Age-dependent nasal immune responses in non-hospitalized bronchiolitis children.

Bronchiolitis in children is associated with significant rates of morbidity and mortality. Many studies have been performed using samples from hospitalized bronchiolitis patients, but little is known about the immunological responses from infants suffering from mild/moderate bronchiolitis that do not require hospitalization. We have studied a collection of nasal lavage fluid (NLF) samples from outpatient bronchiolitis children as a novel strategy to unravel local humoral and cellular responses, which are not fully characterized. The children were age-stratified in three groups, two of them (GI under 2-months, GII between 2-4 months) presenting a first episode of bronchiolitis, and GIII (between 4 months and 2 years) with recurrent respiratory infections. Here we show that elevated levels of pro-inflammatory cytokines (IL1ß, IL6, TNFα, IL18, IL23), regulatory cytokines (IL10, IL17A) and IFNγ were found in the three bronchiolitis cohorts. However, little or no change was observed for IL33 and MCP1, at difference to previous results from bronchiolitis hospitalized patients. Furthermore, our results show a tendency to IL1ß, IL6, IL18 and TNFα increased levels in children with mild pattern of symptom severity and in those in which non RSV respiratory virus were detected compared to RSV+ samples. By contrast, no such differences were found based on gender distribution. Bronchiolitis NLFs contained more IgM, IgG1, IgG3 IgG4 and IgA than NLF from their age-matched healthy controls. NLF from bronchiolitis children predominantly contained neutrophils, and also low frequency of monocytes and few CD4+ and CD8+ T cells. NLF from infants older than 4-months contained more intermediate monocytes and B cell subsets, including naïve and memory cells. BCR repertoire analysis of NLF samples showed a biased VH1 usage in IgM repertoires, with low levels of somatic hypermutation. Strikingly, algorithmic studies of the mutation profiles, denoted antigenic selection on IgA-NLF repertoires. Our results support the use of NLF samples to analyze immune responses and may have therapeutic implications.

High Frequency of Viral Co-Detections in Acute Bronchiolitis.

Over two years (2012-2014), 719 nasopharyngeal samples were collected from 6-week- to 12-month-old infants presenting at the emergency department with moderate to severe acute bronchiolitis. Viral testing was performed, and we found that 98% of samples were positive, including 90% for respiratory syncytial virus, 34% for human rhino virus, and 55% for viral co-detections, with a predominance of RSV/HRV co-infections (30%). Interestingly, we found that the risk of being infected by HRV is higher in the absence of RSV, suggesting interferences or exclusion mechanisms between these two viruses. Conversely, coronavirus infection had no impact on the likelihood of co-infection involving HRV and RSV. Bronchiolitis is the leading cause of hospitalizations in infants before 12 months of age, and many questions about its role in later chronic respiratory diseases (asthma and chronic obstructive pulmonary disease) exist. The role of virus detection and the burden of viral codetections need to be further explored, in order to understand the physiopathology of chronic respiratory diseases, a major public health issue.

Integrated omics endotyping of infants with respiratory syncytial virus bronchiolitis and risk of childhood asthma.

Respiratory syncytial virus (RSV) bronchiolitis is not only the leading cause of hospitalization in U.S. infants, but also a major risk factor for asthma development. While emerging evidence suggests clinical heterogeneity within RSV bronchiolitis, little is known about its biologically-distinct endotypes. Here, we integrated clinical, virus, airway microbiome (species-level), transcriptome, and metabolome data of 221 infants hospitalized with RSV bronchiolitis in a multicentre prospective cohort study. We identified four biologically- and clinically-meaningful endotypes: A) clinicalclassicmicrobiomeM. nonliquefaciensinflammationIFN-intermediate, B) clinicalatopicmicrobiomeS. pneumoniae/M. catarrhalisinflammationIFN-high, C) clinicalseveremicrobiomemixedinflammationIFN-low, and D) clinicalnon-atopicmicrobiomeM.catarrhalisinflammationIL-6. Particularly, compared with endotype A infants, endotype B infants-who are characterized by a high proportion of IgE sensitization and rhinovirus coinfection, S. pneumoniae/M. catarrhalis codominance, and high IFN-α and -γ response-had a significantly higher risk for developing asthma (9% vs. 38%; OR, 6.00: 95%CI, 2.08-21.9; P = 0.002). Our findings provide an evidence base for the early identification of high-risk children during a critical period of airway development.

