Protective and Harmful Immunity to RSV Infection.

Respiratory syncytial virus (RSV) is an exceptional mucosal pathogen. It specializes in infection of the ciliated respiratory epithelium, causing disease of variable severity with little or no direct systemic effects. It infects virtually all children by the age of three years and then repeatedly infects throughout life; this it does despite relatively slight variations in antigenicity, apparently by inducing selective immunological amnesia. Inappropriate or dysregulated responses to RSV can be pathogenic, causing disease-enhancing inflammation that contributes to short- and long-term effects. In addition, RSV's importance as a largely unrecognized pathogen of debilitated older people is increasingly evident. Vaccines that induce nonpathogenic protective immunity may soon be available, and it is possible that different vaccines will be optimal for infants; older children; young to middle-age adults (including pregnant women); and elderly persons. At the dawn of RSV vaccination, it is timely to review what is known (and unknown) about immune responses to this fascinating virus.

Maternal diet modulates the infant microbiome and intestinal Flt3L necessary for dendritic cell development and immunity to respiratory infection.

Poor maternal diet during pregnancy is a risk factor for severe lower respiratory infections (sLRIs) in the offspring, but the underlying mechanisms remain elusive. Here, we demonstrate that in mice a maternal low-fiber diet (LFD) led to enhanced LRI severity in infants because of delayed plasmacytoid dendritic cell (pDC) recruitment and perturbation of regulatory T cell expansion in the lungs. LFD altered the composition of the maternal milk microbiome and assembling infant gut microbiome. These microbial changes reduced the secretion of the DC growth factor Flt3L by neonatal intestinal epithelial cells and impaired downstream pDC hematopoiesis. Therapy with a propionate-producing bacteria isolated from the milk of high-fiber diet-fed mothers, or supplementation with propionate, conferred protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that promotes pDC hematopoiesis in early life and confers disease resistance against sLRIs.

Airway secretory cell fate conversion via YAP-mTORC1-dependent essential amino acid metabolism.

Tissue homeostasis requires lineage fidelity of stem cells. Dysregulation of cell fate specification and differentiation leads to various diseases, yet the cellular and molecular mechanisms governing these processes remain elusive. We demonstrate that YAP/TAZ activation reprograms airway secretory cells, which subsequently lose their cellular identity and acquire squamous alveolar type 1 (AT1) fate in the lung. This cell fate conversion is mediated via distinctive transitional cell states of damage-associated transient progenitors (DATPs), recently shown to emerge during injury repair in mouse and human lungs. We further describe a YAP/TAZ signaling cascade to be integral for the fate conversion of secretory cells into AT1 fate, by modulating mTORC1/ATF4-mediated amino acid metabolism in vivo. Importantly, we observed aberrant activation of the YAP/TAZ-mTORC1-ATF4 axis in the altered airway epithelium of bronchiolitis obliterans syndrome, including substantial emergence of DATPs and AT1 cells with severe pulmonary fibrosis. Genetic and pharmacologic inhibition of mTORC1 activity suppresses lineage alteration and subepithelial fibrosis driven by YAP/TAZ activation, proposing a potential therapeutic target for human fibrotic lung diseases.

Respiratory Syncytial Virus Infects Regulatory B Cells in Human Neonates via Chemokine Receptor CX3CR1 and Promotes Lung Disease Severity.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in infants and is characterized by pulmonary infiltration of B cells in fatal cases. We analyzed the B cell compartment in human newborns and identified a population of neonatal regulatory B lymphocytes (nBreg cells) that produced interleukin 10 (IL-10) in response to RSV infection. The polyreactive B cell receptor of nBreg cells interacted with RSV protein F and induced upregulation of chemokine receptor CX3CR1. CX3CR1 interacted with RSV glycoprotein G, leading to nBreg cell infection and IL-10 production that dampened T helper 1 (Th1) cytokine production. In the respiratory tract of neonates with severe RSV-induced acute bronchiolitis, RSV-infected nBreg cell frequencies correlated with increased viral load and decreased blood memory Th1 cell frequencies. Thus, the frequency of nBreg cells is predictive of the severity of acute bronchiolitis disease and nBreg cell activity may constitute an early-life host response that favors microbial pathogenesis.

