[Show abstract][Hide abstract] ABSTRACT: Background:
The predominant strain during the 2013-2014 influenza season was 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09). This vaccine-component has remained unchanged from 2009.
The US Flu Vaccine Effectiveness Network enrolled subjects aged ≥6 months with medically attended acute respiratory illness (MAARI), including cough, with illness onset ≤7 days before enrollment. Influenza was confirmed by reverse-transcription polymerase chain reaction (RT-PCR). We determined the effectiveness of trivalent or quadrivalent inactivated influenza vaccine (IIV) among subjects ages ≥6 months and the effectiveness of quadrivalent live attenuated influenza vaccine (LAIV4) among children aged 2-17 years, using a test-negative design. The effect of prior receipt of any A(H1N1)pdm09-containing vaccine since 2009 on the effectiveness of current-season vaccine was assessed.
We enrolled 5999 subjects; 5637 (94%) were analyzed; 18% had RT-PCR-confirmed A(H1N1)pdm09-related MAARI. Overall, the effectiveness of vaccine against A(H1N1)pdm09-related MAARI was 54% (95% confidence interval [CI], 46%-61%). Among fully vaccinated children aged 2-17 years, the effectiveness of LAIV4 was 17% (95% CI, -39% to 51%) and the effectiveness of IIV was 60% (95% CI, 36%-74%). Subjects aged ≥9 years showed significant residual protection of any prior A(H1N1)pdm09-containing vaccine dose(s) received since 2009, as did children <9 years old considered fully vaccinated by prior season.
During 2013-2014, IIV was significantly effective against A(H1N1)pdm09. Lack of LAIV4 effectiveness in children highlights the importance of continued annual monitoring of effectiveness of influenza vaccines in the United States.
Preview · Article · Jan 2016 · The Journal of Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants and young children. In addition, RSV causes significant morbidity and mortality in hospitalized elderly and immunocompromised patients. Currently, only palivizumab, a monoclonal antibody against the RSV fusion (F) protein, and inhaled ribavirin, are approved for the prophylactic and therapeutic treatment of RSV, respectively. Therefore, there is a clinical need for a safe and effective therapeutic agents for RSV infections. GS-5806, discovered via chemical optimization of a hit from a high-throughput antiviral screening campaign, selectively inhibits a diverse set of 75 RSV subtype A and B clinical isolates (mean EC
= 0.43 nM). The compound maintained potency in primary human airway epithelial cells and exhibited low cytotoxicity in human cell lines and primary cell cultures (selectivity > 23,000-fold). Time-of-addition and temperature shift studies demonstrated that GS-5806 does not block RSV attachment to cells, but interferes with virus entry. Follow-up experiments showed potent inhibition of RSV F-mediated cell-to-cell fusion. RSV A and B variants resistant to GS-5806, due to mutations in F protein (RSV A: L138F or F140L/N517I and RSV B: F488L or F488S), were isolated and showed cross-resistance to other RSV fusion inhibitors such as VP-14637, but remained fully sensitive to palivizumab and ribavirin. In summary, GS-5806 is a potent and selective RSV fusion inhibitor with antiviral activity against a diverse set of RSV clinical isolates. The compound is currently under clinical investigation for the treatment of RSV infection in pediatric, immunocompromised, and elderly patients.
No preview · Article · Dec 2015 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Background: Our aim was to evaluate the association between viral findings during bronchiolitis and the use of asthma controller medication (primary outcome) and systemic corticosteroids (secondary outcome) during the first post-bronchiolitis year. Methods: We enrolled 408 children hospitalized for bronchiolitis at age <24 months in a prospective, 3-center, 1-year follow-up study in Finland. Viruses were detected with polymerase chain reaction in nasopharyngeal aspirates. The parents underwent a structured interview during hospitalization. Twelve months later, the use of asthma medication was asked in a structured questionnaire. Multivariable logistic regression was used for statistical analysis. Results: In total, 365 (89%) children completed the 1-year follow-up. The use of long-term asthma controller medication was highest in the rhinovirus-positive group (61% vs. 15% in RSV-positive group; adjusted OR 7.5, 95%CI 3.7-15.3), followed by children negative for both RSV and rhinovirus (36%; adjusted OR 2.6, 95%CI 1.3-5.3). Likewise, rhinovirus etiology was associated with more courses of systemic corticosteroids during the follow-up. The main findings were similar in a subset of infants aged <12 months with first wheezing. Conclusions: Children hospitalized for rhinovirus-positive bronchiolitis used long-term asthma controller medication more often than those hospitalized for rhinovirus-negative bronchiolitis during first year after hospitalization. Copyright
No preview · Article · Dec 2015 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: Background:
Despite the research importance of rhinovirus detection in asymptomatic healthy infants, the literature remains sparse.
