Tract Disease In Young Children Research Articles

Impact of Viral Lower Respiratory Tract Infection (LRTI) in Early Childhood (0-2 Years) on Lung Growth and Development and Lifelong Trajectories of Pulmonary Health: A National Institutes of Health (NIH) Workshop Summary.

Viral lower respiratory tract infections (LRTI) are ubiquitous in early life. They are disproportionately severe in infants and toddlers (0-2 years), leading to more than 100,000 hospitalizations in the United States per year. The recent relative resilience to severe Coronavirus disease (COVID-19) observed in young children is surprising. These observations, taken together, underscore current knowledge gaps in the pathogenesis of viral lower respiratory tract diseases in young children and respiratory developmental immunology. Further, early-life respiratory viral infections could have a lasting impact on lung development with potential life-long pulmonary sequelae. Modern molecular methods, including high-resolution spatial and single-cell technologies, in concert with longitudinal observational studies beginning in the prenatal period and continuing into early childhood, promise to elucidate developmental pulmonary and immunophenotypes following early-life viral infections and their impact on trajectories of future respiratory health. In November 2019, under the auspices of a multi-disciplinary Workshop convened by the National Heart Lung Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, experts came together to highlight the challenges of respiratory viral infections, particularly in early childhood, and emphasize the knowledge gaps in immune, virological, developmental, and clinical factors that contribute to disease severity and long-term pulmonary morbidity from viral LRTI in children. We hope that the scientific community will view these challenges in clinical care on pulmonary health trajectories and disease burden not as a window of susceptibility but as a window of opportunity.

Respiratory syncytial virus-induced disease in healthy infants: we need to offload this burden.

In the slipstream of the extraordinary, worldwide natural experiment reducing close human contact to mitigate the spread of SARS-CoV-2, a drastically but temporarily diminished transmission of respiratory syncytial virus (RSV) in children occurred in the winter of 2020–21.1 This glimpse of a world without RSV gained momentum for the urgent need for preventive strategies for this prototypical paediatric pathogen, which causes a spectrum of mild upper-respiratory to severe lower-respiratory tract disease in young children.

In vitro trackable assembly of RNA-specific nucleocapsids of the respiratory syncytial virus

In vitro trackable assembly of RNA-specific nucleocapsids of the respiratory syncytial virus

Biology of Infection and Disease Pathogenesis to Guide RSV Vaccine Development

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease in young children and a substantial contributor to respiratory tract disease throughout life and as such a high priority for vaccine development. However, after nearly 60 years of research no vaccine is yet available. The challenges to developing an RSV vaccine include the young age, 2-4 months of age, for the peak of disease, the enhanced RSV disease associated with the first RSV vaccine, formalin-inactivated RSV with an alum adjuvant (FI-RSV), and difficulty achieving protection as illustrated by repeat infections with disease that occur throughout life. Understanding the biology of infection and disease pathogenesis has and will continue to guide vaccine development. In this paper, we review the roles that RSV proteins play in the biology of infection and disease pathogenesis and the corresponding contribution to live attenuated and subunit RSV vaccines. Each of RSV's 11 proteins are in the design of one or more vaccines. The G protein's contribution to disease pathogenesis through altering host immune responses as well as its role in the biology of infection suggest it can make a unique contribution to an RSV vaccine, both live attenuated and subunit vaccines. One of G's potential unique contributions to a vaccine is the potential for anti-G immunity to have an anti-inflammatory effect independent of virus replication. Though an anti-viral effect is essential to an effective RSV vaccine, it is important to remember that the goal of a vaccine is to prevent disease. Thus, other effects of the infection, such as G's alteration of the host immune response may provide opportunities to induce responses that block this effect and improve an RSV vaccine. Keeping in mind the goal of a vaccine is to prevent disease and not virus replication may help identify new strategies for other vaccine challenges, such as improving influenza vaccines and developing HIV vaccines.

Respiratory syncytial virus entry and how to block it.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease in young children and elderly people. Although the virus was isolated in 1955, an effective RSV vaccine has not been developed, and the only licensed intervention is passive immunoprophylaxis of high-risk infants with a humanized monoclonal antibody. During the past 5 years, however, there has been substantial progress in our understanding of the structure and function of the RSV glycoproteins and their interactions with host cell factors that mediate entry. This period has coincided with renewed interest in developing effective interventions, including the isolation of potent monoclonal antibodies and small molecules and the design of novel vaccine candidates. In this Review, we summarize the recent findings that have begun to elucidate RSV entry mechanisms, describe progress on the development of new interventions and conclude with a perspective on gaps in our knowledge that require further investigation.

