Viral Lower Respiratory Infections Research Articles

Association between early viral LRTI and subsequent wheezing development, a meta-analysis and sensitivity analyses for studies comparable for confounding factors.

Consideration of confounding factors about the association between Lower Respiratory Tract Infections (LRTI) in childhood and the development of subsequent wheezing has been incompletely described. We determined the association between viral LRTI at ≤ 5 years of age and the development of wheezing in adolescence or adulthood by a meta-analysis and a sensitivity analysis including comparable studies for major confounding factors. We performed searches through Pubmed and Global Index Medicus databases. We selected cohort studies comparing the frequency of subsequent wheezing in children with and without LRTI in childhood regardless of the associated virus. We extracted the publication data, clinical and socio-demographic characteristics of the children, and confounding factors. We analyzed data using random effect model. The meta-analysis included 18 publications (22 studies) that met the inclusion criteria. These studies showed that viral LRTI in children ≤ 3 years was associated with an increased risk of subsequent development of wheezing (OR = 3.1, 95% CI = 2.4-3.9). The risk of developing subsequent wheezing was conserved when considering studies with comparable groups for socio-demographic and clinical confounders. When considering studies with comparable groups for most confounding factors, our results provided strong evidence for the association between neonatal viral LRTI and the subsequent wheezing development. Further studies, particularly from lower-middle income countries, are needed to investigate the role of non-bronchiolitis and non-HRSV LRTI in the association between viral LRTI in childhood and the wheezing development later. In addition, more studies are needed to investigate the causal effect between childhood viral LRTI and the wheezing development later. Review registration: PROSPERO, CRD42018116955; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018116955.

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.

Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract.

Influenza viruses cause annual epidemics and occasional pandemics of respiratory tract infections that produce a wide spectrum of clinical disease severity in humans. The novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and has since caused a pandemic. Both viral and host factors determine the extent and severity of virus-induced lung damage. The host’s response to viral infection is necessary for viral clearance but may be deleterious and contribute to severe disease phenotypes. Similarly, tissue repair mechanisms are required for recovery from infection across the spectrum of disease severity; however, dysregulated repair responses may lead to chronic lung dysfunction. Understanding of the mechanisms of immunopathology and tissue repair following viral lower respiratory tract infection may broaden treatment options. In this Review, we discuss the pathogenesis, the contribution of the host response to severe clinical phenotypes and highlight early and late epithelial repair mechanisms following influenza virus infection, each of which has been well characterized. Although we are still learning about SARS-CoV-2 and its disease manifestations in humans, throughout the Review we discuss what is known about SARS-CoV-2 in the context of this broad knowledge of influenza virus, highlighting the similarities and differences between the respiratory viruses.

Bronchiolitis: State-of-the-art

The commonest cause of respiratory distress in young children is bronchiolitis. Bronchiolitis is an acute viral lower respiratory tract infection which predominantly affects children up to two years of age. It is a seasonal disease, dominating winter months, with a peak over 6 to 8 weeks around the winter solstice. The evidence and guideline recommendations consistently support a clinical diagnosis with the limited role for diagnostic testing for children who present with the typical clinical features of viral upper respiratory infection progressing to the lower respiratory tract. Management is largely supportive, focusing on maintaining oxygenation and hydration. Evidence suggest no benefit from bronchodilator or corticosteroid use in infants with first episode of bronchiolitis. Evidence for other treatment such as hypertonic saline is evolving. In case of severe bronchiolitis, there is some role for high-flow nasal cannula and continuous positive airway pressure use.&#x0D; Bangladesh J Child Health 2020; VOL 44 (3) :161-169

