Maarten O. Blanken

Respiratory syncytial virus and recurrent wheeze in healthy preterm infants

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.).

Prospective Validation of a Prognostic Model for Respiratory Syncytial Virus Bronchiolitis in Late Preterm Infants: A Multicenter Birth Cohort Study

Objectives This study aimed to update and validate a prediction rule for respiratory syncytial virus (RSV) hospitalization in preterm infants 33–35 weeks gestational age (WGA). Study Design The RISK study consisted of 2 multicenter prospective birth cohorts in 41 hospitals. Risk factors were assessed at birth among healthy preterm infants 33–35 WGA. All hospitalizations for respiratory tract infection were screened for proven RSV infection by immunofluorescence or polymerase chain reaction. Multivariate logistic regression analysis was used to update an existing prediction model in the derivation cohort (n = 1,227). In the validation cohort (n = 1,194), predicted versus actual RSV hospitalization rates were compared to determine validity of the model. Results RSV hospitalization risk in both cohorts was comparable (5.7% versus 4.9%). In the derivation cohort, a prediction rule to determine probability of RSV hospitalization was developed using 4 predictors: family atopy (OR 1.9; 95%CI, 1.1–3.2), birth period (OR 2.6; 1.6–4.2), breastfeeding (OR 1.7; 1.0–2.7) and siblings or daycare attendance (OR 4.7; 1.7–13.1). The model showed good discrimination (c-statistic 0.703; 0.64–0.76, 0.702 after bootstrapping). External validation showed good discrimination and calibration (c-statistic 0.678; 0.61–0.74). Conclusions Our prospectively validated prediction rule identifies infants at increased RSV hospitalization risk, who may benefit from targeted preventive interventions. This prediction rule can facilitate country-specific, cost-effective use of RSV prophylaxis in late preterm infants.

Respiratory syncytial virus and recurrent wheeze

n engl j med 369;8 nejm.org august 22, 2013 782 chain fatty acids as the placebo, as suggested by Scaioli and Belluzzi, would have been unlikely to alter our results. With regard to the experimental agent, we chose the same formulation and the same dose of n–3 fatty acids that resulted in a protective effect in other studies.3,4 If the alleged pleiotropic effects of higher doses are assumed as a plausible hypothesis, this could reasonably be tested in another trial. The source of n–3 fatty acids in our trial corresponds to the one used for the products that are available, registered, and administered for the prevention of secondary myocardial infarction and for the treatment of hypertriglyceridemia in many European countries. With regard to the other issues raised, the possible reasons for the lower-than-expected rate of events in the trial are extensively discussed in the article but are definitely not attributable to a similar and positive effect of the experimental and placebo treatments. The trial cannot be described as an equivalence trial, since it was planned, approved by ethics committees, and registered as a superiority trial, and by definition, it must be presented — and has been assessed statistically — as such. We agree that more detailed analyses, as well as pooling of data with information from other studies, could be of interest for exploratory purposes in the female population. M. Carla Roncaglioni, M.Sc.

Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial

BACKGROUND Respiratory syncytial virus (RSV) infection is associated with subsequent wheeze and asthma. We previously reported on the causal relationship between prevention of RSV infection during infancy and reduced frequency of subsequent wheeze using a double-blind, randomised, placebo-controlled trial (MAKI). We continued follow-up and analysed the effect of RSV prevention during infancy on asthma and lung function at age 6 years. METHODS We studied 429 infants born at 32-35 weeks of gestation between 2008-10 who had randomly received either palivizumab for RSV immunoprophylaxis or placebo during the RSV season of their first year of life. After the first year of follow-up, single, assessor-blind follow-up of children continued until they were aged 6 years. Primary outcomes were parent-reported current asthma and forced expiratory volume in 0·5 s (FEV0·5). The trial is registered in the ISRCTN registry, number ISRCTN73641710. FINDINGS 395 (92%) of 429 participants completed this 6-year follow-up study. Parent-reported current asthma was reported in 28 (14·1%) of 199 children in the RSV prevention group and 47 (24·0%) of 196 children in the placebo group (absolute risk reduction [ARR] 9·9%, 95% CI 2·2 to 17·6). The difference in current asthma, which was a composite endpoint, was due to a difference in infrequent wheeze (one to three episodes in the past year; 12 [6·0%] of 199 vs 26 [13·4%] of 194, ARR 7·4%, 95% CI 1·5 to 13·2). FEV0·5 percentage predicted values were similar between the RSV prevention group (89·1% [SD 10·6]) and placebo group (90·1% [11·1]), with a mean difference of 1·0 (95% CI -1·3 to 3·3). The proportion of children with current physician-diagnosed asthma was similar between the RSV prevention group (19 [10·3%] of 185) and placebo group (18 [9·9%] of 182), with an ARR of -0·4 (95% CI -6·5 to 5·8). INTERPRETATION In otherwise healthy preterm infants, this single-blind, randomised, placebo-controlled trial showed that RSV prevention did not have a major effect on current asthma or lung function at age 6 years. Future research will inform on the effect of RSV prevention on asthma at school age in the general population. FUNDING AbbVie.

Interference between respiratory syncytial virus and human rhinovirus infection in infancy

Background Respiratory syncytial virus (RSV) and human rhinovirus (HRV) are the most common viruses associated with acute respiratory tract infections in infancy. Viral interference is important in understanding respiratory viral circulation and the impact of vaccines. Methods To study viral interference, we evaluated cases of RSV and HRV codetection by polymerase chain reaction in 2 prospective birth cohort studies (the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure [INSPIRE] study and the Tennessee Childrens Respiratory Initiative [TCRI]) and a double-blinded, randomized, controlled trial (MAKI), using adjusted multivariable regression analyses. Results Among 3263 respiratory tract samples, 24.5% (798) and 37.3% (1216) were RSV and HRV positive, respectively. The odds of HRV infection were significantly lower in RSV-infected infants in all cohorts, with adjusted odds ratios of 0.30 (95% confidence interval [CI], .22-.40 in the INSPIRE study, 0.18 (95% CI, .11-.28) in the TCRI (adjusted for disease severity), and 0.34 (95% CI, .16-.72) in the MAKI trial. HRV infection was significantly more common among infants administered RSV immunoprophylaxis, compared with infants who did not receive immunoprophylaxis (OR, 1.65; 95% CI, 1.65-2.39). Conclusions A negative association of RSV on HRV codetection was consistently observed across populations, seasons, disease severity, and geographical regions. Suppressing RSV infection by RSV immunoprophylaxis might increase the risk of having HRV infection.

Respiratory Syncytial Virus Preterm (32-36 Completed Weeks of Gestation) Risk Estimation Measure for RSV Hospitalization in Ireland: A Prospective Study.

