Acute Lower Respiratory Tract Disease Research Articles

Unveiling the antiviral activity of interferon epsilon in respiratory infections

Abstract Type I interferons (IFN-I), including IFN-α and IFN-β, have demonstrated efficacy in treatments against some viral infections but with a considerable amount of undesirable side effects. IFN-ɛ, a recently discovered member of the IFN-I family, has been found to be expressed constitutively in several tissues, including the lung. However, the antiviral effect of IFN-ɛ against respiratory viral infections is largely unknown. Human respiratory syncytial virus (RSV) is the most important agent responsible for acute lower respiratory tract diseases in infants worldwide. Each year in the United States, RSV leads to approximately 2.1 million outpatient (non-hospitalization) visits among children younger than five years old, with a considerable number of hospitalizations among children younger than five years old and adults 65 years and older. Currently, no vaccine is available to prevent this respiratory tract infections, and new strategies are necessary to treat patients. Therefore, in this study, we aimed to investigate the antiviral effect of IFN-ɛ against respiratory viruses, such as RSV. Using a human epithelial cell line, we assessed the expression, susceptibility, and antiviral effect of IFN-ɛ on RSV infection. Our results demonstrate that RSV is capable of inducing IFN-ɛ. Moreover, RSV is susceptible to the antiviral activity of the rhIFN-ɛ, reducing the number of infected cells as well as the viral replication. That effect is due to the induction of the expression of ISGs with a low inflammatory profile. Overall, our findings demonstrate that RSV is susceptible to the effect of IFN-ɛ, suggesting a potential therapeutic effect of this novel member of the IFN-I family to treat respiratory viral infections. This work was funded in part by a Louisiana State University School of Veterinary Medicine Competitive Research Program Award

Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults

BackgroundRespiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection.MethodsIn an ongoing, international, placebo-controlled, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive a single dose of an AS01E-adjuvanted RSV prefusion F protein–based candidate vaccine (RSVPreF3 OA) or placebo before the RSV season. The primary objective was to show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season. The criterion for meeting the primary objective was a lower limit of the confidence interval around the efficacy estimate of more than 20%. Efficacy against severe RSV-related lower respiratory tract disease and RSV-related acute respiratory infection was assessed, and analyses according to RSV subtype (A and B) were performed. Safety was evaluated.ResultsA total of 24,966 participants received one dose of the RSVPreF3 OA vaccine (12,467 participants) or placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR–confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% confidence interval [CI], 57.9 to 94.1), with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% (95% CI, 62.4 to 99.9) against severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator) and 71.7% (95% CI, 56.2 to 82.3) against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). High vaccine efficacy was observed in various age groups and in participants with coexisting conditions. The RSVPreF3 OA vaccine was more reactogenic than placebo, but most adverse events for which reports were solicited were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups.ConclusionsA single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions. (Funded by GlaxoSmithKline Biologicals; AReSVi-006 ClinicalTrials.gov number, NCT04886596.)

Severity of Omicron (B.1.1.529) and Delta (B.1.617.2) SARS-CoV-2 infection among hospitalised adults: A prospective cohort study in Bristol, United Kingdom.

There is an urgent public health need to evaluate disease severity in adults hospitalised with Delta and Omicron SARS-CoV-2 variant infections. However, limited data exist assessing severity of disease in adults hospitalised with Omicron SARS-CoV-2 infections, and to what extent patient-factors, including vaccination, age, frailty and pre-existing disease, affect variant-dependent disease severity. A prospective cohort study of adults (≥18 years of age) hospitalised with acute lower respiratory tract disease at acute care hospitals in Bristol, UK conducted over 10-months. Delta or Omicron SARS-CoV-2 infection was defined by positive SARS-CoV-2 PCR and variant identification or inferred by dominant circulating variant. We constructed adjusted regression analyses to assess disease severity using three different measures: FiO2 >28% (fraction inspired oxygen), World Health Organization (WHO) outcome score >5 (assessing need for ventilatory support), and hospital length of stay (LOS) >3 days following admission for Omicron or Delta infection. Independent of other variables, including vaccination, Omicron variant infection in hospitalised adults was associated with lower severity than Delta. Risk reductions were 58%, 67%, and 16% for supplementary oxygen with >28% FiO2 [Relative Risk (RR)=0.42 (95%CI: 0.34-0.52), P<0.001], WHO outcome score >5 [RR=0.33 (95%CI: 0.21-0.50), P<0.001], and to have had a LOS > 3 days [RR=0.84 (95%CI: 0.76-0.92), P<0.001]. Younger age and vaccination with two or three doses were also independently associated with lower COVID-19 severity. We provide reassuring evidence that Omicron infection results in less serious adverse outcomes than Delta in hospitalised patients. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden and an increased admission rate of older patients with Omicron which counteracts some of the benefit arising from less severe disease. AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.

