BACKGROUND:The role of human rhinovirus (HRV) in adult lower respiratory tract infections (LRTIs) remains controversial due to limited direct evidence of alveolar tropism and age-specific clinical characterization. OBJECTIVES:To determine HRV's clinical impact, validate its capacity to infect lower respiratory tract cells, and identify predictors for HRV-associated pneumonia in adults. METHODS:In this retrospective study (January 2020-December 2023), all hospitalized adults screened for HRV via RT-PCR were enrolled for analysis. In bronchoalveolar lavage fluid (BALF)-HRV-RNA-positive patients with available transbronchial lung biopsy (TBLB) or transbronchial cryobiopsy (TBCB) specimens, immunofluorescence (IF) staining was used to assess infection of LRT cells. Multivariable logistic regression analyzed demographics, comorbidities, and symptoms. RESULTS:HRV was detected in 4.6% (437/9544) of patients, with bimodal seasonal peaks (February-April and September-November). Co-infection occurred in 49.0% (214/437), predominantly bacteria (34.1%) and viruses (25.7%). Among the 437 HRV-positive patients, 224 cases complicated with pneumonia, but only 34 (7.8%) met the diagnostic criteria for simple viral pneumonia. Multivariate analysis identified male (OR 2.69, 95% CI 1.04-6.99, P = .042), fever (OR 3.79, 95% CI 1.52-9.44, P = .004), and cough (OR 7.33, 95% CI 1.64-32.83, P = .009) as independent predictors of simple rhinovirus pneumonia. IF staining confirmed HRV VP3 protein in TBLB/TBCB specimens in 61.5% (8/13) of cases, resolving debates about HRV's LRT cells tropism. CONCLUSIONS:This study provides the first histological evidence of HRV's LRT cells infection in immunocompetent adults. Despite high co-infection rates, HRV independently drives pneumonia, particularly in males and those with fever or cough.

By integrating the largest pneumonia GWAS meta-analysis with multiple QTL data, PSMA4 emerged as a likely risk gene for pneumonia as well as a potential therapeutic target https://bit.ly/435kxK0.

BACKGROUND:This guideline aims to address key clinical questions of long COVID, and to provide evidence-based recommendations. The target population is adults with long COVID. The primary users of the guideline are clinical physicians, clinical pharmacists, nurses and general practitioners in community healthcare institutions worldwide. METHODS:The guideline was registered at the Practice guideline REgistration for transPAREncy platform (PREPARE-2024CN123) and followed a pre-specified protocol. A multidisciplinary working group was established and comprised 60 members from 10 countries and 10 areas of expertise, with a strong background in long COVID research and clinical practice, and methodology of guideline development. Through a two-step process, we determined eight PICO (Population, Intervention, Comparator, Outcome) questions focusing on prevention and treatment of long COVID. After comprehensively searching literature, conducting systematic reviews and investigating patients' values and preferences, three rounds of Delphi survey were conducted among 24 international experts to reach consensus. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach was applied to rate the certainty of evidence and determine the strength of recommendations. RESULTS:The guideline presents 10 specific recommendations, each supported by existing, updated or newly conducted systematic reviews. The key recommendations are pertinent to the following issues: 1) suggestion of vaccination or use of antiviral agents during the acute phase of COVID-19 to prevent long COVID; 2) suggestions against the use of nirmatrelvir/ritonavir and glucocorticoids (patients with persistent respiratory symptoms and olfactory disorders) for long COVID treatment; 3) suggestions supporting the use of multispecies probiotics, cognitive behavioural therapy (patients with fatigue), and personalised rehabilitation (after ruling out post-exertional malaise) for long COVID treatment. CONCLUSIONS:This guideline provides evidence-based recommendations for the prevention and treatment of long COVID. Given the limited and often low-methodological-quality evidence, all recommendations are supported by very low to moderate certainty. Further high-quality studies are needed to strengthen the evidence base.

