Paediatric inflammatory multisystem syndrome in Canada: population-based surveillance and role of SARS-CoV-2 linkage.

BACKGROUND: Paediatric inflammatory multisystem syndrome (PIMS) is a rare condition temporally associated with SARS-CoV-2 infection. Using national surveillance data, we compare presenting features and outcomes among children hospitalized with PIMS by SARS-CoV-2 linkage, and identify risk factors for intensive care (ICU). METHODS: Cases were reported to the Canadian Paediatric Surveillance Program by a network of >2800 pediatricians between March 2020 and May 2021. Patients with positive versus negative SARS-CoV-2 linkages were compared, with positive linkage defined as any positive molecular or serologic test or close contact with confirmed COVID-19. ICU risk factors were identified with multivariable modified Poisson regression. RESULTS: We identified 406 children hospitalized with PIMS, including 49.8% with positive SARS-CoV-2 linkages, 26.1% with negative linkages, and 24.1% with unknown linkages. The median age was 5.4 years (IQR 2.5-9.8), 60% were male, and 83% had no comorbidities. Compared to cases with negative linkages, children with positive linkages experienced more cardiac involvement (58.8% vs. 37.4%; p < 0.001), gastrointestinal symptoms (88.6% vs. 63.2%; p < 0.001), and shock (60.9% vs. 16.0%; p < 0.001). Children aged ≥6 years and those with positive linkages were more likely to require ICU. CONCLUSIONS: Although rare, 30% of PIMS hospitalizations required ICU or respiratory/hemodynamic support, particularly those with positive SARS-CoV-2 linkages. IMPACT: We describe 406 children hospitalized with paediatric inflammatory multisystem syndrome (PIMS) using nationwide surveillance data, the largest study of PIMS in Canada to date. Our surveillance case definition of PIMS did not require a history of SARS-CoV-2 exposure, and we therefore describe associations of SARS-CoV-2 linkages on clinical features and outcomes of children with PIMS. Children with positive SARS-CoV-2 linkages were older, had more gastrointestinal and cardiac involvement, and hyperinflammatory laboratory picture. Although PIMS is rare, one-third required admission to intensive care, with the greatest risk amongst those aged ≥6 years and those with a SARS-CoV-2 linkage.

Electroencephalography signals and neurodevelopment after Kawasaki disease: A pilot study.

BACKGROUND: Acute Kawasaki disease (KD) induces central nervous system inflammation and excessive irritability. Long-term impacts on children's neurodevelopment have only been studied marginally. This pilot study aimed to describe the neuropsychological profile of primary school-aged children with a history of KD and to explore the impacts of KD on electroencephalography (EEG) markers associated with attention and brain maturation. METHODS: Fifteen children (8.8 ± 2.5 years) were recruited 4.9 ± 2.7 years after KD onset. Intellectual abilities, long-term memory, and auditory sustained attention were evaluated. Parents completed standardized questionnaires assessing (1) executive functioning; (2) internalizing and externalizing difficulties; (3) attention deficit hyperactivity disorder symptoms; and (4) autism spectrum disorder symptoms. Theta/beta ratio (TBR) and alpha peak (AP) were extracted from resting-state EEG and compared with 32 controls (8.9 ± 2.1 years). The alpha band was analyzed using a feature reduction algorithm to detect potential groupings. RESULTS: Performances showed preserved intellectual abilities and memory. Sustained attention performance was within the lower range for 4/14 participants (29%), with considerable parental reports of inattention (43%), working memory difficulties (50%), and hyperactivity-impulsivity (36%). No alterations in the TBR were found but the KD group presented a significantly lower AP amplitude ratio. A clear separation of KD cohort into two clusters showed that acute irritability is associated with a weaker AP. CONCLUSIONS: Despite overall preserved cognitive functions, there is a possible association between KD and attention deficit concerns. This first EEG-based study indicates alpha peak abnormality after KD, predominantly in children with acute irritability. Longitudinal studies are warranted to better characterize patients' neurodevelopmental trajectory.

