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1.
Artigo em Inglês | MEDLINE | ID: mdl-31520837

RESUMO

BACKGROUND: Respiratory syncytial virus (RSV)- and rhinovirus (RV)-induced bronchiolitis are associated with an increased risk of asthma, but more detailed information is needed on virus types. OBJECTIVE: To study whether RSV or RV types are differentially associated with the future use of asthma control medication. METHODS: Over 2 consecutive winter seasons (2008-2010), we enrolled 408 children hospitalized for bronchiolitis at age less than 24 months into a prospective, 3-center, 4-year follow-up study in Finland. Virus detection was performed by real-time reverse transcription PCR from nasal wash samples. Four years later, we examined current use of asthma control medication. RESULTS: A total of 349 (86%) children completed the 4-year follow-up. At study entry, the median age was 7.5 months, and 42% had RSV, 29% RV, 2% both RSV and RV, and 27% non-RSV/-RV etiology. The children with RV-A (adjusted hazard ratio, 2.3; P = .01), RV-C (adjusted hazard ratio, 3.5; P < .001), and non-RSV/-RV (adjusted hazard ratio, 2.0; P = .004) bronchiolitis started the asthma control medication earlier than did children with RSV bronchiolitis. Four years later, 27% of patients used asthma control medication; both RV-A (adjusted odds ratio, 3.0; P = .03) and RV-C (adjusted odds ratio, 3.7; P < .001) etiology were associated with the current use of asthma medication. The highest risk was found among patients with RV-C, atopic dermatitis, and fever (adjusted odds ratio, 5.0; P = .03). CONCLUSIONS: Severe bronchiolitis caused by RV-A and RV-C was associated with earlier initiation and prolonged use of asthma control medication. The risk was especially high when bronchiolitis was associated with RV-C, atopic dermatitis, and fever.

2.
J Infect Dis ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31402384

RESUMO

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of infant lower respiratory tract disease and hospitalization worldwide. METHODS: Safety and immunogenicity of RSV fusion (F) protein nanoparticle vaccine or placebo were evaluated in 50 healthy third-trimester pregnant women. Assessments included vaccine tolerability and safety in women and infants, and RSV-specific antibody measures in women before and after vaccination, at delivery and postpartum. RESULTS: The vaccine was well tolerated; no meaningful differences in pregnancy or infant outcomes were observed between study groups. RSV-specific antibody levels increased significantly among vaccine recipients, including responses competitive with well-described monoclonal antibodies specific for multiple RSV neutralizing epitopes. No significant antibody increase was seen among placebo-recipients, although a shallow upward trend across the RSV season was noted. Transplacental antibody transfer ranged between 90%-120% across assays for infants of vaccinated women. Women with an interval of ≥30 days between vaccination and delivery demonstrated higher placental antibody transfer rates than women with an interval <30 days. Half-lives of RSV-specific antibodies in infants approximated 40 days. There was no evidence of severe RSV disease in infants of vaccinated mothers. CONCLUSIONS: Data from this phase 2 study support a maternal immunization strategy to protect infants from RSV disease.

3.
Pediatr Infect Dis J ; 38(8): e180-e183, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31306402

RESUMO

In 2 multicenter cohort studies of 2912 infants hospitalized for bronchiolitis during 2007-2014, the 5 most common pathogens were RSV (76.5%), rhinovirus (23.8%), coronavirus (6.9%), adenovirus (6.4%) and human metapneumovirus (6.0%). Hospitalization months significantly differed for these common pathogens (P ≤ 0.01), except for coronavirus (P = 0.30). There was a significant heterogeneity in temporal patterns by region in RSV-A and -B (both P < 0.001).

