Wheeze, Asthma, and Lung Function: Latest Insights on the Long-Term Impact of Severe RSV in Infancy

Transcription

1 Wheeze, Asthma, and Lung Function: Latest Insights on the Long-Term Impact of Severe RSV in Infancy Dr Simoes, thank you for contributing to this Independent Medical Education activity. We invite you to review your presentation, which begins on the following page. The purpose of your review is to ensure the medical accuracy, context, and clinical relevance of your commentary and the corresponding slides. We included a few specific questions for you. These questions are highlighted in yellow. IMPORTANT NOTES & INSTRUCTIONS The slides are mock-ups and can be revised, as needed. All of your commentary here is based on your recent telephone recording. We did not use all of your commentary; let us know if important commentary is missing. Please track all of your comments and revisions/additions to your commentary in this document. 1

2 Wheeze, Asthma, and Lung Function: Latest Insights on the Long-Term Impact of Severe RSV in Infancy About This Activity Learning Objectives Define the long-term healthcare and patient burdens associated with severe RSV infection in infancy Assess the clinical relevance of current data evaluating the impact of RSV prevention on long-term consequences of severe RSV infection in infancy Identify infants at highest risk of severe RSV infection who may benefit from RSV prophylaxis This activity is supported by an educational grant from AbbVie. Faculty Eric Simoes, MD Children's Hospital Colorado Aurora, CO Manuel Sanchez Luna, MD, PhD Complutense University of Madrid Hospital General Universitario Gregorio Marañón Madrid, Spain PeerVoice activities are designed to fill the unmet needs of the medical community by reporting information pertaining to clinically relevant advances and developments in the science and practice of medicine. The preparation of PeerVoice activities is supported by written agreements that clearly stipulate and enforce the editorial independence of PeerVoice and the faculty presenters. The faculty may discuss unapproved products or uses of these products in certain jurisdictions. Faculty presenters have been advised to disclose any reference to an unlabelled or unapproved use. No endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our activities. No responsibility is taken for errors or omissions. For approved prescribing information, please consult the manufacturer's product monograph. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerVoice or any of its supporters. The development of PeerVoice activities follows the requirements of Health Canada, the Canadian Medical Association, and the Innovative Medicines Canada Code of Ethical Practices. 2

3 Severe RSV: Updates on the Prevention of Long-Term Consequences The following is a transcript from a multimedia activity. Content developed in concert with faculty. Slide 1 Abbreviation(s): RSV: respiratory syncytial virus. Eric Simoes, MD: Hello, everyone. This is Eric Simoes from the University of Colorado School of Medicine and the Children s Hospital in Aurora, Colorado, in the United States. Welcome to this PeerVoice activity on RSV. We know that severe RSV infection in infancy is associated with significant morbidity and mortality. But what about the long-term consequences of this infection? And what is the current evidence on whether prevention of RSV can reduce the risk of clinically relevant wheezing and even asthma in later childhood? 3

4 Slide 2 Abbreviation(s): CI: confidence interval. Reference(s): Régnier SA, Huels J. Pediatr Infect Dis J. 2013;32: In 2013, a meta-analysis identified 15 unique studies that included 82,000 unique individuals, including about 1,500 with RSV-confirmed hospitalisation. The summary was that children who had RSV disease in early life had a higher incidence of asthma and wheezing in later life. This association decreased with age at follow-up, and at 12 years the odds ratio was close to zero, though the confidence intervals were higher. 4

5 Slide 3 Abbreviation(s): NS: not significant; WGA: weeks gestational age. Reference(s): Carbonell-Estrany X et al; IRIS Study Group. PLoS One. 2015;10:e doi: /journal.pone The second large study done after this meta-analysis was published was a case-controlled study from Spain that examined the association between RSV hospitalisation in preterm infants between 32 and 35 weeks gestation and controls not hospitalised for RSV. From this analysis, it was clear that in the second and third year of life there was a significant difference in recurrent wheezing between the case and control groups; but no difference in years 4, 5, and 6. 5

6 Slide 4 Abbreviation(s): BD: bronchodilator; ICS: inhaled corticosteroid; LTRA: leukotriene antagonist; OCS: oral corticosteroid. Reference(s): Carbonell-Estrany X et al. PLoS One. 2015;10:e The impact of RSV on long-term healthcare was also significant. There were significant differences between the case and control groups for outpatient care and emergency room [care], bronchodilator and leukotriene use, inhaled steroid use, antibiotic use, and oral steroids. 6

7 Slide 5 Poll Details: Skippable: Yes Show Results: Yes Seconds of Silence: X Question Type: Single Choice Which do you consider the most burdensome consequence of severe RSV infection? Outpatient care and need for inhalers Emergency care Potential for neonatal intensive care unit/pediatric intensive care unit RSV outbreak Potential long-term consequences like wheezing and asthma 7