Detection of Bronchiolitis Obliterans Syndrome after Pediatric Hematopoietic Stem Cell Transplantation: An Official American Thoracic Society Clinical Practice Guideline.

Background: Many children undergo allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common noninfectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent NIH workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. Methods: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of, post-HSCT BOS in children. A systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. Conclusions: This document provides an evidence-based approach to the detection of post-HSCT BOS in children while also highlighting considerations for the implementation of each recommendation. Further, the document describes important areas for future research.

Nasopharyngeal airway long noncoding RNAs of infants with bronchiolitis and subsequent risk of developing childhood asthma.

BACKGROUND: Severe bronchiolitis (ie, bronchiolitis requiring hospitalization) during infancy is a major risk factor for developing childhood asthma. However, the biological mechanisms linking these 2 conditions remain unclear. OBJECTIVE: We sought to investigate the longitudinal relationship between nasopharyngeal airway long noncoding RNA (lncRNA) in infants with severe bronchiolitis and subsequent asthma development. METHODS: In this multicenter prospective cohort study of infants with severe bronchiolitis, we performed RNA sequencing of nasopharyngeal airway lncRNAs at index hospitalization. First, we identified differentially expressed lncRNAs (DE-lncRNAs) associated with asthma development by age 6 years. Second, we investigated the associations of DE-lncRNAs with asthma-related clinical characteristics. Third, to characterize the function of DE-lncRNAs, we performed pathway analysis for mRNA targeted by DE-lncRNAs. Finally, we examined the associations of DE-lncRNAs with nasal cytokines at index hospitalization. RESULTS: Among 343 infants with severe bronchiolitis (median age, 3 months), we identified 190 DE-lncRNAs (false-discovery rate [FDR] < 0.05) associated with asthma development (eg, LINC02145, RAMP2-AS1, and PVT1). These DE-lncRNAs were associated with asthma-related clinical characteristics (FDR < 0.05), for example, respiratory syncytial virus or rhinovirus infection, infant eczema, and IgE sensitization. Furthermore, DE-lncRNAs were characterized by asthma-related pathways, including mitogen-activated protein kinase, FcɛR, and phosphatidylinositol 3-kinase (PI3K)-protein kinase B signaling pathways (FDR < 0.05). These DE-lncRNAs were also associated with nasal cytokines (eg, IL-1ß, IL-4, and IL-13; FDR < 0.05). CONCLUSIONS: In a multicenter cohort study of infants with severe bronchiolitis, we identified nasopharyngeal airway lncRNAs associated with childhood asthma development, characterized by asthma-related clinical characteristics, asthma-related pathways, and nasal cytokines. Our approach identifies lncRNAs underlying the bronchiolitis-asthma link and facilitates the early identification of infants at high risk of subsequent asthma development.

Respiratory Syncytial Virus Infects Peripheral and Spinal Nerves and Induces Chemokine-Mediated Neuropathy.

Respiratory syncytial virus (RSV) primarily infects the respiratory epithelium, but growing evidence suggests that it may also be responsible for neurologic sequelae. In 3-dimensional microphysiologic peripheral nerve cultures, RSV infected neurons, macrophages, and dendritic cells along 2 distinct trajectories depending on the initial viral load. Low-level infection was transient, primarily involved macrophages, and induced moderate chemokine release with transient neural hypersensitivity. Infection with higher viral loads was persistent, infected neuronal cells in addition to monocytes, and induced robust chemokine release followed by progressive neurotoxicity. In spinal cord cultures, RSV infected microglia and dendritic cells but not neurons, producing a moderate chemokine expression pattern. The persistence of infection was variable but could be identified in dendritic cells as long as 30 days postinoculation. This study suggests that RSV can disrupt neuronal function directly through infection of peripheral neurons and indirectly through infection of resident monocytes and that inflammatory chemokines likely mediate both mechanisms.

Single-cell resolution of human airway epithelial cells exposed to bronchiolitis obliterans-associated chemicals.

