Short-Term Immunogenicity of Licensed Subunit RSV Vaccines in Residents of Long-Term Care Facilities (LTCF) Compared to Community-Dwelling Older Adults.

OBJECTIVES: Phase 3 licensing trials for the recently approved respiratory syncytial virus (RSV) vaccines did not include many residents of long-term care facilities (LTCF). Our primary objective was to assess humoral immune responses in LTCF residents, age 60 and older, to the RSV vaccines, and demonstrate noninferiority to antibody responses in community-dwelling (CD) adults who were representative of the phase 3 trial participants in whom the vaccines were highly efficacious. DESIGN: Prospective non-randomized intervention trial of RSV vaccines in LTCF residents. SETTING AND PARTICIPANTS: Research clinic and 2 LTCFs. Adults ≥60 years old, free of immunosuppression and planning to receive an RSV vaccine were eligible. METHODS: LTCF and CD participants received either the GSK or Pfizer RSV vaccine in equal numbers. Blood was collected before and 30 days after vaccination. Total immunoglobulin (Ig)G to the prefusion F protein of RSV group A (FA) and B (FB), and neutralizing activity were measured, and geometric mean titer (GMT) and geometric mean fold rise (GMFR) calculated. Intercurrent respiratory illnesses were tracked. RESULTS: A total of 76 LTCF residents and 76 CD adults were enrolled. Day 30 blood was unavailable from 3 residents and 3 had RSV infection and vaccination was deferred, leaving data for 76 CD and 70 LTCF adults for analysis. Serum IgG GMFR prefusion FA (9.9 vs 12.5, P = .14), prefusion FB (8.7 vs 11.0, P = .17) were not statistically different in CD and LTCF cohorts, respectively, and also equivalent for GMFR in viral neutralization titers (12.8 vs. 15.5, P = .32). As measured by GMT or GMFR, RSV vaccine responses of LTCF residents met noninferiority criteria compared with the CD cohort. CONCLUSIONS AND IMPLICATIONS: This small immunobridging study demonstrates robust antibody responses to RSV vaccines in LTCF residents providing support for their use in this high-risk population.

Efficacy and safety of early postoperative ablation in patients with congenital heart disease.

BACKGROUND: Postoperative arrhythmias are most often transient and medically treated, but some patients may require electrophysiology study (EPS) and ablation. OBJECTIVE: The purpose of this study was to describe the efficacy and safety of early postoperative ablation. METHODS: This study presents a retrospective series of patients who underwent EPS within 12 months of surgery for congenital heart disease between 2000 and 2021. The procedural outcome included complete or partial success, failure or empirical ablation, and complications. The long-term outcome included arrhythmia recurrence and burden according to a 12-point clinical arrhythmia severity score (documented arrhythmia, arrhythmia severity, cardioversion, and antiarrhythmic medication). RESULTS: Among 28,902 surgeries during the study period, 24 patients (0.1%) underwent EPS within 3 months of surgery and 26 (0.1%) 3-12 months after surgery. Most patients had great (n = 27 [50%]) or moderate (n = 21 [42%]) congenital heart disease complexity. Mechanisms of arrhythmias included intra-atrial reentrant tachycardia (n = 23 [46%]), ectopic atrial tachycardia (n = 13 [26%]), accessory pathway (n = 6 [12%]), atrioventricular nodal reentrant tachycardia (n = 7 [14%]), twin atrioventricular node (n = 1 [2%]), atrial fibrillation (n = 1 [2%]), junctional ectopic tachycardia (n = 1 [2%]), and ventricular tachycardia (n = 2 [4%]). The procedure was acutely successful in 41 patients (82%), empirical in 5 (10%), and unsuccessful in 4 (8%). Complications occurred in 4 patients (major in 1, moderate in 1, and minor in 2). The recurrence of arrhythmia was documented in 27 patients (54%), although the burden of arrhythmia was significantly reduced. CONCLUSION: A minority of patients require early postoperative EPS and ablation. For those, the procedure can be performed with reasonable acute success and manageable morbidity even in critically ill patients with complex surgical anatomy.

Ventricular Septation for Double Inlet Ventricle: Avoiding Conduction Injury.