To investigate the prevalence of respiratory syncytial virus (RSV) and rhinovirus (and its species).
We conducted a cross-sectional study of 110 healthy, non-hospitalized infants without acute illness at an academic medical center from November 2013 through May 2014. We tested nasal swab specimens by using polymerase chain reaction and genetic sequencing.
Overall, the median age was 3.8 months (IQR 2.0-5.1 months), 56 % were male, and 90 % were born >37 weeks. RSV was detected in nasal swabs from infants (1.8 %). By contrast, rhinovirus was detected in nasal swabs from 16 infants (14.5 %). Molecular typing assay revealed rhinovirus species: six rhinovirus-A (5.5 %), one rhinovirus-B (0.9 %), eight rhinovirus-C (7.3 %), and one untypeable (0.9 %).
In this cross-sectional study of healthy, community-based infants, RSV was rare (<2 %) in nasal swabs, while rhinovirus was detected in 14.5 % with a predominance of rhinovirus-A and -C. These finding are important for understanding the clinical significance of rhinovirus detection among infants hospitalized for bronchiolitis.
Full-text · Article · Nov 2015 · BMC Research Notes
[Show abstract][Hide abstract] ABSTRACT: Objective:
Among children hospitalized with bronchiolitis, we examined the associations between in utero exposure to maternal cigarette smoking, postnatal tobacco smoke exposure, and risk of admission to the intensive care unit (ICU).
We performed a 16-center, prospective cohort study of hospitalized children age <2 years with a physician admitting diagnosis of bronchiolitis. For 3 consecutive years, from November 1, 2007 until March 31, 2010, site teams collected data from participating families, including information about prenatal maternal smoking and postnatal tobacco exposure. Analyses used χ(2), Fisher's exact, and Kruskal-Wallis tests and multivariable logistic regression.
Among 2,207 enrolled children, 216 (10%) had isolated in utero exposure to maternal smoking, 168 (8%) had isolated postnatal tobacco exposure, while 115 (5%) experienced both. Adjusting for age, sex, race, birth weight, viral etiology, apnea, initial severity of retractions, initial oxygen saturation, oral intake, and postnatal tobacco exposure, children with in utero exposure to maternal smoking had greater odds of being admitted to the ICU (adjusted odds ratio (aOR) 1.51 [95% CI 1.14-2.00]). Among children with in utero exposure to maternal smoking, those with additional postnatal tobacco exposure had a greater likelihood of ICU admission (aOR 1.95 [95% CI 1.13-3.37]) compared with children without postnatal tobacco smoke exposure (aOR 1.47 [95% CI 1.05-2.04]).
Maternal cigarette smoking during pregnancy puts children hospitalized with bronchiolitis at significantly higher risk of requiring intensive care use. Postnatal tobacco smoke exposure may exacerbate this risk. Health care providers should incorporate this information into counseling messages.
No preview · Article · Nov 2015 · Academic pediatrics
[Show abstract][Hide abstract] ABSTRACT: In 169 Finnish infants hospitalized for bronchiolitis at age <6 months in 2008-2010, nasopharyngeal aspirates were tested by PCR for Bordetella pertussis and 16 viruses. Respiratory viruses were detected in 89% (71% with RSV), but no infant had B. pertussis. The latter finding may reflect a positive effect from the broadening of the Finnish pertussis vaccination program in 2005.
No preview · Article · Nov 2015 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: Respiratory Syncytial Virus (RSV) is an important causative agent of lower respiratory tract infections in infants and elderly.
