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1.
Viruses ; 14(5)2022 04 27.
Article in English | MEDLINE | ID: covidwho-1810330

ABSTRACT

RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. We investigated if probenecid, an FDA-approved and safe urate-lowering drug that inhibits organic anion transporters (OATs) has prophylactic or therapeutic efficacy to inhibit RSV replication in three epithelial cell lines used in RSV studies, i.e., Vero E6 cells, HEp-2 cells, and in primary normal human bronchoepithelial (NHBE) cells, and in BALB/c mice. The studies showed that nanomolar concentrations of all probenecid regimens prevent RSV strain A and B replication in vitro and RSV strain A in vivo, representing a potential prophylactic and chemotherapeutic for RSV.


Subject(s)
COVID-19 , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human , Animals , Mice , Probenecid/pharmacology , Probenecid/therapeutic use , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus Infections/prevention & control , Respiratory Syncytial Virus, Human/genetics , SARS-CoV-2 , Virus Replication
2.
Molecules ; 27(7)2022 Mar 31.
Article in English | MEDLINE | ID: covidwho-1785839

ABSTRACT

Respiratory syncytial virus infection (RSVI) is an acute medical and social problem in many countries globally. Infection is most dangerous for infants under one year old and the elderly. Despite its epidemiological relevance, only two drugs are registered for clinical use against RSVI: ribavirin (approved in a limited number of countries due to side effects) and palivizumab (Synagis), which is intended only for the prevention, but not the treatment, of infection. Currently, various research groups are searching for new drugs against RSV, with three main areas of research: small molecules, polymeric drugs (proteins and peptides), and plant extracts. This review is devoted to currently developed protein and peptide anti-RSV drugs.


Subject(s)
Respiratory Syncytial Virus Infections , Respiratory Tract Infections , Aged , Antiviral Agents/therapeutic use , Humans , Infant , Palivizumab/therapeutic use , Peptides/pharmacology , Peptides/therapeutic use , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Tract Infections/drug therapy
3.
EBioMedicine ; 77: 103891, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1709186

ABSTRACT

BACKGROUND: Gut microbiota-derived short-chain fatty-acid (SFCA) acetate protects mice against RSV A2 strain infection by increasing interferon-ß production and expression of interferon-stimulated genes (ISGs). However, the role of SFCA in RSV infection using strains isolated from patients is unknown. METHODS: We first used RSV clinical strains isolated from infants hospitalized with RSV bronchiolitis to investigate the effects of in vitro SCFA-acetate treatment of human pulmonary epithelial cells. We next examined whether SCFA-acetate treatment is beneficial in a mouse model of RSV infection using clinical isolates. We sought to investigate the relationship of gut microbiota and fecal acetate with disease severity among infants hospitalized with RSV bronchiolitis, and whether treating their respiratory epithelial cells with SCFA-acetate ex-vivo impacts viral load and ISG expression. We further treated epithelial cells from SARS-CoV-2 infected patients with SCFA-acetate. FINDINGS: In vitro pre-treatment of A549 cells with SCFA-acetate reduced RSV infection with clinical isolates and increased the expression of RIG-I and ISG15. Animals treated with SCFA-acetate intranasally recovered significantly faster, with reduction in the RSV clinical isolates viral load, and increased lung expression of IFNB1 and the RIG-I. Experiments in RIG-I knockout A549 cells demonstrated that the protection relies on RIG-I presence. Gut microbial profile was associated with bronchiolitis severity and with acetate in stool. Increased SCFA-acetate levels were associated with increasing oxygen saturation at admission, and shorter duration of fever. Ex-vivo treatment of patients' respiratory cells with SCFA-acetate reduced RSV load and increased expression of ISGs OAS1 and ISG15, and virus recognition receptors MAVS and RIG-I, but not IFNB1. These SCFA-acetate effects were not found on cells from SARS-CoV-2 infected patients. INTERPRETATION: SCFA-acetate reduces the severity of RSV infection and RSV viral load through modulation of RIG-I expression. FUNDING: FAPERGS (FAPERGS/MS/CNPq/SESRS no. 03/2017 - PPSUS 17/2551-0001380-8 and COVID-19 20/2551-0000258-6); CNPq 312504/2017-9; CAPES) - Finance Code 001.