5.
J Virol Methods ; 271: 113676, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31181218

RESUMO

Human respiratory syncytial virus (HRSV) is a leading cause of acute respiratory illness in young children worldwide. Reliable detection and identification of HRSV subgroup A and B infections are essential for accurate disease burden estimates in anticipation of licensure of novel HRSV vaccines and immunotherapies. To ensure continued reliability, molecular assays must remain current with evolving virus strains. We have developed a HRSV subgroup-specific real-time RT-PCR (rRT-PCR) assay for detection and subgroup identification using primers and subgroup-specific probes targeting a conserved region of the nucleoprotein gene combined in a single duplex reaction using all genome sequence data currently available in GenBank. The assay was validated for analytical sensitivity, specificity, reproducibility, and clinical performance with a geographically diverse collection of viral isolates and respiratory specimens in direct comparison with an established pan-HRSV rRT-PCR reference test. The assay was sensitive, reproducibly detecting as few as 5-10 copies/reaction of target RNA. The assay was specific, showing no amplification with a panel of 16 other common respiratory pathogens or predicted by in silico primer/probe analysis. The duplex rRT-PCR assay based on the most current available genome sequence data permits rapid, sensitive and specific detection and subgroup identification of HRSV.

6.
Vaccine ; 37(26): 3464-3471, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31085002

RESUMO

OBJECTIVE: To describe the clinical presentation and laboratory diagnosis of pregnant women with respiratory syncytial virus (RSV) infection. METHODS: Pregnant women in their second and third trimester were enrolled during the course of routine prenatal care visits when they were asymptomatic within the preceding two weeks (healthy controls) or when they reported symptoms of acute respiratory illness (ARI) of ≤7 days of duration (cases). Clinical outcomes were assessed at enrollment and two weeks after. Re-enrollment was allowed. Nasal-pharyngeal secretions were evaluated for respiratory pathogens by real-time reverse transcription polymerase chain reaction (PCR). Sera were tested for RSV-specific antibody responses by Western Blot, microneutralization assay, and palivizumab competitive antibody assay. RESULTS: During the 2015-2016 respiratory virus season, 7 of 65 (11%) pregnant women with ARI at their initial enrollment and 8 of 77 (10%) pregnant women with ARI during the study period (initial or re-enrollment) had PCR-confirmed RSV infection. Four (50%) PCR-confirmed RSV ARI cases reported symptoms of a lower respiratory tract illness (LRTI), one was hospitalized. Combining PCR and serology data, the RSV attack rate at initial enrollment was 12% (8 of 65), and 13% (10 of 77) based on ARI episodes. Among healthy controls, 28 of 88 (32%) had a Western Blot profile suggestive of a recent RSV infection either in the prior and/or current season. CONCLUSION: RSV had an attack rate of 10-13% among ambulatory pregnant women receiving routine prenatal care during the respiratory virus season. The serology results of healthy controls suggest a potentially higher attack rate. Future studies should be aware of the combined diagnostic strength of PCR and serology to identify RSV infection. As maternal RSV vaccine candidates are evaluated to protect young infants, additional priority should be placed on outcomes of pregnant women.