P0046 / #639: THE IMPACT OF BENZODIAZEPINES AND OPIOIDS ON NEUROCOGNITIVE DEVELOPMENT IN CHILDREN

Aims & Objectives: General anesthetics and sedatives are widely used for critically ill children admitted to the Pediatric Intensive Care Unit (PICU). Animal studies have indicated that exposure of the immature brain to these agents may cause neurodegeneration. In human adults, studies have shown an inverse association between cumulative doses of benzodiazepines and neurocognitive functioning. Literature on this association in children is scarce. This study aims to explore the impact of benzodiazepines and opioids on neurocognitive development in children. Methods: Children aged 6-12 years admitted to our PICU (age ≤10 months) for respiratory insufficiency due to severe viral lower respiratory tract infections were included. All children required mechanical ventilation for which they also received midazolam and morphine. Healthy peers, matched with patients on age, sex and socio-economic status, acted as controls. We assessed full-scale IQ (FSIQ) and computerized tests of attention, learning and memory, executive functioning and sensory and motor functioning. Results: Included were 41 patients (24 males) and 41 controls (17 males). Mean (SD) age of patients and controls was 8.6 (0.8) and 8.9 (1.0) years, respectively. Preliminary results indicate that, compared to healthy peers, children in the exposure group have a significantly lower FSIQ (d=-0.56, p = 0.02); and a significantly poorer verbal memory, including both short (d=-0.47, p = 0.04) and long-term memory (d=-0.50, p = 0.03). Other results await analyses. Conclusions: Preliminary results suggest that children with a history of mechanical ventilation and exposure to midazolam and morphine are at risk of decreased neurocognitive functioning.

Etiology of Lower Respiratory Tract Infections in Children Requiring Mechanical Ventilation: A Multicenter Prospective Surveillance Study Incorporating Airway Metagenomics

Background: Lower respiratory tract infections (LRTI) are a leading cause of mortality in children with critical illness. Despite this, the pathogenic microbes in this vulnerable demographic frequently remain unknown. Metagenomic next generation sequencing (mNGS) can complement traditional diagnostics in epidemiologic surveillance studies by providing broad-range pathogen detection. Methods: We conducted a prospective, multicenter cohort study of critically ill children ages 31 days to 17 years with respiratory failure requiring prolonged mechanical ventilation. Using a combination of clinically-ordered testing and tracheal aspirate mNGS we determined the prevalence, seasonal variation, and genetic relatedness of respiratory pathogens in children with clinically adjudicated LRTI (n=276) or no LRTI (n=121). Findings: A presumptive microbiologic etiology was identified in 92% of children, with RSV (46%), Haemophilus influenzae (25%) and Moraxella catarrhalis (24%) being most common. mNGS identified uncommon pathogens including Ureaplasma parvum (<1%) and Bocavirus (3%). Co-detection of viral and bacterial pathogens occurred in 52% of cases. Incidental carriage of potentially pathogenic microbes was observed in 68% of children without LRTI, with rhinovirus (25%) most prevalent. RSV, H. influenzae and M. catarrhalis were statistically more prevalent in children under five. Both viral and bacterial LRTI occurred predominantly during winter months, and RSV infection was characterized by seasonal and geographic clusters of related strains. Interpretation: The combination of clinical diagnostics and mNGS enabled comprehensive pathogen surveillance in critically ill children with LRTI. RSV, H. influenzae , and M. catarrhalis were disproportionately represented. Carriage of potentially pathogenic microbes was common in children without LRTI. Funding Statement: NIH, Chan Zuckerberg Biohub Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study was approved by a central IRB at the University of Utah.

Risk Factors for Respiratory Syncytial Virus Lower Respiratory Tract Infections: Evidence from an Indonesian Cohort.

Although risk factors for hospitalization from a respiratory syncytial virus (RSV) are well known, RSV lower respiratory tract infections (LRIs) in the community are much less studied or understood, especially in developing countries. In a prospective, cohort study we studied factors predisposing Indonesian infants and children under 5 years of age to developing RSV LRIs. Subjects were enrolled in two cohorts: a birth cohort and a cross-sectional cohort of children <48 months of age. Subjects were visited weekly at home to identify any LRI, using the World Health Organization’s criteria. RSV etiology was determined through analysis of nasal washings by enzyme immunoassay and polymerase chain reaction. Risk factors for the development of the first documented RSV LRI were identified by multivariate analysis using logistic regression and Cox proportional hazard modeling. Of the 2014 children studied, 999 were enrolled within 30 days of birth. There were 149 first episodes of an RSV. Risk factors for an RSV LRI were poverty (p < 0.01), use of kerosene as a cooking fuel (p < 0.05), and household ownership of rabbits and chickens (p < 0.01). Our findings suggested that in a middle-income country such as Indonesia, with a substantial burden of RSV morbidity and mortality, lower socioeconomic status, environmental air quality, and animal exposure are predisposing factors for developing an RSV LRI.