Subject(s)
Bronchiolitis , COVID-19 , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human , Acetates/metabolism , Acetates/pharmacology , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Bronchiolitis/drug therapy , Bronchiolitis/metabolism , Fatty Acids, Volatile/metabolism , Humans , Infant , Lung/metabolism , Mice , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus, Human/physiology , SARS-CoV-2
4.
Science ; 375(6577): 161-167, 2022 Jan 14.
Article in English | MEDLINE | ID: covidwho-1648160

ABSTRACT

The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and older adults. We describe 4'-fluorouridine (4'-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with high selectivity index in cells and human airway epithelia organoids. Polymerase inhibition within in vitro RNA-dependent RNA polymerase assays established for RSV and SARS-CoV-2 revealed transcriptional stalling after incorporation. Once-daily oral treatment was highly efficacious at 5 milligrams per kilogram (mg/kg) in RSV-infected mice or 20 mg/kg in ferrets infected with different SARS-CoV-2 variants of concern, initiated 24 or 12 hours after infection, respectively. These properties define 4'-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2, and related RNA virus infections.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus, Human/drug effects , SARS-CoV-2/drug effects , Uracil Nucleotides/pharmacology , Administration, Oral , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/metabolism , COVID-19/virology , Cell Line , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Disease Models, Animal , Female , Ferrets , Humans , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Mononegavirales/drug effects , Mononegavirales/physiology , RNA-Dependent RNA Polymerase/metabolism , Respiratory Mucosa/virology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/genetics , Respiratory Syncytial Virus, Human/physiology , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Transcription, Genetic , Uracil Nucleotides/administration & dosage , Uracil Nucleotides/metabolism , Virus Replication/drug effects
5.
Lancet Glob Health ; 10(2): e269-e277, 2022 02.
Article in English | MEDLINE | ID: covidwho-1625222

ABSTRACT

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections and a key driver of childhood mortality. Previous RSV burden of disease estimates used hospital-based surveillance data and modelled, rather than directly measured, community deaths. Given this uncertainty, we conducted a 3-year post-mortem prevalence study among young infants at a busy morgue in Lusaka, Zambia-the Zambia Pertussis RSV Infant Mortality Estimation (ZPRIME) study. METHODS: Infants were eligible for inclusion if they were aged between 4 days and less than 6 months and were enrolled within 48 h of death. Enrolment occurred mainly at the University Teaching Hospital of the University of Zambia Medical School (Lusaka, Zambia), the largest teaching hospital in Zambia. We extracted demographic and clinical data from medical charts and official death certificates, and we conducted verbal autopsies with the guardian or next of kin. RSV was identified using reverse transcriptase quantitative PCR and stratified by age, time of year, and setting (community vs facility deaths). By combining the PCR prevalence data with syndromic presentation, we estimated the proportion of all infant deaths that were due to RSV. FINDINGS: The ZPRIME study ran from Aug 31, 2017, to Aug 31, 2020, except for from April 1 to May 6, 2020, during which data were not collected due to restrictions on human research at this time (linked to COVID-19). We enrolled 2286 deceased infants, representing 79% of total infant deaths in Lusaka. RSV was detected in 162 (7%) of 2286 deceased infants. RSV was detected in 102 (9%) of 1176 community deaths, compared with 10 (4%) of 236 early facility deaths (<48 h from admission) and 36 (5%) of 737 late facility deaths (≥48 h from admission). RSV deaths were concentrated in infants younger than 3 months (116 [72%] of 162 infants), and were clustered in the first half of each year and in the poorest and most densely populated Lusaka townships. RSV caused at least 2·8% (95% CI 1·0-4·6) of all infant deaths and 4·7% (1·3-8·1) of community deaths. INTERPRETATION: RSV was a major seasonal cause of overall infant mortality, particularly among infants younger than 3 months of age. Because most RSV deaths occurred in the community and would have been missed through hospital-based surveillance, the global burden of fatal RSV has probably been underestimated. FUNDING: Bill & Melinda Gates Foundation.


