The effect of steroid use in hospitalized adults with respiratory syncytial virus-related illness.
ABSTRACT: Systemic glucocorticosteroids (steroids) are commonly prescribed for patients with exacerbations of COPD during acute viral infections such as respiratory syncytial virus (RSV). The effects of short-term high-dose steroid treatment on viral load and adaptive immunity to RSV have not been examined in adults.The objectives of this study were to measure peak viral load and duration of viral shedding, serum and nasal cytokines, RSV-specific antibody response, and lymphocyte subsets in patients admitted to the hospital with RSV infection and to compare patients treated with steroids to patients untreated with steroids.Hospitalized adults who tested positive for RSV by reverse transcription-polymerase chain reaction (RT-PCR) on admission had respiratory samples collected for quantitative RT-PCR and cytokine analysis. Serum and nasal secretions were tested for RSV antibody and lymphocyte subsets were analyzed by flow cytometry at 2 days, 2 weeks, and 1 month.Thirty-three of 50 (66%) patients hospitalized with RSV received systemic steroids for a mean duration of 11 days. Those who received steroids more frequently wheezed and were less often febrile. There were no serious adverse events related to steroids and no significant differences in peak viral load, duration of RSV shedding, nasal cytokines, or lymphocyte subsets in patients treated with steroids and patients untreated with steroids. Antibody responses to RSV were slightly blunted in the steroid-treated group.Short courses of systemic steroids in patients hospitalized with RSV infection did not affect viral load or shedding. Humoral immunity may be mildly diminished, and thus potential benefits of systemic steroids must be balanced against potential risks.
Project description:BACKGROUND:Comprehensive analyses of host, viral, and immune factors associated with severe respiratory syncytial virus (RSV) infection in adults have not been performed. METHODS:Adults with RSV infection identified in both outpatient and inpatient settings were evaluated. Upper and lower respiratory tract virus load, duration of virus shedding, select mucosal chemokine and cytokine levels, humoral and mucosal immunoglobulin responses, and systemic T-cell responses were measured. RESULTS:A total of 111 RSV-infected adults (61 outpatients and 50 hospitalized patients) were evaluated. Hospitalized subjects shed virus in nasal secretions at higher titers and for longer durations than less ill outpatients, had greater mucosal interleukin 6 (IL-6) levels throughout infection, and had higher macrophage inflammatory protein 1? (MIP-1?) levels early in infection. Persons >64 years old and those with more severe disease had a higher frequency of activated T cells in the blood than younger, less ill subjects at infection. Multivariate analysis found that the presence of underlying medical conditions, female sex, increased mucosal IL-6 level, and longer duration of virus shedding were associated with severe disease. Older age and increased nasal MIP-1? levels were of borderline statistical significance. CONCLUSIONS:Multiple factors, but not older age, are independently associated with severe RSV infection in adults. The presence of underlying medical conditions had the greatest influence on disease severity.
Project description:Background:Recent data suggest that human coronavirus (HCoV) pneumonia is associated with significant mortality in hematopoietic cell transplant (HCT) recipients. Investigation of risk factors for prolonged shedding and intrahost genome evolution may provide critical information for development of novel therapeutics. Methods:We retrospectively reviewed HCT recipients with HCoV detected in nasal samples by polymerase chain reaction (PCR). HCoV strains were identified using strain-specific PCR. Shedding duration was defined as time between first positive and first negative sample. Logistic regression analyses were performed to evaluate factors for prolonged shedding (?21 days). Metagenomic next-generation sequencing (mNGS) was conducted when ?4 samples with cycle threshold values of <28 were available. Results:Seventeen of 44 patients had prolonged shedding. Among 31 available samples, 35% were OC43, 32% were NL63, 19% were HKU1, and 13% were 229E; median shedding duration was similar between strains (P = .79). Bivariable logistic regression analyses suggested that high viral load, receipt of high-dose steroids, and myeloablative conditioning were associated with prolonged shedding. mNGS among 5 subjects showed single-nucleotide polymorphisms from OC43 and NL63 starting 1 month following onset of shedding. Conclusions:High viral load, high-dose steroids, and myeloablative conditioning were associated with prolonged shedding of HCoV in HCT recipients. Genome changes were consistent with the expected molecular clock of HCoV.
Project description:BACKGROUND: Airway epithelial cells (AEC) from patients with asthma, appear to have an impaired interferon (IFN)-? and -? response to infection with rhinovirus. OBJECTIVES: To determine if impaired IFN responses can be identified in young children at risk of developing asthma due to atopy and/or early life wheeze, and if the site of infection or the infecting virus influence the antiviral response. METHODS: Nasal (N) and tracheal (T) epithelial cells (EC) were collected from children categorised with atopy and/or wheeze based on specific IgE to locally common aeroallergens and a questionnaire concerning respiratory health. Submerged primary cultures were infected with respiratory syncytial virus (RSV) or human metapneumovirus (hMPV), and IFN production, inflammatory cytokine expression and viral replication quantified. RESULTS: Nasal epithelial cells (NEC), but not tracheal epithelial cells (TEC), from children with wheeze and/or atopy produced less IFN-?, but not IFN-?, in response to RSV infection; this was associated with higher viral shedding. However, IFN-regulated factors IRF-7, Mx-1 and CXCL-10, and inflammatory cytokines were not differentially regulated. NECs and TECs from children with wheeze and/or atopy demonstrated no impairment of the IFN response (? or ?) to hMPV infection. Despite this, more hMPV was shed from these cells. CONCLUSIONS: AECs from children with wheeze and/or atopy do not have an intrinsic defect in the production of IFN-? or -?, however, this response is influenced by the infecting virus. Higher viral load is associated with atopy and wheeze suggesting an impaired antiviral response to RSV and hMPV that is not influenced by production of IFNs.
