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Objectives: To investigate the feasibility of using actigraphy to measure physical activity (pA) and heart rate variability (HRV) as study endpoints in pediatric pulmonary arterial hypertension (PAH) and to compare their performance to six-minute-walk distance (6MWD), a common primary endpoint used in PAH clinical trials in adults and children who can walk and understand the test process., Study Design: We conducted a prospective, multicenter, non-interventional study in pediatric PAH patients and healthy children. Actiheart™ and Fitbit Charge 2™ recorded pA and heart rate (HR) data. HRV was defined as standard deviation of daily HR. Actigraphy pA and HRV and 6MWD from the same subjects were analyzed to compare children with PAH with controls, and Panama functional classification (FC) III versus II. Power/sample size simulations were conducted to detect hypothetical treatment effect equivalent to differences seen between FC III and FC II., Results: We enrolled 116 children; 90 and 98 adhered with Actiheart and Fitbit, respectively. Actigraphy daily pA was ∼36% lower (P<0.05) and daily HRV was ∼18% lower (P<0.05) in children with PAH (n=62) than healthy controls (n=54). Daily pA and daily HRV trended ∼17% lower in FC III than FC II, whereas 6MWD showed little difference. Simulation at 80% power showed that pA required 175 subjects per group and HRV required 40 per group to detect the difference/effect, whereas 6MWD required over our maximum sample size of 200., Conclusions: Actigraphy is a feasible measure in pediatric PAH. Compared with 6MWD, pA and HRV may be more sensitive in differentiating Panama FC III from II. HRV may improve actigraphy's utility in pediatric PAH., (Copyright © 2024. Published by Elsevier Inc.)

Background: After introducing IL-1/IL-6 inhibitors, some patients with Still and Still-like disease developed unusual, often fatal, pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease., Objective: To facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not stopping IL-1/IL-6 inhibitors after DReSS reaction began., Methods: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6 inhibitors with 37 cases not stopping these drugs., Results: Before the reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease-onset age for reaction cases with preexisting cardiothoracic comorbidities. After the reaction began, increased rates of pulmonary complications and macrophage activation syndrome differentiated drug-reaction cases from drug-tolerant controls (P = 4.7 × 10 -35 and P = 1.1 × 10 -24 , respectively). The initial DReSS feature was typically reported 2 to 8 weeks after initiating IL-1/IL-6 inhibition. In drug-reaction cases stopping versus not stopping IL-1/IL-6-inhibitor treatment, reaction-related features were indistinguishable, including pulmonary complication rates (75% [39 of 52] vs 76% [28 of 37]). Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of macrophage activation syndrome, and improved survival (P = .005, multivariate regression). Resolution of pulmonary complications occurred in 67% (26 of 39) of drug-reaction cases who stopped and in none who continued inhibitors., Conclusions: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6 inhibitors significantly improved outcomes., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

It is increasingly recognised that diverse genetic respiratory disorders present as severe pulmonary hypertension (PH) in the neonate and young infant, but many controversies and uncertainties persist regarding optimal strategies for diagnosis and management to maximise long-term outcomes. To better define the nature of PH in the setting of developmental lung disease (DEVLD), in addition to the common diagnoses of bronchopulmonary dysplasia and congenital diaphragmatic hernia, we established a multidisciplinary group of expert clinicians from stakeholder paediatric specialties to highlight current challenges and recommendations for clinical approaches, as well as counselling and support of families. In this