Physicians' Self-reported Exercise Testing and Physical Activity Recommendations in Kawasaki Patients.

Recommendations for management of patients with Kawasaki disease (KD) and coronary artery aneurysms (CAA) include physical activity (PA) promotion. This study aimed to characterize self-reported practices of KD providers to evaluate practice variation in use of cardiopulmonary exercise testing (CPET) and PA recommendations. We developed a REDCap survey with different clinical scenarios of KD patients. It was completed by members of the International Kawasaki Disease Registry (IKDR) and community pediatric cardiologists. Twenty-eight physicians responded; 63% practiced in the US, 63% practiced in an academic setting, 48% were general pediatric cardiologists, and 55% were IKDR members. Most respondents (69%) followed < 50 KD patients. The great majority (93%) agreed that patients with no CAA do not require CPET and could be cleared for all PA. For patients with small CAA, 43% of respondents recommended CPET and 75% cleared for all PA if CAAs regressed completely, but only 32% cleared if CAA persisted. For patients with medium CAA, 66% respondents cleared for PA if CAA regressed, and only 7% if CAA persisted; with 66% and 75% recommending CPET, respectively. For patients with large/giant CAA, 81% of respondents recommended CPET. No respondents felt comfortable clearing their patients with persistent large/giant CAA for PA and 19% would restrict from the entire physical education program. There is practice variation in use of CPET in KD patients with CAAs. Providers are hesitant to promote PA in KD patients with CAA despite known benefits and current guidelines.

COVID-19 Positive Versus Negative Complete Kawasaki Disease: A Study from the International Kawasaki Disease Registry.

To determine clinical differences for children with complete Kawasaki disease (KD) with and without evidence of preceding SARS-CoV-2 infection. From January 2020, contemporaneous patients with complete KD criteria were classified as either SARS-CoV-2 positive (KDCOVID+; confirmed household exposure, positive PCR and/or serology) or SARS-CoV-2 negative (KDCOVID-; negative testing and no exposure) and compared. Of 744 patients in the International Kawasaki Disease Registry, 52 were KDCOVID- and 61 were KDCOVID+. KDCOVID+ patients were older (median 5.5 vs. 3.7 years; p < 0.001), and all additionally met diagnostic criteria for multisystem inflammatory syndrome in children (MIS-C). They were more likely to have abdominal pain (60% vs. 35%; p = 0.008) and headache (38% vs. 10%; p < 0.001) and had significantly higher CRP, troponin, and BUN/creatinine, and lower hemoglobin, platelets, and lymphocytes. KDCOVID+ patients were more likely to have shock (41% vs. 6%; p < 0.001), ICU admission (62% vs. 10%; p < 0.001), lower left ventricular ejection fraction (mean lowest LVEF 53% vs. 60%; p < 0.001), and to have received inotropic support (60% vs. 10%; p < 0.001). Both groups received IVIG (2 doses in 22% vs. 18%; p = 0.63), but KDCOVID+ were more likely to have received steroids (85% vs. 35%; p < 0.001) and anakinra (60% vs. 10%; p = 0.002). KDCOVID- patients were more likely to have medium/large coronary artery aneurysms (CAA, 12% vs. 0%; p = 0.01). KDCOVID+ patients differ from KDCOVID-, have more severe disease, and greater evidence of myocardial involvement and cardiovascular dysfunction rather than CAA. These patients may be a distinct KD phenotype in the presence of a prevalent specific trigger.

Cardiac Biomarkers Aid in Differentiation of Kawasaki Disease from Multisystem Inflammatory Syndrome in Children Associated with COVID-19.