Avon Community-Acquired Pneumonia (AvonCAP) Surveillance Study: A Pan-pandemic Acute Lower Respiratory Tract Disease Surveillance Study, and the linked records of the participants in the Avon Longitudinal Study of Parents and Children (ALSPAC)

This data note describes the linking of records of the Avon Community-Acquired Pneumonia (AvonCAP) Surveillance Study – A Pan-pandemic Acute Lower Respiratory Tract Disease Surveillance Study (ISRCTN: 17354061), with the participants of the Avon Longitudinal Study of Parents and Children (ALSPAC – also known as ‘Children of the 90s’). These records were obtained from a database created specifically by AvonCAP operating within the two acute care NHS Trusts in Bristol, which is the centre of the ALSPAC study catchment area. These two trusts are the (a) North Bristol NHS Trust (NBT) based at Southmead Hospital (SMH) and (b) the University Hospitals Bristol and Weston NHS Foundation Trust (UHBWT) based at Bristol Royal Infirmary (BRI). The AvonCAP database was updated by staff using a combination of clinical records and self-reporting by the participant, which was unable to be independently verified. Data was collected using the REDCap (Research Electronic Data Capture) software program. Software code was created to transform the original files into a single data base which was reviewed for data-completeness and for its potential value as a research resource. The AvonCAP records provide a contemporaneous record of a subset of the ALSPAC cohort who experienced Lower Respiratory Tract Disease. It is available for research and may be used in conjunction with other ALSPAC data.

Incidence of community acquired lower respiratory tract disease in Bristol, UK during the COVID-19 pandemic: A prospective cohort study.

SummaryBackgroundThe emergence of COVID-19 and public health measures implemented to reduce SARS-CoV-2 infections have both affected acute lower respiratory tract disease (aLRTD) epidemiology and incidence trends. The severity of COVID-19 and non-SARS-CoV-2 aLRTD during this period have not been compared in detail.MethodsWe conducted a prospective cohort study of adults age ≥18 years admitted to either of two acute care hospitals in Bristol, UK, from August 2020 to November 2021. Patients were included if they presented with signs or symptoms of aLRTD (e.g., cough, pleurisy), or a clinical or radiological aLRTD diagnosis.Findings12,557 adult aLRTD hospitalisations occurred: 10,087 were associated with infection (pneumonia or non-pneumonic lower respiratory tract infection [NP-LRTI]), 2161 with no infective cause, with 306 providing a minimal surveillance dataset. Confirmed SARS-CoV-2 infection accounted for 32% (3178/10,087) of respiratory infections. Annual incidences of overall, COVID-19, and non- SARS-CoV-2 pneumonia were 714.1, 264.2, and 449.9, and NP-LRTI were 346.2, 43.8, and 302.4 per 100,000 adults, respectively. Weekly incidence trends in COVID-19 aLRTD showed large surges (median 6.5 [IQR 0.7–10.2] admissions per 100,000 adults per week), while other infective aLRTD events were more stable (median 14.3 [IQR 12.8–16.4] admissions per 100,000 adults per week) as were non-infective aLRTD events (median 4.4 [IQR 3.5–5.5] admissions per 100,000 adults per week).InterpretationWhile COVID-19 disease was a large component of total aLRTD during this pandemic period, non- SARS-CoV-2 infection still caused the majority of respiratory infection hospitalisations. COVID-19 disease showed significant temporal fluctuations in frequency, which were less apparent in non-SARS-CoV-2 infection. Despite public health interventions to reduce respiratory infection, disease incidence remains high.FundingAvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.

Factors Associated with Unscheduled Emergency Department Revisits in Children with Acute Lower Respiratory Tract Diseases.