review, we characterise clinical features of infants with DEVLD/DEVLD-PH and identify decision-making challenges including genetic evaluations, the role of lung biopsies, the use of imaging modalities and treatment approaches. The importance of working with team members from multiple disciplines, enhancing communication and providing sufficient counselling services for families is emphasised to create an interdisciplinary consensus., Competing Interests: Conflict of interest: E.D. Austin reports grants from the NIH and a leadership role with TBX4Life. C. Galambos reports leadership roles with PPHNet and TBX4Life. D. Yung reports grants from Merck, Janssen and the NIH. S.O. Vargas reports grants from the Chan Zuckerberg Initiative, consultancy fees from Vertex Pharmaceuticals, lecture fees from the American Academy of Allergy, Asthma & Immunology, participation on a data safety monitoring board or advisory board with Millipore Sigma, and a leadership role with the Society for Pediatric Pathology. E.O. Jackson reports support for attending meetings from Seattle Children's Hospital. E.C. Whalen reports consultancy fees from the Pulmonary Hypertension Association Care Center and a leadership role with PPHNet. N.M. Villafranco reports support for attending meetings from the Children's Hospital of Philadelphia. S.H. Abman reports grants from the NHLBI (U01 HL12118), consultancy fees from Chiesi, and participation on a data safety monitoring board or advisory board with Bayer Pharmaceuticals and the NHLBI. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Children with severe Group 1 pulmonary arterial hypertension (PAH) have an unpredictable response to subcutaneous treprostinil (TRE) therapy, which may be influenced by age, disease severity, or other unknown variables at time of initiation. In this retrospective single-center cohort study, we hypothesized that younger age at TRE initiation, early hemodynamic response (a decrease in pulmonary vascular resistance by ≥30% at follow-up catheterization), and less severe baseline hemodynamics (Rp:Rs < 1.1) would each be associated with better clinical outcomes. In 40 pediatric patients with Group I PAH aged 17 days-18 years treated with subcutaneous TRE, younger age (cut-off of 6-years of age, AUC 0.824) at TRE initiation was associated with superior 5-year freedom from adverse events (94% vs. 39%, p  = 0.002), better WHO functional class (I or II: 88% vs. 39% p  = 0.003), and better echocardiographic indices of right ventricular function at most recent follow-up. Neither early hemodynamic response nor less severe baseline hemodynamics were associated with better outcomes. Patients who did not have a significant early hemodynamic response to TRE by first follow-up catheterization were unlikely to show subsequent improvement in PVRi (1/8, 13%). These findings may help clinicians counsel families and guide clinical decision making regarding the timing of advanced therapies., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Objective: To evaluate the feasibility, tolerability, and adherence with wearable actigraphy devices among infants and children with pulmonary arterial hypertension (PAH)., Study Design: This multicenter, prospective, observational study included children ages 0-6 years with and without PAH. Participants wore the ActiGraph wGT3X-BT on the hip and FitBit Inspire on the wrist during waking hours for 14 days. Steps, vector magnitude counts per minute, activity intensity, heart rate, and heart rate variability were compared between groups., Results: Forty-seven participants (18 PAH, 29 control) were enrolled from 10 North American sites. PAH patients were mostly functional class II (n = 16, 89%) and treated with oral medications at the time of enrollment. The number of wear days was not significantly different between the groups (ActiGraph: 10 [95% CI: 5.5, 12.2] in PAH vs 8 [4, 12] in control, P = .20; FitBit 13 [10, 13.8] in PAH vs 12 [8, 14] in control, P = .87). Complete data were obtained in 81% of eligible ActiGraph participants and 72% of FitBit participants. PAH