Metabolic alterations are increasingly recognized during influenza virus infection, but how local lactate accumulation shapes antiviral immunity remains poorly characterized. By integrating time-series targeted energy metabolomics, single-cell RNA sequencing, flow cytometry, and functional perturbation, we show that influenza virus infection preferentially increases lactate within the lung microenvironment, where it restrains pulmonary CD8+ T cell response. Mechanistically, extracellular lactate enters dendritic cells through monocarboxylate transporter (MCT)-dependent transport and induces a tolerogenic-like state marked by impaired maturation, reduced costimulation, and diminished CD8+ T cell-priming capacity. Direct experimental evidence identifies H3K18la as a prominent lactate-responsive histone lactylation mark, while multi-omics integration links it to enhancer accessibility and NRF2 pathway activation. Functional studies further show that NRF2 promotes dendritic cell suppression by reinforcing tolerogenic programs and limiting mtROS-dependent XBP1 splicing. Together, these findings reveal a lactate-driven histone lactylation-NRF2 pathway that modulates antiviral immunity during influenza infection.

BACKGROUND: Severe influenza virus infection often triggers acute lung injury, and the efficacy of respiratory functional recovery critically depends on timely alveolar regeneration. However, the cellular dynamics and regulatory mechanisms underlying post-infectious alveolar repair remain incompletely understood. METHODS: Utilizing Sftpc-CreER; Rosa26-mTmG lineage-tracing model, we determine the main stem cell population responsible for alveolar regeneration following influenza-induced injury. Through integrated single-cell RNA sequencing (scRNA-seq), immunofluorescence, and electron microscopy approaches, we mapped cellular transcriptional landscapes and spatial interactions. Key macrophage-epithelial crosstalk was further investigated via in vitro co-culture systems and in vivo conditional depletion models using diphtheria toxin receptor-transgenic mice. Putative regulatory factors were predicted through ligand-receptor interaction analysis and functionally validated in ex vivo organoid models. RESULTS: In this study, we revealed that the severely damaged alveolar barrier after influenza virus infection was rebuilt by the proliferation and differentiation of residual type II alveolar epithelial (AT2) cells in an inflammatory niche. In particular, monocyte-derived macrophage (Mo-Macs) expand, displaying intimate spatial proximity with AT2 cells. In addition, the cellular transcriptional status determined by scRNA-seq revealed that Mo-Macs regulate epithelial cell proliferation. Mo-Macs promoted the formation of AT2 spheres in vitro. Moreover, Mo-Mac depletion resulted in delayed repair of the alveolar epithelial structure in vivo. In addition, the mechanism by which Mo-Macs regulate alveolar epithelial repair involves the secretion of oncostatin M (OSM), which stimulates p-STAT3 activation and promotes AT2 cell proliferation. CONCLUSIONS: Our findings revealed that residual AT2 cells act as stem cells in the alveolus and are regulated by Mo-Macs through OSM secretion. These findings increase our understanding of the role of inflammatory signals in regulating tissue repair after severe injury, which may provide a potential avenue for therapeutic intervention in recovered patients.

Background Viremia has been detected in a significant proportion of patients with acute respiratory viral infection, yet its clinical value remains underappreciated. Objectives This study synthesized available evidence to comprehensively assess the prevalence of viremia and its impact on clinical outcomes. Data sources Data were retrieved from Medline (via Ovid), Embase, and the WHO COVID-19 database. Study eligibility criteria This review included original clinical studies analyzing the prevalence of viremia in patients with acute respiratory viral infection or its association with clinical outcomes, while excluding non-original research, insufficiently detailed studies, inconsistent pathogen observations, or those with inadequate sample sizes. Participants Patients with acute respiratory viral infection. Exposure Respiratory viral infection-related viremia Methods of data synthesis Data synthesis utilized random-effects models to pool prevalence and hazard ratios (HR), odds ratios (OR), and adjusted HR/OR for clinical outcomes. Results In the comprehensive analysis of viremia prevalence, data were pooled from 101 studies, which included a total of 16,388 non-overlapping patients. Viremia was present in 34% (95% CI: 28%–41%) of patients with acute respiratory viral infection. 45 studies provided information on the clinical outcomes of 2,002 patients with viremia and 3,907 patients without viremia. Viremia was associated with increased risks of mortality (OR 6.83, 95% CI: 4.92–9.48; aHR 2.91, 95% CI: 1.87–4.53; aOR 3.68, 95% CI: 2.37–5.71), ICU admission (OR 4.74, 95% CI: 2.66–8.46; aOR 4.89, 95% CI: 1.61–14.91), mechanical ventilation (OR 4.12, 95% CI: 2.25–7.52), and hepatic complications (OR 3.10, 95% CI: 1.30–7.40). Conclusions Viremia is prevalent in patients with respiratory viral infection and is associated with elevated risks of adverse clinical outcomes.