Nirsevimab reduces medically attended RSV-associated lower respiratory tract infection and hospitalisations in healthy pre-term infants

Review of Griffin MP, Yuan Y, Takas T, et al . Single-dose nirsevimab for prevention of RSV in preterm infants. N Engl J Med 2020;383:415–25. Study design: Randomised clinical trial....

COVID-19 and Pediatric Lung Disease: A South African Tertiary Center Experience.

The COVID-19 pandemic led to rapid global spread with far-reaching impacts on health-care systems. Whilst pediatric data consistently shown a milder disease course, chronic lung disease has been identified as a risk factor for hospitalization and severe disease. In Africa, comprised predominantly of low middle-income countries (LMIC), the additional burden of HIV, tuberculosis, malnutrition and overcrowding is high and further impacts health risk. This paper reviewed the literature on COVID-19 and chronic lung disease in children and provides our experience from an African pediatric pulmonary center in Cape Town, South Africa. South African epidemiological data confirms a low burden of severe disease with children <18 years comprising 8% of all diagnosed cases and 3% of all COVID-19 admissions. A decrease in hospital admission for other viral lower respiratory tract infections was found. While the pulmonology service manages children with a wide range of chronic respiratory conditions including bronchiectasis, cystic fibrosis, asthma, interstitial lung disease and children with tracheostomies, no significant increase in COVID-19 admissions were noted and in those who developed COVID-19, the disease course was not severe. Current evidence suggests that pre-existing respiratory disease in children does not appear to be a significant risk factor for severe COVID-19. Longitudinal data are still needed to assess risk in children with immunosuppression and interstitial lung diseases. The indirect impacts of the pandemic response on child respiratory health are notable and still likely to be fully realized and quantified. Ensuring children have access to full preventive and care services during this time is priority.

1506. Burden of Respiratory Syncytial Virus (RSV) and Other Lower Respiratory Tract Viral Infections During the First Two Years of Life: a Prospective Study

BackgroundLower respiratory tract infections (LRTIs) are a leading cause of pediatric morbidity and mortality worldwide, with ~650,000 deaths recorded in < 5-year-olds in 2016. Cross-sectional studies on hospitalized LRTIs are available, but longitudinal studies on the total burden of viral LRTIs are scarce. This study (NCT01995175) prospectively collected incident RSV and other viral LRTIs in a multinational cohort.MethodsFrom 2013 to 2017, infants in 8 countries were enrolled at birth and followed for LRTIs up to 2 years of age. Infants with suspected LRTIs were clinically examined and swabbed. Nasal swab samples were tested using quantitative real-time PCR for RSV and multiplex PCR panel for 16 other respiratory viruses/subtypes; bacterial culture was not performed. LRTI and severe LRTI episodes were defined per 2015 WHO LRTI case definitions. Viruses detected from nasal swabs collected from participants with WHO-defined LRTI and severe LRTI episodes are reported.ResultsThe 2401 infants followed experienced 1012 LRTI episodes; 259 of these were severe LRTIs. At least 1 virus was detected from 909 (90%) and 235 (91%) LRTI and severe LRTI episodes, respectively. Enteroviruses/Rhinoviruses (EV/RV, 49%) were detected most frequently in samples collected from LRTI episodes, followed by RSV (22%), parainfluenza (PIV, 14%), human metapneumovirus (hMPV, 8%) and seasonal coronavirus (CoV, 6%). RSV was detected in 39% of samples from LRTI episodes in < 3-month-olds and in 18% of 1-year-olds (Table 1). In a similar trend, RSV was detected in 47% of samples from severe LRTI episodes in < 3-month-olds and in 21% of 1-year-olds (Table 2). Co-infection with another virus was common in CoV-positive samples (67%), while most samples positive for RSV (71%), hMPV (70%), EV/RV (67%) and PIV (58%) had no other virus detected.Table 1. Occurrence of laboratory confirmed respiratory viral infections by viral pathogens identified in nasal swab samples from WHO-defined LRTI episodes Table 2. Occurrence of laboratory confirmed respiratory viral infections by viral pathogens identified in nasal swab samples from WHO-defined severe LRTI episodes ConclusionRespiratory viruses are detected in the majority of LRTIs during the first 2 years of life. RSV likely accounts for much of this overall LRTI burden. Our results suggest that RSV most strongly impacted the very young; it was the most commonly detected virus in severe LRTIs in infants aged < 3 months. RSV was also persistently detected at high levels in samples from LRTIs (22%) and severe LRTIs (28%) in children up to 2 years old.FundingGlaxoSmithKline Biologicals SADisclosuresAna Ceballos, MD, GSK group of companies (Scientific Research Study Investigator) Jo Ann Colas, MSc, GSK group of companies (Consultant) Luis Cousin, MD, Tecnología en Investigación (Scientific Research Study Investigator) Ilse Dieussaert, IR, GSK group of companies (Employee, Shareholder) Joseph B. Domachowske, MD, Astra Zeneca (Other Financial or Material Support, Grant/Research Support paid to my Institution on my behalf for sponsored human clinical trial activities)GSK group of companies (Other Financial or Material Support, Grant/Research Support paid to my Institution on my behalf for sponsored human clinical trial activities)Merck (Other Financial or Material Support, Grant/Research Support paid to my Institution on my behalf for sponsored human clinical trial activities) Janet A. Englund, MD, AstraZeneca (Scientific Research Study Investigator)GSK group of companies (Scientific Research Study Investigator)Meissa vaccines (Consultant)Merck (Scientific Research Study Investigator)Sanofi Pasteur (Consultant) Sanjay Gandhi, MD, GSK group of companies (Employee) Mélanie Hercor, PhD, GSK group of companies (Employee) Magali de Heusch, PhD, GSK group of companies (Employee) Joanne M. Langley, MD, GSK group of companies (Research Grant or Support)Immunivaccines Inc (Scientific Research Study Investigator, Research Grant or Support)Janssen (Research Grant or Support)Pfizer (Research Grant or Support)Symvivo (Scientific Research Study Investigator, Research Grant or Support)VBI Vaccines (Research Grant or Support) Amanda Leach, MRCPCH, GSK group of companies (Employee) Timo Vesikari, MD, PhD, Denka (Consultant) Sonia K. Stoszek, PhD, GSK group of companies (Employee, Shareholder)

