6-Thioguanine nucleotide levels are associated with infliximab but not adalimumab levels in inflammatory bowel disease patients on combination therapy.

BACKGROUND: Thiopurine co-therapy with anti-tumour necrosis factor-alpha (anti-TNFα) agents is associated with higher anti-TNFα drug levels and reduced immunogenicity in inflammatory bowel disease (IBD). AIMS: We aimed to evaluate the association between 6-thioguanine nucleotide (6-TGN) and anti-TNFα levels and the optimal 6-TGN threshold level associated with higher anti-TNFα levels in combination therapy. METHODS: We performed a retrospective cross-sectional multicentre study of patients with IBD on combination anti-TNFα and thiopurine maintenance therapy between January 2015 and August 2021. Primary outcomes were infliximab and adalimumab levels. Secondary outcomes were antibodies to infliximab (ATI) or adalimumab (ATA). Univariable and multivariable linear regression were performed to identify variables associated with anti-TNFα levels. Receiver operator characteristic curves were used to define the optimal 6-TGN cut-off levels associated with therapeutic anti-TNFα levels. RESULTS: The study included 743 paired 6-TGN and anti-TNFα levels (640 infliximab and 103 adalimumab). 6-TGN levels were associated with infliximab levels, but not adalimumab levels, on univariable and multivariable regression. The optimal 6-TGN cut-off associated with therapeutic infliximab levels (≥5 mcg/mL) was 261 pmol/8 × 108 red blood cell (RBC) (area under the curve (AUC) = 0.57) for standard infliximab dosing and 227.5 pmol/8 × 108 RBC (AUC = 0.58) for escalated dosing. For therapeutic adalimumab levels (≥7.5 mcg/mL), the 6-TGN cut-off was 218.5 pmol/8 × 108 RBC (AUC = 0.59) for standard adalimumab dosing and 237.5 pmol/8 × 108 RBC (AUC = 0.63) for escalated dosing. CONCLUSION: 6-TGN levels were weakly associated with infliximab but not adalimumab levels in combination therapy. 6-TGN levels in the lower end of the therapeutic range (230-260 pmol/8 × 108 RBC) may be adequate to maintain higher infliximab levels, particularly with escalated infliximab dosing.

Long-Term Outcomes of Mechanical Aortic Valve Replacement in Children.

When the options of aortic valve repair or the Ross procedure are not feasible or have been exhausted, mechanical aortic valve replacement (AVR) may provide a reliable and structurally durable alternative, but with the limitations of long-term anticoagulation, thrombosis risk and lack of valve growth potential. In this article, we review the longitudinal outcomes of mechanical AVR in children in our institution and compare them to those recently reported by others. From 1978 to 2020, 62 patients underwent mechanical AVR at a median age of 12.4 years (interquartile range (IQR): 8.6-16.8 years). The most common underlying diagnoses were: conotruncal anomalies (40%, 25/62), congenital aortic stenosis (16%, 10/62), rheumatic valve disease (16%, 10/62), connective tissue disease (8.1%, 5/62) and infective endocarditis (6.5%, 4/62). Thirty-two patients (52%, 32/62) had at least 1 prior aortic valve surgery prior to mechanical AVR. Early death was 3.2% (2/62). Median follow-up was 14.4 years (IQR: 8.4-28.2 years). Kaplan-Meier survival was 96.8%, 91.9%, 86.3%, and 81.9% at 1, 5, 10, and 20 years. On competing risk analysis, the proportion of patients alive without aortic valve reoperation at 1, 5, 10, and 20 years was 95.2%, 87.0%, 75.5% and 55.4%, respectively, while the proportion of patients that had aortic valve reoperation (with death as a competing event) at 1, 5, 10, and 20 years was 1.6%, 4.9%, 12.8%, and 28.5%, respectively. In conclusion, when the options of aortic valve repair or the Ross procedure are not feasible in children, mechanical AVR is an alternative, yet the long-term rates of mortality and need for aortic valve reoperation are of concern.

Aortic Valve Surgery in Children With Infective Endocarditis.

There is limited data on the outcomes of children who undergo surgery for aortic valve infective endocarditis (IE), and the optimal surgical approach remains controversial. We investigated the long-term outcomes of surgery for aortic valve IE in children, with a particular focus on the Ross procedure. A retrospective review of all children who underwent surgery for aortic valve IE was performed at a single institution. Between 1989 and 2020, 41 children underwent surgery for aortic valve IE, of whom 16 (39.0%) underwent valve repair, 13 (31.7%) underwent the Ross procedure, 9 (21.9%) underwent a homograft root replacement, and 3 (7.3%) underwent a mechanical valve replacement. Median age was 10.1 years (interquartile range, 5.4-14.1). The majority of children (82.9%, 34/41) had underlying congenital heart disease, while 39.0% (16/41) had previous heart surgery. Operative mortality was 0.0% (0/16) for repair, 15.4% (2/13) for the Ross procedure, 33.3% (3/9) for homograft root replacement, and 33.3% (1/3) for mechanical replacement. Survival at 10 years was 87.5% for repair, 74.1% for Ross, and 66.7% for homograft (P > 0.05). Freedom from reoperation at 10 years was 30.8% for repair, 63.0% for Ross, and 26.3% for homograft (P = 0.15 for Ross vs repair, P = 0.002 for Ross vs homograft). Children undergoing surgery for aortic valve IE have acceptable long-term survival, although the need for long-term reintervention is significant. The Ross procedure appears to be the optimal choice when repair is not feasible.