The dynamics of the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infections remain unclear, particularly when compared to responses in naive individuals. In this longitudinal prospective cohort study, 13 participants were recruited. Peripheral blood samples were collected every other day until day 7 after symptom onset. Transcriptome sequencing, single-cell sequencing, T-cell receptor (TCR) sequencing, B-cell receptor (BCR) sequencing, Olink proteomics, and antigen-antibody binding experiments were then performed. During the incubation periods of breakthrough infections, peripheral blood exhibited type 2 cytokine response, which shifted to type 1 cytokine response upon symptom onset. Plasma cytokine levels of C-X-C motif chemokine ligand 10, monocyte chemoattractant protein-1, interferon-γ, and interleukin-6 show larger changes in breakthrough infections than naïve infections. The inflammatory response in breakthrough infections rapidly subsided, returning to homeostasis by day 5 after symptom onset. Notably, the levels of monocyte-derived S100A8/A9, previously considered a marker of severe disease, physiologically significantly increased in the early stages of mild cases and persisted until day 7, suggesting a specific biological function. Longitudinal tracking also revealed that antibodies anti-Receptor Binding Domain (anti-RBD) in breakthrough infections significantly increased by day 7 after symptom onset, whereas cytotoxic T lymphocytes appeared by day 5. This study presents a reference for interpreting the immunological response to breakthrough infectious disease in humans.

Aim:This study attempts to explore the clinical differences of sepsis caused by respiratory viruses and bacteria, and to search for risk factors for mortality in viral sepsis. Methods:This single-centre, retrospective cohort study enrolled patients hospitalised at our medical intensive care unit (ICU) from October 2020 to January 2024 who were diagnosed with pneumonia and sepsis. The primary and secondary pathogens were identified with comprehensive aetiological tests. The baseline clinical information, biochemical tests, treatments and clinical outcomes were collected. Results:This study included 292 patients, comprising 191 with viral sepsis and 101 with bacterial sepsis. Compared with the bacterial sepsis group, patients with respiratory viral sepsis had lower oxygenation index levels upon ICU admission, higher proportions of acute respiratory distress syndrome (85% versus 44%; p<0.001), secondary infection (84% versus 39%; p<0.001) and higher ICU mortality (57% versus 43%; p=0.018). After adjustment, viral sepsis patients had an odds ratio of 2.26 (95% CI 1.26-4.07) for ICU mortality. Risk factors for ICU mortality in viral sepsis included age, sequential organ failure assessment score, secondary infection, immunocompromised status and coronary heart disease. The subgroup analysis showed that secondary infection in viral sepsis contributed to a poorer clinical outcome. Conclusions:ICU patients with respiratory viral sepsis presented a higher incidence of unfavourable outcome, which may partially be attributed to secondary infections.