Subject(s)
Respiratory Syncytial Virus Infections/mortality , Female , Humans , Infant , Infant, Newborn , Male , Public Health Surveillance/methods , Respiratory Syncytial Virus Infections/diagnosis , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus, Human , Reverse Transcriptase Polymerase Chain Reaction , Zambia/epidemiology
6.
Sci Rep ; 11(1): 24442, 2021 12 24.
Article in English | MEDLINE | ID: covidwho-1577650

ABSTRACT

Therapeutic interventions targeting viral infections remain a significant challenge for both the medical and scientific communities. While specific antiviral agents have shown success as therapeutics, viral resistance inevitably develops, making many of these approaches ineffective. This inescapable obstacle warrants alternative approaches, such as the targeting of host cellular factors. Respiratory syncytial virus (RSV), the major respiratory pathogen of infants and children worldwide, causes respiratory tract infection ranging from mild upper respiratory tract symptoms to severe life-threatening lower respiratory tract disease. Despite the fact that the molecular biology of the virus, which was originally discovered in 1956, is well described, there is no vaccine or effective antiviral treatment against RSV infection. Here, we demonstrate that targeting host factors, specifically, mTOR signaling, reduces RSV protein production and generation of infectious progeny virus. Further, we show that this approach can be generalizable as inhibition of mTOR kinases reduces coronavirus gene expression, mRNA transcription and protein production. Overall, defining virus replication-dependent host functions may be an effective means to combat viral infections, particularly in the absence of antiviral drugs.


Subject(s)
Coronavirus/metabolism , Respiratory Syncytial Virus, Human/metabolism , TOR Serine-Threonine Kinases/metabolism , Viral Proteins/metabolism , A549 Cells , Coronavirus/drug effects , Coronavirus/genetics , Gene Expression Regulation, Viral/drug effects , Humans , Protein Biosynthesis/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , RNA Interference , RNA, Small Interfering/metabolism , Rapamycin-Insensitive Companion of mTOR Protein/antagonists & inhibitors , Rapamycin-Insensitive Companion of mTOR Protein/genetics , Rapamycin-Insensitive Companion of mTOR Protein/metabolism , Regulatory-Associated Protein of mTOR/antagonists & inhibitors , Regulatory-Associated Protein of mTOR/genetics , Regulatory-Associated Protein of mTOR/metabolism , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/drug effects , Respiratory Syncytial Virus, Human/isolation & purification , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/genetics , Viral Proteins/genetics
7.
Rev Med Virol ; 31(6): e2234, 2021 11.
Article in English | MEDLINE | ID: covidwho-1574124

ABSTRACT

The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Genetic Predisposition to Disease , Influenza, Human/immunology , Respiratory Syncytial Virus Infections/immunology , Severe Acute Respiratory Syndrome/immunology , Antiviral Agents/therapeutic use , Biological Variation, Individual , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Gene Expression , Humans , Immunity, Innate , Immunologic Factors/therapeutic use , Influenza, Human/drug therapy , Influenza, Human/genetics , Influenza, Human/virology , Mannose-Binding Lectin/genetics , Mannose-Binding Lectin/immunology , Orthomyxoviridae/drug effects , Orthomyxoviridae/immunology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/drug effects , Respiratory Syncytial Viruses/immunology , SARS Virus/drug effects , SARS Virus/immunology , SARS-CoV-2/classification , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology
8.
Acta Med Acad ; 49(2): 130-143, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-1414828

ABSTRACT

In this review, we discuss the latest developments in research pertaining to virus-induced asthma exacerbations and consider recent advances in treatment options. Asthma is a chronic disease of the airways that continues to impose a substantial clinical burden worldwide. Asthma exacerbations, characterised by an acute deterioration in respiratory symptoms and airflow obstruction, are associated with significant morbidity and mortality. These episodes are most commonly triggered by respiratory virus infections. The mechanisms underlying the pathogenesis of virus-induced exacerbations have been the focus of extensive biomedical research. Developing a robust understanding of the interplay between respiratory viruses and the host immune response will be critical for developing more efficacious, targeted therapies for exacerbations. CONCLUSION: There has been significant recent progress in our understanding of the mechanisms underlying virus-induced airway inflammation in asthma and these advances will underpin the development of future clinical therapies.


