Clinical features of paediatric pulmonary hypertension:
`a registry study
`
`Rolf M F Berger, Maurice Beghetti, Tilman Humpl, Gary E Raskob, D Dunbar Ivy, Zhi-Cheng Jing, Damien Bonnet, Ingram Schulze-Neick, Robyn J Barst
`
`Summary
`Background Paediatric pulmonary hypertension, is an important cause of morbidity and mortality, and is insuffi ciently
`characterised in children. The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry
`is a global, prospective study designed to provide information about demographics, treatment, and outcomes in
`paediatric pulmonary hypertension.
`
`Methods Consecutive patients aged 18 years or younger at diagnosis with pulmonary hypertension and increased
`pulmonary vascular resistance were enrolled in TOPP at 31 centres in 19 countries from Jan 31, 2008, to Feb 15, 2010.
`Patient and disease characteristics, including age at diagnosis and at enrolment, sex, ethnicity, presenting symptoms,
`pulmonary hypertension classifi cation, comorbid disorders, medical and family history, haemodynamic indices, and
`functional class were recorded. Follow-up was decided by the patients’ physicians according to the individual’s health-
`care needs.
`
`Findings 362 of 456 consecutive patients had confi rmed pulmonary hypertension (defi ned as mean pulmonary artery
`pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤12 mm Hg, and pulmonary vascular resistance index
`≥3 WU/m–²). 317 (88%) patients had pulmonary arterial hypertension (PAH), which was idiopathic [IPAH] or familial
`[FPAH] in 182 (57%), and associated with other disorders in 135 (43%), of which 115 (85%) cases were associated with
`congenital heart disease. 42 patients (12%) had pulmonary hypertension associated with respiratory disease or
`hypoxaemia, with bronchopulmonary dysplasia most frequent. Finally, only three patients had either chronic
`thromboembolic pulmonary hypertension or miscellaneous causes of pulmonary hypertension. Chromosomal
`anomalies, mainly trisomy 21, were reported in 47 (13%) of patients with confi rmed disease. Median age at diagnosis
`was 7 years (IQR 3–12); 59% (268 of 456) were female. Although dyspnoea and fatigue were the most frequent
`symptoms, syncope occurred in 31% (57 of 182) of patients with IPAH or FPAH and in 18% (eight of 45) of those with
`repaired congenital heart disease; no children with unrepaired congenital systemic-to-pulmonary shunts had syncope.
`Despite severe pulmonary hypertension, functional class was I or II in 230 of 362 (64%) patients, which is consistent
`with preserved right-heart function.
`
`Interpretation TOPP identifi es important clinical features specifi c to the care of paediatric pulmonary hypertension,
`which draw attention to the need for paediatric data rather than extrapolation from adult studies.
`
`Funding Actelion Pharmaceuticals.
`
`Introduction
`Pulmonary hypertension with increased pulmonary
`vascular resistance
`is associated with substantial
`morbidity and mortality. The most recent clinical
`classifi cation defi nes fi ve pulmonary hypertension
`groups, with pulmonary arterial hypertension (PAH)
`being group 1 (the full classifi cation is provided in the
`webappendix).1 PAH can be idiopathic (IPAH), heritable
`(HPAH), or associated with conditions (APAH) such as
`congenital heart disease and can present at any age. It is
`a rare disease with incidence and prevalence estimates of
`2–3 per million and 25–50 per million, respectively.
`Without treatment, median survival after diagnosis of
`IPAH or HPAH has been reported as 2·8 years in adults,
`but survival in children might be worse.2 Clinical trials
`and registries have led to substantial progress in treatment
`of this disorder in adults.2–6 Although pathobiology and
`clinical features share similarities in children and adults,
`paediatric pulmonary hypertension could well diff er from
`
`adult disease.7–9 Adult studies alone cannot provide a basis
`for optimum care for children. However, paediatric
`pulmonary hypertension is insuffi ciently characterised.