Its fusion (F) protein is critical for virus infection. It is targeted by several investigational antivirals and by palivizumab,
a humanised monoclonal antibody used prophylactically in infants considered at high risk of severe RSV disease. ALX-0171 is
a trimeric Nanobody that binds the antigenic site II of RSV F-protein with subnanomolar affinity. ALX-0171 demonstrated superior
in vitro neutralisation compared to palivizumab against prototypic RSV A and B strains. Moreover, ALX-0171 completely blocked
replication below limit of detection in 87% of the viruses tested versus 18% for palivizumab at a fixed concentration. Importantly,
ALX-0171 was highly effective in reducing both nasal and lung RSV titers when delivered prophylactically or therapeutically
directly to the lungs of cotton rats. ALX-0171 represents a potent novel antiviral compound with significant potential to
treat RSV-mediated disease.
Full-text · Article · Oct 2015 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: In 2014, the American Academy of Pediatrics (AAP) updated their recommendations for palivizumab prophylaxis for children who are at high risk for severe respiratory syncytial virus (RSV) infection. To investigate the potential impact of the more restrictive 2014 criteria on the eligibility for palivizumab prophylaxis, we applied the 2012 and 2014 AAP recommendations for palivizumab prophylaxis to a multicenter cohort of 2207 US children hospitalized for bronchiolitis. According to the 2012 AAP recommendations, 215 children (9.7%) were eligible for palivizumab prophylaxis, while 140 children (6.3%) would have been eligible based on the 2014 updated recommendations (34.9% relative decrease; 95%CI: 28.5–41.7%). The decrease was largely driven by the restriction of eligibility to preterm infants with gestational age <29 weeks. Further development of and refinement of cost-effective approaches for the prevention of severe RSV infection are needed.
Full-text · Article · Oct 2015 · Pediatrics International
[Show abstract][Hide abstract] ABSTRACT: We evaluated the cycle threshold (CT) values of 1160 influenza A positive and 806 influenza B positive specimens from two seasons of the US Flu VE Network to identify factors associated with CT values. Low CT values (high genomic load) were associated with shorter intervals between illness onset and specimen collection, young age (ages 3-8 years old), and self-rated illness severity for both influenza A and B. Low CT values were also associated with reported fever/feverishness and age ≥65 years for influenza A. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Sep 2015 · Journal of Medical Virology
[Show abstract][Hide abstract] ABSTRACT: Background:
Respiratory syncytial virus (RSV) is a leading cause of infant morbidity and mortality. A recombinant RSV fusion protein nanoparticle vaccine (RSV F vaccine) candidate for maternal immunization was tested for safety and immunogenicity in women of childbearing age.
Three hundred thirty women (18-35 years) were randomized to receive 1 or 2 doses of RSV F vaccine (60 or 90 µg) with or without aluminum phosphate adjuvant, or placebo at days 0 and 28. Safety was evaluated over 180 days; immunogenicity and RSV infection rates were evaluated over 112 days.
All vaccine formulations were well tolerated, without vaccine-related serious adverse events. Anti-F immunoglobulin G antibodies rose 6.5-15.6-fold, with significantly higher levels in 2-dose, adjuvanted regimens at day 56. Palivizumab-competitive antibody levels were undetectable at day 0 but increased up to 325 µg/mL at day 56. A 2.7- and 3.5-fold rise in RSV/A and RSV/B microneutralization antibodies were noted at day 56. Between days 56 and 112, 21% (12/56) of placebo recipients and 11% of vaccinees (26/244) showed evidence of a recent RSV infection (P = .04).
The vaccine appeared safe, immunogenic, and reduced RSV infections. Further development as a vaccine for use in maternal immunization is warranted.