The Morphology and Assembly of Respiratory Syncytial Virus Revealed by Cryo-Electron Tomography

Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in young children. With repeat infections throughout life, it can also cause substantial disease in the elderly and in adults with compromised cardiac, pulmonary and immune systems. RSV is a pleomorphic enveloped RNA virus in the Pneumoviridae family. Recently, the three-dimensional (3D) structure of purified RSV particles has been elucidated, revealing three distinct morphological categories: spherical, asymmetric, and filamentous. However, the native 3D structure of RSV particles associated with or released from infected cells has yet to be investigated. In this study, we have established an optimized system for studying RSV structure by imaging RSV-infected cells on transmission electron microscopy (TEM) grids by cryo-electron tomography (cryo-ET). Our results demonstrate that RSV is filamentous across several virus strains and cell lines by cryo-ET, cryo-immuno EM, and thin section TEM techniques. The viral filament length varies from 0.5 to 12 μm and the average filament diameter is approximately 130 nm. Taking advantage of the whole cell tomography technique, we have resolved various stages of RSV assembly. Collectively, our results can facilitate the understanding of viral morphogenesis in RSV and other pleomorphic enveloped viruses.

ОСОБЕННОСТИ РЕНТГЕНОЛОГИЧЕСКОЙ СЕМИОТИКИ ПРИ ПНЕВМОНИИ У ДЕТЕЙ РАННЕГО ВОЗРАСТА

Мета дослідження – вивчити особливості рентгенологічної семіотики при пневмонії в дітей раннього віку залежно від терміну гестації при народженні.Матеріали та методи. Проведено клініко-рентгенологічне обстеження 110 дітей раннього віку (від 1 місяця до 3-х років), хворих на пневмонію.Результати дослідження та їх обговорення. Вивчено особливості рентгенологічної семіотики пневмонії залежно від терміну гестації при народженні. У дітей, які народилися недоношеними, при пневмонії виявили рентгенологічні ознаки, характерні для тривалої незрілості легеневої тканини, а саме: помірну гіповентиляцію легень,поширені дрібновогнищеві тіні, обмежену сітчасту деформацію легеневого малюнка і симптом «повітряної бронхограми». Причому у віці від 1 до 3-х років вищевказана симптоматика дещо менш виражена, що узгоджується з наявною інформацією про реакцію з боку інтерстиціальної тканини у віковій динаміці. Характерні для недоношеності неінтенсивні вогнища на тлі незрілих легень і відносно бідна й уповільнена динаміка зворотних змін підтверджують думку про переважання ризику розвитку хронічної легеневої патології саме при наявності в анамнезі даних про недоношеність, а також чіткого взаємозв’язку запальних змін у легенях з перинатальною патологією, незрілістю легень і організму в цілому. Такі рентгенологічні симптоми, як посилення і деформація легеневого малюнка, зниження прозорості легеневих полів за типом «матового скла», дрібновогнищеві тіні, у свою чергу, є рентгенологічними ознаками ранніх стадій, так званих інтерстиціальних хвороб легень, які останнім часом привертають увагу не тільки клініцистів, але й рентгенологів, морфологів через наростання поширеності. У міру прогресування процесу в деяких дітей виявляли ознаки інтерстиціального фіброзу, з’являлися порожнини, формувалася картина стільникової легені. Ця інформація дає підстави припускати, що наявність таких ознак у дітей, які народилися недоношеними, не виключає ймовірності вікової схильності до інтерстиціальних хвороб легень.Висновки. Тривалі ознаки незрілості легеневої тканини в дітей, які народилися недоношеними, накладають відбиток на процес подальшого розвитку захворювань респіраторного тракту в дітей раннього віку і не виключають імовірності вікової схильності до інтерстиціальних хвороб легень.

Interleukin-27 Inhibits Vaccine-Enhanced Pulmonary Disease following Respiratory Syncytial Virus Infection by Regulating Cellular Memory Responses

Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract disease in young children. In the 1960s, infants vaccinated with formalin-inactivated RSV developed a more severe disease characterized by excessive inflammatory immunopathology in lungs upon natural RSV infection. The fear of causing the vaccine-enhanced disease (VED) is an important obstacle for development of safe and effective RSV vaccines. The recombinant vaccine candidate G1F/M2 immunization also led to VED. It has been proved that cellular memory induced by RSV vaccines contributed to VED. Interleukin-27 (IL-27) and IL-23 regulate Th1, Th17, and/or Th2 cellular immune responses. In this study, mice coimmunized with pcDNA3-IL-27 and G1F/M2 were fully protected and, importantly, did not develop vaccine-enhanced inflammatory responses and immunopathology in lungs after RSV challenge, which was correlated with moderate Th1-, suppressed Th2-, and Th17-like memory responses activated by RSV. In contrast, G1F/M2- or pcDNA3-IL-23+G1F/M2-immunized mice, in which robust Th2- and Th17-like memory responses were induced, developed enhanced pulmonary inflammation and severe immunopathology. Mice coimmunized with G1F/M2 and the two cytokine plasmids exhibited mild inflammatory responses as well as remarkable Th1-, suppressed Th2-, and Th17-like memory responses. These results suggested that Th1-, Th2-, and Th17-like memory responses and, in particular, excessive Th2- and Th17-like memory responses were closely associated with VED; IL-27 may inhibit VED following respiratory syncytial virus infection by regulating cellular memory responses.

Central Role of Dendritic Cells in Shaping the Adaptive Immune Response During Respiratory Syncytial Virus Infection

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in young children. Premature infants, immunocompromised individuals and the elderly exhibit the highest risk for the development of severe RSV-induced disease. Murine studies demonstrate that CD8 T cells mediate RSV clearance from the lungs. Murine studies also indicate that the host immune response contributes to RSV-induced morbidity as T-cell depletion prevents the development of disease despite sustained viral replication. Dendritic cells (DCs) play a central role in the induction of the RSV-specific adaptive immune response. Following RSV infection, lung-resident DCs acquire viral antigens, migrate to the lung-draining lymph nodes and initiate the T-cell response. This article focuses on data generated from both in vitro DC infection studies and RSV mouse models that together have advanced our understanding of how RSV infection modulates DC function and the subsequent impact on the adaptive immune response.

Human bocavirus infection in children with acute respiratory tract infection in India

Human bocavirus (HBoV) is a new human parvovirus identified in children with respiratory tract disease. Nasopharyngeal aspirates were collected from 305 children <5 years of age with acute respiratory tract infection from April 2005 to March 2007 and screened for the presence of HBoV by two separate sets of a polymerase chain reaction (PCR) described previously. Twenty-two (7.2%) children who had acute respiratory infection were found to be positive for HBoV by both sets of PCR. The main clinical symptoms were cough (95%), runny nose (64%), and fever (59%). In two samples, HBoV was identified together with respiratory syncytial virus in one sample and influenza A virus in another. HBoV appeared to have no seasonal distribution and is associated with both upper and lower respiratory tract disease in young children in India.

Role of Human Polyomaviruses in Respiratory Tract Disease in Young Children

KI virus was detected in respiratory secretions of 8/367 (2.2%) symptomatic and 0/96 asymptomatic children (p = 0.215). WU virus was detected in 26/367 (7.1%) symptomatic and 6/96 (6.3%) asymptomatic children (p = 1.00). These human polyomaviruses may not independently cause respiratory tract disease in young children.

Overcoming T-Cell-Mediated Immunopathology to Achieve Safe Respiratory Syncytial Virus Vaccination

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in young children. Premature infants, immunocompromised individuals, and the elderly exhibit an increased risk for the development of severe disease after RSV infection. Currently, there is not a safe and effective RSV vaccine available, in part due to our incomplete understanding of how severe immunopathology was induced following RSV infection of children previously immunized with a formalin-inactivated RSV vaccine. Much of our current understanding of RSV vaccine-enhanced disease can be attributed to the establishment of multiple mouse models of RSV vaccination. Studies analyzing the RSV-specific immune response in mice have clearly demonstrated that both CD4 and CD8 memory T cells contribute to RSV-induced immunopathology. In this review we will focus our discussion on data generated from the mouse models of RSV immunization that have advanced our understanding of how virus-specific T cells mediate immunopathology and RSV vaccine-enhanced disease.