Bronchiolitis obliterans (BO) is a fibrotic lung disease characterized by progressive luminal narrowing and obliteration of the small airways. In the nontransplant population, inhalation exposure to certain chemicals is associated with BO; however, the mechanisms contributing to disease induction remain poorly understood. This study's objective was to use single-cell RNA sequencing for the identification of transcriptomic signatures common to primary human airway epithelial cells after chemical exposure to BO-associated chemicals-diacetyl or nitrogen mustard-to help explain BO induction. Primary airway epithelial cells were cultured at air-liquid interface and exposed to diacetyl, nitrogen mustard, or control vapors. Cultures were dissociated and sequenced for single-cell RNA. Differential gene expression and functional pathway analyses were compared across exposures. In total, 75,663 single cells were captured and sequenced from all exposure conditions. Unbiased clustering identified 11 discrete phenotypes, including 5 basal, 2 ciliated, and 2 secretory cell clusters. With chemical exposure, the proportion of cells assigned to keratin 5+ basal cells decreased, whereas the proportion of cells aligned to secretory cell clusters increased compared with control exposures. Functional pathway analysis identified interferon signaling and antigen processing/presentation as pathways commonly upregulated after diacetyl or nitrogen mustard exposure in a ciliated cell cluster. Conversely, the response of airway basal cells differed significantly with upregulation of the unfolded protein response in diacetyl-exposed basal cells, not seen in nitrogen mustard-exposed cultures. These new insights provide early identification of airway epithelial signatures common to BO-associated chemical exposures.NEW & NOTEWORTHY Bronchiolitis obliterans (BO) is a devastating fibrotic lung disease of the small airways, or bronchioles. This original manuscript uses single-cell RNA sequencing for identifying common signatures of chemically exposed airway epithelial cells in BO induction. Chemical exposure reduced the proportion of keratin 5+ basal cells while increasing the proportion of keratin 4+ suprabasal cells. Functional pathways contributory to these shifts differed significantly across exposures. These new results highlight similarities and differences in BO induction across exposures.

Repetitive sulfur dioxide exposure in mice models post-deployment respiratory syndrome.

Soldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than nondeployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the subjects in this cohort reported exposure to sulfur dioxide (SO2), we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular (PV) disease. Although abnormalities in small airways were not sufficient to alter lung mechanics, PV remodeling resulted in the development of pulmonary hypertension and reduced exercise tolerance in SO2-exposed mice. SO2 exposure led to increased formation of isolevuglandins (isoLGs) adducts and superoxide dismutase 2 (SOD2) acetylation in endothelial cells, which were attenuated by treatment with the isoLG scavenger 2-hydroxybenzylamine acetate (2-HOBA). In addition, 2-HOBA treatment or Siruin-3 overexpression in a transgenic mouse model prevented vascular remodeling following SO2 exposure. In summary, our results indicate that repetitive SO2 exposure recapitulates many aspects of PDRS and that oxidative stress appears to mediate PV remodeling in this model. Together, these findings provide new insights regarding the critical mechanisms underlying PDRS.NEW & NOTEWORTHY We developed a mice model of "post-deployment respiratory syndrome" (PDRS), a condition in Veterans with unexplained exertional dyspnea. Our model successfully recapitulates many of the pathological and physiological features of the syndrome, revealing involvement of the ROS-isoLGs-Sirt3-SOD2 pathway in pulmonary vasculature pathology. Our study provides additional knowledge about effects and long-term consequences of sulfur dioxide exposure on the respiratory system, serving as a valuable tool for future PDRS research.

Using the near real-time effective reproduction number rt as an early-warning tool for seasonal bronchiolitis and influenza-like illness epidemics.

BACKGROUND: Yearly bronchiolitis and influenza-like illness epidemics in France often involve high morbidity and mortality, which severely impacts healthcare. Epidemics are declared by the French National Institute of Public Health based on syndromic surveillance of primary care and emergency departments (ED), using statistics-based alarms. Although the effective reproduction number (Rt) is used to monitor the dynamics of epidemics, it has never been used as an early warning tool for bronchiolitis or influenza-like illness epidemics in France.We assessed whether Rt is useful for detecting seasonal epidemics by comparing it to the tool currently used (MASS) by epidemiologists to declare epidemic phases. METHODS: We used anonymized ED syndromic data from the Île-de-France region in France from 2010 to 2022. We estimated Rt and compared the indication of accelerated transmission (Rt >1) to the MASS epidemic alarm time points. We computed the difference between those two time points, time to epidemic peak, and the daily cases documented at first indication and peak. RESULTS: Rt provided alarms for influenza-like illness and bronchiolitis epidemics that were, respectively, 6 days (IQR[4;8]) and 64 days (IQR[52;80]) - in median - earlier than the alarms provided by MASS. CONCLUSION: Rt detected earlier signals of bronchiolitis and influenza-like illness epidemics. Using this early-warning indicator in combination with others to declare an annual epidemic could provide opportunities to improve healthcare system readiness.

