Respiratory Syncytial Virus–induced Acute Disease Severity and Long-Term Wheezing. Uncovering the Unexpected

Respiratory syncytial virus (RSV) is a major pathogen that causes severe lower respiratory tract infection in infants, the elderly and the immunocompromised worldwide. At present no approved specific drugs or vaccines are available to treat this pathogen. Recently, several promising candidates targeting RSV entry and multiplication steps are under investigation. However, it is possible to lead to drug resistance under the long-term treatment. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). The statistical program MacSynergy II was employed to determine synergism, additivity or antagonism between drugs. From the result, we found that combinations of ALS8176 and Ziresovir or GS5806 exhibit additive effects against RSV in vitro, with interaction volume of 50 µM2% and 31 µM2% at 95% confidence interval, respectively. On the other hand, all combinations between fusion inhibitors showed antagonistic effects against RSV in vitro, with volume of antagonism ranging from −50 µM2 % to −176 µM2 % at 95% confidence interval. Over all, our results suggest the potentially therapeutic combinations in combating RSV in vitro could be considered for further animal and clinical evaluations.

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Respiratory Syncytial Virus Group A and B Genotypes and Disease Severity among Cuban Children

Archives of Medical Research ◽

10.1016/j.arcmed.2005.08.007 ◽

2006 ◽

Vol 37 (4) ◽

pp. 543-547 ◽

Cited By ~ 7

Author(s):

Clara Savón ◽

Angel Goyenechea ◽

Odalys Valdés ◽

José Aguilar ◽

Grehete González ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Disease Severity ◽

Virus Group ◽

Group A ◽

Syncytial Virus

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Long-term consequences of respiratory syncytial virus (RSV) bronchiolitis

Paediatric Respiratory Reviews ◽

10.1053/prrv.2000.0052 ◽

2000 ◽

Vol 1 (3) ◽

pp. 221-227 ◽

Cited By ~ 22

Author(s):

L. Bont ◽

W.M.C.van Aalderen ◽

J.L.L. Kimpen

Keyword(s):

Respiratory Syncytial Virus ◽

Long Term Consequences ◽

Syncytial Virus

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Viral Load Dynamics and Clinical Disease Severity in Infants With Respiratory Syncytial Virus Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy655 ◽

2018 ◽

Vol 219 (8) ◽

pp. 1207-1215 ◽

Cited By ~ 23

Author(s):

Cristina Garcia-Mauriño ◽

Melissa Moore-Clingenpeel ◽

Jessica Thomas ◽

Sara Mertz ◽

Daniel M Cohen ◽

...

Keyword(s):

Viral Load ◽

Respiratory Syncytial Virus ◽

Virus Infection ◽

Disease Severity ◽

Respiratory Syncytial Virus Infection ◽

Clinical Disease ◽

Syncytial Virus

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Infantile respiratory syncytial virus and human rhinovirus infections: respective role in inception and persistence of wheezing

European Respiratory Journal ◽

10.1183/09031936.00062714 ◽

2014 ◽

Vol 45 (3) ◽

pp. 774-789 ◽

Cited By ~ 62

Author(s):

Giovanni A. Rossi ◽

Andrew A. Colin

Keyword(s):

Respiratory Syncytial Virus ◽

Airway Disease ◽

Epidemiological Studies ◽

Human Rhinovirus ◽

Allergic Sensitisation ◽

Cytokines And Chemokines ◽

Rsv Infection ◽

History Of ◽

Syncytial Virus

There is evidence that respiratory viruses play a key role in the development and exacerbation of obstructive respiratory diseases in children. This review attempts to juxtapose the separate profiles and prototypes of pathogenenetic mechanisms represented by the two most common amongst such viruses: respiratory syncytial virus (RSV) and human rhinovirus (HRV).RSV represents the most common agent of severe airway disease in infants and young children, and is predominant in winter months. Large epidemiological studies have revealed an unequivocal relationship between RSV infection and subsequent wheezing into childhood, thought to be related to long-term changes in neuroimmune control of the airways rather than allergic sensitisation.HRV is a highly diverse group of viruses that affect subjects of all ages, is ubiquitous and occurs year-round. In contrast to RSV, infections with HRV cause minimal cytotoxicity but induce a rapid production of cytokines and chemokines with amplification of the inflammatory response. The susceptibility to HRV-induced bronchiolitis and subsequent wheezing appears to be linked to individual predisposition since it is often associated with a family or personal history of asthma/atopy.Thus, RSV probably serves as an “inducer” rather than a “trigger”. Conversely, HRVs seem to serve as a “trigger” rather than an “inducer” in predisposed individuals.