Human bocavirus DNA detected by quantitative real-time PCR in two children hospitalized for lower respiratory tract infection

Viral pathogens such as respiratory syncytial virus, human metapneumovirus, rhinovirus, adenovirus, parainfluenza virus and influenza virus are the most frequent causes of acute respiratory tract infection and hospitalization in infants and young children. However, no pathogen can be identified in about 30% of suspected respiratory infections [1]. Recently, a new human virus belonging to the Bocavirus genus of the subfamily Parvovirinae was cloned from pooled human respiratory samples and its pathogenic potential was proposed according to its association with respiratory illness [2]. Later studies suggested human bocavirus (HBoV) may be causative for lower respiratory tract disease in young children [3–6]. In this report, we describe the detection by quantitative real-time PCR of HBoV DNA in the nasopharyngeal aspirates of two German children hospitalized for pneumonia. Sequencing of an NP-1 gene fragment and phylogenetic analysis revealed high sequence identity for this HBoV strain compared with the prototype strain HBoV st1 [2] and other strains worldwide [2–6]. Our finding of a high viral load combined with symptoms of acute respiratory tract infection may support the assertion of others that HBoV is an important emerging pathogen [2–6]. In March 2004, a 32-month-old boy presented with a 3day history of high fever and cough. He was treated with corticosteroids and bronchodilators to control acute bronchoconstriction. No antibiotics were administered. Due to increasing tachypnea and dyspnea, the child was hospitalized. Clinical examination upon admission revealed a body temperature of 39°C, tachypnea and dyspnea, as well as subcostal retractions. Wheezing and dry bilateral fine rales were present upon lung auscultation. Transcutaneously measured oxygen saturation was decreased to 87% and the patient required oxygen supplementation (4 l/min) for 6 days and intravenous treatment with corticosteroids for persistent bronchoconstriction. Laboratory tests showed a leukocyte count of 7.7×10/l, a blood pH level of 7.4, base excess of −4.7 mmol/l, and a C-reactive protein value of 5.6 mg/l. Chest radiograph revealed beginning right paracardial pulmonary infiltration without pleural effusion, indicating pneumonia. Under antiobstructive therapy with sultanol and intravenous corticosteroids, the boy’s respiratory condition improved. On day 4 after admission, he developed rotavirus gastroenteritis, probably of nosocomial origin, which rapidly improved under symptomatic therapy. By discharge on day 9, his general condition was good, although a mild fever (38°C) was still present. In the same period, an 18-month-old boy presented with a 2-day history of increasing dyspnea, fever (39.5°C), and cough. Clinical examination revealed a weakened general condition, tachypnea, a body temperature of 38.8°C, and modest wheezing as well as bilateral basal rales upon auscultation. The patient required oxygen supplementation (2 l/min) for 4 days. Initial laboratory tests showed an elevated leukocyte count of 12.5×10/l, a blood pH level of Eur J Clin Microbiol Infect Dis (2007) 26:147–149 DOI 10.1007/s10096-006-0244-6

An S101P Substitution in the Putative Cleavage Motif of the Human Metapneumovirus Fusion Protein Is a Major Determinant for Trypsin-Independent Growth in Vero Cells and Does Not Alter Tissue Tropism in Hamsters

Human metapneumovirus (hMPV), a recently described paramyxovirus, is a major etiological agent for lower respiratory tract disease in young children that can manifest with severe cough, bronchiolitis, and pneumonia. The hMPV fusion glycoprotein (F) shares conserved functional domains with other paramyxovirus F proteins that are important for virus entry and spread. For other paramyxovirus F proteins, cleavage of a precursor protein (F0) into F1 and F2 exposes a fusion peptide at the N terminus of the F1 fragment, a likely prerequisite for fusion activity. Many hMPV strains have been reported to require trypsin for growth in tissue culture. The majority of these strains contain RQSR at the putative cleavage site. However, strains hMPV/NL/1/00 and hMPV/NL/1/99 expanded in our laboratory contain the sequence RQPR and do not require trypsin for growth in Vero cells. The contribution of this single amino acid change was verified directly by generating recombinant virus (rhMPV/NL/1/00) with either proline or serine at position 101 in F. These results suggested that cleavage of F protein in Vero cells could be achieved by trypsin or S101P amino acid substitution in the putative cleavage site motif. Moreover, trypsin-independent cleavage of hMPV F containing 101P was enhanced by the amino acid substitution E93K. In hamsters, rhMPV/93K/101S and rhMPV/93K/101P grew to equivalent titers in the respiratory tract and replication was restricted to respiratory tissues. The ability of these hMPV strains to replicate efficiently in the absence of trypsin should greatly facilitate the generation, preclinical testing, and manufacturing of attenuated hMPV vaccine candidates.

Identification of small-animal and primate models for evaluation of vaccine candidates for human metapneumovirus (hMPV) and implications for hMPV vaccine design.