Subject(s)
Anti-Asthmatic Agents/therapeutic use , Antiviral Agents/therapeutic use , Asthma/drug therapy , Respiratory Tract Infections/drug therapy , Virus Diseases/drug therapy , Adenovirus Infections, Human/drug therapy , Adenovirus Infections, Human/immunology , Adenovirus Infections, Human/physiopathology , Administration, Inhalation , Asthma/immunology , Asthma/physiopathology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Disease Progression , Humans , Influenza, Human/drug therapy , Influenza, Human/immunology , Influenza, Human/physiopathology , Interferon-beta/therapeutic use , Macrolides/therapeutic use , Omalizumab/therapeutic use , Paramyxoviridae Infections/drug therapy , Paramyxoviridae Infections/immunology , Paramyxoviridae Infections/physiopathology , Picornaviridae Infections/drug therapy , Picornaviridae Infections/immunology , Picornaviridae Infections/physiopathology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/physiopathology , Respiratory Tract Infections/immunology , Respiratory Tract Infections/physiopathology , Virus Diseases/immunology , Virus Diseases/physiopathology
9.
Pediatr Pulmonol ; 57(1): 239-244, 2022 01.
Article in English | MEDLINE | ID: covidwho-1453650

ABSTRACT

BACKGROUND: The seasonality of respiratory syncytial virus (RSV) epidemics have been disrupted during the COVID-19 pandemic, possibly because of lockdowns and social restrictions reducing viral transmission. Given uncertainties around the severity of upcoming RSV bronchiolitis epidemics, debate exists whether palivizumab (RSV prophylaxis) should be administered to infants with Congenital Diaphragmatic Hernia (CDH), who may be vulnerable due to lung hypoplasia and pulmonary hypertension. AIM: To evaluate (1) if CDH infants have higher risk of admission with RSV bronchiolitis than infants in the general population; (2) if palivizumab prophylaxis may reduce this risk. METHODS: We included all eligible studies examining the risk(s) of RSV-positive bronchiolitis requiring hospital admission in (1) CDH infants without palivizumab prophylaxis versus infants in the general population and (2) CDH infants with prophylaxis versus CDH infants without prophylaxis. The primary outcome evaluated was the risk of admission with RSV bronchiolitis. Data are reported descriptively and meta-analysed when appropriate. RESULTS: Three eligible retrospective cohort studies were identified: one study found CDH to be an independent risk factor for RSV hospitalisation (odds ratio, 3.30; 95% confidence interval [CI], 2.01-4.4); two studies compared RSV hospitalisation rates in CDH patients who had palivizumab versus those that did not. The pooled risk ratio was 1.11 (95% CI, 0.29-4.23; p = .88). Overall, the quality of evidence was considered poor and one study was industry funded. CONCLUSION: Whether CDH infants are at particular risk of severe bronchiolitis remains unclear. There is no evidence from this current systematic review that CDH infants should routinely receive palivizumab vaccination prophylaxis.


Subject(s)
Bronchiolitis , COVID-19 , Hernias, Diaphragmatic, Congenital , Respiratory Syncytial Virus Infections , Respiratory Syncytial Virus, Human , Antiviral Agents/therapeutic use , Bronchiolitis/drug therapy , Bronchiolitis/epidemiology , Bronchiolitis/prevention & control , Communicable Disease Control , Hospitalization , Humans , Infant , Palivizumab/therapeutic use , Pandemics , Prevalence , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/epidemiology , Respiratory Syncytial Virus Infections/prevention & control , Retrospective Studies , SARS-CoV-2
10.
Eur J Med Chem ; 224: 113684, 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1292698