Association between cytomegalovirus viremia and long-term outcomes in lung transplant recipients.

Although cytomegalovirus (CMV) viremia/DNAemia has been associated with reduced survival after lung transplantation, its association with chronic lung allograft dysfunction (CLAD) and its phenotypes is unclear. We hypothesized that, in a modern era of CMV prophylaxis, CMV DNAemia would still remain associated with death, but also represent a risk factor for CLAD and specifically restrictive allograft syndrome (RAS)/mixed phenotype. This was a single-center retrospective cohort study of all consecutive adult, first, bilateral-/single-lung transplants done between 2010-2016, consisting of 668 patients. Risks for death/retransplantation, CLAD, or RAS/mixed, were assessed by adjusted cause-specific Cox proportional-hazards models. CMV viral load (VL) was primarily modeled as a categorical variable: undetectable, detectable to 999, 1000 to 9999, and ≥10 000 IU/mL. In multivariable models, CMV VL was significantly associated with death/retransplantation (≥10 000 IU/mL: HR = 2.65 [1.78-3.94]; P < .01), but was not associated with CLAD, whereas CMV serostatus mismatch was (D+R-: HR = 2.04 [1.30-3.21]; P < .01). CMV VL was not associated with RAS/mixed in univariable analysis. Secondary analyses with a 7-level categorical or 4-level ordinal CMV VL confirmed similar results. In conclusion, CMV DNAemia is a significant risk factor for death/retransplantation, but not for CLAD or RAS/mixed. CMV serostatus mismatch may have an impact on CLAD through a pathway independent of DNAemia.

Factors Associated with Inhaled Bronchodilator and Oral Corticosteroid Use in Young Children with First Lower Respiratory Tract Infection.

OBJECTIVES: To examine factors associated with claims for and potential overuse of inhaled bronchodilators (IBs) and oral corticosteroids (OCSs) for children <2 years old at first lower respiratory tract infections (LRTIs). STUDY DESIGN: Retrospective cohort study using Colorado All Payer Claims data from 2009 through 2019. Children with asthma were excluded. Primary outcomes were 1) IB and 2) OCS claims within 7 days of index LRTI. Primary predictors were previous IB or OCS claims for each outcome respectively. Covariates included demographics, atopy, family history of asthma, complex chronic conditions, prior inhaled corticosteroid claim, and location of index LRTI. Separate multivariable logistic regression models were used for each outcome. RESULTS: Of 10 194 eligible children, 1468 (14.4%) had an IB and 741 (7.3%) an OCS claim at or within 7 days of index LRTI. Index LRTIs were most often at outpatient visits (64%). Adjusting for covariates, prior IB prescription was associated with the IB outcome (aOR 1.9; 95% CI 1.3, 2.8), and prior OCS prescription was associated with the OCS outcome (AOR 2.2; 95% CI 1.7, 2.9). Other variables associated with either outcome included age, sex, insurance, location, and atopy. Prior inhaled corticosteroid claim, asthma family history, and complex chronic conditions were not associated with either outcome. CONCLUSIONS: This study identifies factors that might serve as opportunities for de-implementation strategies for IB and OCS overuse in young children with LRTI.

Race-Neutral Equations and Pulmonary Function Test Interpretation in Two Pediatric Cohorts.