Balancing precision versus cohort transcriptomic analysis of acute and recovery phase of viral bronchiolitis.

Viral infections affecting the lower respiratory tract place enormous burdens on hospitals. As neither vaccines nor antiviral agents exist for many viruses, understanding risk factors and outcomes in each patient using minimally invasive analysis, such as blood, can lead to improved health care delivery. A cohort of PAXgene RNA sequencing of infants admitted with moderate or severe acute bronchiolitis and respiratory syncytial virus were compared with case-control statistical analysis and cohort-based outlier mapping for precision transcriptomics. Patients with severe bronchiolitis had signatures connected to the immune system, interferon signaling, and cytokine signaling, with marked sex differences in XIST, RPS4Y1, KDM5D, and LINC00278 for severity. Several patients had unique secondary infections, cytokine activation, immune responses, biological pathways, and immune cell activation, highlighting the need for defining patient-level transcriptomic signatures. Balancing relative contributions of cohort-based biomarker discoveries with patient's biological responses is needed to understand the totality of mechanisms of adverse outcomes in viral bronchiolitis.

For which infants with viral bronchiolitis could it be deemed appropriate to use albuterol, at least on a therapeutic trial basis?

Although there is increasing evidence showing that infants with viral bronchiolitis exhibit a high degree of heterogeneity, a core uncertainty shared by many clinicians is with regard to understanding which patients are most likely to benefit from bronchodilators such as albuterol. Based on our review, we concluded that older infants with rhinovirus (RV) bronchiolitis, especially those with a nasopharyngeal microbiome dominated by Haemophilus influenzae; those affected during nonpeak months or during non-respiratory syncytial virus (RSV) predominant months; those with wheezing at presentation; those with clinical characteristics such as atopic dermatitis or a family history of asthma in a first-degree relative; and those infants infected with RSV genotypes ON1 and BA, have the greatest likelihood of benefiting from albuterol. Presently, this patient profile could serve as the basis for rational albuterol administration in patients with viral bronchiolitis, at least on a therapeutic trial basis, and it could also be the starting point for future targeted randomized clinical trials (RCTs) on the use of albuterol among a subset of infants with bronchiolitis.

Identifying and managing bronchiolitis.

Bronchiolitis is a common viral illness that affects the lower respiratory tract of infants and young children. The disease is characterized by wheezing and increased mucus production and can range from mild to severe in terms of respiratory distress. This article reviews the epidemiology, clinical presentation, and treatment of bronchiolitis.

In vivo comparison of a laboratory-adapted and clinical-isolate-based recombinant human respiratory syncytial virus.

Human respiratory syncytial virus (HRSV) is the leading cause of severe respiratory tract disease in infants. Most HRSV infections remain restricted to the upper respiratory tract (URT), but in a small percentage of patients the infection spreads to the lower respiratory tract, resulting in bronchiolitis or pneumonia. We have a limited understanding of HRSV pathogenesis and what factors determine disease severity, partly due to the widespread use of tissue-culture-adapted viruses. Here, we studied early viral dissemination and tropism of HRSV in cotton rats, BALB/cJ mice and C57BL/6 mice. We used a novel recombinant (r) strain based on a subgroup A clinical isolate (A11) expressing EGFP [rHRSVA11EGFP(5)]. A recombinant laboratory-adapted HRSV strain [rHRSVA2EGFP(5)] was used as a direct comparison. Our results show that rHRSVA11EGFP(5) replicated to higher viral titres than laboratory-adapted rHRSVA2EGFP(5) in the URT of cotton rats and mice. HRSV-infected cells were detected as early as 2 days post-inoculation in both species in the nasal septa and lungs. Infection was predominantly present in ciliated epithelial cells in cotton rats and in the olfactory mucosa of mice. In our opinion, this study highlights that the choice of virus strain is important when studying HRSV pathogenesis in vivo and demonstrates that A11 is a representative clinical-based virus. Additionally, we show critical differences in tropism and inflammation when comparing HRSV infection of cotton rats and mice.