`The Tracking Outcomes and Practice
`in Pediatric
`Pulmonary Hypertension (TOPP) registry is a global,
`prospective, observational study designed to provide
`information about demographics, course, treatment, and
`outcomes in paediatric pulmonary hypertension.10
`
`Methods
`Study design
`TOPP is a centre-based, comprehensive registry, which
`was initiated on Jan 31, 2008. Enrolled patients undergo
`assessment, treatment, and follow-up according to the
`judgment of their physicians. No specifi c therapy or
`follow-up protocols are part of TOPP. Patients in clinical
`trials are eligible. Patients were enrolled from 31 centres
`in 19 countries in fi ve continents (sites and investigators
`are listed at the end of the report). Patients with
`
`Articles
`
`Lancet 2012; 379: 537–46
`Published Online
`January 11, 2012
`DOI:10.1016/S0140-
`6736(11)61621-8
`See Comment page 500
`Centre for Congenital Heart
`Diseases—Paediatric
`Cardiology, Beatrix Children’s
`Hospital, University Medical
`Centre Groningen, University
`of Groningen, Netherlands
`(Prof R M F Berger MD);
`Paediatric Cardiology,
`Children’s University Hospital,
`Geneva, Switzerland
`(Prof M Beghetti MD); Paediatric
`Cardiology and Critical Care
`Medicine, The Hospital for Sick
`Children University of Toronto,
`Toronto, ON, Canada
`(T Humpl MD); College of Public
`Health, University of Oklahoma
`Health Sciences Centre,
`Oklahoma City, OK, USA
`(G E Raskob MD); Paediatrics,
`University of Colorado School
`of Medicine, Aurora, CO, USA
`(D D Ivy MD); Department of
`Cardio-Pulmonary Circulation,
`Shanghai Pulmonary Hospital,
`Tongji University School of
`Medicine, Shanghai, China
`(Z-C Jing MD); Paediatric
`Cardiology, Université Paris
`Descartes, Necker Enfants
`Malade, Paris, France
`(D Bonnet MD); Great Ormond
`Street Hospital, London, UK
`(I Schulze-Neick MD); and
`Columbia University College
`of Physicians and Surgeons,
`New York, NY, USA
`(Prof R J Barst MD)
`Correspondence to:
`Rolf M F Berger, Department of
`Paediatric Cardiology, Beatrix
`Children’s Hospital, University
`Medical Centre Groningen,
`PO Box 30 001,
`Groningen 9700 RB, Netherlands
`r.m.f.berger@umcg.nl
`
`See Online for webappendix
`
`www.thelancet.com Vol 379 February 11, 2012
`
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`pulmonary hypertension caused by left-heart disease
`(group 2) were excluded unless the left-heart disease had
`been corrected and the patient had persistent pulmonary
`hypertension with
`increased pulmonary vascular
`resistance at least a year post-repair and no residual left-
`sided disease.
`The study was designed and supervised by the
`Executive Board of the Association for Pediatric
`Pulmonary Hypertension (Board members are listed at
`the end of the report). Data management and analyses
`were done by a contract organisation working with the
`Executive Board.
`
`Study population
`We prespecifi ed diagnosis on or after Jan 1, 2001, to
`provide a population representative of present practice.
`To minimise selection bias, physicians at all sites
`screened all consecutive patients presenting with
`suspected or confi rmed PAH or pulmonary hypertension
`groups 3–5 (classifi ed according to the 2003 3rd World
`Pulmonary Hypertension Symposium11) with increased
`pulmonary vascular resistance. Patients aged between
`3 months and 18 years at the time of diagnosis with PAH
`(group 1), pulmonary hypertension associated with
`respiratory disorders (group 3), chronic thromboembolic
`pulmonary hypertension (group 4), or miscellaneous
`causes of pulmonary hypertension (group 5) were eligible
`if they met the prespecifi ed haemodynamic enrolment
`criteria: pulmonary hypertension, increased pulmonary
`vascular resistance, and normal left-sided fi lling pressures
`irrespective of pulmonary hypertension group.11 We
`included both newly diagnosed patients (incident;
`diagnosis within 3 months of enrolment) and previously
`diagnosed patients (prevalent; diagnosis more than
`3 months before enrolment).
`According to the 2003 classifi cation,11 cases with
`familial aggregation of the disease were classifi ed as
`familial PAH (FPAH), although the most recent
`classifi cation would use HPAH.1 Patients with congenital
`heart disease with left-sided obstruction and persistent
`pulmonary hypertension at least a year post repair
`(without residual obstruction—ie, mean pulmonary
`capillary wedge pressure [mPCWP] ≤12 mm Hg at
`≥1 year post repair with right-heart catheterisation) were
`also eligible (included in group 1). We did not include
`pulmonary
`venous hypertension
`irrespective of
`pulmonary vascular resistance index (PVRi, classically
`defi ned group 2) because therapy for these patients is
`initially directed towards treating the left-sided heart
`disease. Patients with APAH associated with congenital
`heart disease were classifi ed as having an open, clinically
`signifi cant congenital systemic-to-pulmonary shunt
`(unrepaired or repaired but with a substantial residual
`shunt), a corrected (closed) congenital systemic-to-
`pulmonary shunt, or as congenital heart disease that had
`never been associated with a congenital systemic-to-
`pulmonary shunt.