PurposeTo identify factors associated with unscheduled emergency department (ED) revisits within 72 hours in children with acute dyspnea from lower respiratory tract diseases.Patients and MethodsThis retrospective cohort study included pediatric patients (age group: one month to 15 years old) who visited the ED with acute lower respiratory tract diseases between January 1st, 2017 and February 28th, 2019. The medical records were reviewed and discharged patients were dichotomized into revisit and non-revisit groups, based on whether the patients needed a revisit or not. Baseline characteristics, vital signs, diagnosis, treatment, pediatrician consultation, ED length of stay, and primary doctor of both groups were compared. Univariate and multivariate analyses by logistic regression were used to determine the significant factors associated with the revisits.ResultsMedical records of 918 eligible pediatric patients (1417 visits) were reviewed. Factors significantly associated with the revisits were history of asthma or current controller use (odds ratio [OR]: 3.08: 95% confidence interval [CI]: 1.86–5.1). Not prescribing systemic corticosteroids (P < 0.001), or prescribing them upon discharge without first dose in the ED (P = 0.022) were significantly associated with revisits.ConclusionNo prescription of systemic corticosteroids or prescription upon discharge, without an immediate dose at the ED, in children with history of asthma or current controller use were associated with revisits.

Incidence of acute lower respiratory tract disease hospitalisations, including pneumonia, among adults in Bristol, UK, 2019, estimated using both a prospective and retrospective methodology

ObjectivesTo determine the disease burden of acute lower respiratory tract disease (aLRTD) and its subsets (pneumonia, lower respiratory tract infection (LRTI) and heart failure) in hospitalised adults in Bristol, UK.SettingSingle-centre,...

Altered cytokine and chemokine profiles in the lungs of vitamin A deficient mice with respiratory syncytial virus infection

Abstract Human respiratory syncytial virus (RSV) is a leading cause of severe acute lower respiratory tract disease worldwide in infants and young children. Epidemiologically, low levels of vitamin A (VA) are known to increase susceptibility to severe respiratory infection. However, little is known regarding how VA impacts lung immune function, specifically during RSV infection. Here, we investigated the impact of VA deficiency (VAD) on innate immunity in the lungs following RSV infection using a BALB/c mouse model. Groups of VA sufficient (VAS) and VAD, 6 to 8-week-old mice were intranasally infected with RSV, and lung tissues were collected at 3, 4, and 8 days post-infection for evaluation of vitamin A status, flow cytometry for innate immune populations, and Luminex bead-based multiplex assays for inflammatory cytokines. Acute RSV infection negatively impacted lung VA status in vitamin-replete mice. Although no differences in morbidity were observed between treatment groups, VAD mice had more neutrophils recruited to the lungs. VAD also altered the phenotype of γδ T cell populations in the lung, resulting in significantly increased frequencies of CD27+ γδ T cells, and fewer CD27 negative γδ T cells compared to VAS mice. Moreover, cytokine and chemokine production was altered in the lung of VAD animals after RSV infection, with reduced production of IL-1β, IL-6, IL-17, and KC (CXCL1). These results suggest that VAD alters the inflammatory environment in the lung, which may contribute to disease susceptibility. Future experiments will focus on further changes to the innate and adaptive immune systems in the lungs during VAD after RSV infection. Supported by Roy J. Carver Charitable Trust Grant #20-5306

Immunization with a mucosal, post-fusion F/G protein-based polyanhydride nanovaccine protects against BRSV infection in neonatal calves

Abstract Human respiratory syncytial virus (HRSV) is a leading cause of severe acute lower respiratory tract (LRT) disease in young children worldwide. Currently, there is no approved vaccine for HRSV. Bovine RSV (BRSV) is closely related to HRSV and is the cause of severe acute LRT disease in young cattle. A neonatal calf model presents an opportunity to test HRSV vaccines and study a naturally susceptible host-pathogen interaction similar to HRSV infection. We tested the efficacy of a polyanhydride nanoparticle-vaccine (nanovaccine) encapsulating the post-fusion F and G proteins from BRSV and CpG adjuvant in neonatal calves with maternally-derived antibodies (MDA). A prime-boost immunization of neonatal calves with the BRSV post-fusion F/G CpG nanovaccine induced clinical protection in the presence of MDA. Vaccinated calves developed moderate or no clinical symptoms and were mostly protected from virus-associated lung pathology compared to unvaccinated controls. Calves that received a mucosal/systemic nanovaccine immunization had complete virological protection against BRSV infection in the lungs, which correlated with BRSV-specific immune responses in the bronchoalveolar lavage. Vaccination with the nanovaccine induced anamnestic BRSV-specific IgA titers in the lungs and systemic T cell responses with BRSV-specific CD4+ T cell proliferation and antigen-specific IL-17 and IFNγ secretion. Overall, the BRSV post-fusion F/G CpG nanovaccine is a promising candidate for further studies to protect neonatal calves and infants from RSV infection.