A 14-year Prospective Study of Human Coronavirus Infections in Hospitalized Children: Comparison With Other Respiratory Viruses.

BACKGROUND: Human coronaviruses (HCoVs) have been recognized as causative agents of respiratory tract infections.Our aim was to describe HCoV infections in hospitalized children in a prospective surveillance study for 14 years and compare them with other respiratory viruses. METHODS: As a part of an ongoing prospective study to identify the etiology of viral respiratory infections in Spain, we performed the analysis of HCoV infections in children hospitalized in a secondary hospital in Madrid, between October 2005 and June 2018. Clinical data of HCoV patients were compared with those infected by rhinovirus, respiratory syncytial virus and influenza. RESULTS: The study population consisted of 5131 hospitalizations for respiratory causes in children. A total of 3901 cases (75.9%) had a positive viral identification and 205 cases (4.1%) were positive for HCoV. Only 41 cases (20%) of HCoV infection were detected as single infections. Episodes of recurrent wheezing were the most common diagnosis, and 112 children (54%) had hypoxia. Clinical data in HCoV cases were similar to those associated with rhinovirus; however, patients with HCoV were younger. Other viruses were associated with hypoxia more frequently than cases with HCoV; high fever was more common in influenza infections and bronchiolitis in respiratory syncytial virus group. Although a slight peak of circulation appears mostly in winter, HCoV has been detected throughout the year as well. CONCLUSIONS: HCoV infections represent a small fraction of respiratory infections that require hospitalization in children and their characteristics do not differ greatly from other respiratory viral infections.

Risk Factors for Respiratory Syncytial Virus Bronchiolitis Admissions.

Aim Determine the seasonal incidence of hospital Respiratory Syncytial Virus (RSV) bronchiolitis and explore the variables associated with admission to ward versus the Paediatric Intensive Care Unit (PICU). Method Retrospective case-control study. Children, aged ≤2 years, between November and March, over a 3 year period with a positive RSV nasopharyngeal aspirate test. Results A total of 557 children were included; 19% (n=106) required PICU admission. Children admitted to the PICU were younger in age, median (IQR) 6.93 (3.96, 11.89) weeks compared to children who remained on the wards 11.00 (5.86, 24.14) weeks. Being underweight at the point of admission (adjusted odds ratio 3.15, 95% 1.46, 6.70, p=0.003) was associated with a PICU admission. Conclusion Number of RSV bronchiolitis hospitalisations are increasing each year. Age, weight and the use of HFNC were independent predictors for PICU admission.

Predictors for the prescription of albuterol in infants hospitalized for viral bronchiolitis.

INTRODUCTION AND OBJECTIVES: Despite the recommendation against routine use of inhaled bronchodilators in infants with viral bronchiolitis given in the main clinical practice guidelines (CPGs) on viral bronchiolitis, albuterol is widely prescribed to patients with this disease. The aim of this study was to identify predictors of prescription of albuterol in a population of infants hospitalized for viral bronchiolitis. MATERIAL AND METHODS: An analytical cross-sectional study performed during the period from March 2014 to August 2015, in a random sample of patients <2 years old hospitalized in the Fundacion Hospital La Misericordia, a hospital located in Bogota, Colombia. After reviewing the electronic medical records, we collected demographic, clinical, and disease-related information, including prescription of albuterol at any time during the course of hospitalization as the outcome variable. RESULTS: For a total of 1365 study participants, 1042 (76.3%) were prescribed with albuterol therapy. After controlling for potential confounders, it was found that age (OR 1.11; CI 95% 1.08-1.15; p<0.001), and a prolonged length of stay (LOS) (OR 1.93; CI 95% 1.44-2.60; p<0.001) were independent predictors of prescription of albuterol in our sample of patients. By contrast, albuterol prescription was less likely in the post-guideline assessment period (OR 0.41; CI 95% 0.31-0.54; p<0.001), and in infants with RSV isolation (OR 0.71; CI 95% 0.52-0.97; p=0.035). CONCLUSIONS: Albuterol was highly prescribed in our population of inpatients with the disease. The independent predictors of prescription of albuterol in our sample of patients were age, implementation of a CPG on viral bronchiolitis, RSV isolation, and LOS.