7.
JAMA Pediatr ; 173(6): 544-552, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30933255

RESUMO

Importance: Rhinovirus infection in early life, particularly with allergic sensitization, is associated with higher risks of developing recurrent wheeze and asthma. While emerging evidence links different rhinovirus species (eg, rhinovirus C) to a higher severity of infection and asthma exacerbation, to our knowledge, little is known about longitudinal associations of rhinovirus C infection during infancy with subsequent morbidities. Objective: To examine the association of different viruses (respiratory syncytial virus [RSV], rhinovirus species) in bronchiolitis with risks of developing recurrent wheeze. Design, Setting, and Participants: This multicenter prospective cohort study of infants younger than 1 year who were hospitalized for bronchiolitis was conducted at 17 hospitals across 14 US states during 3 consecutive fall to winter seasons (2011-2014). Exposures: Major causative viruses of bronchiolitis, including RSV (reference group) and 3 rhinovirus species (rhinovirus A, B, and C). Main Outcomes and Measures: Development of recurrent wheeze (as defined in national asthma guidelines) by age 3 years. Results: This analytic cohort comprised 716 infants who were hospitalized for RSV-only or rhinovirus bronchiolitis. The median age was 2.9 months (interquartile range, 1.6-3.8 months), 541 (76%) had bronchiolitis with RSV only, 85 (12%) had rhinovirus A, 12 (2%) had rhinovirus B, and 78 (11%) had rhinovirus C infection. Overall, 231 (32%) developed recurrent wheeze by age 3 years. In the multivariable Cox model, compared with infants with RSV-only infection, the risk of recurrent wheeze was not significantly different in those with rhinovirus A or B (rhinovirus A: hazard ratio [HR], 1.27; 95% CI, 0.86-1.88; rhinovirus B: HR, 1.39; 95% CI, 0.51-3.77; both P > .10). By contrast, infants with rhinovirus C had a significantly higher risk (HR, 1.58; 95% CI, 1.08-2.32). There was a significant interaction between virus groups and IgE sensitization on the risk of recurrent wheeze (P for interaction < .01). Only infants with both rhinovirus C infection and IgE sensitization (to food or aeroallergens) during infancy had significantly higher risks of recurrent wheeze (HR, 3.03; 95% CI, 1.20-7.61). Furthermore, compared with RSV-only, rhinovirus C infection with IgE sensitization was associated with significantly higher risks of recurrent wheeze with subsequent development of asthma at age 4 years (HR, 4.06; 95% CI, 1.17-14.1). Conclusions and Relevance: This multicenter cohort study of infants hospitalized for bronchiolitis demonstrated between-virus differences in the risk of developing recurrent wheeze. Infants with rhinovirus C infection, along with IgE sensitization, had the highest risk. This finding was driven by the association with a subtype of recurrent wheeze: children with subsequent development of asthma.

9.
Front Immunol ; 10: 706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984206

RESUMO

Background: Recent studies of human sera showed that the majority of the respiratory syncytial virus (RSV) neutralizing antibodies are directed against pre-fusion conformation of the fusion (F) protein of RSV and revealed the importance of pre-fusion antigenic site Ø specific antibodies. However, detailed analysis of multiple antigenic site-specific competitive antibody responses to RSV F protein and their contribution to virus clearance in humans are lacking. Methods: We prospectively enrolled a cohort of RSV infected hematopoietic cell transplantation (HCT) adults (n = 40). Serum samples were collected at enrollment (acute, n = 40) and 14 to 60 days post-enrollment (convalescent, n = 40). Antigenic site-specific F protein antibodies were measured against pre-fusion site Ø, post-fusion site I, and sites II and IV present in both the pre-fusion and post-fusion F protein conformations utilizing four different competitive antibody assays developed with biotinylated monoclonal antibodies (mAb) D25, 131-2A, palivizumab, and 101F, respectively. The lower limit of detection were 7.8 and 1.0 µg/mL for the competitive antibody assays that measured site Ø specific response, as well as sites I, II, and IV specific responses, respectively. Neutralizing antibody titers to RSV A and B subgroups was determined by microneutralization assays. Results: The overall findings in RSV infected HCT adults revealed: (1) a significant increase in antigenic site-specific competitive antibodies in convalescent sera except for site Ø competitive antibody (p < 0.01); (2) comparable concentrations in the acute and convalescent serum samples of antigenic site-specific competitive antibodies between RSV/A and RSV/B infected HCT adults (p > 0.05); (3) significantly increased concentrations of the antigenic site-specific competitive antibodies in HCT adults who had genomic RSV detected in the upper respiratory tract for <14 days compared to those for ≥14 days (p < 0.01); and (4) statistically significant correlation between the antigenic site-specific competitive antibody concentrations and neutralizing antibody titers against RSV/A and RSV/B (r ranged from 0.33 to 0.83 for acute sera, and 0.50-0.88 for convalescent sera; p < 0.05). Conclusions: In RSV infected HCT adults, antigenic site-specific antibody responses were induced against multiple antigenic sites found in both the pre-fusion and post-fusion F conformations, and were associated with a more rapid viral clearance and neutralizing antibody activity. However, the association is not necessarily the cause and the consequence.