Kawasaki disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 show clinical overlap and both lack definitive diagnostic testing, making differentiation challenging. We sought to determine how cardiac biomarkers might differentiate KD from MIS-C. The International Kawasaki Disease Registry enrolled contemporaneous KD and MIS-C pediatric patients from 42 sites from January 2020 through June 2022. The study population included 118 KD patients who met American Heart Association KD criteria and compared them to 946 MIS-C patients who met 2020 Centers for Disease Control and Prevention case definition. All included patients had at least one measurement of amino-terminal prohormone brain natriuretic peptide (NTproBNP) or cardiac troponin I (TnI), and echocardiography. Regression analyses were used to determine associations between cardiac biomarker levels, diagnosis, and cardiac involvement. Higher NTproBNP (≥ 1500 ng/L) and TnI (≥ 20 ng/L) at presentation were associated with MIS-C versus KD with specificity of 77 and 89%, respectively. Higher biomarker levels were associated with shock and intensive care unit admission; higher NTproBNP was associated with longer hospital length of stay. Lower left ventricular ejection fraction, more pronounced for MIS-C, was also associated with higher biomarker levels. Coronary artery involvement was not associated with either biomarker. Higher NTproBNP and TnI levels are suggestive of MIS-C versus KD and may be clinically useful in their differentiation. Consideration might be given to their inclusion in the routine evaluation of both conditions.

Access to Care and Therapy for Kawasaki Disease in the Arab Countries: A Kawasaki Disease Arab Initiative (Kawarabi) Multicenter Survey.

Kawasaki Disease (KD) is still the most common acquired heart disease in children below the age of five years; it has been well described in the developed world; however, data from the Arab world are limited to case reports or single-center case series. In an effort of optimizing KD research in the Arab world, a group of physicians and researchers established the KD Arab Initiative (Kawarabi) in 2021, and published the first survey, which showed disparities in the availability of intravenous immunoglobulin (IVIG); this had prompted Kawarabi to assess the access to care and therapy of KD patients in Arab countries. A 32 structured questions survey was conducted in thirteen Arab countries and addressed KD patients' access to healthcare in urban and rural settings. The survey results showed that access to care was uniform across large, mid-size cities and rural areas in 7/13 (54%) countries, while in 6/13 (46%) countries, it was in favor of large and mid-size cities over rural areas. The quality of medical services received by children with KD in large cities was rated as excellent in 6/13 or good in 7/13 countries compared to fair in 4/13 or poor in 4/13 countries in rural areas. Availability of IVIG was limited (23%) in mid-size cities and almost impossible (23%) in rural areas. The KD patients in mid-size cities and rural areas have limited access to standard healthcare in the Arab world. This survey laid the foundation for future Kawarabi endeavors to improve the care of children with KD.

Etanercept with IVIg for acute Kawasaki disease: a long-term follow-up on the EATAK trial.

BACKGROUND: The Etanercept as Adjunctive Treatment for Acute Kawasaki Disease, a phase-3 clinical trial, showed that etanercept reduced the prevalence of IVIg resistance in acute Kawasaki disease. In patients who presented with coronary artery involvement, it reduced the maximal size and short-term progression of coronary artery dilation. Following up with this patient group, we evaluated the potential long-term benefit of etanercept for coronary disease. METHODS: Patients were followed for at least 1 year after the trial. The size of dilated arteries (z-score ≥ 2.5) was measured at each follow-up visit. The z-score and size change from baseline were evaluated at each visit and compared between patients who received etanercept versus placebo at the initial trial. RESULTS: Forty patients who received etanercept (22) or placebo (18) in the Etanercept as Adjunctive Treatment for Acute Kawasaki Disease trial were included. All patients showed a persistent decrease in coronary artery size measurement: 23.3 versus 5.9% at the 6-month visit, 24 versus 13.1% at the 1-year visit, and 20.8 versus 19.3% at the ≥ 2-year visit for etanercept or placebo, respectively, with similar results for decrease in coronary artery z-scores. In a multivariate analysis, correcting for patients' growth, a greater size reduction for patients on the etanercept arm versus placebo was proved significant for the 6-month (p = 0.005) and the 1-year visits (p = 0.019) with a similar end outcome at the ≥ 2-year visit. DISCUSSION: Primary adjunctive therapy with etanercept for children with acute Kawasaki disease does not change the end outcome of coronary artery disease but may promote earlier resolution of artery dilation.