A novel approach to calculate disease incidence for hospital-based health events in England

BackgroundDisease incidence is a key indicator for the assessment of population health and to guide public health policies. Defining accurate population denominators is challenging for incidence studies of hospital-based events, for which hospital catchment areas depend on patient choice and geographic proximity and often do not match established town or city boundaries. We describe a new method to accurately define a hospital's population denominator, which we developed for a study designed to estimate the incidence of hospitalisation for adult acute lower respiratory tract disease in Bristol, UK. MethodsWe examined hospital data for adult acute lower respiratory tract disease to identify general practitioner (GP) practices (n=82) whose patients were treated for adult acute lower respiratory tract disease at study hospitals and confirmed that nearly all patients (9230 [94·5%] of 9764) were registered with practices within the National Health Service's Bristol, North Somerset, and South Gloucestershire Clinical Commissioning Group (CCG). Hospital admission data were linked to aggregated GP practice patient registration data within this CCG for April 1, 2017, to March 31, 2020. The proportion of GP practices' patients who were hospitalised for adult acute lower respiratory tract disease that occurred at a specific study hospital was multiplied by their patient registration count for six age groups to obtain the practices' contribution to that hospital's denominator (eg, if 50% of GP practice admissions were at a specific study hospital among patients aged 50–64 years, the practice contributed half of their patients aged 50–64 years to the denominator). Alternate denominators were calculated using population census data matched to 20-minute drivetime estimates for study hospitals (the method used to define hospital catchment for local health service purposes). FindingsThe percentage of admissions at study hospitals varied substantially by GP practice (0–100%). 231 342 (86·3%) of 268 093 of the CCG's GP practice registrants aged 18–34 years received treatment at study hospitals (compared with 19 229 [80%] of 23 938 registrants aged or older than 85 years); some received treatment at another local hospital to the south. With 20-minute drivetime as an estimate measure, hospital catchment would be 550 155 (66·5%) of 827 304 individuals in the CCG population. InterpretationUsing health-care data stratified by local CCG enables the estimation of local population denominators to support accurate incidence ascertainment within hospital-based surveillance studies. FundingThis work was funded by Pfizer.

Impacts of vitamin A deficiency on mucosal immunity to respiratory syncytial virus infection

Abstract Human respiratory syncytial virus (RSV) is a leading cause of severe acute lower respiratory tract disease in infants and young children worldwide. Vitamin A (VA) deficiency (VAD) is one of the most prevalent nutrition-related health problems globally. Acute childhood infections have been linked to an increased risk of VAD, while conversely, VAD leads to increased susceptibility to severe respiratory infections. To date, however, the impact of VAD on RSV infection specifically, or on adaptive immune responses in the respiratory tract, remains unexplored. Here, we used the BALB/c mouse model to determine the impact of VAD on RSV infection and lung virus-specific CD8 T cell immunity. Groups of VA sufficient (VAS) and VAD mice were infected with RSV strain A2. On day 8 after infection, antigen-specific CD8 T cell responses were evaluated using tetramer and intracellular cytokine staining and ELISA assays for IFNγ secretion in cell supernatants. Although no changes in morbidity and mortality were observed between groups, CD8 T cells from VAD animals showed significantly impaired production of IFNγ, suggesting changes in the Th1 balance of the lungs in the context of VAD. Future experiments will focus on changes in the innate and adaptive immune systems in the lungs during VAD and downstream effects on the response to RSV infection.