10.
J Vis Exp ; (146)2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-31009009

RESUMO

An uptick in recent pandemics (Ebola, Zika, MERS, influenza, etc.) underlines the need for a more 'nimble,' coordinated response that addresses a multitude of issues ranging from transportation, access, facilities, equipment, and communication to provider training. To address this need, we have developed an innovative, scalable, logistics-enhanced, mobile, laboratory facility for emergencies and epidemics in resource-constrained global settings. Utilizing a background in clinical operations as an academic medical center, we designed a rapidly-deployable, modular BSL-2 and BSL-3 facility with user-friendly software for tracking and management of drugs and supplies in remote regions during epidemics and outbreaks. Here, we present our intermodal, mobile, expandable shipping-container laboratory units. The design of the laboratory facilitates off-grid usage by minimizing power consumption and allowing alternate water sources. The unit's information communication technology (ICT) platform provides (i) user-friendly tablet-based documentation, (ii) enhanced tracking of patients and supplies, and (iii) integrated communication onsite with built-in telehealth capabilities. To ensure quality in remote environments, we have developed a checklist for a basic laboratory workflow and a protocol for respiratory viral diagnosis using reverse-transcription polymerase chain reaction (RT-PCR). As described, this innovative and comprehensive approach allows for the provision of laboratory capability in resource-limited global environments.

11.
Pediatr Infect Dis J ; 38(4): 355-361, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30882724

RESUMO

BACKGROUND: Molecular diagnostic methods enhance the sensitivity and broaden the spectrum of detectable respiratory viruses in febrile infants ≤90 days of life. We describe the occurrence of respiratory viruses in this population, as well as the rates of serious bacterial infection (SBI) and respiratory viral coinfection with regard to viral characteristics. METHODS: This was a prospective observational cohort study performed in the emergency department that included previously healthy febrile infants ≤90 days of life. Clinical and historical characteristics were documented, and a respiratory nasal wash specimen was obtained from each patient. This sample was tested for 17 common respiratory pathogens, and a chart review was conducted to ascertain whether the infant was diagnosed with an SBI. RESULTS: In a 12-month period, 67% of the 104 recruited febrile infants were positive for a respiratory virus. The most commonly detected viruses were rhinovirus, respiratory syncytial virus, enterovirus and influenza. The rate of respiratory viral and SBI coinfection was 9% overall, and infants with either a systemic respiratory virus or negative viral testing were 3 times more likely to have an SBI than those with viruses typically restricted to the respiratory mucosa (95% confidence interval: 1.1, 9.7). CONCLUSIONS: Respiratory viruses are readily detectable via nasopharyngeal wash in febrile infants ≤90 days of life. With the enhanced sensitivity of molecular respiratory diagnostics, rates of coinfection of respiratory viruses and SBI may be higher than previously thought. Further investigation utilizing molecular diagnostics is needed to guide usage in febrile infants ≤90 days.

14.
Pediatrics ; 143(2)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30617238
15.
J Infect Dis ; 219(11): 1804-1808, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30590603

RESUMO

The relation of nasopharyngeal microbiota to the clearance of respiratory syncytial virus (RSV) in infants hospitalized for bronchiolitis is not known. In a multicenter cohort, we found that 106 of 557 infants (19%) hospitalized with RSV bronchiolitis had the same RSV subtype 3 weeks later (ie, delayed clearance of RSV). Using 16S ribosomal RNA gene sequencing and a clustering approach, infants with a Haemophilus-dominant microbiota profile at hospitalization were more likely than those with a mixed profile to have delayed clearance, after adjustment for 11 factors, including viral load. Nasopharyngeal microbiota composition is associated with delayed RSV clearance.