Variation in Pharmacologic Management of Patients with Kawasaki Disease with Coronary Artery Aneurysms.

OBJECTIVE: To evaluate practice variation in pharmacologic management in the International Kawasaki Disease Registry (IKDR). STUDY DESIGN: Practice variation in intravenous immunoglobulin (IVIG) therapy, anti-inflammatory agents, statins, beta-blockers, antiplatelet therapy, and anticoagulation was described. RESULTS: We included 1627 patients from 30 IKDR centers with maximum coronary artery aneurysm (CAA) z scores 2.5-4.99 in 848, 5.0-9.99 in 349, and ≥10.0 (large/giant) in 430 patients. All centers reported IVIG and acetylsalicylic acid (ASA) as primary therapy and use of additional IVIG or steroids as needed. In 23 out of 30 centers, (77%) infliximab was also used; 11 of these 23 centers reported using it in <10% of their patients, and 3 centers used it in >20% of patients. Nonsteroidal anti-inflammatory agents were used in >10% of patients in only nine centers. Beta-blocker (8.8%, all patients) and abciximab (3.6%, all patients) were mainly prescribed in patients with large/giant CAAs. Statins (2.7%, all patients) were mostly used in one center and only in patients with large/giant CAAs. ASA was the primary antiplatelet modality for 99% of patients, used in all centers. Clopidogrel (18%, all patients) was used in 24 centers, 11 of which used it in >50% of their patients with large/giant CAAs. CONCLUSIONS: In the IKDR, IVIG and ASA therapy as primary therapy is universal with common use of a second dose of IVIG for persistent fever. There is practice variation among centers for adjunctive therapies and anticoagulation strategies, likely reflecting ongoing knowledge gaps. Randomized controlled trials nested in a high-quality collaborative registry may be an efficient strategy to reduce practice variation.

Deep Learning-Based Approach to Automatically Assess Coronary Distensibility Following Kawasaki Disease.

Kawasaki disease is an acute vasculitis affecting children, which can lead to coronary artery (CA) aneurysms. Optical coherence tomography (OCT) has identified CA wall damage in KD patients, but it is unclear if these findings correlate with any distensibility changes in the CA and how these changes evolve over time. This paper seeks to establish the link between OCT findings and vessel distensibility with a novel deep learning coronary artery segmentation system and use the segmentation framework to automatically analyze the temporal evolution of coronary stiffness over many years. 27 KD patients underwent catheterization with coronary angiography of the left coronary artery (LCA), followed by OCT of proximal and distal segments of the LCA. Changes in the CA caliber over the cardiac cycle were measured automatically and compared against OCT findings suggestive of KD-related vascular damage. In addition, 34 KD patients with regressed or persistent CA aneurysms were followed with serial CA angiography over an average of 14.5 years. Distensibility changes were calculated using a deep learning coronary artery segmentation framework and evaluated longitudinally. Distensibility in the coronary arteries after KD negatively correlated with increasing severity of OCT findings of KD-related vessel damage. KD patients have a significant increase in CA wall stiffness at 1 year after diagnosis, which then plateaus subsequently, compared to controls. Also, patients with persistent CA aneurysms have a statistically significant increase in wall stiffness over time in comparison to those with regressed CA aneurysms. Distensibility changes in the CA of KD patients calculated using our automated deep learning approach correlates with the severity of OCT findings of KD-related CA damage. This decreased distensibility peaks at 1 year in KD patients when following longitudinally and is more severe in those with persistent CA aneurysms.

Kawasaki Disease Arab Initiative [Kawarabi]: Establishment and Results of a Multicenter Survey.