LOW BIRTH WEIGHT AND IMMUNIZATIONS STATUS: RISK FACTORS OF ACUTE RESPIRATORY INFECTION IN CHILDREN 2-5 YEARS

Background: Acute Respiratory Infection (ARI) is one of the most important causes of morbidity and mortality in children under five years old (toddlers) worldwide, especially in developing countries. ARI is an acute upper or lower respiratory tract disease that occurs acutely, usually transmitted with mild to lethal symptoms. Various risk factors cause a high incidence of ARI cases in infants, including low birth weight (LBW) and incomplete immunization. Children aged 2-5 years are expected to have received basic immunizations and complete tests according to age to have a stronger immunity to ARI than children aged less than two years. Objective: To determine the relationship of LBW and immunization history with ARI events in children aged 2-5 years.Methods: This is an analytic observational study with a cross-sectional design using 31 samples of ARI and non-ARI pediatric patients treated at the PKU Muhammadiyah Hospital Surakarta. Samples were determined using a purposive technique - meaning that samples were taken according to specific criteria. The population was pediatric patients aged 2-5 years diagnosed with ARI: common cold, nasopharyngitis, tonsillitis, laryngitis, bronchitis, bronchiolitis, pneumonia, and SARS. This study's study populations are pediatric patients aged 2-5 years who were outpatient at PKU Muhammadiyah Hospital Surakarta in December 2019. Therefore, the number of samples is calculated using the Sample Formula for Study Groups with Different Sample Sizes, and data was taken employing a patient's parent interview.Results: There were 31 patients with details of 17 ARI and 14 non-ARI. Fisher's test showed there was no relationship between LBW and ARI (p-value = 0.597, p&gt; 0.05 and Prevalence Ratio = 1.286). And there was no significant relationship between the history of immunization with ARI (p-value = 0.287, p&gt; 0.05 and Prevalence Ratio = 2.5).Conclusions: There is no significant relationship between LBW and immunization history with ARI in children aged 2-5 years.

A role of thiamphenicol glycinate acetylcysteinate for therapy of respiratory diseases (a review)

This article is a review of published studies on the clinical application of thiamphenicol glycinate acetylcysteinate (TGA) in the treatment of acute and chronic upper and lower respiratory tract diseases. Search for literature in Medline and eLibrary databases was performed. The special place that the drug holds in clinical practice, due to the specific properties of its components - mucolytic N-acetylcysteine (NAC) and antibiotic tiamphenicol. In addition to the usual mucolytic effects, NAC has antioxidant properties, which extends the range of its clinical effectiveness. The antibiotic thiamphenicol has antimicrobial activity against staphylococci, streptococci and gram-negative microorganisms. TGA can be administered by parenteral and inhalation routes. Inhalation route of drug injection is preferable in the treatment of acute and chronic bronchopulmonary diseases, because it allows to create a higher concentration of the drug in the respiratory tract, is associated with much less systemic effects and less often accompanied by the development of side effects. The results of TGA application in the treatment of both acute and chronic upper respiratory diseases (rhinosinusitis, otitis, pharyngotonsillitis) and bronchopulmonary diseases (chronic obstructive pulmonary disease, bronchoectasis) are considered in this review. It has been shown that the drug is quite effective in most patients and its effectiveness sometimes exceeds that of standard oral antibiotics. TGA also allows you to effectively combat biofilms, which have high antibacterial resistance. Thus, the published data allow us to speak about the high antibacterial effectiveness of TGA in acute and chronic infectious diseases of the upper and lower respiratory tract, including cases with the formation of biofilms.

The incidence of non-tumour diseases of the respiratory organs of offspring of the first generation of residents of radiation-contaminated territories of Ukraine under the age of 18 years

There was conducted an epidemiological study of the morbidity of non-tumour diseases of the respiratory organs of the first-generation offspring born by residents of radioactively contaminated territories, until they reached 18 years. The observation period from 1987 to 2016. The total cohort was 35893 individuals, among whom male offspring constituted 18138 individuals, while female offspring constituted 17755 individuals. There were created 4 groups to study offspring up to 3 years old, depending on the time of birth of offspring after an accident – years of birth:(first – 01.03.1987– 28.02.1990, second – 01.03.1990– 28.02.1993, third – 01.03.1993– 28.02.1996, fourth – 01.03.1996– 28.02.1999), with a three-year observation period.During the observation period, there were detected 7845 cases of non-tumour respiratory diseases, which is 36.6% of the total pathology and 59,59±0,65 cases by 103 man-years observations. Of whom male offspring 4146 cases (С –38,8%, ID–62,42±0,94 by 103 man-years), and female offspring – 3699 (С –34,6%, ID– 56,72±0,91).The formation of non-tumour respiratory diseases occurred mainly due to the groups of diseases: "acute respiratory infections of the upper respiratory tract" (J00-J06.9) and "influenza and pneumonia" (J10-J18.9), "other upper respiratory tract diseases (J30.0-J39.9)" and "other acute respiratory infections of the lower respiratory tract (J20- J22), which amounted to 98.84%.For all the years of observation among the studied groups, the highest rates of respiratory disease in each period on the first or second, and the lowest - on the fourth.An analysis of the incidence showed that up to 6 years, offspring were mainly affected by acute respiratory infections of the upper respiratory tract and chronic tonsillitis and adenoids, and in the younger school-age, the incidence increased due to acute upper and lower respiratory tract diseases. In adolescence, the morbidity of the respiratory system is complicated by more severe nosological forms: chronic obstructive pulmonary disease, asthma.