Treatment of Acute Bronchiolitis in a Resource-limited Setting in Port Sudan City: A simple Effective Regimen

Background: Bronchiolitis is an acute lower respiratory viral infection, caused by the Respiratory Syncytial Virus (RSV) in 60–85% of cases and other respiratory viruses in remaining ones. It is the leading cause of hospitalization for infants and toddlers during the winter and early spring months. At the moment, there is no consensus on its treatment worldwide. The prevalence is increasing in port Sudan eastern Sudan, while we have no admission policy or a unified management protocol. Therefore, the aim of this study is: (1) to formulate an admission policy and a new simple management protocol; (2) to determine the factor(s) that increased the prevalence in port Sudan as a secondary objective; and (3) to compare the outcome in the study (119 infants) and historical (135 infants) groups concerning the hospitalization length and death rate as a primary objectives.&#x0D; Method: This is a hospital-based, controlled clinical trial (CCT) study, demographic data were collected by a questionnaire, and data were analyzed manually. Severity criteria for acute bronchiolitis are defined. A management guideline was defined and applied to bronchiolitis cases (119 case) with intention to treat, from October to April each year (2013–2015). All infants aged between 1 and 23 months with only acute bronchiolitis were included, while cases with bronchiolitis and associated dysmorphic features, heart disease, tracheo-oesophageal fistula, other respiratory diseases, other morbidities, infants below one month or above two years were excluded from this study. The outcome was compared to a group of matched infants with bronchiolitis (135 cases) who received antibiotics, B2 agonist, and steroids, between October and April of years 2011–2012.&#x0D; Results: While several new lifestyle factors increased the prevalence, the new guidelines decreased the admission rate (9.6 vs 5.7 mo), is simple and effective, less expensive, and the duration of hospitalization also reduced (p = 0.04).&#x0D; Key words:&#x0D; acute bronchiolitis, resource-limited settings, advanced respiratory intervention, simple effective intervention,S-7Pro3NO regimen

Clinical Utility of In-house Metagenomic Next-generation Sequencing for the Diagnosis of Lower Respiratory Tract Infections and Analysis of the Host Immune Response.