participants demonstrated fewer steps, lower vector magnitude counts per minute, more sedentary activity, and less intense physical activity at all levels compared with control participants. No statistically significant differences in heart rate variability were demonstrated between the 2 groups., Conclusions: Measurement of physical activity and other end points using wearable actigraphy devices was feasible in young children with PAH. Larger studies should determine associations between physical activity and disease severity in young patients with PAH to identify relevant end points for pediatric clinical trials., Competing Interests: Declaration of Competing Interest Funding for the study was provided by the Department of Health and Human Services/Food and Drug Administration BAA-18-00 123, University of Colorado. The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pediatric precapillary pulmonary hypertension can develop in response to systemic atrial hypertension. Systemic atrial decompression following ventricular assist device (VAD) implantation may not sufficiently lower pulmonary vascular resistance (PVR) to consider heart transplant candidacy. Prostacyclins have been used in adult VAD patients with success, but pediatric data on safety and efficacy in this population are limited. We sought to describe our center's experience to show its safety and to present our current protocol for perioperative use. We reviewed our use of prostacyclin therapy in pediatric patients on VAD support with high PVR from 2016 to 2021. Of the 17 patients who met inclusion, 12 survived to transplant and 1 is alive with VAD in situ . All patients survived posttransplant. With continuous intravenous (IV) epoprostenol or treprostinil therapy, there were no bleeding complications or worsening of end-organ function. A significant reduction was observed in vasoactive inotropic scores by 49% in the first 24 hours post-prostacyclin initiation. The proportion of patients surviving to transplant in this high-risk cohort is favorable. In conclusion, prostacyclins may be safe to use in patients with elevated PVR as part of their VAD and transplant course and may provide a transplant option in those otherwise not candidates., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

Background: Elevated pulmonary vascular resistance (PVR) in the setting of left heart failure may contribute to poor outcomes after pediatric heart transplant (HTx), but peri-transplant management is variable., Methods: We sought to characterize international practice by surveying physicians at pediatric HTx centers., Results: We received 49 complete responses from 39 centers in 16 countries. Most respondents are pediatric cardiologists (90%), practice at centers offering heart (86%) and lung (55%) transplant, and perform pre-HTx acute vasoreactivity testing (AVT, 88%) in patients with elevated PVR. Half (51%) reported defining a PVR cutoff for HTx eligibility as ≤6 WU m 2 (56%) post-AVT (84%). The highest post-AVT PVR ever accepted for HTx ranged from 3-14.4 (median 6) WU m 2 . To treat elevated pre-transplant PVR, phosphodiesterase type 5 inhibitors are most common (65%) followed by oxygen (31%), nitric oxide (14%), endothelin receptor antagonists (11%), and prostacyclins (6%). Nearly a third (31%) do not routinely use pulmonary vasodilators without implantation of a left ventricular assist device (LVAD). Case scenarios highlight treatment variability: in a restrictive cardiomyopathy scenario, HTx listing with post-transplant vasodilator therapy was favored, whereas in a Shone's complex patient with fixed PVR, LVAD ± pulmonary vasodilators followed by repeat catheterization was most common. Management of dilated cardiomyopathy with reactive PVR was variable. Most continue vasodilator therapy until HTx (16%), PVR normalizes (16%) or ≤6 months., Conclusions: Management of elevated PVR in children awaiting HTx is heterogenous. Evidence-based guidelines are needed to allow for longitudinal determination of optimal outcomes and standardized care., (© 2023 Wiley Periodicals LLC.)