OBJECTIVES: Although conduction location can reliably be predicted in double inlet ventricle (DIV), ventricular septation continues to carry a significant risk of CHB. This study describes our experience with ventricular septation and intraoperative conduction mapping. METHODS: Patients undergoing ventricular septation from 2017-2023 were identified. Conduction mapping was performed on the open, decompressed, beating heart to identify the His bundle. Mapped His bundle locations were compared to those predicted from MRI diagnoses by a senior pediatric cardiac electrophysiologist blinded to mapping results. RESULTS: Ventricular septation was performed in 31 patients, 25 with hypoplastic RV and 6 with hypoplastic LV. Two-stage septation was performed in 25 patients and single-stage septation in 6. Mapped was performed in the last 25 consecutive patients. Mapped conduction location was concordant with expected location in 21/22 patients with predictions. CHB requiring a permanent pacemaker occurred in 4 patients despite successful mapping, while 10 patients required other reoperations, most commonly to address residual AV valve regurgitation or subpulmonary obstruction from the VSD patch. There has been no perioperative mortality, need for single-ventricle palliation or heart transplantation. All 13 patients who have progressed to complete septation and 18 patients with interstage circulation have acceptable hemodynamics, preserved ventricular function, and no heart failure symptoms at latest follow-up. CONCLUSIONS: Ventricular septation represents an alternative to Fontan that can be performed safely in a subset of patients with acceptable early outcomes. Conduction mapping is an adjunct strategy that may add precision to the well-established rules for reliably predicting conduction location.

Residency in Long-Term Care Facilities: An Important Risk Factor for RSV Hospitalization.

Older age and comorbid conditions increase risk for severe RSV. Skilled nursing (SNF) and assisted living (AL) facilities represent an intersection of risk factors. In a 3-year prospective study (Rochester, NY) we compared population-based incidence of RSV-associated hospitalization for community-dwelling, SNF and AL adults ≥65 years. Median age was 76, 83 and 86 years, respectively, and dementia and CHF more prevalent among SNF and assisted living residents. Average annual incidence was 117 (95%CI:104-132), 440 (95%CI:307-629) and 740/100,000 persons (95%CI:523-1045) for community-dwelling, SNF and AL adults ≥65 years, respectively, demonstrating need for unequivocal RSV vaccine recommendations in SNF and AL residents.

Association of disease severity and genetic variation during primary Respiratory Syncytial Virus infections.

BACKGROUND: Respiratory Syncytial Virus (RSV) disease in young children ranges from mild cold symptoms to severe symptoms that require hospitalization and sometimes result in death. Studies have shown a statistical association between RSV subtype or phylogenic lineage and RSV disease severity, although these results have been inconsistent. Associations between variation within RSV gene coding regions or residues and RSV disease severity has been largely unexplored. METHODS: Nasal swabs from children (< 8 months-old) infected with RSV in Rochester, NY between 1977-1998 clinically presenting with either mild or severe disease during their first cold-season were used. Whole-genome RSV sequences were obtained using overlapping PCR and next-generation sequencing. Both whole-genome phylogenetic and non-phylogenetic statistical approaches were performed to associate RSV genotype with disease severity. RESULTS: The RSVB subtype was statistically associated with disease severity. A significant association between phylogenetic clustering of mild/severe traits and disease severity was also found. GA1 clade sequences were associated with severe disease while GB1 was significantly associated with mild disease. Both G and M2-2 gene variation was significantly associated with disease severity. We identified 16 residues in the G gene and 3 in the M2-2 RSV gene associated with disease severity. CONCLUSION: These results suggest that phylogenetic lineage and the genetic variability in G or M2-2 genes of RSV may contribute to disease severity in young children undergoing their first infection.

A Natural History Study of Timothy Syndrome.

Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene CACNA1C . Timothy syndrome patients were first identified as having a cardiac presentation of Long QT and syndactyly of the fingers and/or toes, and an identical variant in CACNA1C , Gly406Arg. However, since this original identification, more individuals harboring diverse variants in CACNA1C have been identified and have presented with various cardiac and extra-cardiac symptoms. Furthermore, it has remained underexplored whether individuals harboring canonical Gly406Arg variants in mutually exclusive exon 8A (Timothy syndrome 1) or exon 8 (Timothy syndrome 2) have additional symptoms. Here, we describe the first Natural History Study for Timothy syndrome, providing a thorough resource describing the current understanding of disease manifestation in Timothy syndrome patients. Parents of Timothy syndrome children were queried regarding a wide-ranging set of symptoms and features via a survey. Importantly, we find that in addition to cardiac concerns, Timothy syndrome patients commonly share extra-cardiac features including neurodevelopmental impairments, hypoglycemia, and respiratory problems. Our work expands the current understanding of the disorder to better inform the care of Timothy syndrome patients.

Assessment of Illness Severity in Adults Hospitalized With Acute Respiratory Tract Infection due to Influenza, Respiratory Syncytial Virus, or Human Metapneumovirus.