AIMS:Influenza virus infection may lead to fatal complications including multi-organ failure and sepsis. The influenza virus was detected in various extra-pulmonary organs in autopsy studies during the 2009 pandemic. However, limited research has been conducted on the presence of viral particle or viral components in the peripheral blood. METHODS AND RESULTS:We established a mouse model for severe H1N1 influenza. The bile and blood samples were collected over time and inoculated into embryonated chicken eggs. We detected live influenza virus in bile and blood samples in early infection. Immunofluorescence showed influenza viral components in the liver tissue. No live virus was isolated in the bile in mice intragastrically administered with influenza virus, indicating that the virus was spread from the blood stream. Targeted metabolomics analysis of bile acid and liver tissues showed that a secondary bile acid (3-dehydrocholic acid) was decreased after influenza H1N1 infection. Genes related with fatty acid metabolism and bile secretion pathways were down-regulated in liver after influenza virus infection. CONCLUSION:Our study indicated that influenza virus viremia is present in severe influenza, and that the liver is a target organ for influenza viral sepsis.

Human metapneumovirus (HMPV) is an important cause of acute lower respiratory infection in children and adults worldwide. There are four genetic subgroups of HMPV and both neutralizing antibodies and T cells contribute to protection. However, little is known about mechanisms of pathogenesis and most published work is based on a few extensively passaged, laboratory-adapted strains of HMPV. In this study, we isolated and characterized a panel of low passage HMPV clinical isolates representing all four genetic subgroups. The clinical isolates exhibited lower levels of in vitro replication compared to a lab-adapted strain. We compared disease phenotypes using a well-established mouse model. Several virulent isolates caused severe weight loss, lung pathology, airway dysfunction, and fatal disease in mice, which was confirmed in three inbred mouse strains. Disease severity did not correlate with lung viral titer, as virulent strains exhibited restricted replication in the lower airway. Virulent HMPV isolates were associated with markedly increased proinflammatory cytokine production and neutrophil influx; however, depletion of neutrophils or genetic ablation of inflammasome components did not reverse disease. Virulent clinical isolates induced markedly increased type I and type III interferon (IFN) secretion in vitro and in vivo. STAT1/2-deficient mice lacking both type I and type III IFN signaling showed reduced disease severity and increased lung viral replication. Inhibition of type I IFN signaling using a blocking antibody or genetic ablation of the type I IFN receptor reduced pathology with minimal effect on viral replication. Conversely, blockade of type III IFN signaling with a neutralizing antibody or genetic ablation of the IFN-lambda receptor had no effect on pathogenesis but restored viral replication. Collectively, these results demonstrate distinct roles for type I and type III IFN in HMPV pathogenesis and immunity.

BackgroundGrowing evidence suggests that symptoms associated with post-COVID-19 condition (also known as long COVID) can affect multiple organs and systems in the human body, but their association with viral persistence is not clear. The aim of this study was to investigate the persistence of SARS-CoV-2 in diverse tissues at three timepoints following recovery from mild COVID-19, as well as its association with long COVID symptoms.MethodsThis single-centre, cross-sectional cohort study was done at China–Japan Friendship Hospital in Beijing, China, following the omicron wave of COVID-19 in December, 2022. Individuals with mild COVID-19 confirmed by PCR or a lateral flow test scheduled to undergo gastroscopy, surgery, or chemotherapy, or scheduled for treatment in hospital for other reasons, at 1 month, 2 months, or 4 months after infection were enrolled in this study. Residual surgical samples, gastroscopy samples, and blood samples were collected approximately 1 month (18–33 days), 2 months (55–84 days), or 4 months (115–134 days) after infection. SARS-CoV-2 was detected by digital droplet PCR and further confirmed through RNA in-situ hybridisation, immunofluorescence, and immunohistochemistry. Telephone follow-up was done at 4 months post-infection to assess the association between the persistence of SARS-CoV-2 RNA and long COVID symptoms.FindingsBetween Jan 3 and April 28, 2023, 317 tissue samples were collected from 225 patients, including 201 residual surgical specimens, 59 gastroscopy samples, and 57 blood component samples. Viral RNA was detected in 16 (30%) of 53 solid tissue samples collected at 1 month, 38 (27%) of 141 collected at 2 months, and seven (11%) of 66 collected at 4 months. Viral RNA was distributed across ten different types of solid tissues, including liver, kidney, stomach, intestine, brain, blood vessel, lung, breast, skin, and thyroid. Additionally, subgenomic RNA was detected in 26 (43%) of 61 solid tissue samples tested for subgenomic RNA that also tested positive for viral RNA. At 2 months after infection, viral RNA was detected in the plasma of three (33%), granulocytes of one (11%), and peripheral blood mononuclear cells of two (22%) of nine patients who were immunocompromised, but in none of these blood compartments in ten patients who were immunocompetent. Among 213 patients who completed the telephone questionnaire, 72 (34%) reported at least one long COVID symptom, with fatigue (21%, 44 of 213) being the most frequent symptom. Detection of viral RNA in recovered patients was significantly associated with the development of long COVID symptoms (odds ratio 5·17, 95% CI 2·64–10·13, p<0·0001). Patients with higher virus copy numbers had a higher likelihood of developing long COVID symptoms.InterpretationOur findings suggest that residual SARS-CoV-2 can persist in patients who have recovered from mild COVID-19 and that there is a significant association between viral persistence and long COVID symptoms. Further research is needed to verify a mechanistic link and identify potential targets to improve long COVID symptoms.FundingNational Natural Science Foundation of China, National Key R&D Program of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and New Cornerstone Science Foundation.TranslationFor the Chinese translation of the abstract see Supplementary Materials section.