Objective: To characterize distinct comorbidities, outcomes, and treatment patterns in children with Down syndrome and pulmonary hypertension in a large, multicenter pediatric pulmonary hypertension registry., Study Design: We analyzed data from the Pediatric Pulmonary Hypertension Network (PPHNet) Registry, comparing demographic and clinical characteristics of children with Down syndrome and children without Down syndrome. We examined factors associated with pulmonary hypertension resolution and a composite outcome of pulmonary hypertension severity in the cohort with Down syndrome., Results: Of 1475 pediatric patients with pulmonary hypertension, 158 (11%) had Down syndrome. The median age at diagnosis of pulmonary hypertension in patients with Down syndrome was 0.49 year (IQR, 0.21-1.77 years), similar to that in patients without Down syndrome. There was no difference in rates of cardiac catheterization and prescribed pulmonary hypertension medications in children with Down syndrome and those without Down syndrome. Comorbidities in Down syndrome included congenital heart disease (95%; repaired in 68%), sleep apnea (56%), prematurity (49%), recurrent respiratory exacerbations (35%), gastroesophageal reflux (38%), and aspiration (31%). Pulmonary hypertension resolved in 43% after 3 years, associated with a diagnosis of pulmonary hypertension at age <6 months (54% vs 29%; P = .002) and a pretricuspid shunt (65% vs 38%; P = .02). Five-year transplantation-free survival was 88% (95% CI, 80%-97%). Tracheostomy (hazard ratio [HR], 3.29; 95% CI, 1.61-6.69) and reflux medication use (HR, 2.08; 95% CI, 1.11-3.90) were independently associated with a composite outcome of severe pulmonary hypertension., Conclusions: Despite high rates of cardiac and respiratory comorbidities that influence the severity of pulmonary hypertension, children with Down syndrome-associated pulmonary hypertension generally have a survival rate similar to that of children with non-Down syndrome-associated pulmonary hypertension. Resolution of pulmonary hypertension is common but reduced in children with complicated respiratory comorbidities., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Single ventricle (SV) patients with pulmonary vascular disease (SV-PVD) are considered poor surgical candidates for Glenn or Fontan palliation. Given limited options for Stage 1 (S1) and Stage 2 (S2) SV patients with SV-PVD, we report on the use of subcutaneous treprostinil (TRE) to treat SV-PVD in this population. This single-center, retrospective cohort study examined SV patients who were not candidates for subsequent surgical palliation due to SV-PVD and were treated with TRE. The primary outcome was ability to progress to the next surgical stage; secondary outcomes included changes in hemodynamics after TRE initiation. Between 3/2014 and 8/2021, 17 SV patients received TRE for SV-PVD: 11 after S1 and 6 after S2 (median PVR 4.1 [IQR 3.2-4.8] WU*m 2 and 5.0 [IQR 1.5-6.1] WU*m 2 , respectively). Nine of 11 (82%) S1 progressed to S2, and 2 (18%) underwent heart transplant (HTx). Three of 6 (50%) S2 progressed to Fontan, 1 underwent HTx and 2 are awaiting Fontan on TRE. TRE significantly decreased PVR in S1 patients with median post-treatment PVR of 2.0 (IQR 1.5-2.6) WU*m 2 . TRE can allow for further surgical palliation in select pre-Fontan patients with SV-PVD, obviating the need for HTx. Improvement in PVR was significant in S1 patients and persisted beyond discontinuation of therapy for most patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Left atrial hypertension (LAH) may contribute to pulmonary hypertension (PH) in premature infants with bronchopulmonary dysplasia (BPD). Primary causes of LAH in infants with BPD include left ventricular diastolic dysfunction or hemodynamically significant left to right shunt. The incidence of LAH, which is definitively diagnosed by cardiac catheterization, and its contribution to PH is unknown in patients with BPD-PH. We report the prevalence of LAH in an institutional cohort with BPD-PH with careful examination of hemodynamic contributors and impact on patient outcomes. This single-center, retrospective cohort study examined children <2 years of age with BPD-PH who underwent cardiac catheterization at Lucile Packard Children's Hospital Stanford. Patients with unrepaired simple shunt congenital heart disease (CHD) and pulmonary vein stenosis (only 1 or 2 vessel disease) were included. Patients with complex CHD were excluded. From April 2010 to December 2021, 34 patients with BPD-PH underwent cardiac catheterization. We define LAH as pulmonary capillary wedge pressure (PCWP) or left atrial pressure (LAP) of at least 10 mmHg. In this cohort, median PCWP was 8 mmHg, with LAH present in 32% ( n = 11) of the total cohort. A majority (88%, n = 30) of the cohort had severe BPD. Most patients had some form of underlying CHD and/or pulmonary vein stenosis: 62% ( n = 21) with an atrial septal defect or patent foramen ovale, 62% ( n = 21) with patent ductus arteriosus, 12% ( n = 4) with ventricular septal defect, and 12% ( n = 4) with pulmonary vein stenosis. Using an unadjusted logistic regression model, baseline requirement for positive pressure ventilation at time of cardiac catheterization was associated with increased risk for LAH (odds ratio 8.44, 95% CI 1.46-48.85, p = 0.02). Small for gestational age birthweight, sildenafil use, and CHD were not associated with increased risk for LAH. LAH was associated with increased risk for the composite outcome of tracheostomy and/or death, with a hazard ratio of 6.32 (95% CI 1.72, 22.96; p = 0.005). While the etiology of BPD-PH is multifactorial, LAH is associated with PH in some cases and may play a role in clinical management and patient outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sullivan, Tandel, Bhombal, Adamson, Boothroyd, Tracy, Moy and Hopper.)

