Richard Taylor’s research while affiliated with Victoria General Hospital and other places

Background Respiratory Syncytial Virus (RSV) is a leading cause of hospital admission for acute lower respiratory tract infections (LRTI) in young children. Infants with congenital heart disease (CHD) are at a higher risk of severe infection, specifically those with hemodynamically significant intra-cardiac shunts, impaired cardiac function or pulmonary hypertension. Palivizumab prevents RSV-related hospitalizations in children with higher risk indications, including CHD, however the number of doses required to achieve optimal protection remains controversial. We report the clinical outcomes of children with CHD who received an abbreviated Palivizumab 4-dose schedule, with an increased inter-dose interval in our region. Objectives To report hospitalization outcomes in children with CHD who received an abbreviated 4-dose Palivizumab dose schedule through the centrally managed regional RSV Immunoprophylaxis Program. Design/Methods Retrospective population-based study of children with CHD enrolled into the regional RSV Program between 2012–2016. Children received palivizumab between November and April. Eligibility was defined according to our provincial guidelines and this defined our sample size. The primary outcome was in-season hospitalizations for RSV-confirmed or potentially RSV-related (unknown) LRTI determined by cross referencing the RSV Program database and the Canadian Institute of Health Informatics (CIHI) discharge abstract database (DAD) using seven RSV-related ICD-10 diagnostic codes. Children were categorized according to CHD subtype. Analysis was by intention-to-treat. Results A total of 325 children ([mean ± SD] gestational age 37.9±6.2 weeks; birth weight 2870±871 grams) were approved to receive 406 palivizumab courses. Between November 2012 and April 2016, 89 hospitalizations occurred in CHD patients. Of this, seventeen were RSV-confirmed hospitalizations (median age 5.9 [IQR 4 to 10]months); 8 additional cases were not tested for RSV, for a maximum rate of hospitalizationsfor RSV-confirmed or unknown of 6.2 per 100 approvals (95%CI: 4.0 to 9.0%). 24/25 RSV-confirmed or potentially RSV-related hospitalizations occurred before the 4thPalivizumab dose. Only one RSV-confirmed hospitalization occurred (52 days) after the 4th Palivizumab dose. Clinical characteristics of children with RSV-confirmed hospitalizations (n=17) were similar to those with RSV-unrelated hospitalizations (n=40). Conclusion Our data provide population-based evidence of the protection achieved by a 4-dose Palivizumab dose schedule in infants with CHD. This clinical practice yields substantial benefits to children, their families, and to the health care system, such as reduced visits, injections, and costs, compared to a standard 5-dose schedule. Our results warrant confirmation in other geographic areas.

Background RSV palivizumab prophylaxis remains controversial in infants 29-34w GA without bronchopulmonary dysplasia (BPD). In our RSV Program these infants only qualify if they cumulate risk factors (e.g. # siblings, breastfeeding, smoking at home, daycare attendance, etc.; for risk score>42 pts) and their date of discharge is after Oct01. This risk score was developed from the literature (including FLIP and PICNIC studies) and has been in use since 2013. We track all seasonal RSV=related admissions in infants ≤24 months. Objectives To compare RSV-related hospitalizations between infants who exceeded the risk threshold versus those who did not, across 4 RSV seasons. Design/Methods The RSV season runs from Nov01 to Apr30, so by definition all first season infants are <6mo age at the start of the RSV season. All ages were defined at the start of RSV season: Group 1: infants 29-34w, age ≤2 months with a risk score >42 pts; Group 2: infants 29-34w, age ≤2 months with a risk score ≤42 pts; Group 3: infants 29-34w, age 2–6 months with a risk score ≤42 pts. RSV-related admissions were obtained by linking 3 databases: Discharge Abstract Database using 7 RSV-related ICD-10 diagnostic codes, Perinatal Services regional Perinatal Data Registry (to establish the gestational age of infants), and RSV Program database. Results Only 355/2652 (13.3%) of infants 29-34w were admitted into the Program. Despite prophylaxis, Group 1 infants had higher RSV-related hospitalization rates than infants in Group 2. In subgroup analysis, infants born 29-32w were at increased risk in Groups 1 and 3, whereas infants 29-32w in Group 2 were not at increased risk, compared to infants 33–34 weeks (by 95% confidence intervals – not shown). Table shows proportions of RSV-related admissions with p-values defined between groups. Conclusion The regional risk score safely and effectively selects the 13% of 29 to 34w infants ≤2mo with a high risk of RSV-related hospitalizations.