Only few pathogens that cause lower respiratory tract infections (LRTIs) can be identified due to limitations of traditional microbiological methods and the complexity of the oropharyngeal normal flora. Metagenomic next-generation sequencing (mNGS) has the potential to solve this problem. This prospective observational study sequentially enrolled 93 patients with LRTI and 69 patients without LRTI who visited Peking University People's Hospital in 2019. Pathogens in bronchoalveolar lavage fluid (BALF) specimens were detected using mNGS (DNA and RNA) and traditional microbiological assays. Human transcriptomes were compared between LRTI and non-LRTI, bacterial and viral LRTI, and tuberculosis and nontuberculosis groups. Among 93 patients with LRTI, 20%, 35%, and 65% of cases were detected as definite or probable pathogens by culture, all microbiological tests, and mNGS, respectively. Our in-house BALF mNGS platform had an approximately 2-working-day turnaround time and detected more viruses and fungi than the other methods. Taking the composite reference standard as a gold standard, it had a sensitivity of 66.7%, specificity of 75.4%, positive-predictive value of 78.5%, and negative-predictive value of 62.7%. LRTI-, viral LRTI-, and tuberculosis-related differentially expressed genes were respectively related to immunity responses to infection, viral transcription and response to interferon-γ pathways, and perforin 1 and T-cell receptor B variable 9. Metagenomic DNA and RNA-seq can identify a wide range of LRTI pathogens, with improved sensitivity for viruses and fungi. Our in-host platform is likely feasible in the clinic. Host transcriptome data are expected to be useful for the diagnosis of LRTIs.

Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT

AbstractRespiratory viral infections are frequent in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) and can potentially progress to lower respiratory tract infection (LRTI). The intestinal microbiota contributes to resistance against viral and bacterial pathogens in the lung. However, whether intestinal microbiota composition and associated changes in microbe-derived metabolites contribute to the risk of LRTI following upper respiratory tract viral infection remains unexplored in the setting of allo-HCT. Fecal samples from 360 allo-HCT patients were collected at the time of stem cell engraftment and subjected to deep, 16S ribosomal RNA gene sequencing to determine microbiota composition, and short-chain fatty acid levels were determined in a nested subset of fecal samples. The development of respiratory viral infections and LRTI was determined for 180 days following allo-HCT. Clinical and microbiota risk factors for LRTI were subsequently evaluated using survival analysis. Respiratory viral infection occurred in 149 (41.4%) patients. Of those, 47 (31.5%) developed LRTI. Patients with higher abundances of butyrate-producing bacteria were fivefold less likely to develop viral LRTI, independent of other factors (adjusted hazard ratio = 0.22, 95% confidence interval 0.04-0.69). Higher representation of butyrate-producing bacteria in the fecal microbiota is associated with increased resistance against respiratory viral infection with LRTI in allo-HCT patients.

Tissue-resident CD8+ T cells drive age-associated chronic lung sequelae after viral pneumonia.

Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-β present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia.

Nebulised ALX-0171 for respiratory syncytial virus lower respiratory tract infection in hospitalised children: a double-blind, randomised, placebo-controlled, phase 2b trial

Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection, with a high global health burden. There are no effective treatments available. ALX-0171 is a novel trivalent Nanobody with antiviral properties against RSV. We aimed to assess the safety and antiviral activity of nebulised ALX-0171 in children admitted to hospital with RSV lower respiratory tract infection. This double-blind, randomised, placebo-controlled, phase 2b trial was done in 50 hospital paediatric departments across 16 countries. Previously healthy children aged between 28 days to younger than 24 months who were admitted to hospital with RSV acute severe lower respiratory tract infection were randomly assigned in three sequential safety cohorts (3:1) to receive nebulised ALX-0171 (cohort 1 received 3 mg/kg, cohort 2 received 6 mg/kg, and cohort 3 received 9 mg/kg) or placebo once daily for 3 days using web-based randomisation in the sequential safety part (first block size 12, subsequently four). In a parallel part of the study, participants (cohort 4) were randomly assigned (parallel 1:1:1:1) to receive nebulised ALX-0171 3 mg/kg, 6 mg/kg, 9 mg/kg, or placebo (blocks of eight by restricted randomisation). Study drug masking was by two consecutive nebulisations (each either ALX-0171 or placebo) depending on assigned treatment group. The primary outcome was to evaluate time for the RSV viral load to drop to below quantifiable limit, measured by plaque assay on mid-turbinate nasal swabs. Safety, clinical efficacy, pharmacokinetics, viral load by RT-qPCR, and immunogenicity were secondary outcomes. Analysis, including of the primary outcome, was by modified intention to treat (participants receiving at least one dose of study drug as assigned), and safety was assessed in all children who received at least one administration of study drug, as treated. This trial is registered with EudraCT, 2016-001651-49. Between Jan 10, 2017, and April 26, 2018, 175 children (median age 4·8 months [IQR 2·0-10·8]), received at least one dose of study drug (45 received 3 mg/kg of ALX-0171, 43 received 6 mg/kg of ALX-0171, 45 received 9 mg/kg of ALX-0171, and 42 received placebo; the modified intention-to-treat population) commencing at a mean 3·3 days (SD 1·1) from symptom onset. Median time for the viral load to drop to below quantifiable limit on plaque assay was significantly faster for the 3 mg/kg group (median 14·2 h [IQR 5·0-28·0]), 6 mg/kg group (5·1 h [4·7-28·5]), and 9 mg/kg group (5·1 h [4·6-5·9]) than the placebo group (46·1 h [25·2-116·7]; hazard ratio [HR] all ALX-0171 groups vs placebo 2·6 [1·7-3·9]; p<0·0001). Median time for the viral load to drop below quantification limit with RT-qPCR was 95·9 h (IQR 26·7 to not estimable) for the placebo group (n=35) versus 49·4 h (25·1 to 351·4) for all ALX-0171 groups (n=118). Clinical outcomes were not improved by ALX-0171 compared with placebo, with no difference in time to clinical response (oxygen saturation >92% for 4 h in room air and adequate oral feeding) in ALX-0171 groups and the placebo group (median 43·8 h [IQR 21·7-68·5] vs 47·9 h [22·5-76·4]; HR 1·1 [95% CI 0·8-1·6]) or change in the global severity score from baseline to 5 h post-dose on day 2 (-4 [IQR -6 to -2] vs -4 [-6 to -1]; difference in least-squares mean -0·45 [95% CI -1·39 to 0·49]). Serum concentrations of ALX-0171 on day 2 exceeded the concentration estimated to give full RSV neutralisation in the lung at 6 mg/kg and 9 mg/kg doses. Treatment-emergent antidrug antibodies were detected at day 14 in 46 (34%) of 135 patients who received ALX-0171 and ten (26%) of 39 patients who received placebo. Serious adverse events were reported in five (13%) of 40 children in the placebo group and ten (7%) of 135 children in all ALX-0171 groups, leading to study drug discontinuation in three children (two in the 3 mg/kg group and one in the 6 mg/kg group). 13 of 15 serious adverse events (three of four in the 3 mg/kg group, two of three in the 6 mg/kg group, three of three in the 9 mg/kg group, and five of five in the placebo group) were related to worsening respiratory status, and none were considered to be related to the study drug. Antivirals against RSV might be unable to improve clinical course once RSV lower respiratory tract infection is established. Future studies of RSV antivirals should focus on earlier intervention and more precise measurement of objective outcomes before the onset of significant lower respiratory tract inflammation. Ablynx, a Sanofi Company.

Early-life respiratory syncytial virus lower respiratory tract infection in a South African birth cohort: epidemiology and effect on lung health

SummaryBackgroundRespiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) in children. Early-life RSV LRTI might affect long-term health but there are few data from low-income and middle-income countries. We investigated the epidemiology and effect of early-life RSV LRTI on lung health in a South African birth cohort.MethodsWe conducted the Drakenstein Child Health Study (DCHS), an ongoing birth cohort longitudinal study in the Western Cape province, South Africa. We enrolled pregnant women aged 18 years or older during their second trimester of pregnancy at two public health clinics. We followed up study children from birth to 2 years. The primary outcome of the study was LRTI and RSV LRTI. LRTI and wheezing episodes were identified through active surveillance; respiratory samples were tested for RSV and other pathogens. Wheezing was longitudinally identified by caregiver report and ascertainment at health facilities. Lung function was measured from 6 weeks to 2 years. We analysed the associations between RSV LRTI and subsequent LRTI, wheezing, and lung function using generalised estimating equations and mixed-effects linear regression.FindingsWe enrolled 1137 mothers between March 5, 2012, and March 31, 2015. Among their 1143 infants, accruing 2093 child-years of follow-up, there were 851 cases of LRTI (incidence 0·41 episodes per child-year, 95% CI 0·38–0·43). Admission to hospital owing to LRTI occurred in 169 (20%) cases (incidence 0·08 episodes per child-year, 0·07–0·09), with a case-fatality ratio of 0·5%. RSV was detected in 164 (21%) of 785 LRTI events with a specimen available for qPCR, an incidence of 0·08 episodes per child-year (0·07–0·09); highest at age 0–6 months (0·15 episodes per child-year, 0·12–0·19). Children with a first RSV LRTI were three times as likely to develop recurrent LRTI compared with those with non-RSV LRTI (0·32 [0·22–0·48] vs 0·10 [0·07– 0·16] episodes per child-year; p<0·0001), particularly following hospitalised RSV LRTI. RSV LRTI and hospitalisation for all-cause LRTI were independently associated with recurrent wheezing (adjusted incident rate ratio 1·41, 95% CI 1·25–1·59, for RSV LRTI and 1·48, 1·30–1·68, for hospitalisation). LRTI or recurrent LRTI was associated with impaired lung function, but a similar outcome was observed following RSV LRTI or non-RSV LRTI. All-cause LRTI was associated with an average 3% higher respiratory rate (95% CI 0·01–0·06; p=0·013) and lower compliance (–0·1, −0·18 to 0·02) at 2 years compared with no LRTI. Recurrent LRTI was associated with further increased respiratory rate (0·01, 0·001–0·02), resistance (0·77 hPa s L−1, 0·07–1·47), and lower compliance (–0·6 mL hPa−1, −0·09 to −0·02) with each additional event.InterpretationRSV LRTI was common in young infants and associated with recurrent LRTI, particularly after hospitalised RSV. Hospitalisation for all-cause LRTI, especially for RSV-LRTI, was associated with recurrent wheezing. Impairments in lung function followed LRTI or recurrent episodes, but were not specific to RSV. New preventive strategies for RSV might have an effect on long-term lung health.FundingBill & Melinda Gates Foundation; South African Medical Research Council; National Research Foundation South Africa; National Institutes of Health, Human Heredity and Health in Africa; Wellcome Trust.

Probiotics: An Alternative Therapeutic Strategy for Covid-19

ABSTRACT: The COVID- 19 pandemic has made the scientists today all around the globe to look for its specific prevention and treatment modalities. The disease presents itself as asymptomatic to mild to severe respiratory symptoms along with lesser common gastrointestinal symptoms of diarrhea, nausea, and vomiting. The situation worsens due to lack of precise treatment strategy. The Healthcare system is being overwhelmed, emphasizing on the need to look for alternate supportive therapy that can not only enhance the immune status of people worldwide but at the same time, ensure better prognosis. The relationship between the gut microbiota and upper and lower respiratory tract viral infections are well studied. Oral administration of probiotic microorganisms of genera Lactobacillus, Bifidobacterium and Bacillusin mice suffering from influenza infection have shown increased TNFα, IFN-γ and NK cell responses along with the production of anti-Influenza IgG. At the same time they have shown immunomodulation by producing anti-inflammatory cytokines as well as cytotoxic T-cells and T-suppressor cells. Hence, probiotic strains of generaLactobacillus, Bifidobacterium and Bacillushave shown a probability to be used as preventive and therapeutic agents for SARS- CoV-2.

A study on aetiology and outcomes of viral lower respiratory tract infections in hospitalized children from South India

Introduction: Viral respiratory infection is a common cause of morbidity and mortality in children, especially those less than 5 years old. Objectives: To study the aetiology and seasonal variation of viral lower respiratory tract infection (LRTI) in hospitalized children and to assess the morbidity and mortality. Method: A retrospective cohort study was done on children, aged 1 month to 16 years, admitted in G. Kuppuswamy Naidu Memorial hospital, a tertiary care hospital in Coimbatore, South India. Case records of children hospitalized with features of LRTI, for whom respiratory viral panel was sent, were retrospectively reviewed and were analysed from July 2017 to June 2018. The aetiology of viral infection, age wise distribution, severity of illness and seasonal variation were studied. Multiplex PCR panel was done from either throat swab or nasopharyngeal aspirate in 69 children admitted with a clinician diagnosis of LRTI. Results: Respiratory viruses were identified in 33 (47.8%) of the 69 children. Respiratory syncytial virus (RSV), Influenza viruses A and B, parainfluenza virus and boca virus were the common viruses isolated from hospitalized children with LRTI. RSV and bocavirus were common among children less than 2 years old. RSV infection began in July, peaked during September and October and continued till January. Influenza virus was common among children more than 2 years and occurred between September and March. Conclusions: RSV, Influenza A and B viruses, parainfluenza virus and bocavirus were the common viruses isolated from hospitalized children with LRTI. RSV infection peaked from September to October whilst influenza virus infection peaked from January to March. Sri Lanka Journal of Child Health, 2020; 49(3): 218-222