ABSTRACT

Respiratory syncytial virus (RSV) causes serious lower respiratory tract infections. Currently, the only clinical anti-RSV drug is ribavirin, but ribavirin has serious toxic side effect and can only be used by critically ill patients. A series of benzimidazole derivatives were synthesized starting from 1,4:3,6-dianhydro-d-fructose and a variety of o-phenylenediamines. Evaluation of their antiviral activity showed that compound a27 had the highest antiviral activity with a half maximal effective concentration (EC50) of 9.49 µM. Investigation of the antiviral mechanism of compound a27 indicated that it can inhibit the replication of RSV by inhibiting apoptosis and autophagy pathways. Retinoic acid-inducible gene (RIG)-I, TNF receptor associated factor (TRAF)-3, TANK binding kinase (TBK)-1, interferon regulatory factor (IRF)-3, nuclear factor Kappa-B (NF-κB), interferon (IFN)-ß, Toll-like receptor (TLR)-3, interleukin (IL)-6 were suppressed at the cellular level. Mouse lung tissue was subjected to hematoxylin and eosin (HE) staining and immunohistochemistry, which showed that RSV antigen and M gene expression could be reduced by compound a27. Decreased expression of RIG-I, IRF-3, IFN-ß, TLR-3, IL-6, interleukin (IL)-8, interleukin (IL)-10, inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α was also found in vivo.


Subject(s)
Antiviral Agents/chemical synthesis , Benzimidazoles/chemistry , Drug Design , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Apoptosis/drug effects , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Benzimidazoles/therapeutic use , Cell Line , Cytokines/metabolism , Humans , Isomerism , Lung/metabolism , Lung/pathology , Mice , Molecular Conformation , Reactive Oxygen Species/metabolism , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus, Human/drug effects , Respiratory Syncytial Virus, Human/physiology , Structure-Activity Relationship , Toll-Like Receptor 3/metabolism , Virus Replication/drug effects
11.
J Med Chem ; 64(8): 5001-5017, 2021 04 22.
Article in English | MEDLINE | ID: covidwho-1174625

ABSTRACT

A discovery program targeting respiratory syncytial virus (RSV) identified C-nucleoside 4 (RSV A2 EC50 = 530 nM) as a phenotypic screening lead targeting the RSV RNA-dependent RNA polymerase (RdRp). Prodrug exploration resulted in the discovery of remdesivir (1, GS-5734) that is >30-fold more potent than 4 against RSV in HEp-2 and NHBE cells. Metabolism studies in vitro confirmed the rapid formation of the active triphosphate metabolite, 1-NTP, and in vivo studies in cynomolgus and African Green monkeys demonstrated a >10-fold higher lung tissue concentration of 1-NTP following molar normalized IV dosing of 1 compared to that of 4. A once daily 10 mg/kg IV administration of 1 in an African Green monkey RSV model demonstrated a >2-log10 reduction in the peak lung viral load. These early data following the discovery of 1 supported its potential as a novel treatment for RSV prior to its development for Ebola and approval for COVID-19 treatment.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , Prodrugs/pharmacology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus, Human/drug effects , Adenosine Monophosphate/pharmacology , Alanine/pharmacology , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Caco-2 Cells , Cells, Cultured , Chlorocebus aethiops , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical/methods , Epithelial Cells/virology , Humans , Macaca fascicularis , Male , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Rats, Sprague-Dawley , Respiratory Syncytial Virus Infections/virology , Structure-Activity Relationship , Tissue Distribution , Tubercidin/analogs & derivatives , Tubercidin/chemistry , Viral Load
12.
BMC Infect Dis ; 20(1): 606, 2020 Aug 17.
Article in English | MEDLINE | ID: covidwho-718135