Rationale: Hemodynamic assessments direct care among children with pulmonary hypertension, yet the use of cardiac catheterization is highly variable, which could impact patient care and research. Objectives: We analyzed hemodynamic findings from right heart catheterization (RHC) and left heart catheterization and acute vasodilator testing (AVT) and the safety of catheterization in children with World Symposium on Pulmonary Hypertension (WSPH) group 1 and 3 subtypes in a large multicenter North American cohort. Methods: Of 1,475 children enrolled in the Pediatric Pulmonary Hypertension Network Registry (2014-2020), there were 1,383 group 1 and 3 patients, of whom 671 (48.5%) underwent RHC at diagnosis and were included for analysis. Results: Compared with those without diagnostic RHC, these children were older, less likely to be an infant or preterm, more often female, treated with targeted pulmonary hypertension medications at diagnosis, and had advanced World Health Organization functional class. Catheterization was performed without a difference in complication rates between WSPH groups. Pulmonary capillary wedge pressure was well correlated with left ventricular end-diastolic pressure and left atrial pressures. Results of AVT using three different methods were comparable; positive AVT results were observed in 8.0-11.8% of subjects, did not differ between WSPH groups 1 and 3, and were not associated with freedom from the composite endpoint of lung transplantation or death during follow-up. Conclusions: In a large pediatric pulmonary hypertension cohort, diagnostic RHC with or without left heart catheterization in WSPH group 1 and 3 patients was performed safely at experienced pediatric pulmonary hypertension centers. Hemodynamic differences were noted between group 1 and 3 subjects. Higher mean pulmonary arterial pressure and mean pulmonary arterial pressure/mean systemic arterial pressure ratio were associated with a higher risk of death/transplantation. Findings suggest overall safety and potential value of RHC as a standard diagnostic approach to guide pulmonary hypertension management in children.

Competing Interests: Conflict of interest: S.H. Abman has nothing to disclose. Conflict of interest: M.P. Mullen reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; personal fees from Actelion, outside the submitted work. Conflict of interest: L.A. Sleeper reports grants from the National Heart, Lung, and Blood Institute (subcontract from University of Colorado), during the conduct of the study. Conflict of interest: E.D. Austin has nothing to disclose. Conflict of interest: E.B. Rosenzweig reports grants from the National Institutes of Health, during the conduct of the study. Conflict of interest: J.P. Kinsella has nothing to disclose. Conflict of interest: The University of Colorado contracts with Actelion, Bayer, Gilead and United Therapeutics for D. Ivy to be a consultant and preform clinical research trials. Conflict of interest: R.K. Hopper has nothing to disclose. Conflict of interest: J.U. Raj has nothing to disclose. Conflict of interest: J. Fineman has nothing to disclose. Conflict of interest: R.L. Keller reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study. Conflict of interest: A. Bates has nothing to disclose. Conflict of interest: U.S. Krishnan has nothing to disclose. Conflict of interest: C.M. Avitabile has nothing to disclose. Conflict of interest: A. Davidson has nothing to disclose. Conflict of interest: M.D. Natter reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study. Conflict of interest: K.D. Mandl reports no specific conflicts, however in the interest of full disclosure, reports personal fees from Merck, and philanthropy from Eli Lily to his lab, during the conduct of the study.