Project description:<h4>Background</h4>Presatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI).<h4>Methods</h4>Patients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality.<h4>Results</h4>From January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (-1.12 vs -1.09 log10 copies/mL; treatment difference -0.02 log10 copies/mL, 95% confidence interval: -.62, .57; P = .94), median supplemental oxygen-free days (26 vs 28 days, P = .84), incident respiratory failure (10.3 vs 10.7%, P = .98), or all-cause mortality (0 vs 7.1%, P = .19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients.<h4>Conclusions</h4>Presatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo.<h4>Clinical trials registration</h4>www.clinicaltrials.gov, NCT02254421; EudraCT, #2014-002475-29.
Project description:Background:Maternally derived serum antibody and viral load are thought to influence disease severity in primary respiratory syncytial virus (RSV) infection. As part of the AsPIRES study of RSV pathogenesis, we correlated various serum antibody concentrations and viral load with disease severity. Methods:Serum neutralizing antibody titers and levels of immunoglobulin G (IgG) to RSV fusion protein (F), attachment proteins of RSV group A and B, the CX3C region of G, and nasal viral load were measured in 139 full-term previously healthy infants with primary RSV infection and correlated with illness severity. Results:Univariate analysis showed no relationship between measures of serum antibody and severity. However, a multivariate model adjusting for age at the time of infection found a significant 0.56 decrease in severity score for each 2-fold increase in antibody concentration to RSV F. The benefit of antibody was greatest in infants ≤ 2 months of age. Additionally, estimated antibody titer at birth was correlated with age at infection, suggesting that higher antibody titers delay infection. Viral load did not differ by illness severity. Conclusion:Our data support the concept of maternal immunization with an RSV vaccine during pregnancy as a strategy for reducing the burden of RSV infection in full-term healthy infants exposed to RSV during their first winter.
Project description:To study the transcriptional profile of patients with acute RSV or Influenza infection,children of median age 2.4 months (range 1.5-8.6) hospitalized with acute RSV and influenza virus infection were offered study enrollment after microbiologic confirmation of the diagnosis. Blood samples were collected from them within 42-72 hours of hospitalization. We excluded children with suspected or proven polymicrobial infections, with underlying chronic medical conditions (i.e congenital heart disease, renal insufficiency), with immunodeficiency, or those who received systemic steroids or other immunomodulatory therapies. The RSV cohort consisted of 51 patients with median age of 2 months (range 1.5-3.9) and the influenza cohort had 28 patients with median age of 5.5 months (range 1.4-21). Control samples were obtained from healthy children undergoing elective surgical procedures or at outpatient clinic visits. To exclude viral co-infections we performed nasopharyngeal viral cultures of all subjects. We recruited 10 control patients for the RSV cohort with median age of 6.7 months (range 5-10), and 12 control patients for the influenza cohort with median age of18.5 months (range 10.5-26). We used microarrays to obtain the transcriptional profile of PBMCs from patients with acute RSV or Influenza infection and compared these signatures with the transcriptional profile of primary airway epithelial cells infected with RSV or Influenza.
Project description:Respiratory syncytial virus (RSV) is the leading cause of childhood lower respiratory infection, yet viable therapies are lacking. Two major challenges have stalled antiviral development: ethical difficulties in performing pediatric proof-of-concept studies and the prevailing concept that the disease is immune-mediated rather than being driven by viral load.The development of a human experimental wild-type RSV infection model to address these challenges.Healthy volunteers (n = 35), in five cohorts, received increasing quantities (3.0-5.4 log plaque-forming units/person) of wild-type RSV-A intranasally.Overall, 77% of volunteers consistently shed virus. Infection rate, viral loads, disease severity, and safety were similar between cohorts and were unrelated to quantity of RSV received. Symptoms began near the time of initial viral detection, peaked in severity near when viral load peaked, and subsided as viral loads (measured by real-time polymerase chain reaction) slowly declined. Viral loads correlated significantly with intranasal proinflammatory cytokine concentrations (IL-6 and IL-8). Increased viral load correlated consistently with increases in multiple different disease measurements (symptoms, physical examination, and amount of nasal mucus).Viral load appears to drive disease manifestations in humans with RSV infection. The observed parallel viral and disease kinetics support a potential clinical benefit of RSV antivirals. This reproducible model facilitates the development of future RSV therapeutics.