Outcomes of Mitral Valve Repair in Children With Infective Endocarditis: A Single-Center Experience.

Mitral valve infective endocarditis (IE) in children is rare, and there are few reports on the outcomes of surgery in these patients. This study investigated the long-term outcomes of mitral valve repair in children with IE. Data were retrospectively obtained from medical records and correspondence. Univariable regression analyses were performed and outcomes including survival and freedom from reoperation were analyzed using the Kaplan-Meier method. Surgery for native mitral valve IE was performed in 39 patients between 1987 and 2020. Of these, 92.3% (36/39) of patients underwent mitral valve repair, while 7.7% (3/39) required replacement. Median age was 8 years. Preoperatively, 80.5% (29/36) of patients had moderate or greater mitral regurgitation. Congenital heart disease was present in 38.9% (14/36), while 11.1% (4/36) had rheumatic heart disease and 25.0% (9/36) had prior cardiac surgery. Postoperatively, only 1 patient (2.8%, 1/36) had moderate or greater residual mitral regurgitation. There were 2 early deaths (5.6%, 2/36), with survival being 94.1% (95%CI, 78.5-98.5) at 15 years. At 10 years, freedom from reoperation was 62.9% (95%CI, 41.0-78.5) while freedom from mitral valve replacement was 80.2% (95%CI, 55.5-92.3). Larger vegetation size was a risk factor for embolic events both pre- and postoperatively (OR, 1.15, P = 0.02). Mitral valve repair is feasible in the majority of children requiring surgery for mitral valve IE. Survival is excellent, and at 10 years, approximately two-thirds of patients are free from mitral reoperation, and 80% are free from replacement. Larger vegetation size is associated with an increased risk of embolic events.

Aortic valve repair versus the Ross procedure in children.

BACKGROUND: Aortic valve repair and the Ross procedure are widely used in children; however, it is unclear which provides the best outcomes. METHODS: Patients who underwent primary aortic valve surgery from 1980 to 2018 were included. Propensity score matching was performed to adjust for baseline differences. RESULTS: Of 415 children, 82.7% (343/415) underwent repair and 17.3% (72/415) underwent the Ross procedure. At 15 years, survival was higher for aortic valve repair (93.9% ± 1.8% vs 80.9% ± 6.4%, P = .04); freedom from reoperation (45.7% ± 4.9% vs 48.5% ± 9.0%, P = .29) did not differ, and freedom from aortic valve reoperation was higher in the Ross procedure group (45.7% ± 4.9% vs 70.7% ± 8.0%, P < .001). When analyzed by quality of repair, acceptable repair provided the highest survival (P = .01). Acceptable repair and the Ross procedure had similar freedom from reoperation at 15 years, whereas suboptimal repair performed worse (acceptable: 54.9% ± 6.7%; Ross procedure: 48.5% ± 9.0%; suboptimal: 27.0% ± 7.7%, P < .001). Acceptable repair and the Ross procedure had similar freedom from aortic valve reoperation at 15 years, whereas suboptimal repair showed worse results (acceptable: 54.9 ± 6.7; Ross procedure: 70.7% ± 8.0%; suboptimal: 27.0% ± 7.7%, P < .001). Propensity score matching paired 66 patients who underwent the Ross procedure with 198 patients who underwent repair. At 15 years, repair was associated with better survival (98.0% ± 1.2% vs 78.5% ± 7.2%, P = .03), whereas freedom from reoperation was similar (42.6% ± 7.6% vs 50.7% ± 9.8%, P = .50). However, the Ross procedure was associated with higher freedom from aortic valve reoperation (42.6% ± 7.6% vs 72.3% ± 8.5%, P = .002). CONCLUSIONS: Primary aortic valve repair was associated with better survival than the Ross procedure, whereas overall freedom from reoperation was similar. When an acceptable intraoperative result was achieved, outcomes of repair were favorable. However, when the intraoperative result of repair was suboptimal, the Ross procedure showed better results.

Surgery for paravalvular abscess in children.