Alternative Virus-Like Particle-Associated Prefusion F Proteins as Maternal Vaccines for Respiratory Syncytial Virus.

Maternal vaccination may be the most effective and safest approach to the protection of infants from respiratory syncytial virus (RSV) infection, a severe acute lower respiratory tract disease in infants and young children worldwide. We previously compared five different virus-like particle (VLP)-associated, mutation-stabilized prefusion F (pre-F) proteins, including the prototype DS-Cav1 F VLPs. We showed that alternative versions of prefusion F proteins have different conformations and induce different populations of anti-F protein antibodies. Two of these alternative pre-F VLPs, the UC-2 F and UC-3 F VLPs, stimulated in mice higher titers of neutralizing antibodies than DS-Cav1 F VLPs (M. L. Cullen, R. M. Schmidt, M. G. Torres, A. A. Capoferri, et al., Vaccines 7:21-41, 2019, https://doi.org/10.3390/vaccines7010021). Here we describe a comparison of these two pre-F VLPs with DS-Cav1 F VLPs as maternal vaccines in cotton rats and report that UC-3 F VLPs significantly increased the neutralizing antibody (NAb) titers in pregnant dams compared to DS-Cav1 F VLPs. The neutralizing antibody titers in the sera of the offspring of the dams immunized with UC-3 F VLPs were significantly higher than those in the sera of the offspring of dams immunized with DS-Cav1 VLPs. This increase in serum NAb titers translated to a 6- to 40-fold lower virus titer in the lungs of the RSV-challenged offspring of dams immunized with UC-3 F VLPs than in the lungs of the RSV-challenged offspring of dams immunized with DS-Cav1 F VLPs. Importantly, the offspring of UC-3 F VLP-immunized dams showed significant protection from lung pathology and from induction of inflammatory lung cytokine mRNA expression after RSV challenge. Immunization with UC-3 F VLPs also induced durable levels of high-titer neutralizing antibodies in dams.IMPORTANCE Respiratory syncytial virus (RSV) is a significant human pathogen severely impacting neonates and young children, but no vaccine exists to protect this vulnerable population. Furthermore, direct vaccination of neonates is likely ineffective due to the immaturity of their immune system, and neonate immunization is potentially unsafe. Maternal vaccination may be the best and safest approach to the protection of neonates through the passive transfer of maternal neutralizing antibodies in utero to the fetus after maternal immunization. Here we report that immunization of pregnant cotton rats, a surrogate model for human maternal immunization, with novel RSV virus-like particle (VLP) vaccine candidates containing stabilized prefusion RSV F proteins provides significant levels of protection of the offspring of immunized dams from RSV challenge. We also found that antibodies induced by VLPs containing different versions of the prefusion F protein varied by 40-fold in the extent of protection provided to the offspring of vaccinated dams upon RSV challenge.

Respiratory syncytial virus nonstructural proteins 1 and 2: Exceptional disrupters of innate immune responses.