Project description:In 2011 and 2012, a large outbreak of respiratory syncytial virus (RSV) infections affecting 57 laboratory-confirmed patients occurred in an adult hematology unit in Heidelberg, Germany. During the outbreak investigation, we performed molecular genotyping of RSV strains to differentiate between single versus multiple introductions of the virus into the unit. Furthermore, we assessed the time of viral shedding of consecutive samples from the patients in order to better understand the possible impact of prolonged shedding for outbreak control management. We used subtype-specific reverse transcription-PCR on nasopharyngeal and bronchoalveolar specimens for routine diagnostics and for measuring the viral shedding period. Samples of 47 RSV-infected patients involved in the outbreak were genotyped by sequence analysis and compared to samples from RSV-infected hospitalized children representing the timing of the annual RSV epidemic in the community. Molecular investigation of the virus strains from clinical samples revealed a unique cluster with identical nucleotide sequences of RSV type A (RSV A outbreak strain) for 41 patients, while 3 patients were infected with different RSV A (nonoutbreak) strains and three other patients with RSV type B. Outbreak strains were identified in samples from November 2011 until January 2012, while nonoutbreak strains were from samples coinciding with the community epidemic in February and March 2012. Median duration of viral shedding time was 24.5 days (range, 1 to 168 days) with no difference between outbreak and nonoutbreak strains (P = 0.45). Our investigation suggests a single introduction of the RSV A outbreak strain into the unit that spread among the immunocompromised patients. Prolonged viral shedding may have contributed to nosocomial transmission and should be taken into account in the infection control management of RSV outbreaks in settings with heavily immunosuppressed patients.
Project description:BACKGROUND:Hematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind phase 2 trial in HCT recipients with RSV upper respiratory tract infection (URTI). METHODS:Patients were randomized, stratified by lymphopenia (<200/µL) and ribavirin use, to receive oral presatovir 200 mg or placebo on days 1, 5, 9, 13, and 17, and followed through day 28. The coprimary efficacy endpoints were time-weighted average change in nasal RSV viral load between days 1 and 9, and proportion of patients developing lower respiratory tract complications (LRTC) through day 28. RESULTS:From January 23, 2015, to June 16, 2017, 189 patients were randomized (96 presatovir, 93 placebo). Presatovir vs placebo treatment did not significantly affect (prespecified ? = 0.01) time-weighted average decline in RSV viral load from day 1 to 9 (treatment difference: -0.33 log10 copies/mL; 95% CI: -0.64, -0.02 log10 copies/mL; p = 0.040) or progression to LRTC (11.2% vs 19.5%; odds ratio [95% CI], 0.50 [0.22, 1.18]; p = 0.11). In post hoc analysis among patients with lymphopenia, presatovir vs placebo treatment decreased LRTC development by day 28 (2/15 [13.3%] vs 9/14 [64.3%], p = 0.008). Adverse events were similar for patients receiving presatovir vs placebo. CONCLUSIONS:Presatovir had a favorable safety profile in adult HCT recipients with RSV but did not achieve the coprimary endpoints. Exploratory analyses suggest an antiviral effect among patients with lymphopenia.
Project description:Respiratory viruses are a cause of upper respiratory tract infections (URTI), but can be associated with severe lower respiratory tract infections (LRTI) in immunocompromised patients. The objective of this study was to investigate the genetic variability of influenza virus, parainfluenza virus and respiratory syncytial virus (RSV) and the duration of viral shedding in hematological patients. Nasopharyngeal swabs from hematological patients were screened for influenza, parainfluenza and RSV on admission as well as on development of respiratory symptoms. Consecutive swabs were collected until viral clearance. Out of 672 tested patients, a total of 111 patients (17%) were infected with one of the investigated viral agents: 40 with influenza, 13 with parainfluenza and 64 with RSV; six patients had influenza/RSV or parainfluenza/RSV co-infections. The majority of infected patients (n = 75/111) underwent stem cell transplantation (42 autologous, 48 allogeneic, 15 autologous and allogeneic). LRTI was observed in 48 patients, of whom 15 patients developed severe LRTI, and 13 patients with respiratory tract infection died. Phylogenetic analysis revealed a variety of influenza A(H1N1)pdm09, A(H3N2), influenza B, parainfluenza 3 and RSV A, B viruses. RSV A was detected in 54 patients, RSV B in ten patients. The newly emerging RSV A genotype ON1 predominated in the study cohort and was found in 48 (75%) of 64 RSV-infected patients. Furthermore, two distinct clusters were detected for RSV A genotype ON1, identical RSV G gene sequences in these patients are consistent with nosocomial transmission. Long-term viral shedding for more than 30 days was significantly associated with prior allogeneic transplantation (p = 0.01) and was most pronounced in patients with RSV infection (n = 16) with a median duration of viral shedding for 80 days (range 35-334 days). Long-term shedding of respiratory viruses might be a catalyzer of nosocomial transmission and must be considered for efficient infection control in immunocompromised patients.