Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
- Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. [Journal Article, Research Support, Non-U.S. Gov't]
- N Engl J Med 2013 May 9; 368(19):1791-9.
Respiratory syncytial virus (RSV) infection is associated with subsequent recurrent wheeze. Observational studies cannot determine whether RSV infection is the cause of recurrent wheeze or the first indication of preexistent pulmonary vulnerability in preterm infants. The monoclonal antibody palivizumab has shown efficacy in preventing severe RSV infection in high-risk infants.In the double-blind, placebo-controlled MAKI trial, we randomly assigned 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to receive either monthly palivizumab injections (214 infants) or placebo (215 infants) during the RSV season. The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life. Nasopharyngeal swabs were taken during respiratory episodes for viral analysis.Palivizumab treatment resulted in a relative reduction of 61% (95% confidence interval, 56 to 65) in the total number of wheezing days during the first year of life (930 of 53,075 days in the RSV-prevention group [1.8%] vs. 2309 of 51,726 days [4.5%] in the placebo group). During this time, the proportion of infants with recurrent wheeze was 10 percentage points lower in patients treated with palivizumab (11% vs. 21%, P=0.01).In otherwise healthy preterm infants, palivizumab treatment resulted in a significant reduction in wheezing days during the first year of life, even after the end of treatment. These findings implicate RSV infection as an important mechanism of recurrent wheeze during the first year of life in such infants. (Funded by Abbott Laboratories and by the Netherlands Organization for Health Research and Development; MAKI Controlled Clinical Trials number, ISRCTN73641710.).
- Intranasal administration of antibody-bound respiratory syncytial virus particles efficiently primes virus specific immune responses in mice. [JOURNAL ARTICLE]
- J Virol 2013 May 1.
Infants are protected from a severe RSV infection in the first months of life by maternal antibodies, or by prophylactic administered neutralizing antibodies. Efforts are underway to produce RSV-specific antibodies with increased neutralizing capacity compared to the currently licensed palivizumab. While clearly beneficial during primary infections, pre-existing antibodies might affect the onset of adaptive immune responses and the ability to resist subsequent RSV infections. Therefore, we addressed the question how virus neutralizing antibodies influence the priming of subsequent adaptive immune responses. To test a possible role of the neonatal Fc-Receptor (FcRn) in this process, we compared the response in C57BL/6 WT and FcRn(-/-) mice. We observed substantial virus specific T cell priming and B cell responses in mice primed with IgG-RSV complexes resulting in predominantly Th1-type CD4(+) T cell and IgG2c antibody responses upon live virus challenge. RSV-specific CD8(+) T cells were primed as well. Activation of these adaptive immune responses was independent of FcRn. Thus neutralizing antibodies that localize to the airways and prevent infection-related routes of antigen processing can still facilitate antigen presentation of neutralized virus particles and initiate adaptive immune responses against RSV.
- Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. [Journal Article]
- Cochrane Database Syst Rev 2013.:CD006602.
Respiratory syncytial virus (RSV) is one of the most important viral pathogens causing acute respiratory infections in children. It results in about 3.4 million hospitalisations annually in children under five. Palivizumab is an anti-RSV monoclonal antibody, administered intramuscularly at a dose of 15 mg/kg once every 30 days. The efficacy and safety of palivizumab has been evaluated in multicentre, randomised controlled trials (RCTs) and a large number of economic evaluations (EEs) have tested its cost-effectiveness.To assess the effectiveness and safety of palivizumab prophylaxis compared with placebo, or another type of prophylaxis, in reducing the risk of complications (hospitalisation due to RSV infection) in high-risk infants and children. To assess the cost-effectiveness (or cost-utility) of palivizumab prophylaxis compared with no prophylaxis in infants and children in different risk groups.We searched CENTRAL 2012, Issue 7, MEDLINE (1996 to July week 4, 2012), EMBASE (1996 to August 2012), CINAHL (1996 to August 2012) and LILACS (1996 to August 2012) for studies of effectiveness and safety. We searched the NHS Economic Evaluations Database (NHS EED 2012, Issue 4), Health Economics Evaluations Database (HEED, 9 August 2012) and Paediatric Economic Database Evaluations (PEDE, 1980 to 2009), MEDLINE (1996 to July week 4, 2012) and EMBASE (1996 to August 2012) for economic evaluations.We included RCTs comparing palivizumab prophylaxis with a placebo, no prophylaxis or another type of prophylaxis in preventing serious lower respiratory tract disease caused by RSV in paediatric patients at high risk. We included cost-effectiveness analyses and cost-utility analyses comparing