The impact of viral bronchiolitis phenotyping: Is it time to consider phenotype-specific responses to individualize pharmacological management?

Although recent guidelines recommend a minimalist approach to bronchiolitis, there are several issues with this posture. First, there are concerns about the definition of the disease, the quality of the guidelines, the method of administration of bronchodilators, and the availability of tools to evaluate the response to therapies. Second, for decades it has been assumed that all cases of viral bronchiolitis are the same, but recent evidence has shown that this is not the case. Distinct bronchiolitis phenotypes have been described, with heterogeneity in clinical presentation, molecular immune signatures and clinically relevant outcomes such as respiratory failure and recurrent wheezing. New research is critically needed to refine viral bronchiolitis phenotyping at the molecular and clinical levels as well as to define phenotype-specific responses to different therapeutic options.

Association between multiple respiratory viral infections and pediatric intensive care unit admission among infants with bronchiolitis.

BACKGROUND: It is unclear whether multiple respiratory viral infections are associated with more severe bronchiolitis requiring pediatric intensive care unit (PICU) admission. We aimed to identify the association between multiple respiratory viral infections and PICU admission among infants with bronchiolitis. METHODS: We performed a 1:1 case-control study enrolling previously healthy full-term infants (≤12 months) with bronchiolitis admitted to the PICU as cases and those to the general pediatric ward as controls from 2015 to 2017. Multiplex polymerase chain reaction (PCR) was used for detection of the respiratory viruses. We summarized the characteristics of infants admitted to the PICU and the general pediatric unit. Multivariable logistic regression analysis was used to fit the association between multiple respiratory viral infections (≥2 strains) and PICU admission. RESULTS: A total of 135 infants admitted to the PICU were compared with 135 randomly selected control infants admitted to the general pediatric unit. The PICU patients were younger (median: 2.2 months, interquartile range: 1.3-4.2) than the general ward patients (median: 3.2 months, interquartile range: 1.6-6.4). Respiratory syncytial virus (74.1%), rhinovirus (28.9%), and coronavirus (5.9%) were the most common viruses for bronchiolitis requiring PICU admission. Patients with bronchiolitis admitted to the PICU tended to have multiple viral infections compared with patients on the general ward (23.0% vs. 10.4%, P<0.001). In the multivariable logistic regression analysis, bronchiolitis with multiple viral infections was associated with higher odds of PICU admission (adjusted odds ratio: 2.56, 95% confidence interval: 1.17-5.57, P=0.02). CONCLUSION: Infants with multiviral bronchiolitis have higher odds of PICU admission compared with those with a single or nondetectable viral infection.

[Respiratory syncytial virus]. / Respiratorisches Synzytialvirus.

Respiratory syncytial virus (RSV) is worldwide a very important virus leading to infection of the respiratory system. In particular preterm babies, infants and elderly adults are prone to developing severe diseases such as bronchiolitis or pneumonia, which require intensive care and cause increased mortality. Although RSV is rapidly detected, preventive and therapeutic measures are limited. New antivirals are already in clinical trials.

Complicaciones neurológicas en casos de bronquiolitis por virus respiratorio sincitial: estado febril y otras manifestaciones neurológicas / Neurological complications in cases of bronchiolitis due to respiratory syncytial virus: febrile status and other neurological manifestations

No disponible

Does exposure of pregnant women to epidemic respiratory syncytial virus affect the severity of bronchiolitis? / ¿Afecta la exposición de la embarazada al virus respiratorio sincitial epidémico a la gravedad de la bronquiolitis?