Studies on Kawasaki disease (KD) in Arab countries are scarce, often providing incomplete data. This along with the benefits of multicenter research collaboratives led to the creation of the KD Arab Initiative [Kawarabi] consortium. An anonymous survey was completed among potential collaborative Arab medical institutions to assess burden of KD in those countries and resources available to physicians. An online 32-item survey was distributed to participating institutions after conducting face validity. One survey per institution was collected. Nineteen physicians from 12 countries completed the survey representing 19 out of 20 institutions (response rate of 95%). Fifteen (79%) institutions referred to the 2017 American Heart Association guidelines when managing a patient with KD. Intravenous immunoglobulin (IVIG) is not readily available at 2 institutions (11%) yet available in the country. In one center (5%), IVIG is imported on-demand. The knowledge and awareness among countries' general population was graded (0 to 10) at median/interquartiles (IQR) 3 (2-5) and at median/IQR 7 (6-8) in the medical community outside their institution. Practice variations in KD management and treatment across Arab countries require solid proactive collaboration. The low awareness and knowledge estimates about KD among the general population contrasted with a high level among the medical community. The Kawarabi collaborative will offer a platform to assess disease burden of KD, among Arab population, decrease practice variation and foster population-based knowledge.

Variation in the management of Kawasaki disease in Australia and New Zealand: A survey of paediatricians.

AIM: This study aimed to describe the current management practices for Kawasaki disease (KD) in Australia and New Zealand. METHODS: We performed a secondary analysis on the Australian and New Zealand responses to a large international survey of clinicians' perspectives on KD diagnosis and management. RESULTS: There was general consensus among Australian and New Zealand clinicians regarding the indications for intravenous immunoglobulin and aspirin in the management of acute KD. There was less consensus on the dose of these agents, the definition and management of treatment-resistant KD and the approach to long-term thromboprophylaxis. CONCLUSION: Most clinicians use intravenous immunoglobulin for primary treatment of KD. There is variation regarding other aspects of KD diagnosis and important management issues. Future studies should confirm whether this reported variation occurs in real-world practice and assess potential impacts on patient outcome.

Supravalvular and Valvular Pulmonary Stenosis: Predictive Features and Responsiveness to Percutaneous Dilation.

Supravalvular pulmonary stenosis (SVPS) is considered a rare form of pulmonary stenosis (PS) and represents both a diagnostic and therapeutic challenge. There currently exist no reliable echocardiographic criteria to accurately predict the supravalvular form. The aims of the study were to describe the response to treatment of the different PS presentations and to outline the diagnostic capacity of echocardiogram to differentiate the SVPS from valvular PS (VPS). This retrospective study included 106 patients who underwent percutaneous angioplasty between 2006 and 2017. Interventional outcomes of patients with SVPS were compared to those of patients with VPS. Diagnosis of VPS vs. SVPS by echocardiogram was compared to diagnosis obtained by angiogram. Echocardiogram yielded a sensitivity of 56%, a specificity of 82.5%, a positive predictive value of 50%, and a negative predictive value of 85.7%. Patients with SVPS had a significantly smaller pulmonary artery to pulmonary valve (PA:PV) ratio. At 6-12 months of follow-up, the VPS group had a mean right ventricular to pulmonary artery (RV-PA) gradient of 21.68 ± 19.85 mmHg compared to 45.27 ± 24.58 mmHg in the SVPS group. Patients with SVPS had a higher rate of reintervention than patients with VPS (32% vs. 6.2%, p < 0.001). There was no difference in major complications between groups, whereas VPS patients had a higher proportion of pulmonary insufficiency. Percutaneous angioplasty for PS is less effective in patients with a supravalvular component. A better understanding of the underlying histopathology of different PS subtypes could lead to development of different techniques to improve outcomes, with fewer reinterventions, in this population.

Comparison Between Currently Recommended Long-Term Medical Management of Coronary Artery Aneurysms After Kawasaki Disease and Actual Reported Management in the Last Two Decades.