Human respiratory syncytial virus (RSV) is the most important cause of acute lower respiratory tract disease in infants worldwide. As a first line of defense against respiratory infections, innate immune responses, including the production of type I and III interferons (IFNs), play an important role. Upon infection with RSV, multiple pattern recognition receptors (PRRs) can recognize RSV-derived pathogen-associated molecular patterns (PAMPs) and mount innate immune responses. Retinoic-acid-inducible gene-I (RIG-I) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) have been identified as important innate receptors to mount type I IFNs during RSV infection. However, type I IFN levels remain surprisingly low during RSV infection despite strong viral replication. The poor induction of type I IFNs can be attributed to the cooperative activity of 2 unique, nonstructural (NS) proteins of RSV, i.e., NS1 and NS2. These viral proteins have been shown to suppress both the production and signaling of type I and III IFNs by counteracting a plethora of key host innate signaling proteins. Moreover, increasing numbers of IFN-stimulated genes (ISGs) are being identified as targets of the NS proteins in recent years, highlighting an underexplored protein family in the identification of NS target proteins. To understand the diverse effector functions of NS1 and NS2, Goswami and colleagues proposed the hypothesis of the NS degradasome (NSD) complex, a multiprotein complex made up of, at least, NS1 and NS2. Furthermore, the crystal structure of NS1 was resolved recently and, remarkably, identified NS1 as a structural paralogue of the RSV matrix protein. Unfortunately, no structural data on NS2 have been published so far. In this review, we briefly describe the PRRs that mount innate immune responses upon RSV infection and provide an overview of the various effector functions of NS1 and NS2. Furthermore, we discuss the ubiquitination effector functions of NS1 and NS2, which are in line with the hypothesis that the NSD shares features with the canonical 26S proteasome.

Human bocavirus infection in Belgian children with respiratory tract disease.

Human bocavirus (HBoV) has been detected primarily in children with acute lower respiratory tract disease (LRTD), but its occurrence, clinical profile, and role as a causative agent of RTD are not clear. The aim of this study was to investigate the prevalence and the potential clinical relevance of HBoV. Using molecular tests, we tested 1352 nasopharyngeal samples obtained between October 1, 2017 and April 30, 2018 from children up to the age of 16 with RTD for the presence of HBoV DNA and 20 other respiratory pathogens at three different hospitals in Belgium. HBoV was detected in 77 children with a median age of 10.6 months. Consecutive samples were available for 15 HBoV-positive children and showed persistent HBoV positivity in four of them. Monoinfection was observed in six infants. Four of them were born prematurely and were infected during hospitalization at the neonatal intensive care unit (NICU). Only one of these six monoinfected children was diagnosed with recurrent wheezing due to HBoV. This child was carried to term and had a high viral load. Coinfections, most frequently with rhinovirus (52.1%) and adenovirus (49.3%), were observed in 72 patients. In seventeen of them in which HBoV was present at high viral load or higher viral load than its copathogens, bronchi(oli)tis (n = 8), recurrent wheezing (n = 8) or episodic wheezing (n = 1) were diagnosed. Our results suggest that HBoV infection at high viral load in infants is associated with wheezing (P = 0.013, Cramer’s V = 0.613).Electronic supplementary materialThe online version of this article (10.1007/s00705-019-04396-6) contains supplementary material, which is available to authorized users.

Pulmonary hypertension during respiratory syncytial virus bronchiolitis: a risk factor for severity of illness.

Respiratory syncytial virus infection is the most frequent cause of acute lower respiratory tract disease in infants. A few reports have suggested that pulmonary hypertension is associated with increased severity of respiratory syncytial virus infection. We sought to determine the association between the pulmonary hypertension detected by echocardiography during respiratory syncytial virus bronchiolitis and clinical outcomes. We retrospectively reviewed 154 children admitted with respiratory syncytial virus bronchiolitis who had an echocardiography performed during the admission. The association between pulmonary hypertension and clinical outcomes including mortality, intensive care unit (ICU) admission, prolonged ICU stay (&gt;10 days), tracheal intubation, and need of high frequency oscillator ventilation was evaluated. Echocardiography detected pulmonary hypertension in 29 patients (18.7%). Pulmonary hypertension was observed more frequently in patients with congenital heart disease (CHD) (n = 11/33, 33%), chronic lung disease of infancy (n = 12/25, 48%), prematurity (&lt;37 weeks gestational age, n = 17/59, 29%), and Down syndrome (n = 4/10, 40%). The presence of pulmonary hypertension was associated with morbidity (p &lt; 0.001) and mortality (p = 0.02). However, in patients without these risk factors (n = 68), pulmonary hypertension was detected in five patients who presented with shock or poor perfusion. Chronic lung disease was associated with pulmonary hypertension (OR = 5.9, 95% CI 2.2-16.3, p = 0.0005). Multivariate logistic analysis demonstrated that pulmonary hypertension is associated with ICU admission (OR = 6.4, 95% CI 2.2-18.8, p = 0.0007), intubation (OR = 4.7, 95% CI 1.8-12.3, p = 0.002), high frequency oscillator ventilation (OR = 8.4, 95% CI 2.95-23.98, p &lt; 0.0001), and prolonged ICU stay (OR = 4.9, 95% CI 2.0-11.7, p = 0.0004). Pulmonary hypertension detected by echocardiography during respiratory syncytial virus infection was associated with increased morbidity and mortality. Chronic lung disease was associated with pulmonary hypertension detected during respiratory syncytial virus bronchiolitis. Routine echocardiography is not warranted for previously healthy, haemodynamically stable patients with respiratory syncytial virus bronchiolitis.