OBJECTIVE: To investigate the changes in predicted lung function measurements when using race-neutral equations in children, based upon the new Global Lung Initiative (GLI) reference equations, utilizing a race-neutral approach in interpreting spirometry results compared with the 2012 race-specific GLI equations. STUDY DESIGN: We analyzed data from 2 multicenter prospective cohorts comprised of healthy children and children with history of severe (requiring hospitalization) bronchiolitis. Spirometry testing was done at the 6-year physical exam, and 677 tests were analyzed using new GLI Global and 2012 GLI equations. We used multivariable logistic regression, adjusted for age, height, and sex, to examine the association of race with the development of new impairment or increased severity (forced expiratory volume in the first second (FEV1) z-score ≤ -1.645) as per 2022 American Thoracic Society (ATS) guidelines. RESULTS: Compared with the race-specific GLI, the race-neutral equation yielded increases in the median forced expiratory volume in the first second and forced vital capacity (FVC) percent predicted in White children but decreases in these two measures in Black children. The prevalence of obstruction increased in White children by 21%, and the prevalence of possible restriction increased in Black children by 222%. Compared with White race, Black race was associated with increased prevalence of new impairments (aOR 7.59; 95%CI, 3.00-19.67; P < .001) and increased severity (aOR 35.40; 95%CI, 4.70-266.40; P = .001). Results were similar across both cohorts. CONCLUSIONS: As there are no biological justifications for the inclusion of race in spirometry interpretation, use of race-neutral spirometry reference equations led to an increase in both the prevalence and severity of respiratory impairments among Black children.

The Role of Lung Resident Mesenchymal Stromal Cells in the Pathogenesis and Repair of Chronic Lung Disease.

Mesenchymal stromal/stem cells are multipotent adult cells that can be extracted from numerous tissues, including the lungs. Lung-resident MSCs (LR-MSCs) are localized to perivascular spaces where they act as important regulators of pulmonary homeostasis, mediating the balance between lung injury/damage and repair processes. LR-MSCs support the integrity of the lung tissue via modulation of the immune response and release of trophic factors. However, in the context of chronic lung diseases, the ability of LR-MSCs to maintain pulmonary homeostasis and facilitate repair is diminished. In this setting, LR-MSC can contribute to the pathogenesis of disease, through their altered secretory and immunomodulatory properties. In addition, they are capable of differentiating into myofibroblasts, thereby contributing to the fibrotic aspects of numerous lung diseases. For example, in idiopathic pulmonary fibrosis, a variety of factors can stimulate their differentiation into myofibroblasts including tumor necrosis factor-α (TNF-(α), transforming growth factor-ß1 (TGF-ß1), endoplasmic reticulum (ER) stress, Hedgehog (HH), and Wingless/integrated (Wnt) signaling. Here, we review the current literature on the characterization of LR-MSCs and describe their roles in pulmonary homeostasis/repair and in the pathogenesis of chronic lung disease.

Nirsevimab immunization's real-world effectiveness in preventing severe bronchiolitis: A test-negative case-control study.

BACKGROUND: Several clinical trials have shown that nirsevimab, an antibody targeting the respiratory syncytial virus (RSV), reduces RSV bronchiolitis requiring admission. In 2023-2024, Catalonia and Andorra adopted immunization strategies for children <6 months and those born during the epidemic season. This study evaluates the effectiveness of nirsevimab in preventing hospitalizations from RSV bronchiolitis. METHODS: In the epidemic season of 2023-2024, a test-negative case-control study was conducted in three hospitals from Catalonia and Andorra. Patients <12 months old admitted with bronchiolitis and tested for RSV using molecular microbiology tests were included. The effectiveness in preventing RSV bronchiolitis hospitalization and severe disease was estimated using multivariate models. Comparisons between immunized, non-immunized, and non-eligible patients were made in prospectively collected epidemiological, clinical, and microbiological variables. RESULTS: Two hundred thirty-four patients were included. RSV was detected in 141/234 (60.2%), being less common in the immunized group (37% vs 75%, p < .001). The rate of immunized patients among those eligible was 59.7%. The estimated effectiveness for RSV-associated lower respiratory tract infection was 81.0% (95% confidence interval: 60.9-90.7), and for preventing severe disease (the need for NIV/CMV), 85.6% (41.7-96.4%). No significant differences by immunization status were observed in patients with RSV concerning viral coinfections, the need for NIV/CMV or length of hospital stay. CONCLUSIONS: This study provides real-world evidence of the effectiveness of nirsevimab in preventing RSV-lower respiratory tract infection hospitalization and severe disease in infants during their first RSV season following a systematic immunization program. Immunized patients did not exhibit a higher rate of viral coinfections nor differences in clinical severity once admitted.