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Respiratory syncytial virus and airway microbiota -- A complex interplay and its reflection on morbidity

10.22541/au.160638847.70128113/v1 ◽

2020 ◽

Author(s):

Giovanni Rossi ◽

Stefania Ballarini ◽

Michela Silvestri ◽

Oliviero Sacco ◽

Andrew Colin

Keyword(s):

Respiratory Syncytial Virus ◽

Disease Severity ◽

Respiratory Infections ◽

Pediatric Population ◽

Bacterial Species ◽

Severe Disease ◽

Microbial Community Composition ◽

Positive Role ◽

Syncytial Virus ◽

Tract Infections

The immunopathology of respiratory syncytial virus (RSV) infection, the most common cause of lower respiratory tract infections (LRTI) in the pediatric population, with severe disease being the exception. The variability of the clinical presentation is incompletely explained by host, viral and environmental factors but, in infants and young children, disease severity is certainly linked to the physiological immune immaturity. There is evidence that the maturation of the host immune response is, at least in part, promoted by the composition of the nasopharyngeal microbiome that, modulating excessive inflammation, can counteract the predisposition to develop viral respiratory infections and lower the risk of disease severity. However, interaction between the nasopharyngeal microbiota and respiratory viruses can be bidirectional. Microbial dysbiosis can drive disease pathogenesis but may also represents a reflection of the disease-induced alterations of the local milieu. Moreover, viruses like RSV, can also increase the virulence of potential pathogens in nasopharynx, which is a main reservoir of bacteria, and therefore promote their spread to the lower airways causing superinfection. Negative changes in microbial community composition in early life may constitute a heightened risk towards severe RSV respiratory infection and bacterial superinfection, whilst specific groups of microorganisms can be associated with protection. A better understanding into the potential negative and positive role of the different nasopharyngeal bacterial species in disease prevention as well as into the possible benefits of microbiome therapeutic manipulation, may improve patient outcomes.

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A Randomized, Placebo-Controlled, Respiratory Syncytial Virus Human Challenge Study of the Antiviral Efficacy, Safety, and Pharmacokinetics of RV521, an Inhibitor of the RSV-F Protein

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01884-19 ◽

2019 ◽

Vol 64 (2) ◽

Cited By ~ 9

Author(s):

John DeVincenzo ◽

Dereck Tait ◽

John Efthimiou ◽

Julie Mori ◽

Young-In Kim ◽

...

Keyword(s):

Viral Load ◽

Respiratory Syncytial Virus ◽

Adverse Events ◽

Disease Severity ◽

Controlled Trial ◽

Primary Analysis ◽

Double Blind ◽

Challenge Virus ◽

F Protein ◽

Syncytial Virus

ABSTRACT Effective treatments for respiratory syncytial virus (RSV) infection are lacking. Here, we report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial, healthy adults were challenged with RSV-A Memphis-37b. After infection was confirmed (or 5 days after challenge virus inoculation), subjects received RV521 (350 mg or 200 mg) or placebo orally every 12 h for 5 days. The primary endpoint was area under the curve (AUC) for viral load, as assessed by reverse transcriptase quantitative PCR (RT-qPCR) of nasal wash samples. The primary efficacy analysis set included subjects successfully infected with RSV who received ≥1 dose of study drug. A total of 66 subjects were enrolled (n = 22 per group); 53 were included in the primary analysis set (RV521 350 mg: n = 16; 200 mg: n = 18; placebo: n = 19). The mean AUC of RT-qPCR-assessed RSV viral load (log10 PFU equivalents [PFUe]/ml · h) was significantly lower with RV521 350 mg (185.26; standard error [SE], 31.17; P = 0.002) and 200 mg (224.35; SE, 37.60; P = 0.007) versus placebo (501.39; SE, 86.57). Disease severity improved with RV521 350 mg and 200 mg versus placebo (P = 0.002 and P = 0.009, respectively, for AUC total symptom score [score × hours]). Daily nasal mucus weight was significantly reduced (P = 0.010 and P = 0.038 for RV521 350 mg and 200 mg, respectively, versus placebo). All treatment-emergent adverse events were grade 1 or 2. No subjects discontinued due to adverse events. There was no evidence of clinically significant viral resistance, and only three variants were detected. RV521 effectively reduced RSV viral load and disease severity in humans and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT03258502.)

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Temporal Dysbiosis of Infant Nasal Microbiota Relative to Respiratory Syncytial Virus Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa577 ◽

2020 ◽

Author(s):

Alex Grier ◽

Ann L Gill ◽

Haeja A Kessler ◽

Anthony Corbett ◽

Sanjukta Bandyopadhyay ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Respiratory Disease ◽

Disease Severity ◽

Temporal Dynamics ◽

Disease Risk ◽

Developmental Trajectory ◽

Microbiota Composition ◽

Rsv Infection ◽

Syncytial Virus ◽

Nasal Microbiota

Abstract Rationale Respiratory Syncytial Virus (RSV) is a leading cause of infant respiratory disease. Infant airway microbiota has been associated with respiratory disease risk and severity. The extent to which interactions between RSV and microbiota occur in the airway, and their impact on respiratory disease susceptibility and severity, are unknown. Objectives Characterize temporal associations between microbiota and RSV infection before, during, and after infants’ first respiratory illness. Methods 16S rRNA microbiota profiling of two infant cohorts in the first year of life: 1) a cross-sectional cohort of 89 RSV infected infants sampled during illness and 102 matched healthy controls, and 2) a matched longitudinal cohort of 12 infants who developed RSV infection and 12 who did not, sampled before, during, and after infection. Results We identified 12 taxa significantly associated with RSV infection. All 12 taxa were differentially abundant during infection, with 8 associated with disease severity. Nasal microbiota composition was more discriminative of healthy vs. infected than of disease severity. Conclusions Our findings elucidate the chronology of nasal microbiota dysbiosis and suggest an altered developmental trajectory associated with RSV infection. Microbial temporal dynamics reveal indicators of disease risk, correlates of illness and severity, and impact of RSV infection on microbiota composition.

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