8 Slide 6 Abbreviation(s): FEV 1 : forced expiratory volume in 1 second; FVC: forced vital capacity. Reference(s): Wenzel S et al. Am J Med. 2002;112: So these studies raise the question of whether preventing RSV infection in the first year of life would also prevent recurrent wheezing and asthma later on. The first study that actually examined this was a randomised controlled trial of RSV immune globulin intravenous (IgIV) compared to placebo. Children with chronic lung disease in that trial were followed up at one centre 7 to 9 years later. Thirteen children in the trial [given RSV IgIV] and 26 controls showed that there were significant differences in [the ratio of] FEV 1 /FVC. It suggested that prophylaxis with RSV IgIV may be associated with significant improvements in pulmonary function, and it suggested that preventing RSV infections may decrease the risk for asthma later on. However, these were children with chronic lung disease. 8

9 Slide 7 Reference(s): Simoes EA et al; Palivizumab Long-Term Respiratory Outcomes Study Group. J Pediatr. 2007;151:34-42, 42.e1. About the same time that that study was being done, we had an opportunity to follow premature children between 32 and 35 weeks gestational age who had and did not have treatment with palivizumab. We followed them for 24 months after the first year of palivizumab treatment. We found that there was a 50% relative reduction in recurrent wheezing. Now, some of the children who were untreated with palivizumab were not hospitalised. So we did an analysis that looked at the group of palivizumab-treated infants (all of whom were non-hospitalised) with those untreated with palivizumab who were also not hospitalised. We found that there was actually a similar protection. We used a more-stringent criterion of physician-diagnosed recurrent wheezing, and that showed a 50% relative reduction in physician-diagnosed recurrent wheezing [among children who had received pavilizumab treatment]. Similar effects were seen in a time-to-event analysis. 9

10 Slide 8 Reference(s): Simoes EA et al; Palivizumab Long-Term Respiratory Outcomes Study Group. J Allergy Clin Immonol. 2010;126: We subsequently analysed the data to determine the influence of family history of other atopic diseases on this association. The theory was that in those with atopy, there would still be recurrent wheezing, regardless of whether palivizumab was used or not. We were trying to attempt the question: Was RSV the cause for recurrent wheezing, or was it part of an atopic background? We showed that, once again, the effect of palivizumab was significant in those with no history of atopy compared to those with a history of atopy. That is shown by a protective effect in those with no history of atopy compared to those with a history of atopy, in whom there was no effect. 10

11 Slide 9 Reference(s): Blanken MO et al; Dutch RSV Neonatal Network. N Engl J Med. 2013;368: So at the time that we were doing this study in Europe, Louis Bont designed a randomised controlled trial of palivizumab in preterm infants without chronic lung disease to ask the question: What are the long-term effects? He had about 430 children in the trial. At 12 months after birth, it was quite clear that those who had received palivizumab had significantly less recurrent wheezing than placebo. 11

12 Slide 10 Abbreviation(s): FEV 0.5 : forced expiratory volume in 0.5 second. Reference(s): Scheltema NM et al. Lancet Respir Med. 2018;6: The MAKI study followed up children that were recruited in the previous placebo-controlled trial. In this study, the lung function studies and current asthma were studied at 6 years of age. There was no significant difference in lung function studies; however, there was a relative reduction of about 40% in current [parent-reported] asthma between those who had received RSV prevention and those who had not. 12

13 Slide 11 Poll Details: Skippable: Yes Show Results: Yes Seconds of Silence: X Question Type: Single Choice Do you notice a reduction in subsequent doctor or hospital visits for respiratory problems for premature infants who receive RSV prophylaxis versus those who don t? Yes No I don t know 13

14 Slide 12 Dr Simoes, we were wondering whether the numbers for recurrent wheezing with family history of allergy in the slide are correct since the 95% interval is below the central tendency? The publication has 0.54 ( ); does it seem odd to you? Thank you! Reference(s): Mochizuki H et al; Scientific Committee for Elucidation of Infantile Asthma. Am J Respir Crit Care Med. 2017;196: About the time that this study was completed, we had also completed a 6-year study in Japan that examined the effect of palivizumab prophylaxis administered to preterm infants without chronic lung disease. And we, too, found that while palivizumab prophylaxis prevented recurrent wheezing, this effect was seen in those with a family history of allergy only. There was no difference at 6 years in atopic asthma between the population that received palivizumab prophylaxis and the controls who did not. 14

15 Slide 13 Abbreviation(s): ED: emergency department So in summary, epidemiologic studies have shown that RSV appears to cause long-term increases in healthcare utilisation and incurs significant healthcare costs, as well as recurrent wheezing. There appears to be a clear association between RSV prevention and recurrent wheezing in preterm infants at least up to 6 years but no clear association between RSV prevention and asthma, the main reason being that the sample sizes for both of the studies that we discussed, which showed no association, were small. In none of the studies were lung functions measured in the first year of life to answer the question of whether predisposition to RSV is what causes asthma, or whether RSV itself de novo causes asthma. Thank you for your attention. 15