Background RSV prophylaxis with palivizumab is restricted to evidence-based indications in infants at relatively higher hospital admission risk. The RSV Program’s criteria follow CPS and AAP guidelines, but adjudication is needed in conditions of questionable efficacy or in infants who have a moderate risk of contracting RSV. In 2015–16, a blinded simple-majority Panel-of-Three adjudication (PoTA) process was implemented where adjudicators are from different specialities (e.g. neonatology, Peds ID, etc.) and are neither caregivers nor have funding that can be traced to the manufacturer/vendor for conflict of interest (COI) and bias avoidance. Objectives To review adjudications across 3 RSV seasons (2015–2018) and determine the benefits and challenges associated with the PoTA structure. Design/Methods All cases of PoTAs were reviewed and categorized based on age of infant, season, and diagnosis. Seasonal admissions with RSV & LRTI were ascertained provincially using 7 RSV-related acute respiratory infection ICD-10 codes, and cross-checked using the Program’s palivizumab database. The reliability of agreement within PoTAs during each season was measured with average pairwise percent agreement (APPA) and Fleiss kappa. Results In the 2015–16, 2016–17, and 2018-18 seasons, 67/467 applications (14.2%), 64/416 (15.4%), and 64/452 (13.9%) were adjudicated, with overall approval rates of 51%, 42% and 33% respectively. There was a trend towards lower approval rates from 2015–16 (range: 42–60%) to 2017–18 (25–38%), with a median approval turnaround time of 3 days. Infants with “exceptional conditions” (e.g. progressive neuromuscular and central nervous system disorders) comprised the largest category of applicants undergoing PoTA, followed by infants with significant pulmonary disabilities. Infants with immunodeficiencies were consistently approved in >80% of cases. In 2015–16, 2016–17 and 2017–18, the APPA and Fleiss kappa were found to be 78.1% and 0.57, 76.0% and 0.51 (moderate agreements) and 83.3% and 0.63 (moderate-to-substantial agreement). Unanimous decisions were reached in 46%, 47%, and 48% of cases amongst 3 adjudicators, for each season, respectively. Hospitalization rates were 20/82 (5 RSV+) in approved, and 3/113 (2 RSV+) in non-approved cases over 3 seasons. Conclusion We describe an adjudication process that balances transparency and independence of adjudicators from one another. Timely decisions were reached in most cases, and the rates of hospitalized infants in the non-approved category remained small. The PoTA reached agreement in the adjudication decision in most cases and the low hospitalization rates in non-approved infants suggest that the decision process is both safe and efficient.

Background: It has been hypothesized that 4 doses of palivizumab, a neutralizing monoclonal antibody against respiratory syncytial virus (RSV), administered during a fixed-date RSV season may reduce hospital admissions comparably to the standard 5-dose schedule. We report outcomes in children with congenital heart disease approved to receive this 4-dose palivizumab schedule in British Columbia. Methods: We performed a population-based descriptive cohort analysis of all 406 approved palivizumab courses over 4 seasons (2012/13 to 2015/16) in 325 children with hemodynamically significant congenital heart disease enrolled in the British Columbia RSV Immunoprophylaxis Program. The primary outcome was in-season hospital admission for potential RSV-related lower respiratory tract infection (LRTI). Secondary outcomes include timing of admission in relation to dosing. Analysis was by intention-to-treat. Results: Of the 406 approved palivizumab courses, 391 were administered. In 33 cases (8.4%), an additional dose was given immediately after cardiac bypass surgery. There were 17 RSV-confirmed hospital admissions (median age of children 5.9 mo [interquartile range 4-10 mo]) and 8 admissions in which the child was not tested for RSV, for a maximum of 25 potential RSV-related admissions (6.2 per 100 approvals [95% confidence interval 4.0-9.0]). Twenty-four (96%) of the 25 admissions occurred within the 4-dose palivizumab dosing period, and the remaining admission occurred 52 days after the fourth dose. Sixty-four (72%) of 89 admissions were RSV-negative; the baseline clinical characteristics of these children were not different from those of children with RSV-confirmed admissions. Interpretation: In infants with hemodynamically significant congenital heart disease, a 4-dose fixed-date palivizumab schedule over a 6-month season provided seasonal protection comparable to that in a clinical trial involving a standard 5-dose schedule. Because RSV was responsible for only 19% of admissions for LRTI in our cohort, it is critical to continue to emphasize other preventive measures, including family education toward proper hand hygiene, breast-feeding and limiting infectious exposures in children at high risk.

Individual deidentified data. A, B and C: Subtables with individual deidentified data including NT95 values, relevant clinical and demographic characteristics of infants who received palivizumab (A) as well as of control groups of infants ≤12 months of age (B) and healthy adults (C) and who did not receive any palivizumab. (XLS)

Background Monthly injections of palivizumab during the respiratory syncytial virus (RSV) season in at-risk infants reduces RSV-associated hospitalizations. However, the additive effect of naturally acquired immunity remains unclear. The objective of this study was to assess total neutralizing serum antibodies (NAb) against RSV in at-risk infants who had received an abbreviated course of palivizumab prophylaxis. Methods Serum samples were collected from infants enrolled in the RSV Immunoprophylaxis Program in British Columbia, Canada over 2 consecutive RSV seasons (2013 to 2015). Infants in this program had received an abbreviated course of palivizumab in accordance with the provincial guidelines. Data were compared to adults and infants less than 12 months of age who did not receive palivizumab. Anti-RSV NAb titers were measured using an RSV microneutralization assay. Findings Infants who received palivizumab had anti-RSV NAb titers at the end of the RSV season that persisted beyond what is expected from the pharmacokinetics of palivizumab alone. Moreover, 54% of the control infants who did not receive palivizumab and all tested adults had protective anti-RSV NAb titers. Conclusions Based on our observations, we hypothesize that naturally acquired NAb provide additive protection, which may significantly reduce the need for additional doses of palivizumab in infants at risk of severe RSV infections.

This study details the experience of using an abbreviated palivizumab dosing schedule in infants at higher risk for respiratory syncytial virus hospitalization.Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants younger than 1 year. Premature infants, infants with chronic lung disease, infants with major congenital heart diseases, or infants with severe immunodeficiencies are at highest risk of hospital admission for RSV. Palivizumab, a monoclonal antibody, reduces pulmonary viral replication by 100-fold at serum drug levels greater than 40 μg/mL in the cotton rat model.1 On the basis of randomized clinical trials, monthly administration of 15 mg/kg of palivizumab reduces hospitalizations by approximately 55% in these infants.2 However, the costliness of this drug restrains its broader use. The American Academy of Pediatrics recommends a maximum of 5 palivizumab doses in selected risk groups during the RSV season,2 although pharmacokinetic analyses suggest that equivalent antibody protection may be sustainably achieved with fewer doses.3,4