Human metapneumovirus (hMPV), a recently identified paramyxovirus, is the causative agent of respiratory tract disease in young children. Epidemiological studies have established the presence of hMPV in retrospective as well as current clinical samples in Europe, USA, Canada, Hong Kong and Australia. The hMPV disease incidence rate varied from 7 to 12 %. This rate of disease attack places hMPV in severity between respiratory syncytial virus and human parainfluenza virus type 3, two common respiratory pathogens of young children, the elderly and immunosuppressed individuals. To evaluate the effectiveness and safety of future hMPV antiviral drugs, therapeutic and prophylactic monoclonal antibodies (mAbs), and vaccine candidates, it was necessary to identify small-animal and primate models that efficiently supported hMPV replication in the respiratory tract and produced neutralizing serum antibodies, commonly a clinical correlate of protection in humans. In this study, various rodents (mice, cotton rats, hamsters and ferrets) and two primate species, rhesus macaques and African green monkeys (AGMs), were evaluated for hMPV replication in the respiratory tract. The results showed that hamsters, ferrets and AGMs supported hMPV replication efficiently and produced high levels of hMPV-neutralizing antibody titres. Hamsters vaccinated with subgroup A hMPV were protected from challenge with subgroup A or subgroup B hMPV, which has implications for hMPV vaccine design. Although these animal models do not mimic human hMPV disease signs, they will nevertheless be invaluable for the future evaluation of hMPV antivirals, mAbs and vaccines.

Respiratory syncytial virus: concerns and control.

1. Carol A. McCarthy, MD* 2. Caroline Breese Hall, MD† 1. *Director, Pediatric Infectious Disease, Maine Medical Center; Associate Professor of Pediatrics, University of Vermont College of Medicine, Montpelier, VT 2. †Professor of Pediatrics and of Medicine, The University of Rochester School of Medicine and Dentistry, Rochester, NY After completing this article, readers should be able to: 1. Describe the clinical manifestations of respiratory syncytial virus (RSV) infection. 2. Delineate the infants who are at increased risk for serious RSV infection. 3. Explain why older children and adults who have immunosuppression and the elderly may have significant RSV disease. 4. Explain why timely identification of RSV by antigen detection or culture may be helpful. 5. Describe for whom prophylaxis with immunoglobulin and treatment with antivirals should be considered. RSV is the major pathogen responsible for yearly outbreaks of lower respiratory tract disease in young children. Approximately 75,000 to 125,000 infants in the United States are estimated to be hospitalized yearly because of bronchiolitis or pneumonia from RSV. Although its significance in the young pediatric population has been recognized for more than 40 years, only more recently has RSV been confirmed as an important cause of respiratory tract illness throughout life. Increased understanding of the virus and the host response to it has resulted in expanded therapeutic and preventive options. Although elimination of RSV disease currently does not appear to be a realistic objective, control of RSV infection is possible and is being rigorously pursued. RSV is a member of the Paramyxoviridae family, genus pneumovirus. It was identified initially in chimpanzees that had coryza and was named chimpanzee coryza agent. Subsequently, this virus was isolated from infants who had respiratory symptoms and was renamed respiratory syncytial virus because of the characteristic syncytial pattern observed in tissue culture. It is an enveloped virus that has a single, negative-strand genome of 5×106 kD. The genome encodes 10 mRNAs, each of which codes for an individual protein. Five proteins (F, G, SH, M, M2) are associated with the viral envelope. The F or fusion protein appears to initiate the fusion of viral and cellular membranes. The …

RESPIRATORY SYNCYTIAL VIRUS INFECTION CAUSES OBSTRUCTIVE AIRWAY DISEASE IN BALB/C MICE, AS DETECTED BY PLETHYSMOGRAPHY. ▴ 1107

Respiratory Syncytial Virus (RSV) is a major cause of lower respiratory tract disease in young children and infants. Since possibilities to study RSV infection in humans are limited, various animal models have been developed. Balb/C mice permit spread of RSV in the lungs upon nasal inoculation with the virus, but they have not been found to develop signs of respiratory distress. However, inflammatory infiltrates have been observed in the lung after infection. The aim of the present study was to determine if mice infected with RSV developed evidence of respiratory illness detectable by plethysmography.

Respiratory Syncytial Virus — From Chimps with Colds to Conundrums and Cures

Three and a half decades ago Morris et al.1 recovered from a chimpanzee with a cold a virus that had infected the entire colony and its handler. In subsequent years this contagious chimpanzee coryza agent earned a new name, respiratory syncytial virus. It is now recognized as the most important cause of lower respiratory tract disease in young children. Each year 95,000 children in the United States are hospitalized with lower respiratory tract disease due to respiratory syncytial virus, and more than 4500 die. Logarithmically greater numbers of children with respiratory syncytial virus infection are treated as outpatients. Recognition of . . .