BACKGROUND: Influenza, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) are common respiratory viruses causing similar symptoms. Optimal tools to assess illness severity for these viruses have not been defined. Using the Hospitalized Acute Respiratory Tract Infection (HARTI) study data, we report symptom severity by clinician-rated clinical severity scores (CSS) in adults with influenza, RSV, or hMPV and correlations between CSS and patient-reported outcomes (PROs). METHODS: HARTI was a global epidemiologic study in adults hospitalized with acute respiratory tract infections. Patients were assessed at enrollment within 24 h of admission with CSS and twice during hospitalization with CSS, Respiratory Infection Intensity and Impact Questionnaire™ (RiiQ™), and EQ-5D-5L. Data were summarized descriptively, stratified by pathogen and baseline and hospitalization characteristics. Domain (general, upper respiratory, and lower respiratory) and sign/symptom subscores are presented for CSS; sign/symptom subscores are presented for RiiQ™ results. RESULTS: Data from 635 patients with influenza, 248 with RSV, and 107 with hMPV were included. At enrollment, total CSS and general and lower respiratory signs/symptoms (LRS) scores were higher for RSV and hMPV than influenza. Between-pathogen differences were greatest for LRS scores. Dyspnea, rales/rhonchi, wheezing, and shortness of breath scores trended higher for RSV and hMPV than influenza. RiiQ™ scores for cough, fatigue, and short of breath were strongly correlated with corresponding clinician-rated symptoms. CONCLUSIONS: These findings support the use of PROs (e.g., the RiiQ™) correlating with clinician assessments to gauge patient well-being and aid patient management by accurately assessing respiratory illness severity due to RSV, hMPV, or influenza.

Surgical debulking of large ventricular fibromas in children.

OBJECTIVE: This study aims to provide an update on the clinical presentation, diagnostic workup, operative strategies, and midterm outcomes in children undergoing ventricular fibroma resection. METHODS: Single-center, retrospective cohort study of patients undergoing ventricular fibroma resection between 2000 and 2023. RESULTS: Among 52 patients, median age at surgery was 2.0 years (interquartile range, 0.8-4.6) and median tumor volume index was 69 mL/m2 (interquartile range, 49-169). Tumor distorted the atrioventricular valve/subvalvar apparatus in 30 patients (58%) and abutted major epicardial coronary arteries in 41 patients (79%). Surgery was indicated for arrythmia (n = 45, 86%), symptoms (n = 14, 27%), or hemodynamic compromise (n = 11, 21%). Tumor was debulked in 34 patients (65%), including the last 21 patients. Concomitant atrioventricular valvuloplasty was performed in 18 patients and ventricular cavity closure in 15 patients (29%). During a median follow-up of 2.4 years (interquartile range, 0.8-6.2), there was no mortality, cardiac arrests, heart transplants, or single ventricle palliation. The 15-year risk of reoperation and clinical ventricular tachycardia/fibrillation was 6.7% (95% CI, 0-14.3) and 2.4% (95% CI, 0-7.2), respectively. On latest imaging, pre- and postdebulking left ventricular ejection fraction did not significantly differ (P = .069), whereas no patients had signs of outflow tract obstruction, inflow tract obstruction, or moderate or greater atrioventricular valve regurgitation. CONCLUSIONS: Large ventricular fibromas can be resected safely with appropriate surgical planning and an emphasis on debulking. Most children maintain left ventricular function and remain free of recurrent ventricular arrhythmias at follow-up. Extended follow-up is warranted to understand whether patients remain at risk for scar-based ventricular arrhythmias in the future.

Respiratory Syncytial Virus Prefusion F Vaccination: Antibody Persistence and Revaccination.

BACKGROUND: Respiratory syncytial virus (RSV) causes substantial respiratory disease. Bivalent RSV prefusion F (RSVpreF) vaccine is licensed in ≥60-year-olds. RSVpreF was well-tolerated and immunogenic in a phase 1/2 study. We evaluated antibody persistence after initial vaccination and safety and immunogenicity after revaccination from this study. METHODS: Healthy adults were randomized to receive both initial vaccination and revaccination 12 months later with either placebo or RSVpreF 240 µg (±Al(OH)3). RSV-A and RSV-B geometric mean neutralizing titers (GMTs) were measured through 12 months after both vaccinations. Tolerability/safety was assessed. RESULTS: There were 263 participants revaccinated (18-49-years-old, n=134; 65-85-years-old, n=129). Among 18-49-year-olds and 65-85-year-olds, respectively, geometric mean fold rises (GMFRs) for both RSV subgroups (RSV-A; RSV-B) 1 month after initial RSVpreF vaccination were 13.3-20.4 and 8.9-15.5 compared with levels before initial vaccination; corresponding GMFRs 12 months after initial vaccination were 4.1-5.0 and 2.6-4.1. GMFRs 1 month after revaccination compared with levels before revaccination were 1.4-2.3 and 1.4-2.2 for 18-49-year-olds and 65-85-year-olds, respectively. Peak GMTs after revaccination were lower than those after initial vaccination. GMTs 12 months after initial vaccination and revaccination were similar, with GMFRs ranging from 0.7-1.6. No safety signals occurred. CONCLUSIONS: RSVpreF revaccination was immunogenic and well-tolerated among adults. NCT03529773.