In the 2017 American Heart Association (AHA) Kawasaki disease (KD) guidelines, risk levels (RLs) for long-term management are defined by both maximal and current coronary artery (CA) dimensions normalized as z-scores. We sought to determine the degree to which current recommended practice differs from past actual practice, highlighting areas for knowledge translation efforts. The International KD Registry (IKDR) included 1651 patients with CA aneurysms (z-score > 2.5) from 1999 to 2016. Patients were classified by AHA RL using maximum CA z-score (RL 3 = small, RL 4 = medium, RL 5 = large/giant) and subcategorized based on decreases over time. Medical management provided was compared to recommendations. Low-dose acetylsalicylic acid (ASA) use ranged from 86 (RL 3.1) to 95% (RL 5.1) for RLs where use was "indicated." Dual antiplatelet therapy (ASA + clopidogrel) use ranged from 16% for RL 5.2 to 9% for RL 5.4. Recommended anticoagulation (warfarin or low molecular weight heparin) use was 65% for RL 5.1, while 12% were on triple therapy (anticoagulation + dual antiplatelet). Optional statin use ranged from 2 to 8% depending on RL. Optional beta-blocker use was 2-25% for RL 5, and 0-5% for RLs 3 and 4 where it is not recommended. Generally, past practice was consistent with the latest AHA guidelines, taking into account the flexible wording of recommendations based on the limited evidence, as well as unmeasured patient-specific factors. In addition to strengthening the overall evidence base, knowledge translation efforts may be needed to address variation in thromboprophylaxis management.

Echocardiographic Parameters During and Beyond Onset of Kawasaki Disease Correlate with Onset Serum N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP).

The N-terminal proBNP (NT-proBNP), produced by cardiomyocytes, has several reported utilities and associations in acute Kawasaki disease (KD). The objective of this study is to examine the relationship between serum values of NT-proBNP at time of KD diagnosis with cardiac systolic, diastolic function and electrocardiographic changes, at onset of the disease and during the first year of follow-up. KD was diagnosed in 127 children between March 2007 and July 2014, mean diagnostic age 3.5 ± 2.9 years. Coronary artery maximum z score was 2.6 ± 2.8 (range - 0.6 to + 18.9), with giant aneurysm in 5/122 (4.1%). Age-adjusted NT-proBNP was 2.6 ± 1.6 z score, 78/122 (63.9%) > 2.0. There was a crescendo correlation between onset NT-proBNP z score and C-Reactive protein (CRP) serum levels (slope + 0.49, p < 0.001). There was a crescendo correlation between NT-proBNP z score and indexed left ventricular (LV) mass (slope + 1.86, p = 0.02), LV diastolic function parameter E/e' ratio (slope + 0.31, p = 0.04) and a decrescendo correlation with age-adjusted LV shortening fraction (SF) (- 0.63, p = 0.02). Lower SF z score, higher left ventricular mass index and E/e' ratio were associated with higher NT-proBNP z score, but without correlation with CRP levels. Within 2-3 months from the onset of the disease, there was a resolution of the systolic dysfunction. Electrocardiographic parameter changes were associated with decreased LV shortening fraction but not with NT-proBNP. KD patients with elevated NT-proBNP at onset have sub-clinical myocardial involvement and might benefit from follow-up and continued evaluation, even in the absence of coronary artery involvement.

Prenatal Identification of Restrictive and Non-restrictive Ventricular Septal Defects Based on End-Systolic Flow Patterns in the Fetal Aortic Isthmus.

Fetuses with large ventricular septal defects (VSDs) must be closely monitored during the perinatal period. Intrauterine assessment of size of septal defects with bidimensional echocardiography are unreliable. The objective of the present study is to document the contribution of flow pattern analysis in the fetal aortic isthmus for prenatal identification of large non-restrictive VSDs requiring immediate postnatal attention. We conducted a cross-sectional retrospective study of Doppler recordings from patients referred to our Fetal Cardiology Unit and diagnosed with one or multiple VSDs from January 2006 to November 2015. Three groups were defined: (1) large non-restrictive VSDs (n = 11) with postnatal cardiac failure (2) small restrictive VSDs (n = 28) asymptomatic, and (3) absence of cardiac abnormality (n = 66). The Isthmic end-Systolic Index (ISI) was computed to quantify aortic isthmus flow and compared between the three groups. Fetuses with restrictive VSD and control group showed similar ISI: stable at 0.20 ± 0.01 up to 27 weeks of gestation and dropping later due to the fall of end-systolic velocities in the aortic isthmus. By 35 weeks, a brief end-systolic retrograde flow was present, associated with a further fall of ISI down to -0.26 ± 0.05. In contrast, ISI of fetuses with large non-restrictive VSDs were unchanged throughout gestation (0.18 ± 0.06), becoming significantly higher during the last weeks of gestation compared to the two other groups (p < 0.001). In fetuses with VSDs, the ISI measurement from the aortic isthmus Doppler flow during the second half of gestation is a reliable predictor of a large non-restrictive defect with risk of major postnatal clinical impact.