Background: In several countries, respiratory syncytial virus prophylaxis is offered to late preterm infants who are at escalated risk of respiratory syncytial virus hospitalization (RSVH). However, targeted prophylaxis should be informed by country-specific data. This study, which uniquely includes 36 weeks of gestational age (GA) infants, aims to establish the risk factors for RSVH in 32–36 weeks of GA infants in Ireland. Methods: A prospective observational study at 13 hospitals of laboratory-confirmed RSVH in nonprophylaxed 32–36 weeks of GA infants was conducted from July 2011 to February 2014. Baseline and first-year clinical data were analyzed by using SPSS software Version 22 (IBM Corp, Armonk, NY). Significant (P < 0.05) variables were entered into multiple logistic regression to determine the independent risk factors for RSVH. Results: Sixty-three percent of eligible infants (1825 of 2877) were recruited. The RSVH rate was 3.6% (65 of 1807 analyzed infant records). There was no RSV-attributable mortality. Twelve infants required intensive care. Of the 15 variables correlating to RSVH, 5 independent risk factors were identified: older siblings [odds ratio (OR): 3.8; 95% confidence interval (CI): 1.97–7.41], being Caucasian (OR: 2.3; 95% CI: 1.04–5.29), neonatal respiratory morbidity (OR: 2.2; 95% CI: 1.28–3.94); birth July 15 to December 15 (OR: 2.1; 95% CI: 1.09–3.92) and family history of asthma (OR: 1.9; 95% CI: 1.01–3.39). Birth from 36 weeks to 36 + 6 days mitigated RSVH risk (relative risk: 0.58; 95% CI: 0.34–0.99); however, risk factors were similar to the 32–35 weeks of GA cohort. Conclusion: Neonatal respiratory morbidity or being Caucasian were the population-specific independent risk factors for RSVH in 32–36 weeks of GA in Ireland, whereas the other identified independent risk factors mirrored those established in previous studies.

Burden of Severe Respiratory Syncytial Virus Disease Among 33-35 Week Gestational Age Infants Born During Multiple Respiratory Syncytial Virus Seasons

Background: Moderate-late preterm infants, 33–35 weeks’ gestational age (wGA), are at increased risk for respiratory syncytial virus hospitalization (RSVH). The objective of this study is to quantify the burden of RSVH in moderate-late preterm infants. Methods: A pooled analysis was conducted on RSVH from 7 prospective, observational studies in the Northern Hemisphere from 2000 to 2014. Infants’ 330–356 wGA without comorbidity born during the respiratory syncytial virus season who did not receive respiratory syncytial virus immunoprophylaxis were enrolled. Data for the first confirmed RSVH during the season (+1 month) were analyzed. Incidence and hospitalization rate per 100 patient-seasons, intensive care unit admission and length of stay (LOS), oxygen support, mechanical ventilation and overall hospital LOS were assessed. Results: The pooled analysis comprised 7,820 infants; 267 experienced a confirmed RSVH at a median age of 8.4 weeks. The crude pooled RSVH incidence rate was 3.41% and the rate per 100 patient-seasons was 4.52. Median hospital LOS was 5.7 days. A total of 22.2% of infants required intensive care unit admission for a median LOS of 8.3 days. A total of 70.4% received supplemental oxygen support for a median of 4.9 days, and 12.7% required mechanical ventilation for a median of 4.8 days. Conclusions: The burden of RSVH in moderate-late, 33–35 weeks’ wGA preterm infants without comorbidities born during the viral season in Northern Hemisphere countries is substantial. Severe cases required prolonged and invasive supportive therapy.

Ethical considerations and rationale of the MAKI trial: A multicenter double-blind randomized placebo-controlled trial into the preventive effect of palivizumab on recurrent wheezing associated with respiratory syncytial virus infection in children with a gestational age of 33-35 weeks

BACKGROUND Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is the most frequent cause of bronchiolitis during infancy. Long-term airway morbidity with recurrent post bronchiolitis wheezing (PBW) episodes, which are probably associated with respiratory infections, occurs in 30 to 70% of infants that were hospitalised with RSV LRTI. METHODS We set up a multicenter, placebo-controlled double-blind randomized clinical trial in healthy preterm infants born between 33 and 35 weeks gestational age (WGA). The children received either one-monthly intramuscular palivizumab or placebo injection during the RSV season with a minimum of 2 injections. RESULTS The primary objective was to determine the preventive effect of RSV immunoprophylaxis (palivizumab) on the development of recurrent wheezing during the first year of life. The primary outcome measure was the number of wheezing days during the first year of life as obtained by daily logs. As a secondary outcome nasal swabs were taken for viral analysis in case of respiratory symptoms. We will also examine wheezing at age 1, 3 and 6 years both reported by the parents and the general practitioner and quality of life as secondary outcomes. This trial is possible because RSV immunoprophylaxis, although effective in this population, is not completely used in the Netherlands due to its high costs. CONCLUSION The Institutional review board (IRB) concluded the study has high clinical relevance because the benefit of 50% chance of protection by palivizumab outweighs the risk of side adverse events due to intramuscular administration of placebo.