INTRODUCTION: Passive transplacental immunity against respiratory syncytial virus (RSV) appears to mediate in the protection of the infant for the first 6 months of life. Lower environmental exposure in pregnant women to RSV epidemic may influence the susceptibility of these infants to infection by lowering the levels of antibodies that are transferred to the fetus. OBJECTIVES: To contrast the risk of severe disease progression in infants with acute bronchiolitis by RSV, according to the mother's level of exposure to epidemic. METHOD: Retrospective cohort study of previously healthy infants with RSV-acute bronchiolitis during 5 epidemics was made. We compared the severity of the infection in those born during the period of risk (when is less likely the mother's exposure to epidemic and the transfer of antibodies to the fetus: October 15th-December 15 th in our latitude) with the rest of acute bronchiolitis. Bivariate analysis was performed regarding birth in period of risk and the rest of variables, using the Chi-square test. Multivariate logistic regression analysis was performed to study possible classical confounding factors. RESULTS: 695 infants were included in the study. 356 infants were born during the period of risk. Of the 56 patients requiring admission to PICU, 40 of them (71.4%) were born in this period (p = 0.002). In the multivariate analysis, the birth in the period of risk showed a 6.5 OR (95% CI: 2.13-19.7) independently of the rest of variables. CONCLUSIONS: The worst clinical disease progression of the acute bronchiolitis by the RSV in less than 6 months age is related to lower exposure of the pregnant woman to the RSV epidemic

INTRODUCCIÓN: La inmunidad pasiva transplacentaria contra el virus respiratorio sincitial (VRS) parece mediar en la protección del lactante durante los primeros 6 meses de vida. La menor exposición ambiental en embarazadas a la epidemia del VRS puede influir en la susceptibilidad de estos niños a la infección al disminuir los niveles de anticuerpos que se transfieren al feto. OBJETIVOS: Contrastar el riesgo de progresión grave de la enfermedad en los lactantes con bronquiolitis aguda por VRS, de acuerdo con el nivel de exposición de la madre a la epidemia. MÉTODO: Se realizó un estudio de cohortes retrospectivo de recién nacidos previamente sanos con bronquiolitis aguda por VRS durante 5 epidemias. Comparamos la gravedad de la infección en los nacidos durante el período de riesgo (cuando es menos probable la exposición de la madre a la epidemia en nuestra latitud y la transferencia de anticuerpos al feto: del 15 de octubre al 15 de diciembre) con el resto de las bronquiolitis agudas. El análisis bivariante se realizó con respecto al nacimiento en el período de riesgo y el resto de las variables, utilizando la prueba de Chi-cuadrado. Posteriormente un análisis de regresión logística multivariable para estudiar los posibles factores de confusión. RESULTADOS: Seiscientos noventa y cinco bebés fueron incluidos en el estudio. Trescientos cincuenta y seis bebés nacieron durante el período de riesgo. De los 56 pacientes que requieren ingreso en la UCIP, 40 de ellos (71,4%) nacieron en este período (p = 0,002). En el análisis multivariante, el nacimiento en el período de riesgo mostró una OR de 6,5 (IC 95%: 2,13-19,7) independientemente del resto de las variables. CONCLUSIONES: La evolución más grave de la enfermedad clínica de la bronquiolitis aguda por el VRS en menores de 6 meses de edad se relaciona con una menor exposición de la embarazada a la epidemia del VRS

Distinct transcriptional modules in the peripheral blood mononuclear cells response to human respiratory syncytial virus or to human rhinovirus in hospitalized infants with bronchiolitis.