Parent's perception of respiratory syncytial virus and subsequent wheezing burden: A multi-country cross-sectional survey.

BACKGROUND: Respiratory Syncytial Virus (RSV) is the leading cause of hospitalization in infants. RSV bronchiolitis is associated with an increased risk of subsequent wheezing. We aimed to document the parents' perception of the link between RSV infection and subsequent wheezing, wheezing-related healthcare and family resources use, and its impact on family daily life. METHODS: This cross-sectional online survey enrolled 1200 parents with at least one child ≤6y living in the United States, United Kingdom, Spain, and Italy. Children diagnosed with RSV bronchiolitis before age of 2 years were included in the RSV group, and those never diagnosed with RSV bronchiolitis in the Reference group. RESULTS: The odds of wheezing were 4.5-fold (95%CI 3.5-5.9) higher in the RSV than in the Reference group. The odds increased to 7.7-fold (95%CI 5.4-11.1) among children who were hospitalized, and 9-fold (95%CI 5.1-16.6) among those admitted to pediatric intensive care with RSV bronchiolitis. Similar trends were observed across all countries. In total, 57% of parents reported their child's wheezing to have moderate to severe impact on their emotional well-being, and 53% on their daily life activities and/or social life. 64% of parents reported moderate-severe impact of wheezing on child's quality of sleep and 49% and 46% reported a moderate-severe impact on their children's emotional well-being and physical activities. CONCLUSIONS: This survey suggests an association between RSV infection and subsequent wheezing in children across different countries. Wheezing, especially in association with RSV infection, was associated with increased healthcare utilization and costs, and significantly impacted parents' and children daily life.

Short- and mid-term morbidity and primary-care burden due to infant respiratory syncytial virus infection: A Spanish 6-year population-based longitudinal study.

BACKGROUND: The morbidity burden of respiratory syncytial virus (RSV) in infants extends beyond hospitalization. Defining the RSV burden before implementing prophylaxis programs is essential for evaluating any potential impact on short- to mid-term morbidity and the utilization of primary healthcare (PHC) and emergency services (ES). We established this reference data using a population-based cohort approach. METHODS: Infants hospitalized for RSV from January 2016 to March 2023 were matched with non-hospitalized ones based on birthdate and sex. We defined the exposure as severe RSV hospitalization. The main study outcomes were as follows: (1) PHC and ES visits for RSV, categorized using the International Classification of Primary Care codes, (2) prescriptions for respiratory airway obstructive disease, and (3) antibacterial prescriptions. Participants were followed up from 30 days before hospitalization for severe RSV until the outcome occurrence or end of the study. Adjusted incidence rate ratios (IRRs) of the outcomes along with their 95% confidence intervals (CI) were estimated using Poisson regression models. Stratified analyses by type of PHC visit (nurse, pediatrician, or pharmacy) and follow-up period were undertaken. We defined mid-term outcomes as those taking place up to 24 months of follow-up period. RESULTS: The study included 6626 children (3313 RSV-hospitalized; 3313 non-hospitalized) with a median follow-up of 53.7 months (IQR = 27.9, 69.4). After a 3-month follow-up, severe RSV was associated with a considerable increase in PHC visits for wheezing/asthma (IRR = 4.31, 95% CI: 3.84-4.84), lower respiratory infections (IRR = 4.91, 95% CI: 4.34-5.58), and bronchiolitis (IRR = 4.68, 95% CI: 2.93-7.65). Severe RSV was also associated with more PHC visits for the pediatrician (IRR = 2.00, 95% CI: 1.96-2.05), nurse (IRR = 1.89, 95% CI: 1.75-1.92), hospital emergency (IRR = 2.39, 95% CI: 2.17-2.63), primary healthcare emergency (IRR: 1.54, 95% CI: 1.31-1.82), as well as with important increase in prescriptions for obstructive airway diseases (IRR = 5.98, 95% CI: 5.43-6.60) and antibacterials (IRR = 4.02, 95% CI: 3.38-4.81). All findings remained substantial until 2 years of post-infection. CONCLUSIONS: Severe RSV infection in infants significantly increases short- to mid-term respiratory morbidity leading to an escalation in healthcare utilization (PHC/ES attendance) and medication prescriptions for up to 2 years afterward. Our approach could be useful in assessing the impact and cost-effectiveness of RSV prevention programs.