ABSTRACT

BACKGROUND: Infections due to Respiratory Syncytial Virus (RSV) and Influenza virus (FLU) are leading causes of hospitalization in young children. Yet, there is little data on factors associated with antibiotic use in these patients. METHODS: We conducted a retrospective, single-center study of all patients below 2 years of age hospitalized between 2014 and 2018. We compared children with RSV infection to children with FLU infection analyzing clinical characteristics and factors contributing to an increased rate of antimicrobial utilization. RESULTS: RSV infection was diagnosed in 476/573 (83.1%), FLU in 95/573 (16.6%), and RSV-FLU-co-infection in 2/573 (0.3%) patients. Median age was lower for RSV compared to FLU (4 vs. 12 months; p < 0.0001). Children with RSV had longer hospitalization (5 vs. 4 days; p = 0.0023) and needed oxygen more frequently (314/476 vs. 23/95; p < 0.0001) than FLU patients. There was no significant difference in the overall antibiotic utilization between RSV and FLU patients (136/476 vs. 21/95; p = 0.2107). Logistic regression analyses revealed that septic appearance on admission (odds ratio [OR] 8.95, 95% confidence interval [CI] 1.5-54.1), acute otitis media (OR 4.5, 95% CI 2.1-9.4), a longer oxygen therapy (OR 1.40; 95% CI 1.13-1.74) and a higher C-reactive protein (CRP) (OR 1.7, 95% CI 1.5-2.0) were significantly associated with antibiotic use in both groups, but not age or pneumonia. CONCLUSIONS: In our cohort, the rate of antibiotic utilization was comparable between RSV and FLU patients, while for both groups distinct clinical presentation and a high CRP value were associated with higher antibiotic use.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Influenza, Human/diagnosis , Respiratory Syncytial Virus Infections/diagnosis , C-Reactive Protein/analysis , Coinfection/diagnosis , Female , Humans , Hyperbaric Oxygenation , Infant , Influenza, Human/drug therapy , Influenza, Human/virology , Length of Stay , Logistic Models , Male , Odds Ratio , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/virology , Retrospective Studies , Risk Factors
13.
Med Sci Monit ; 27: e929783, 2021 Jan 03.
Article in English | MEDLINE | ID: covidwho-1005108

ABSTRACT

BACKGROUND This retrospective study aimed to investigate co-infections with common respiratory pathogens and SARS-CoV-2 and laboratory biochemistry findings in patients with COVID-19 in the Zhuzhou area of China, in order to provide a reference for the disease assessment and clinical treatment of COVID-19. MATERIAL AND METHODS The clinical data of COVID-19 patients admitted to the hospital of Zhuzhou City from January 28 to March 15, 2020, as well as laboratory test results for respiratory pathogens and biochemical indicators, were collected to conduct correlation analyses. All patients were diagnosed based on fluorescence-based PCR assay for SARS-CoV-2. RESULTS Eleven of the 78 patients (14.1%) were co-infected with other respiratory pathogens, among which Mycoplasma pneumoniae (n=5, 45.5%) and respiratory syncytial virus (n=4, 36.4%) were the most frequent. There were 8 patients co-infected with 1 other pathogen and 3 patients co-infected with 2 other pathogens. Compared with mono-infected COVID-19 patients, patients with co-infections had significantly higher levels of procalcitonin (P=0.002). CONCLUSIONS The findings showed that Mycoplasma pneumonia and respiratory syncytial virus were the most common co-infections in patients with COVID-19 pneumonia. Increased levels of PCT in patients with COVID-19 pneumonia were associated with co-infection.


Subject(s)
COVID-19/epidemiology , Coinfection/epidemiology , Pandemics , Respiratory Tract Infections/epidemiology , SARS-CoV-2/isolation & purification , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Infective Agents/therapeutic use , Biomarkers , C-Reactive Protein/analysis , COVID-19/blood , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19 Nucleic Acid Testing , Child , Child, Preschool , China/epidemiology , Creatine Kinase/blood , Cross-Sectional Studies , Female , Humans , L-Lactate Dehydrogenase/blood , Male , Middle Aged , Pneumonia, Mycoplasma/blood , Pneumonia, Mycoplasma/epidemiology , Procalcitonin/blood , Respiratory Syncytial Virus Infections/blood , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/epidemiology , Respiratory Tract Infections/blood , Respiratory Tract Infections/microbiology , Respiratory Tract Infections/virology , Retrospective Studies , Severity of Illness Index , Young Adult
14.
Thorax ; 76(1): 64-72, 2021 01.
Article in English | MEDLINE | ID: covidwho-978826