palivizumab prophylaxis with no prophylaxis.Two review authors independently assessed risk of bias for the included studies and extracted data for both the RCTs and EEs. We calculated risk ratios (RRs) and their associated 95% confidence intervals (CIs) for dichotomous outcomes and for adverse events (AEs). We provided a narrative summary of results for continuous outcomes, due to missing data on standard deviations. We performed fixed-effect meta-analyses for the estimation of pooled effects whenever there was no indication of heterogeneity between included RCTs. We summarised the results reported in included EEs, such as incremental costs, incremental effectiveness, and incremental cost-effectiveness and/or cost-utility ratios (ICERs), and we calculated ICER present values in 2011 Euros for all studies.Of the seven available RCTs, three compared palivizumab with a placebo in a total of 2831 patients, and four compared palivizumab with motavizumab in a total of 8265 patients. All RCTs were sponsored by the drug manufacturing company. The overall quality of RCTs was good, but for most of the outcomes assessed only data from two studies contributed to the analysis. Palivizumab prophylaxis was associated with a statistically significant reduction in RSV hospitalisations (RR 0.49, 95% CI 0.37 to 0.64) when compared to placebo. When compared to motavizumab, palivizumab recipients showed a non-significant increase in the risk of RSV hospitalisations (RR 1.36, 95% CI 0.97 to 1.90). In both cases, the proportion of children with any AE or any AE related to the study drug was similar between the two groups.In terms of economic evidence, we included 34 studies that reported cost-effectiveness and/or cost-utility data for palivizumab prophylaxis compared with no prophylaxis, in high-risk children with different underlying medical conditions. The overall quality of EEs was good, but the variations in modelling approaches were considerable across the studies, leading to big differences in cost-effectiveness results. The cost-effectiveness of palivizumab prophylaxis depends on the consumption of resources taken into account by the study authors; and on the cost-effectiveness threshold set by the healthcare sector in each country.There is evidence that palivizumab prophylaxis is effective in reducing the frequency of hospitalisations due to RSV infection, i.e. in reducing the incidence of serious lower respiratory tract RSV disease in children with chronic lung disease, congenital heart disease or those born preterm.Results from economic evaluations of palivizumab prophylaxis are inconsistent, implying that economic findings must be interpreted with caution. ICER values varied considerably across studies, from highly cost-effective to not cost-effective. The availability of low-cost palivizumab would reduce its inequitable distribution, so that RSV prophylaxis would be available to the poorest countries where children are at greatest risk.
- Respiratory syncytial virus prophylaxis in children with cardiac disease: a retrospective single-centre study. [JOURNAL ARTICLE]
- Cardiol Young 2013 Apr 29.:1-7.
OBJECTIVES:To examine the characteristics of congenital heart disease patients hospitalised with respiratory syncytial virus infection after prophylaxis and determine the associated comorbidities and the incidence of breakthrough respiratory syncytial virus infections. Study design This is a retrospective, single-centre study that was conducted over a period of 7 years. Respiratory syncytial virus infection was identified by classification codes and confirmed by virological tests. Data on baseline demographics, cardiac anomalies, other underlying disease, criteria for hospitalisation, type of respiratory illness and management, complications, and palivizumab prophylaxis were analysed by standard descriptive methods and comparative statistics.
RESULTS:A total of 30 patients were enrolled. The majority were ≤2 years (n = 24). The mean admission age was 15.1 months (standard deviation = 18.3). In all, 90% were acyanotic, 40% had haemodynamically significant disease, and 60% had ≥1 underlying medical illness. Patients were admitted with: respiratory distress (86.7%), hypoxaemia (66.7%), fever (60%), inability to maintain oral intake (36.7%), and apnoea (16.7%). More than 50% required mechanical ventilation and intensive care with a median stay of 11 days (range: 1-43); the length of hospital stay for all children was 10 days (range: 1-65). Complications included: concurrent bacterial sepsis (20%), electrolyte abnormalities (16.7%), and worsening pulmonary hypertension (13.3%). Of 10 infants ≤2 years with haemodynamically significant heart disease, four had received prophylaxis. There was one death, which was attributed to respiratory syncytial virus infection.
CONCLUSIONS:Overall, 185 infants ≤2 years with haemodynamically significant cardiac disease received prophylaxis. In all, six qualifying infants missed immunisation and were hospitalised. Breakthrough respiratory syncytial virus infections occurred in 2.2%, demonstrating good efficacy of palivizumab in this population compared with the original, multi-centre, randomised trial.
- Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody. [JOURNAL ARTICLE]
- Science 2013 Apr 25.
The respiratory syncytial virus (RSV) fusion (F) glycoprotein prefusion conformation is the target of most RSV-neutralizing activity in human sera, but its metastability has hindered characterization. To overcome this obstacle, we identified prefusion-specific antibodies which were substantially more potent than the prophylactic antibody palivizumab. The co-crystal structure for one of these antibodies, D25, in complex with the F glycoprotein revealed that D25 locks F in its prefusion state by binding to a quaternary epitope at the trimer apex. Electron microscopy showed that two other antibodies, AM22 and 5C4, also bind to the newly identified site of vulnerability, which we named antigenic site Ø. These studies should enable design of improved vaccine antigens and guide new approaches for passive prevention of RSV-induced disease.
- Potential for Palivizumab Interference with Commercially Available Antibody-Antigen Based Respiratory Syncytial Virus Diagnostic Assays. [JOURNAL ARTICLE]
- Pediatr Infect Dis J 2013 Apr 11.
Palivizumab is a monoclonal antibody indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) infection in infants. The potential for palivizumab to interfere with commercially available RSV diagnostic tests was demonstrated. Negative test results in palivizumab-treated subjects should be interpreted with caution and confirmed by a nucleic acid amplification-based assay.
- Seasonal Respiratory Syncytial Virus Prophylaxis Based on Predetermined Dates versus Regional Surveillance Data. [JOURNAL ARTICLE]
- Pediatr Infect Dis J 2013 Mar 29.
BACKGROUND::In Ontario, Canada, the respiratory syncytial virus (RSV) prophylaxis period onset is defined by a fixed-date set provincially each year and offset by local hospital RSV admission activity. Inaccurate timing can result in inadequate or more costly prophylaxis.
METHODS::RSV positivity (2002/03-2010/11) was obtained from a local database. RSV activity was described: season start/end dates, duration and optimum number of palivizumab doses required compared to doses administered for the final 4 RSV seasons (2007-2011). Three prophylaxis period-setting methods were evaluated for seasons 2007/08-2010/11; 1) the provincial method currently in use, 2) a local fixed-date method based on laboratory data accrued from the previous five seasons and 3) an exploratory prospective method based on surveillance of laboratory data. These were compared with the observed RSV seasons.
RESULTS::The local RSV pattern closely reflects provincial seasonality. The local median season duration was 125 days (range 90-181). Median season onset and offset dates were December 19 and April 16 respectively. The prophylactic period definitions corresponded similarly, but the provincially-set and local fixed-date methods provided longer immunity periods than required for the actual RSV season and involved the administration of more than 5 palivizumab doses compared to the prospective method.
CONCLUSIONS::The provincial prophylactic period aligned with the local fixed-date and prospective methods. However the adoption of any of the first two strategies merits close observation to minimize excess healthcare expenditure. The prospective surveillance of laboratory isolates should be further explored as a preferred option to better define prophylactic periods.
- Three monthly doses of palivizumab are not adequate for 5-month protection: A population pharmacokinetic analysis. [JOURNAL ARTICLE]
- Pulm Pharmacol Ther 2013 Mar 19.
Recent guidelines in British Columbia, Canada have suggested that the use of a maximum of 3 monthly doses of palivizumab 15 mg/kg intramuscularly for RSV immunoprophylaxis of high risk infants born prior to the RSV season is adequate to provide protection against severe RSV disease for a 5-month RSV season. Efficacy was established, however, with 2 large, randomized controlled clinical studies using 5 monthly doses of immunoprophylaxis. To evaluate the differences in expected palivizumab exposures between the 2 dosing regimens (3 vs 5 monthly doses across a 5-month period), we used a population pharmacokinetic (PK) model that was developed using palivizumab PK data collected from 22 clinical studies with a total of 1800 subjects. This model adequately described observed palivizumab concentrations from the different pediatric studies and was subsequently used to simulate expected palivizumab serum concentrations for 3 monthly doses compared with 5 monthly doses in children younger than 24 months with chronic lung disease of prematurity and infants younger than 6 months postnatal age who were born at ≤35 weeks gestational age. Results from the population PK model indicated lower serum concentrations of palivizumab during the fourth and fifth months, after an abbreviated 3-monthly-dose regimen when compared with the mean trough concentrations seen with the 5-monthly-dose regimen studied in the pivotal clinical trials in premature infants. Specifically, during the fourth and fifth months, 52% and 85%, respectively, would have levels below the lowest concentration (fifth percentile) in those receiving the 5-monthly-dose regimen. Simulations using this model did not support a 3-monthly-dose regimen to protect against severe RSV disease during the typical 5-month season.
