Publications by authors named "Maarten O Blanken"

13 Publications

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Correction to: Cost-effectiveness of rule-based immunoprophylaxis against respiratory syncytial virus infections in preterm infants.

Eur J Pediatr 2020 Feb;179(2):355

Division of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, P.O. Box 85090, 3508 AB, Utrecht, the Netherlands.

The name of the co-author Wendy J. Ungar was inadvertently omitted on the original published article. Her name and affiliation have now been added to the author list.
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http://dx.doi.org/10.1007/s00431-019-03526-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645511PMC
February 2020

RSV hospitalization in infancy increases the risk of current wheeze at age 6 in late preterm born children without atopic predisposition.

Eur J Pediatr 2019 Apr 12;178(4):455-462. Epub 2019 Jan 12.

Department of Pediatric Infectious Diseases and Immunology, Wilhelmina Children's Hospital University Medical Center Utrecht, P.O. Box 85090, 3508 AB, Utrecht, The Netherlands.

Severe respiratory syncytial virus (RSV) infection during infancy is associated with ongoing respiratory morbidity. In a large birth cohort of 2210 healthy preterm infants born at 32-35 weeks of gestation, we aimed to determine the role of atopy in the link between RSV hospitalization and current wheeze at age 6. We defined current wheeze as parent-reported wheeze or the use of respiratory medication in the past 12 months. Based on a positive family history of atopic disease, we distinguished between children with and without atopic predisposition. Six-year follow-up data was obtained in 997/1559 (64%) children of which 102 (10.2%) children had been hospitalized with RSV during infancy. Current wheeze was present in 184/997 (18.6%) children. RSV hospitalization was an independent risk factor for current wheeze in children without atopic predisposition (aOR 4.05 [95% CI 1.22-12.52]) but not in children with this atopic background (aOR 1.50 [95% CI 0.81-2.71]).Conclusion: This is the largest published birth cohort demonstrating that in late preterm infants, atopic predisposition defines the relationship between RSV hospitalization and current wheeze. Future RSV prevention trials aiming to prevent ongoing respiratory symptoms should be analyzed separately for atopic status. What is Known: • RSV infection is responsible for a significant burden of disease in young children worldwide. • Severe RSV infection in early life is associated with asthmatic symptoms later in life. What is New: • This is the largest published birth cohort reporting about the role of atopic predisposition in the link between severe RSV infection and current wheeze at school age. • We show that RSV hospitalization in infancy is an independent risk factor for current wheeze in late preterm children without atopic predisposition at age 6. This was not seen in children with atopic predisposition.
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http://dx.doi.org/10.1007/s00431-018-03309-0DOI Listing
April 2019

RSV prevention in infancy and asthma in later life - Authors' reply.

Lancet Respir Med 2018 07;6(7):e33

Department of Pediatric Infectious Diseases and Immunology, University Medical Center Utrecht, Utrecht, Netherlands; Wilhelmina Children's Hospital, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(18)30232-7DOI Listing
July 2018

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

Lancet Respir Med 2018 04 27;6(4):257-264. Epub 2018 Feb 27.

Department of Pediatric Infectious Diseases and Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands; Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands. Electronic address:

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 (FEV). 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). FEV 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.
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http://dx.doi.org/10.1016/S2213-2600(18)30055-9DOI Listing
April 2018

Risk scoring tool to predict respiratory syncytial virus hospitalisation in premature infants.

Pediatr Pulmonol 2018 05 6;53(5):605-612. Epub 2018 Feb 6.

Neonatology Service, Hospital Clinic, Institut d'Investigacions Biomediques August Pi Suñer (IDIBAPS), Barcelona, Spain.

Background: The objective was to develop a risk scoring tool which predicts respiratory syncytial virus hospitalisation (RSVH) in moderate-late preterm infants (32-35 weeks' gestational age) in the Northern Hemisphere.

Methods: Risk factors for RSVH were pooled from six observational studies of infants born 32 weeks and 0 days to 35 weeks and 6 days without comorbidity from 2000 to 2014. Of 13 475 infants, 484 had RSVH in the first year of life. Logistic regression was used to identify the most predictive risk factors, based on area under the receiver operating characteristic curve (AUROC). The model was validated internally by 100-fold bootstrapping and externally with data from a seventh observational study. The model coefficients were converted into rounded multipliers, stratified into risk groups, and number needed to treat (NNT) calculated.

Results: The risk factors identified in the model included (i) proximity of birth to the RSV season; (ii) second-hand smoke exposure; and (iii) siblings and/or daycare. The AUROC was 0.773 (sensitivity: 68.9%; specificity: 73.0%). The mean AUROC from internal bootstrapping was 0.773. For external validation with data from Ireland, the AUROC was 0.707 using Irish coefficients and 0.681 using source model coefficients. Cut-off scores for RSVH were ≤19 for low- (1.0%), 20-45 for moderate- (3.3%), and 50-56 (9.5%) for high-risk infants. The high-risk group captured 62.0% of RSVHs within 23.6% of the total population (NNT 15.3).

Conclusions: This risk scoring tool has good predictive accuracy and can improve targeting for RSVH prevention in moderate-late preterm infants.
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http://dx.doi.org/10.1002/ppul.23960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099524PMC
May 2018

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

Eur J Pediatr 2018 Jan 22;177(1):133-144. Epub 2017 Nov 22.