ABSTRACT

INTRODUCTION: Human respiratory syncytial virus (HRSV) is a common cause of respiratory tract infections (RTIs) globally and is one of the most fatal infectious diseases for infants in developing countries. Of those infected, 25%-40% aged ≤1 year develop severe lower RTIs leading to pneumonia and bronchiolitis, with ~10% requiring hospitalisation. Evidence also suggests that HRSV infection early in life is a major cause of adult asthma. There is no HRSV vaccine, and the only clinically approved treatment is immunoprophylaxis that is expensive and only moderately effective. New anti-HRSV therapeutic strategies are therefore urgently required. METHODS: It is now established that viruses require cellular ion channel functionality to infect cells. Here, we infected human lung epithelial cell lines and ex vivo human lung slices with HRSV in the presence of a defined panel of chloride (Cl-) channel modulators to investigate their role during the HRSV life-cycle. RESULTS: We demonstrate the requirement for TMEM16A, a calcium-activated Cl- channel, for HRSV infection. Time-of-addition assays revealed that the TMEM16A blockers inhibit HRSV at a postentry stage of the virus life-cycle, showing activity as a postexposure prophylaxis. Another important negative-sense RNA respiratory pathogen influenza virus was also inhibited by the TMEM16A-specific inhibitor T16Ainh-A01. DISCUSSION: These findings reveal TMEM16A as an exciting target for future host-directed antiviral therapeutics.


Subject(s)
Anoctamin-1/pharmacology , Antibodies, Viral/immunology , Neoplasm Proteins/pharmacology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus, Human/immunology , Cells, Cultured , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus Infections/virology
15.
BMC Infect Dis ; 20(1): 132, 2020 Feb 12.
Article in English | MEDLINE | ID: covidwho-827577

ABSTRACT

BACKGROUND: Community-acquired pneumonia (CAP) is one of the leading worldwide causes of childhood morbidity and mortality. Its disease burden varies by age and etiology and is time dependent. We aimed to investigate the annual and seasonal patterns in etiologies of pediatric CAP requiring hospitalization. METHODS: We conducted a retrospective study in 30,994 children (aged 0-18 years) with CAP between 2010 and 2015 at 23 nationwide hospitals in South Korea. Mycoplasma pneumoniae (MP) pneumonia was clinically classified as macrolide-sensitive MP, macrolide-less effective MP (MLEP), and macrolide-refractory MP (MRMP) based on fever duration after initiation of macrolide treatment, regardless of the results of in vitro macrolide sensitivity tests. RESULTS: MP and respiratory syncytial virus (RSV) were the two most commonly identified pathogens of CAP. With the two epidemics of MP pneumonia (2011 and 2015), the rates of clinical MLEP and MRMP pneumonia showed increasing trends of 36.4% of the total MP pneumonia. In children < 2 years of age, RSV (34.0%) was the most common cause of CAP, followed by MP (9.4%); however, MP was the most common cause of CAP in children aged 2-18 years of age (45.3%). Systemic corticosteroid was most commonly administered for MP pneumonia. The rate of hospitalization in intensive care units was the highest for RSV pneumonia, and ventilator care was most commonly needed in cases of adenovirus pneumonia. CONCLUSIONS: The present study provides fundamental data to establish public health policies to decrease the disease burden due to CAP and improve pediatric health.