The Cost-Effectiveness of Palivizumab in the Prevention of Respiratory Syncytial Virus Bronchiolitis: A Systematic Review

Summary Background: RSV bronchiolitis is the most common cause of infant morbidity during the winter season and is associated with a large burden of disease and high costs. The costeffectiveness of RSV immunoprophylaxis with the only available preventive treatment, palivizumab is subject of vigorous debate. It is recognised that a policy of using palivizumab for all children who meet the licensed indication is not cost-effective, but most clinicians feel that its use is justified in certain subgroups. Objective: To systematically review the literature on the cost-effectiveness of palivizumab prophylaxis in the following subgroups: 1) preterm infants born before 32 weeks gestational age (WGA), 2) preterm infants born between 32 and 35 WGA, 3) children with chronic lung disease, and 4) children with congenital heart disease. Methods: We searched Pubmed, EMBASE, and the latest versions of the DARE, NHS EED and HTA databases from inception to June 2012. Relevant studies were first selected on title and abstract and full text of the selected papers was reviewed. Results: Nineteen studies evaluating the cost-effectiveness of palivizumab performed in 13 different countries were included. The cost-effectiveness of palivizumab for the subgroups of children born before 32 WGA, children born between 32 and 35 WGA, children with chronic lung disease (CLD), and children with congenital heart disease was studied in 9, 9, 8, and 7 studies, respectively. The incremental cost-effectiveness ratios varied considerably both within and between subgroups. Sensitivity analyses showed that cost-effectiveness was mainly driven by the mortality rate due to RSV infection. Differences in hospitalisation rates, industry sponsoring and study year were also associated with differences in costeffectiveness, but these differences could be attributed to differences in mortality rates. Conclusion: The cost-effectiveness of prophylactic treatment of RSV infection with palivizumab in subgroups varies considerably. The cost-effectiveness is mainly sensitive to mortality rates of RSV infection. This systematic review indicates that future research should focus on the major uncertainties in cost-effectiveness, particularly RSV-related mortality rate, high-risk populations and long term sequelae. Interpretation of RSV cost-effectiveness studies should be done cautiously due to transferability issues.

Cost-effectiveness of rule-based immunoprophylaxis against respiratory syncytial virus infections in preterm infants

AbstractThe objective of the paper is to assess the cost-effectiveness of targeted respiratory syncytial virus (RSV) prophylaxis based on a validated prediction rule with 1-year time horizon in moderately preterm infants compared to no prophylaxis. Data on health care consumption were derived from a randomised clinical trial on wheeze reduction following RSV prophylaxis and a large birth cohort study on risk prediction of RSV hospitalisation. We calculated the incremental cost-effectiveness ratio (ICER) of targeted RSV prophylaxis vs. no prophylaxis per quality-adjusted life year (QALYs) using a societal perspective, including medical and parental costs and effects. Costs and health outcomes were modelled in a decision tree analysis with sensitivity analyses. Targeted RSV prophylaxis in infants with a first-year RSV hospitalisation risk of > 10% resulted in a QALY gain of 0.02 (0.931 vs. 0.929) per patient against additional cost of €472 compared to no prophylaxis (ICER €214,748/QALY). The ICER falls below a threshold of €80,000 per QALY when RSV prophylaxis cost would be lowered from €928 (baseline) to €406 per unit. At a unit cost of €97, RSV prophylaxis would be cost saving. Conclusions: Targeted RSV prophylaxis is not cost-effective in reducing RSV burden of disease in moderately preterm infants, but it can become cost-effective if lower priced biosimilar palivizumab or a vaccine would be available.