- Evaluation of a novel web-based prior approval application for palivizumab prophylaxis of respiratory syncytial virus in a state Medicaid program. [Journal Article]
- J Manag Care Pharm 2013 Mar; 19(2):115-24.
Recent disproportionate increases in use of specialty medications, such as palivizumab (Synagis), compared with steady utilization of traditional medication use, have prompted complex utilization management strategies that require frequent evaluation to facilitate cost-effectiveness while preserving patient access. Clinical criteria utilized by North Carolina (NC) Medicaid for use of palivizumab for respiratory syncytial virus (RSV) prophylaxis are consistent with the most recent guidelines published in the Red Book: Report of the Committee on Infectious Diseases. Prior to the 2011-2012 RSV season, prior approval (PA) requests were submitted by facsimile using the NC Medicaid Synagis PA form. A web-based PA application, which includes automatic approval capability, monthly dose prompts to providers, and a standardized dose projection formula, was developed for the 2011-2012 RSV season.To evaluate the timeliness of palivizumab coverage determination, compliance with palivizumab prophylaxis regimen, and the accuracy of the dose projection formula achieved with this novel web-based PA application for palivizumab prophylaxis in NC Medicaid recipients.A historically controlled retrospective cohort study was conducted in which all palivizumab PA submissions and supporting documentation from the 2010-2011 and 2011-2012 RSV seasons were retrospectively reviewed for date and time of original submission and final coverage determination. Submissions from the 2011-2012 season were also retrospectively reviewed for number of doses approved, number of doses administered, date of administration of each dose, and actual dosage administered. These data were used to evaluate compliance and the projected versus actual beneficiary weight and dose to assess the accuracy of the dose projection formula. Submissions lacking required information were excluded. Time from PA submission to coverage determination was compared between seasons using a 2-sample t-test. The proportion of compliant recipients was calculated based on number of doses received and dosing interval of no more than 35 days. Accuracy of the dose projection formula was evaluated using a paired Student's t-test.Time to coverage determination decreased overall, on average, by 3.7 days (mean [SD] 8.5 [15.4] vs. 4.8 [9.3]; P<0.001) for the 2011-2012 season using the electronic web-based PA application compared with the traditional facsimile-based system used in the 2010-2011 season. Decreased time to coverage determination was observed in both PA requests that required medical review and those that did not. Of all palivizumab recipients who were eligible to receive at least 2 doses (n=1,233), 61.1% were fully compliant with all doses, and 86.9% received all but one documentable dose. Of those who received at least 2 documented doses (n=1,091), 62.8% received all doses within 35 days of the previous dose. When both definitions of compliance were applied concurrently, 39.3% of all palivizumab recipients were considered compliant; the mean difference between projected and actual doses was 7.1 mg (95% CI: 6.8-7.5; P=0.001) or 8.6% (95% CI: 8.0-10.0). Projected and actual doses did not vary significantly in the sensitivity analysis when excluding entries with ≥50% difference.The 2011-2012 web-based PA application improved the timeliness of palivizumab coverage determination compared with the 2010-2011 facsimile-based system. Observed compliance rates for NC Medicaid recipients were slightly lower than those reported in the literature when defined by number of doses received but were higher when defined by interval between doses. The dose projection formula used for the web-based application appears to be accurate for infants 0-2 years of age.
- Should respiratory care in preterm infants include prophylaxis against respiratory syncytial virus? The case against. [JOURNAL ARTICLE]
- Paediatr Respir Rev 2013 Feb 16.
Preterm infants are at increased risk of severe respiratory syncytial virus (RSV) infection. The monoclonal antibody palivizumab reduces the frequency of preterm infants being admitted to hospital with RSV infection. However, palivizumab is expensive, has to be given by intramuscular injection monthly for 5 months and has to be given prophylactically to 17 preterm children to prevent one hospital admission with RSV and to 59 children to prevent one intensive care admission. Cost-effectiveness analyses have not shown that palivizumab is cost-effective for any sub-group with sufficient certainty to recommend its public funding. Palivizumab will only be cost-effective if the price drops. Paying for palivizumab is an opportunity cost; the money could be spent better on other more cost-effective health care interventions. Palivizumab should not be prescribed for any preterm child unless it can be shown to be cost-effective in that situation.