Division of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, P.O. Box 85090, 3508 AB, Utrecht, the Netherlands.

The 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.
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http://dx.doi.org/10.1007/s00431-017-3046-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748402PMC
January 2018

Interference Between Respiratory Syncytial Virus and Human Rhinovirus Infection in Infancy.

J Infect Dis 2017 Apr;215(7):1102-1106

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine.

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 Children's 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.
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http://dx.doi.org/10.1093/infdis/jix031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426371PMC
April 2017

Population-Attributable Risk of Risk Factors for Recurrent Wheezing in Moderate Preterm Infants During the First Year of Life.

Paediatr Perinat Epidemiol 2016 07 16;30(4):376-85. Epub 2016 May 16.

Division of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Recurrent wheezing in young infants has a high prevalence, influences quality of life, and generates substantial health care costs. We previously showed that respiratory syncytial virus infection is an important mechanism of recurrent wheezing in moderate preterm infants. We aimed to provide population-attributable risks (PAR) of risk factors for recurrent wheezing during the first year of life in otherwise healthy moderate preterm infants.

Methods: RISK is a multicentre prospective birth cohort study of 4424 moderate preterm infants born at 32-35 weeks gestation. We estimated PAR of risk factors for recurrent wheezing, which was defined as three or more parent-reported wheezing episodes during the first year of life.

Results: We evaluated 3952 (89%) children at 1 year of age, of whom 705 infants (18%) developed recurrent wheezing. Fourteen variables were independently associated with recurrent wheezing. Hospitalisation for respiratory syncytial virus bronchiolitis had a strong relationship with recurrent wheezing (RR 2.6; 95% confidence interval, CI, 2.2, 3.1), but a relative modest PAR (8%; 95% CI 6, 11%) which can be explained by a low prevalence (13%). Day-care attendance showed a strong relationship with recurrent wheezing (RR 1.9; 95% CI 1.7, 2.2) and the highest PAR (32%; 95% CI 23, 37%) due to a high prevalence (67%). The combined adjusted PAR for the 14 risk factors associated with recurrent wheezing was 49% (95% CI 46, 52%).

Conclusions: In moderate preterm infants, day-care attendance has the largest PAR for recurrent wheezing. Trial evidence is needed to determine the potential benefit of delayed day-care attendance in this population.
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http://dx.doi.org/10.1111/ppe.12295DOI Listing
July 2016

Prediction model of RSV-hospitalization in late preterm infants: An update and validation study.

Early Hum Dev 2016 Apr 27;95:35-40. Epub 2016 Feb 27.

Division of Paediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

Background: New vaccines and RSV therapeutics have been developed in the past decade. With approval of these new pharmaceuticals on the horizon, new challenges lie ahead in selecting the appropriate target population. We aimed to improve a previously published prediction model for prediction of RSV-hospitalization within the first year of life.

Methods: Two consecutive prospective multicenter birth cohort studies were performed from June 2008 until February 2015. The first cohort (RISK-I, n=2524, 2008-2011) was used to update the existing model. The updated model was subsequently validated in the RISK-II cohort (n=1564, 2011-2015). We used the TRIPOD criteria for transparent reporting.

Results: 181 infants (n=127 in RISK-I, n=54 in RISK-II) were hospitalized for RSV within their first year of life. The updated model included the following predictors; day care attendance and/or siblings (OR: 5.3; 95% CI 2.8-10.1), birth between Aug. 14th and Dec. 1st (OR: 2.4; 1.8-3.2), neonatal respiratory support (OR 2.2; 1.6-3.0), breastfeeding ≤4 months (OR 1.6; 1.2-2.2) and maternal atopic constitution (OR 1.5; 1.1-2.1). The updated models' discrimination was superior to the original model in the RISK-II cohort (AUROC 0.72 95% CI 0.65-0.78 versus AUROC 0.66, 95% CI 0.60-0.73, respectively). The updated model was translated into a simple nomogram to be able to distinguish infants with high versus low risk of RSV-hospitalization.

Conclusion: We developed and validated a clinical prediction model to be able to predict RSV-hospitalization in preterm infants born within 32-35 weeks gestational age. A simple nomogram was developed to target RSV therapeutics to those children who will benefit the most.
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http://dx.doi.org/10.1016/j.earlhumdev.2016.01.020DOI Listing
April 2016

Cesarean section and hospitalization for respiratory syncytial virus infection.

Pediatr Infect Dis J 2015 Feb;34(2):227

Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1097/INF.0000000000000612DOI Listing
February 2015

Respiratory syncytial virus and recurrent wheeze in healthy preterm infants.

N Engl J Med 2013 May;368(19):1791-9

Division of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.

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.).
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http://dx.doi.org/10.1056/NEJMoa1211917DOI Listing
May 2013

Prospective validation of a prognostic model for respiratory syncytial virus bronchiolitis in late preterm infants: a multicenter birth cohort study.

PLoS One 2013 12;8(3):e59161. Epub 2013 Mar 12.

Department Pediatric Immunology and Infectious Diseases, University Medical Center, Utrecht, Utrecht, The Netherlands.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0059161PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595233PMC
September 2013