6 Factors associated with treatment failure of high flow nasal cannula (HFNC) among children with bronchiolitis: a single centre retrospective study

Abstract Background Bronchiolitis is the most common viral lower respiratory tract infection in children under two years of age and is the leading cause of hospital admission for children under the age of one year. Respiratory support for bronchiolitis with high flow nasal cannula (HFNC) is increasingly being used outside of critical care areas and in community hospitals. It is important to understand the patient factors associated with HFNC treatment failure in order to identify which patients are at higher risk for requiring escalation of respiratory support and transfer to a pediatric critical care centre. Objectives The primary objective of this study was to evaluate the patient characteristics that are associated with HFNC treatment failure in bronchiolitis. Design/Methods We completed a retrospective review of patients under 24 months of age with a clinical diagnosis of bronchiolitis admitted to a single tertiary level children’s hospital for supportive management with HFNC between January 2014 and December 2018. Patients who were mechanically ventilated or on non-invasive positive pressure ventilation prior to the initiation of HFNC during their hospital stay were excluded. HFNC treatment failure was the primary endpoint of the study, with treatment failure defined as escalation to non-invasive positive pressure or invasive mechanical ventilation. Multivariable logistic regression analysis was used to identify the patient demographic, clinical, and biochemical parameters associated with HFNC failure. Results Four hundred and thirty-five patient charts were identified, of which 208 patients met inclusion criteria for the study. Of these patients, 61 (29%) were classified as HFNC treatment failures. The likelihood of failing HFNC support was reduced with older age (OR 0.89; 95% CI 0.81, 0.97; p= 0.011) and greater time spent on HFNC (OR 0.94; 95% CI 0.92, 0.96; p&amp;lt;0.001). Patients with a Modified Tal score greater than 5 at 4 hours of HFNC treatment had a greater likelihood of failing HFNC support (OR 2.81; 95% CI 1.04, 7.64; p= 0.042). Conclusion This was the first study to examine predictors of HFNC failure among Canadian children with bronchiolitis. We found that patient age, time spent on HFNC, and severity of bronchiolitis as defined using a Modified Tal score were associated with HFNC failure. These patient factors should be considered when initiating HFNC for bronchiolitis, and may identify patients at risk for escalation of respiratory support, warranting earlier referral to pediatric critical care centres.

Evidence on the Link between Respiratory Syncytial Virus Infection in Early Life and Chronic Obstructive Lung Diseases.

There is growing evidence in medical literature to support an association between early-life respiratory syncytial virus lower respiratory tract-lower respiratory tract infection (RSV-LRTI) and recurrent wheezing/asthma-like symptoms. It has been estimated that children with a history of RSV-LRTI have a 2- to 12-fold higher risk of developing asthma. The connection between RSV infection and a developmental trajectory of reduced lung function remains throughout adolescence and early adulthood, suggesting a possible role for RSV even in the inception of chronic obstructive pulmonary disease. That is why the postnatal period appears to offer a specific window of opportunity for early intervention to prevent chronic obstructive lung diseases. The mechanisms by which RSV contributes to the onset of wheezing/asthma and lung function impairment are not fully understood but appear to relate to injury caused directly by the virus and/or to pre-existing predisposing factors. While awaiting a deeper understanding of the association between RSV and chronic lung diseases, the crucial role of pediatricians and physicians is to develop strategies to prevent RSV infections to try and protect children's lifelong respiratory health. KEY POINTS: · Several evidence suggest a link between RSV infection in early life and wheezing/asthma development.. · RSV infection appears to have long term respiratory effects.. · The prevention of RSV infections could reduce the incidence of chronic obstructive respiratory diseases..