The Impact of Donor-Recipient Human Leukocyte Antigen Matching on Bronchiolitis Obliterans-Free Survival Among Lung Transplant Recipients With Connective Tissue Diseases.

BACKGROUND: The development of connective tissue disease-associated lung diseases (CTD-LD) occurs in association with specific human leukocyte antigens (HLA). For CTD-LD patients who require lung transplant, it is unknown whether utilization of donor organs expressing these same HLA impacts posttransplant outcomes. METHODS: Using the Scientific Registry of Transplant Recipients, we assessed whether CTD-LD lung transplant recipients in the United States have worse bronchiolitis obliterans (BOS)-free survival based on the degree of donor HLA matching. This included overall degree of donor-recipient HLA matching, donor-recipient matching at DR loci, and recipient matching with specific donor HLA antigens associated with the development of pulmonary disease in their condition. RESULTS: Among 1413 patients with CTD-ILD, highly HLA-matched donor-recipients did not have worse adjusted survival (hazard ratio [HR] = 0.93, 95% confidence interval [CI] = 0.58-1.51, p = 0.77). Recipients who were fully matched at HLA DR did not have worse survival (HR = 0.82, 95% CI = 0.56-1.19, p = 0.29). Finally, among individual CTD-LD, including rheumatoid arthritis, systemic sclerosis, the idiopathic inflammatory myopathies, and systemic lupus erythematous, transplant with a donor expressing HLA antigens associated with lung manifestations in these conditions was not associated with worse BOS-free survival. CONCLUSIONS: Among transplant recipients with CTD-LD, HLA donor-recipient matching, including at the DR loci, does not result in worse BOS-free survival. Based on these findings, there is no reason to treat these as unacceptable antigens when considering donor offers for CTD-LD candidates.

Respiratory syncytial virus subtypes in children with bronchiolitis: does it correlate with clinical severity?

BACKGROUND: In this retrospective study, we aimed to evaluate the factors associated with the severity of respiratory syncytial virus (RSV) bronchiolitis in children aged under 2 years who were admitted to the Children's Hospital of Hebei between June 2018 and January 2019. METHODS: Sputum samples positive for RSV via multiplex PCR were subtyped using real-time PCR. Data collected included risk factors for disease severity, demographics, microbiology, and outcomes. RESULTS: Of the 82 children with RSV bronchiolitis, 79 were treated and discharged with improvement, while 3 died. All three patients had underlying medical conditions, including complex congenital heart disease and severe combined immunodeficiency. Further, disease severity was associated with preexisting underlying disease, fever duration, and bacterial co-infection, but not with the RSV subtype. CONCLUSIONS: Our findings suggest that an appropriate therapeutic regimen should include the detection of bacterial co-infections and the identification of underlying diseases for the effective management of severe RSV bronchiolitis.

Human bocavirus respiratory infection: Tracing the path from viral replication and virus-cell interactions to diagnostic methods.

Human bocaviruses were first described between 2005 and 2010, identified in respiratory and enteric tract samples of children. Screening studies have shown worldwide distribution. Based on phylogenetic analysis, they were classified into four genotypes (HBoV1-4). From a clinical perspective, human bocavirus 1 (HBoV1) is considered the most relevant, since it can cause upper and lower acute respiratory tract infection, mainly in infants, including common cold, bronchiolitis, and pneumonia, as well as wheezing in susceptible patients. However, the specific processes leading to structural, biochemical, and functional changes resulting in the different clinical presentations have not been elucidated yet. This review surveys the interactions between the virus and target cells that can potentially explain disease-causing mechanisms. It also summarises the clinical phenotype of cases, stressing the role of HBoV1 as an aetiological agent of lower acute respiratory infection in infants, together with laboratory tests for detection and diagnosis. By exploring the current knowledge on the epidemiology of HBoV1, insights into the complex scenario of paediatric respiratory infections are presented, as well as the potential effects that changes in the circulation can have on the dynamics of respiratory agents, spotlighting the benefits of comprehensively increase insights into incidence, interrelationships with co-circulating agents and potential control of HBoV1.