Human Respiratory Syncytial Virus NS 1 Targets TRIM25 to Suppress RIG-I Ubiquitination and Subsequent RIG-I-Mediated Antiviral Signaling.

Respiratory syncytial virus (RSV) causes severe acute lower respiratory tract disease. Retinoic acid-inducible gene-I (RIG-I) serves as an innate immune sensor and triggers antiviral responses upon recognizing viral infections including RSV. Since tripartite motif-containing protein 25 (TRIM25)-mediated K63-polyubiquitination is crucial for RIG-I activation, several viruses target initial RIG-I activation through ubiquitination. RSV NS1 and NS2 have been shown to interfere with RIG-I-mediated antiviral signaling. In this study, we explored the possibility that NS1 suppresses RIG-I-mediated antiviral signaling by targeting TRIM25. Ubiquitination of ectopically expressed RIG-I-2Cards domain was decreased by RSV infection, indicating that RSV possesses ability to inhibit TRIM25-mediated RIG-I ubiquitination. Similarly, ectopic expression of NS1 sufficiently suppressed TRIM25-mediated RIG-I ubiquitination. Furthermore, interaction between NS1 and TRIM25 was detected by a co-immunoprecipitation assay. Further biochemical assays showed that the SPRY domain of TRIM25, which is responsible for interaction with RIG-I, interacted sufficiently with NS1. Suppression of RIG-I ubiquitination by NS1 resulted in decreased interaction between RIG-I and its downstream molecule, MAVS. The suppressive effect of NS1 on RIG-I signaling could be abrogated by overexpression of TRIM25. Collectively, this study suggests that RSV NS1 interacts with TRIM25 and interferes with RIG-I ubiquitination to suppress type-I interferon signaling.

Feasibility of high-flow nasal cannula implementation for children with acute lower respiratory tract disease in rural Kenya

ABSTRACTBackground: High-flow nasal cannula (HFNC) is a well-established respiratory support device in high-income countries, but to our knowledge, its use in sub-Saharan Africa has not been reported. This feasability study describes the implementation process of HFNC in rural Kenya.Methods: HFNC was implemented in intensive care and high dependency units at Kijabe Hospital, Kenya for children with acute lower respiratory disease. Rate of intubation was compared with historical controls and challenges of implementation described.Results: Fifteen patients received HFNC between January and November 2016, and compared to 25 historical control patients. Both groups had many comorbidities, and control patients were significantly younger. There were no significant differences in clinical outcome between the groups: 5 (33%) HFNC vs 12 (48%) controls required intubation; 10 (67%) HFNC vs 22 (88%) controls survived to discharge; and the HFNC required 3 vs the controls’ 4 days on respiratory support. The greatest technical issues encountered were large pressure differences between air from a wall outlet (wall air) and oxygen and an inability to automatically refill humidifier water chambers.Conclusion: HFNC in limited-resource settings is feasible but there were technical challenges and concern about the increased workload. The small sample size, heterogeneous population, availability of oxygen and blending of wall air at the study site limit inferences for other sites in low- and middle-income countries.Abbreviations: ALRI, acute lower respiratory infection; CPAP, continuous positive airway pressure; ETAT, emergency triage, assessment and treatment; HDU, high dependency unit; HFNC, high-flow nasal cannula; HIC, high-income country; HR, heart rate; ICU, intensive care unit; LMIC, low- and middle-income countries; PSI, pounds per square inch; RR, respiratory rate; mRISC, modified Respiratory Index of Severity in Children.