a distinct profile of immune-associated miRNA. miR-125a has important functions within NF-κB signaling and macrophage function. The lack of downregulation of miR-125a and miR-429 in severe disease may help explain differences in disease manifestations on infection with RSV.

Downregulation of IL7R, CCR7, and TLR4 in the cord blood of children with respiratory syncytial virus disease.

The association between gene expression at birth of 11 candidate genes with important innate and adaptive immune functions and later respiratory syncytial virus (RSV) disease was investigated. Cord blood was collected from 2108 newborns. Forty-seven were subsequently RSV positive. Gene expression analysis by quantitative reverse transcription-polymerase chain reaction was compared to 17 controls. There was downregulation of interleukin 7 receptor (IL7R) (P = .0001) and chemokine receptor 7 (CCR7) (P = .002), and in the severe disease subcategory, downregulation of Toll-like receptor 4 (TLR4) (P = .003). IL7R and CCR7 facilitate communication between adaptive and innate immune systems. TLR4 activates the innate immune system on RSV exposure. Delayed innate and adaptive immune activation may predispose children to more severe RSV disease.

Infectious burden of respiratory syncytial virus in relation to time of birth modifies the risk of lower respiratory tract infection in infancy: the Norwegian Mother and Child Cohort.

OBJECTIVE: The risk of respiratory syncytial virus (RSV) infection according to calendar month of birth has previously been demonstrated. We hypothesize that the real-time infectious burden (IB) of RSV, in relation to time and county of birth, modifies the risk of lower respiratory tract infection (LRTI) in infants, an association that has not been investigated previously, and may be used as an alternative measure of RSV risk when drafting RSV immunoprophylaxis guidelines. METHODS: Thirty thousand eighty-seven pregnancies were included from July 1, 2003, to July 31, 2006. IB was defined by month and county as the number of RSV detections per inhabitant. IB for 5 periods ante- and postnatally was calculated for each child. Outcome variables were maternally reported hospitalization for LRTI before age 6 months and LRTI before age 12 months. Logistic regression was used to estimate associations between IB and LRTI. RESULTS: The odds of hospitalization for LRTI rise with increased IB the first 3 months after birth. Low IB: odds ratio (OR) 1.17 (95% confidence interval [CI]: 0.98-1.39); medium IB: OR 1.42 (95% CI: 1.21-1.68); high IB: OR 2.51 (95% CI: 2.15-2.94). High IB 3-0 months before birth confers a lower odds of hospitalization for LRTI the first 6 months of life, OR 0.51 (95% CI: 0.43-0.61). Similar results were seen for maternally reported LRTI the first 12 months of life. CONCLUSIONS: We find an association between real-time RSV infectious burden and LRTI in infancy: high burden before birth is protective and high burden after birth increases the risk.

Reduced Dicer expression in the cord blood of infants admitted with severe respiratory syncytial virus disease.

BACKGROUND: Respiratory syncytial virus (RSV) is one of the most important causes of pediatric hospital admissions in the developed world. The ribonuclease Dicer is an important regulator of gene expression and cellular function via RNA interference, and may also have anti-viral functions. A previous microarray analysis of the cord blood of 5 patients with RSV disease suggested downregulation of Dicer. In order to further investigate whether reduced Dicer expression can predispose newborns to RSV disease, we have analyzed the gene expression of Dicer in the cord blood of 37 infants with confirmed RSV disease. METHODS: The cord blood of 2108 newborns was collected. 51 had a positive nasopharyngeal aspirate for RSV <1 year, and were grouped according to disease severity. 37 had sufficient cord blood RNA of good quality. Dicer gene expression was assessed by qPCR analysis of cord blood using a TaqMan low-density array and compared to control infants who did not present with RSV disease using the Mann-Whitney test. RESULTS: There was significant downregulation of Dicer in the severe disease group: relative quantity 0.69 (95% CI: 0.56 - 0.87), p = 0.002. There was no significant downregulation in the mild disease group. CONCLUSIONS: We demonstrate reduced Dicer expression in the cord blood of infants with severe RSV disease, prior to RSV exposure. We theorize that this may predispose to RSV disease by disruption of leukocyte gene regulation or direct anti-viral RNA interference mechanisms.