Subject(s)
Community-Acquired Infections/etiology , Pneumonia, Mycoplasma/epidemiology , Pneumonia, Viral/epidemiology , Respiratory Syncytial Virus Infections/epidemiology , Adenoviridae Infections/drug therapy , Adenoviridae Infections/epidemiology , Adenoviridae Infections/etiology , Adolescent , Anti-Bacterial Agents/therapeutic use , Child , Child, Preschool , Community-Acquired Infections/drug therapy , Community-Acquired Infections/epidemiology , Female , Hospitals, Pediatric/statistics & numerical data , Humans , Infant , Infant, Newborn , Intensive Care Units, Pediatric/statistics & numerical data , Macrolides/therapeutic use , Male , Pneumonia, Mycoplasma/drug therapy , Pneumonia, Mycoplasma/etiology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/etiology , Republic of Korea/epidemiology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/etiology , Respiratory Syncytial Virus, Human/pathogenicity , Retrospective Studies , Seasons
16.
Pharmacol Ther ; 214: 107613, 2020 10.
Article in English | MEDLINE | ID: covidwho-632413

ABSTRACT

Resveratrol has been widely studied for its therapeutic potential due to its antioxidant, anti-inflammatory and anti-microbial properties. In particular, resveratrol has shown promising antiviral activity against numerous viruses responsible for severe respiratory infections. Amongst these, influenza virus, respiratory syncytial virus and the emerging SARS-cov-2 are known to cause pneumonia, acute respiratory distress syndrome or multi-organ failure, especially, in vulnerable individuals like immunocompromised patients or the elderly, leading to a considerable economic burden worldwide. In this context, resveratrol may have potential value for its anti-inflammatory activity, since most of the severe virus-associated complications are related to the overactivation of the host-immune response, leading to lung damage. Herein, we present an overview of the antiviral activity and potential mechanisms of resveratrol against the respiratory tract viruses considered as a public threat for their rapid transmission and high morbidity and mortality in the general population.


Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Respiratory Tract Infections/drug therapy , Resveratrol/pharmacology , Resveratrol/therapeutic use , Virus Diseases/drug therapy , Antiviral Agents/pharmacokinetics , Betacoronavirus , COVID-19 , Communicable Diseases, Emerging/drug therapy , Coronavirus Infections/drug therapy , Humans , Influenza, Human/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Tract Infections/virology , Resveratrol/pharmacokinetics , SARS-CoV-2 , Virus Diseases/virology
17.
Am J Transplant ; 20(12): 3529-3537, 2020 12.
Article in English | MEDLINE | ID: covidwho-361387

ABSTRACT

Respiratory tract infection with pneumoviruses (PVs) and paramyxoviruses (PMVs) are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTRs). Ribavirin may be a treatment option but its effectiveness is unclear, especially with respect to infection severity. We retrospectively analyzed 10 years of PV/PMV infections in LTRs. The main end points were forced expiratory volume in 1 second (FEV1 ) at 3 and 6 months postinfection, expressed as a percentage of pre-infection FEV1 and incidence of new or progressed CLAD 6 months postinfection. A total of 139 infections were included: 88 severe infections (63%) (defined as >10% FEV1 loss at infection) and 51 mild infections (37%) (≤10% FEV1 loss). Overall postinfection CLAD incidence was 20%. Associations were estimated on postinfection FEV1 for ribavirin vs no ribavirin (+13.2% [95% CI: 7.79; 18.67]) and severe vs mild infection (-11.1% [95% CI: -14.76; -7.37]). Factors associated with CLAD incidence at 6 months were ribavirin treatment (odds ratio (OR [95% CI]) 0.24 [0.10; 0.59]), severe infection (OR [95% CI] 4.63 [1.66; 12.88]), and mycophenolate mofetil use (OR [95% CI] 0.38 [0.14; 0.97]). These data provide valuable information about the outcomes of lung transplant recipients with these infections and suggests possible associations of ribavirin use and infection severity with long-term outcomes. Well-designed prospective trials are needed to confirm these findings.


Subject(s)
Lung Transplantation , Metapneumovirus , Respiratory Syncytial Virus Infections , Respiratory Tract Infections , Antiviral Agents/therapeutic use , Humans , Lung , Lung Transplantation/adverse effects , Prospective Studies , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/epidemiology , Respiratory Syncytial Virus Infections/etiology , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/etiology , Retrospective Studies , Ribavirin/therapeutic use , Transplant Recipients
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