Human respiratory syncytial virus (HRSV) is the main cause of bronchiolitis during the first year of life, when infections by other viruses, such as rhinovirus, also occur and are clinically indistinguishable from those caused by HRSV. In hospitalized infants with bronchiolitis, the analysis of gene expression profiles from peripheral blood mononuclear cells (PBMC) may be useful for the rapid identification of etiological factors, as well as for developing diagnostic tests, and elucidating pathogenic mechanisms triggered by different viral agents. In this study we conducted a comparative global gene expression analysis of PBMC obtained from two groups of infants with acute viral bronchiolitis who were infected by HRSV (HRSV group) or by HRV (HRV group). We employed a weighted gene co-expression network analysis (WGCNA) which allows the identification of transcriptional modules and their correlations with HRSV or HRV groups. This approach permitted the identification of distinct transcription modules for the HRSV and HRV groups. According to these data, the immune response to HRSV infection-comparatively to HRV infection-was more associated to the activation of the interferon gamma signaling pathways and less related to neutrophil activation mechanisms. Moreover, we also identified host-response molecular markers that could be used for etiopathogenic diagnosis. These results may contribute to the development of new tests for respiratory virus identification. The finding that distinct transcriptional profiles are associated to specific host responses to HRSV or to HRV may also contribute to the elucidation of the pathogenic mechanisms triggered by different respiratory viruses, paving the way for new therapeutic strategies.

New therapies for acute RSV infections: where are we?

Respiratory syncytial virus (RSV) infection is one of the main causes of infant hospitalization and mortality. The single-stranded RNA virus codes for 11 proteins of which the F protein, a surface epitope responsible for RSV fusion, is the most targeted for developing antiviral medicines and vaccines. The peak of symptoms occurs around day 4 to 6 of illness and the airway obstruction is merely caused by the host immune inflammatory response. Risk factors for severe bronchiolitis are prematurity, comorbidity, and/or being immunocompromised. At present, there are no curative therapies available for RSV infections and treatment is supportive only. Development of new antiviral medicines is however promising. The aim of this review is to give a summary of the most important new antiviral therapies in clinical development for RSV infection and to explain their mode of action. We therefore performed a literature search on this topic.Conclusion: There are currently at least eight antivirals being investigated in clinical trials. They all use different approaches to either focus on preventing viral fusion with host cells or inhibiting virus replication. Some target RSV surface epitopes like the F protein to halt fusion, others aim for RNA chain termination, while small interfering RNAs downregulate viral protein production. What is known: • RSV bronchiolitis is a very important pediatric disease as it is one of the main causes of infant hospitalization and mortality. By the age of 2 years, 95% of all the infants worldwide will have been infected. • The only recommended therapy is supportive since there are no existing curative therapies yet. What this study adds: • This review gives an overview of the current progress in the research field of RSV antivirals with background information on their mode of action.

Does exposure of pregnant women to epidemic respiratory syncytial virus affect the severity of bronchiolitis?

INTRODUCTION: Passive transplacental immunity against respiratory syncytial virus (RSV) appears to mediate in the protection of the infant for the first 6 months of life. Lower environmental exposure in pregnant women to RSV epidemic may influence the susceptibility of these infants to infection by lowering the levels of antibodies that are transferred to the fetus. OBJECTIVES: To contrast the risk of severe disease progression in infants with acute bronchiolitis by RSV, according to the mother's level of exposure to epidemic. METHOD: Retrospective cohort study of previously healthy infants with RSV-acute bronchiolitis during 5 epidemics was made. We compared the severity of the infection in those born during the period of risk (when is less likely the mother's exposure to epidemic and the transfer of antibodies to the fetus: October 15th-December 15th in our latitude) with the rest of acute bronchiolitis. Bivariate analysis was performed regarding birth in period of risk and the rest of variables, using the Chi-square test. Multivariate logistic regression analysis was performed to study possible classical confounding factors. RESULTS: 695 infants were included in the study. 356 infants were born during the period of risk. Of the 56 patients requiring admission to PICU, 40 of them (71.4%) were born in this period (p=0.002). In the multivariate analysis, the birth in the period of risk showed a 6.5 OR (95% CI: 2.13-19.7) independently of the rest of variables. CONCLUSIONS: The worst clinical disease progression of the acute bronchiolitis by the RSV in less than 6 months age is related to lower exposure of the pregnant woman to the RSV epidemic.