Objective: To investigate the outcomes of surgery in children with paravalvular abscess at our institution. Methods: A retrospective review of all patients who underwent surgery for paravalvular abscess was performed. Results: Between 1989 and 2020, 30 patients underwent surgery for paravalvular abscess, of whom 5 (16.7%) had an intracardiac fistula and 6 (20.0%) had a pseudoaneurysm. Aortic annulus abscesses were most common, occurring in 23 patients (76.7%). Aortic root replacement was performed in 17 patients (56.7%), root reconstruction was performed in 4 (13.3%), and reconstruction of the central fibrous body was required in 5 (16.7%). Postoperatively, 7 patients (23.3%) required extracorporeal membrane oxygenation (ECMO) support, and 1 patient (3.3%) required permanent pacemaker insertion. There were 6 early deaths, 5 of whom were on ECMO, and no late deaths, with a 15-year survival of 79.7% (95% confidence interval [CI], 60.2%-90.3%). Deaths were from sudden cardiac arrest resulting in brain death in 3 patients, inability to wean from ECMO due to severe cardiac dysfunction in 2 patients, and cerebral mycotic aneurysm and hemorrhage in 1 patient. Freedom from reoperation was 40.0% (95% CI, 17.0%-62.3%) at 15 years Reoperation due to recurrence was rare, occurring in only 2 patients (6.7%). Streptococcus pneumoniae (hazard ratio [HR], 9.2; 95% CI, 1.6-51.7) and preoperative shock (HR, 6.4; 95% CI, 1.3-32.0) were associated with mortality. Central fibrous body reconstruction was associated with reoperation (HR, 4.4; 95% CI, 1.2-16.1). Conclusions: Although paravalvular abscess in children is associated with high early mortality, hospital survivors have good long-term survival. Reoperation is frequent, but is rarely due to recurrence of endocarditis.

Outcomes of total anomalous pulmonary venous drainage repair in neonates and the impact of pulmonary hypertension on survival.

Background: Mortality after repair of total anomalous pulmonary venous drainage (TAPVD) in neonates has remained high. Analysis of risk factors may help identify therapeutic targets to improve survival. Methods: Retrospective analysis of all neonates who underwent simple TAPVD repair. Results: Between 1973 and 2021, 175 neonates underwent TAPVD repair, at a median age of 6 days (interquartile range, 2-15 days) and a mean weight of 3.2 ± 0.6 kg. TAPVD was supracardiac in 42.3% of the patients (74 of 175), cardiac in 14.3% (25 of 175), infracardiac in 40% (70 of 175), and mixed type in 3.4% (6 of 175), with obstruction in 65.7% (115 of 175). Pulmonary hypertension (PHT) crisis occurred in 12% (21 of 175). Early mortality was 9.7% (17 of 175) and late mortality was 5.1% (8 of 158), with most deaths occurring within 1 year (75%; 6 of 8). Survival was 86.5% (95% CI, 80.3%-90.8%) at 1 year and 85.8% (95% CI, 79.6%-90.3%) at 5, 10, 15, and 20 years. Survival was lower in patients with obstructed TAPVD, patients with emergent surgery, and those with PHT crisis. PHT crisis (hazard ratio [HR], 4.93; 95% CI, 1.95-12.51; P = .001), urgency of surgery (HR, 2.51; 95% CI, 1.11-5.68; P = .027), and higher pulmonary artery pressure-to-systemic blood pressure percentage ratio (HR, 1.06; 95% CI, 1.01-1.11; P = .026) were identified as risk factors for mortality. Histopathological analysis of 17 patients (9.7%; 17 of 175) showed signs of pulmonary arterial hypertension with media hypertrophy in 58.8% (10 of 17). Conclusions: Mortality after TAPVD repair occurred mainly within the first year of life. Urgency of surgery and persistent PHT appears to be risk factors for mortality. Lung biopsy might be useful for identifying patients at risk and guiding newer treatment modalities.

Early repair of complete atrioventricular septal defect has better survival than staged repair after pulmonary artery banding: A propensity score-matched study.

OBJECTIVES: Complete atrioventricular septal defect (cAVSD) repair is usually performed between 3 and 6 months of age. However, some children present with early heart failure requiring intervention. It is unclear whether primary complete repair or initial pulmonary artery banding (PAB) provides better outcomes. METHODS: All patients (n = 194) who underwent surgery for cAVSD younger than 3 months of age between 1990 and 2019 were included. Propensity score matching was performed on risk factors for mortality. RESULTS: Primary complete repair was performed in 77.8% (151/194), whereas PAB was performed in 22.2% (43/194). Children who had PAB were younger (P < .01), had lower weight (P < .001), and less trisomy 21 (P = .04). Interstage mortality for PAB was 18.6% (8/43), whereas early mortality for primary repair was 3.3% (5/151). Survival at 20 years was 92.0% (95% confidence interval [CI], 85.6%-95.7%) for primary repair and 63.2% (95% CI, 42.5%-78.1%) for PAB (P < .001). There was no difference in left atrioventricular valve (LAVV) reoperation rates (P = .94). Propensity score matching produced 2 well-matched groups. Survival at 20 years was 94.2% (95% CI, 85.1%-98.8%) for primary repair, and 58.4% (95% CI, 33.5%-76.7%) for PAB (P = .001). There was no difference in LAVV reoperation rates (P = .71). Neonatal repair was achieved with no early deaths and 100% survival at 10 years. CONCLUSIONS: In children younger than 3 months of age, complete repair of cAVSD is associated with better survival than PAB. Both strategies have similar rates of LAVV reoperation. Neonatal repair of cAVSD can be achieved with excellent results. Primary repair of cAVSD should be the preferred strategy in children younger than 3 months of age.