Pharmacokinetics and safety of tadalafil in a paediatric population with pulmonary arterial hypertension: A multiple ascending-dose study.

AIMS: To evaluate the pharmacokinetics and safety of once-daily (QD) tadalafil in paediatric patients with pulmonary arterial hypertension (PAH) to establish an appropriate dose range for further research. METHODS: This was an open-label, multicentre, international, multiple-ascending-dose study. Patients aged ≥2 years were enrolled into 1 of 3 cohorts based on body weight: heavy-weight (≥40 kg), middle-weight (25 to <40 kg), and light-weight (<25 kg). Each patient received tadalafil QD for 10 weeks: 5 weeks at a low dose, then 5 weeks at a high dose. The doses for each cohort were intended to produce plasma tadalafil concentrations within the range produced by 5-10 mg (for the low dose) or 20-40 mg (for the high dose) of tadalafil in adults with PAH. Area under the plasma concentration-time curve during 1 dosing interval (AUCτ ), maximum concentration, and apparent clearance were assessed throughout the trial, as were safety and tolerability. RESULTS: The study enrolled 19 patients aged 2-17 years, weighing 9.9-76.0 kg. Tadalafil's median (range) steady-state AUCτ at the high dose was 7243 (3131-13 088) ng•h/mL across all patients. Concentrations were higher in no bosentan-treated patients than in bosentan-treated patients, but both populations were within the range of respective adult patients taking 20-40 mg QD. Tadalafil had an acceptable safety profile consistent with the known safety profile of tadalafil in adults. CONCLUSIONS: Tadalafil 40 mg QD for patients ≥40 kg, and 20 mg QD for patients <40 kg and aged ≥2 years, are suitable for further research in paediatric patients with PAH.

Clinical applications of QT/RR hysteresis assessment: A systematic review.

BACKGROUND: QT/RR hysteresis (QT-hys) is an index of the time accommodation of ventricular repolarization to heart rate changes. This report comprehensively reviews studies addressing QT-hys as a biomarker of medical conditions. METHODS: This is a secondary analysis of data from a recent systematic review pertaining to methods of assessment of QT-hys. Articles included in the former review were filtered in order to select original articles investigating the association of QT-hys with medical conditions in humans. RESULTS: Nineteen articles fulfilled our inclusion criteria. Given the heterogeneity of the methods and investigated conditions, no pooled analysis of data could be implemented. QT-hys was mostly studied as a risk marker of severe arrhythmias, as a predictor of the long QT syndrome (LQTS) phenotypes and genotypes and as a marker of exercise-induced ischemia. An increased QT-hys appears to be implicated in arrhythmogenesis, although the evidence in this regard relies on few human studies. An augmented QT-hys was reported in the LQTS, predominantly in the LQT2 genotype, but conflicting results were obtained between studies using different methods of assessment. In addition, QT-hys appears to be a useful marker of stress-induced myocardial ischemia in patients suspected of coronary artery disease. CONCLUSIONS: QT-hys evaluation has potential clinical utility in at least some clinical conditions. Further studies of the clinical validity of QT-hys assessment are warranted, particularly condition specific studies based on QT-hys evaluation methods that provide separate estimates of QT-hys and QT/RR dependency.