17.
Vaccine ; 36(52): 8069-8078, 2018 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-30389195

RESUMO

Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in newborns, young children, elderly, and immune-compromised. The RSV fusion (F) glycoprotein is a major focus of vaccine development and the target of palivizumab (Synagis®) which is licensed as an immuno-prophylactic for use in newborn children at high risk of infection. However, clinical use of a narrowly targeted monoclonal antibodies leads to the generation of escape mutant strains that are fully resistant to neutralization by the antibody. Herein, we evaluated the RSV F nanoparticle vaccine (RSV F vaccine), produced as near-full-length, pre-fusogenic F trimers that form stable protein-detergent nanoparticles. The RSV F vaccine induces polyclonal antibodies that bind to antigenic site II as well as other epitopes known to be broadly neutralizing. Cotton rats immunized with the RSV F vaccine produced antibodies that were both neutralizing and protected against wild-type RSV infection, as well as against a palivizumab-resistant mutant virus. Use of aluminum phosphate adjuvant with the RSV F vaccine increased site II antibody avidity 100 to 1000-fold, which correlated with enhanced protection against challenge. The breadth of the vaccine-induced antibody response was demonstrated using competitive binding with monoclonal antibodies targeting antigenic sites Ø, II, IV, and VIII found on pre-fusion and post-fusion conformations of RSV F. In summary, we found the RSV F vaccine induced antibodies that bind to conserved epitopes including those defined as pre-fusion F specific; that use of adjuvant increased antibody avidity that correlated with enhanced protection in the cotton rat challenge model; and the polyclonal, high-avidity antibodies neutralized and protected against both wild-type and palivizumab-resistant mutant virus. These data support the ongoing clinical development of the aluminum phosphate adjuvanted RSV F nanoparticle vaccine.

18.
Clin Infect Dis ; 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30215689

RESUMO

Background: Epidemiological studies conducted in low and high-income countries showed that infants exposed to maternal HIV but not infected themselves by the virus have a high risk of severe infections. Immune alterations during fetal life have been proposed as a possible mechanism. Methods: This prospective study was conducted to assess the relative risk of hospitalization for infection in HIV-exposed uninfected (HEU) infants as compared to HIV-unexposed (HU) infants born in a high-income country (HIC). Markers of monocyte activation and levels of vaccine and pathogen specific antibodies were measured at birth in maternal and cord blood to identify correlates of infant susceptibility. Results: 27 of 132 HEU infants and 14 of 123 HU infants were hospitalized for infection during the first year of life (adjusted HR, 95% CI: 2.33, 1.10-4.97). Most of this increased risk was associated with time of initiation of maternal anti-retroviral therapy (ART). As compared to HU infants, risk of hospitalization for infection of HEU infants was four-fold higher (3.84, 1.69-8.71) when mothers initiated ART during pregnancy and was not significantly increased (1.42, 0.58-3.48) when ART was initiated before pregnancy. Activation of maternal and newborn monocytes and reduced transfer of maternal antibodies were most intense following ART initiation during pregnancy and predicted the risk of infant hospitalization. Conclusions: These observations indicate that initiation of maternal ART before pregnancy reduces the susceptibility of HEU infants born in a HIC to severe infections and that this effect could be related to the prevention of immune alterations during fetal life.

19.
J Infect Dis ; 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-30215722
20.
Pediatr Infect Dis J ; 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30169487

RESUMO

BACKGROUND: Molecular diagnostic methods enhance the sensitivity and broaden the spectrum of detectable respiratory viruses in febrile infants ≤90 days of life. We describe the occurrence of respiratory viruses in this population as well as the rates of serious bacterial infection (SBI) and respiratory viral co-infection with regard to viral characteristics. METHODS: This was a prospective observational cohort study performed in the emergency department that included previously healthy febrile infants ≤90 days of life. Clinical and historical characteristics were documented and a respiratory nasal wash specimen was obtained from each patient. This sample was tested for 17 common respiratory pathogens and a chart review was conducted to ascertain if the infant was diagnosed with an SBI. RESULTS: In a 12-month period, 67% of the 104 recruited febrile infants were positive for a respiratory virus. The most commonly detected viruses were rhinovirus, respiratory syncytial virus, enterovirus and influenza. The rate of respiratory viral and SBI co-infection was 9% overall and infants with either a systemic respiratory virus or negative viral testing were 3 times more likely to have an SBI than those with viruses typically restricted to the respiratory mucosa (95% CI: 1.1, 9.7). CONCLUSIONS: Respiratory viruses are readily detectable via nasopharyngeal wash in febrile infants ≤90 days of life. With the enhanced sensitivity of molecular respiratory diagnostics, rates of co-infection of respiratory viruses and SBI may be higher than previously thought. Further investigation utilizing molecular diagnostics is needed to guide usage in febrile infants ≤90 days.

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