Clinical trials registration:
No preview · Article · Aug 2015 · The Journal of Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Respiratory syncytial virus (RSV) continues to cause significant clinical and economic burden around the world. Historically, RSV-associated hospitalization was used as a primary endpoint for RSV prophylaxis trials in infants. However,due to the changing epidemiology and healthcare system landscape, this endpoint has become a critical bottleneck on the pathway to licensure for new therapeutics. A panel of seven RSV experts was convened (Chicago, Illinois, 22 May, 2014) to evaluate the challenges of defining RSV prevention endpoints for clinical trials and to develop endpoints that are clinically meaningful while minimizing subjectivity and bias to achieve sufficient consistency of response for regulatory approval. Particular consideration was given to the ability to collect data systematically and consistently in countries with different healthcare practices and systems, while capturing the greatest proportion of disease impact. The group consensus was that a clinically meaningful primary endpointcould include medically attended RSV illness in settingsbeyond RSV-associated hospitalizations alone,in particular: a composite reduction in hospitalization, emergency room, or urgent care center visits due to an RSV respiratory Infection. Relevant secondary endpoints included reductions in: RSV lower respiratory tract infection, RSV related ICU rates, subsequent recurrent wheezing or asthma, and direct and indirect costs.
Full-text · Article · Jun 2015 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: In the United States (U.S.), Bordetella pertussis incidence has increased. Cough and apnea are common findings in pertussis and also in bronchiolitis, the most common cause of hospitalization in U.S. infants. The objective was to determine the prevalence of B. pertussis infection in children hospitalized with bronchiolitis and to describe its clinical course.
Children hospitalized with bronchiolitis and age <2 years were eligible for a prospective, multicenter cohort study during 3 consecutive winter seasons (November-March) from 2007 to 2010. Sixteen sites in 12 states participated using a standardized enrollment protocol. Families were asked the 2010 Centers for Disease Control and Prevention pertussis classification questions. Nasopharyngeal aspirates were obtained and tested by real-time polymerase chain reaction for 16 viruses, Mycoplasma pneumoniae and B. pertussis.
Two thousand sixty-eight (94%) of 2207 children had 1 or more respiratory pathogens. B. pertussis was identified in 4 children [0.2%; 95% confidence interval (CI): 0.1-0.5%] with 3 having a viral co-infection. All 4 were younger than 4 months; 2 met the Centers for Disease Control and Prevention definition of probable pertussis; and 3 had received at least 1 dose of an acellular pertussis vaccine. During the hospitalization, 2 had paroxysmal cough, 1 required intensive care unit care and the median length of stay was 13 days.
Our data support that B. pertussis is an uncommon pathogen in U.S. children hospitalized with bronchiolitis in the winter. Making a diagnosis of pertussis can be challenging because the disease can be atypical and may not meet the Centers for Disease Control and Prevention definition of probable infection.
No preview · Article · Jun 2015 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: Objective:
To examine risk factors for transfer of bronchiolitis patients from the ward to the intensive care unit (ICU) and/or initiation of critical care interventions.
We performed a 16-center, prospective cohort study of hospitalized children age <2 years with bronchiolitis. During the winters of 2007 to 2010, researchers collected clinical data and nasopharyngeal aspirates from study participants. The primary outcome was late intensive care use, defined as a transfer to the ICU and/or use of mechanical ventilation (regardless of location) after the child's first inpatient day.
Among 2104 children hospitalized with bronchiolitis, 1762 (84%) were identified as initial ward patients, comprising the analysis cohort. The median age was 4 months (interquartile range, 2-9 months), and 1048 (59%) were boys. The most frequently detected pathogens were respiratory syncytial virus (72%) and rhinovirus (25%). After the first inpatient day, 47 (3%; 95% confidence interval, 2-4) were subsequently transferred to the ICU or required mechanical ventilation. In the multivariable logistic regression model predicting subsequent transfer to the ICU or mechanical ventilation use, the significant predictors were birth weight <5 pounds (odds ratio, 2.28; 95% confidence interval, 1.30-4.02; P = .004) and respiratory rate high of ≥ 70 breaths/min on the first inpatient day (odds ratio, 4.64; 95% confidence interval, 2.86-7.53; P < .001).
In this multicenter study of children hospitalized with bronchiolitis, low birth weight and tachypnea were significantly associated with subsequent transfer to the ICU and/or use of mechanical ventilation.
Full-text · Article · Feb 2015 · Academic Pediatrics