X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency with susceptibility and vulnerability to Epstein-Barr virus (EBV) infection. Most patients were diagnosed in early childhood and do not survive into adulthood. Here we reported an adult-onset XLP patient presenting with fever, dyspnea, and pulmonary nodules, mimicking respiratory infection at disease onset. Diagnosis was made based on whole-exon sequencing and pedigree analysis. Chest CT showed bilateral nodular lesions partially responsive to steroid therapy. The symptoms were managed with high-dose steroid, together with broad-spectrum anti-infective treatment for mixed secondary opportunistic infections. Pathology studies revealed non-Langerhans histiocytosis and T cell infiltration in lungs. Our case highlights the importance of genetic sequencing in managing young patients with unexplained infection and potential immuno-deficiency. We also added to the understanding of XLP by carrying detailed investigation into the pulmonary lesions.

Antimicrobials are powerful tools for managing infectious diseases and provide a safe cornerstone for breakthroughs in other medical practices (surgery, chemotherapy, immunomodulatory treatments, etc.) Since the discovery of penicillin, antimicrobials have revolutionized modern medicine. However, the emergence of antimicrobial resistance (AMR) has threatened to reverse the advancement [ [1] Marston H.D. Dixon D.M. Knisely J.M. Palmore T.N. Fauci A.S. Antimicrobial resistance. JAMA. 2016; 316: 1193-1204https://doi.org/10.1001/jama.2016.11764 Crossref PubMed Scopus (417) Google Scholar ]. Inappropriate use of broad-spectrum antimicrobials promotes the emergence of AMR through the selection of resistant mutants. Facing the challenge of AMR, various antimicrobial stewardship (AMS) programmes have been implemented to promote appropriate and responsible antimicrobial use [ [2] Dyar O.J. Huttner B. Schouten J. Pulcini C. ESGAP (ESCMID Study Group for Antimicrobial stewardshiP). What is antimicrobial stewardship?. Clin Microbiol Infect. 2017; 23: 793-798https://doi.org/10.1016/j.cmi.2017.08.026 Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar ], but the current situation is still challenging, especially in the primary healthcare facility (PHF). Inappropriate antibiotic prescribing in primary healthcare facilities in China: a nationwide survey, 2017–2019Clinical Microbiology and InfectionVol. 29Issue 5PreviewWe aimed to generate comprehensive estimates of the appropriateness of outpatient antibiotic prescriptions at primary healthcare facilities (PHFs) in China. Full-Text PDF