`
`The diagnosis of confi rmed pulmonary hypertension
`required right-heart catheterisation with mean pul-
`monary arterial pressure (mPAP) 25 mm Hg or more,
`PVRi 3 WU/m–² or more, and mPCWP 12 mm Hg or
`less. In cases in which right-heart catheterisation could
`not be done for specifi c clinical reasons (eg, patient died
`before scheduled procedure), patients could be con-
`sidered for enrolment on the basis of confi rmatory
`echocardiography or histopathology, or both, provided
`that the executive board, masked to site, validated the
`diagnosis and agreed with why
`the right-heart
`catheterisation was not done. All patients who met
`enrolment criteria were informed of the registry and
`were eligible to provide written informed consent to
`participate. Parental consent was obtained for patients
`younger than 18 years The protocol was approved by
`institutional review boards and ethics committees.
`
`Patient follow-up and data collection
`We obtained patient and disease characteristics, including
`age at diagnosis and at enrolment, sex, ethnicity,
`presenting symptoms, pulmonary hypertension classi-
`fi cation, comorbid disorders, medical and family history,
`haemodynamic indices, and functional class with an
`electronic case record form. Follow-up was decided by
`the patients’ physicians according to the individual’s
`health-care needs. No visits were required, but consistent
`with standard practice, physicians were encouraged to
`schedule follow-up at least yearly. All patients will be
`followed up for at least 3 years.
`
`Statistical methods and analysis
`TOPP was designed to enrol about 450 patients. A
`priori, we decided that the sample population would
`include incident and prevalent patients. To ensure
`enrolment of a suffi cient number of incident cases, a
`2 to 1 ratio of prevalent to incident patients was
`prespecifi ed with the ability to stop enrolment of
`prevalent patients once the two-thirds target was
`reached. Further,
`the protocol prespecifi ed
`that
`enrolment of patients with PAH associated with
`congenital heart disease could be stopped, either at a
`specifi c site or at all sites, if the number of such patients
`exceeded 50% of the total target population. Last, to
`maximise the global generalisability of the data, patient
`enrolment at a particular site could be stopped to
`prevent overrepresentation of one site.
`The statistical analysis plan was designed to meet the
`registry objectives and was fi nalised before we did any
`analyses. For the aims of this report, analyses are
`descriptive. The populations analysed were the all-
`patients cohort, and the confi rmed pulmonary hyper-
`tension cohort, which included only patients who met all
`enrolment criteria. We summarised continuous data
`using
`standard descriptive
`statistics—mean, SD,
`95% CIs, and median, minimum, maximum, 25th and
`75th percentiles—when appropriate, and categorical data
`
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`using counts and percentages. The denominator for
`percentages was the total number of patients with no
`missing data for each variable analysed. Missing data
`were not imputed. We calculated 95% CIs using the
`normal approximation for the binomial distribution. We
`did not do a formal sample size calculation and hence the
`sample was not powered a priori for specifi c comparisons.
`For formal statistical analyses, we examined categorical
`data with χ² tests and continuous data using analysis of
`variance (ANOVA). The assumptions underlying the
`ANOVA were checked and appropriate non-parametric
`analyses done when the assumption of normality was
`in doubt. We used SAS statistical software package
`(version 8.2 or higher) for the analyses. The cutoff date
`for data inclusion was Feb 15, 2010.
`
`Role of the funding source
`The TOPP registry is supported by a research grant
`from Actelion Pharmaceuticals. Actelion does not
`participate in the management of the registry, nor does
`it have access to the database, the individual sites, or
`patient data. The sponsor had no role in study design,
`analysis, inter pretation of data, writing of the manu-
`script, or the decision to submit the paper for
`publication. All decisions related to the registry lie
`solely with the executive board of the Association for
`Pediatric Pulmonary Hypertension. The executive
`board decided to submit the paper for publication and
`wrote the report with contributions from all authors.
`All authors had access to the data and analyses. The
`corresponding author had full access to all the data in
`
`All patients
`
`Patients with confi rmed pulmonary hypertension
`
`All
`
`Incident
`
`Prevalent
`
`Patients
`Female
`Preterm
`Age at diagnosis (years)
`Weight (kg)
`Height (cm)
`BMI (kg/m²)
`BSA (m²)
`Ethnicity
`White or Hispanic
`Black
`Asian
`Other
`Unknown
`Time from onset symptoms to diagnosis (months)
`Median (IQR)
`Time from diagnosis to enrolment (months)
`Median (range)
`Group I*
`IPAH or FPAH
`APAH-congenital heart disease
`Systemic-to-pulmonary shunt
`Unrepaired
`Repaired
`Never shunt
`Repaired left obstruction
`APAH-connective tissue disease
`APAH-chronic liver disease
`APAH-HIV
`APAH-drugs or toxins
`APAH-HHT
`APAH-thyroid
`APAH-other
`PVOD or PCH
`None of the above
`
`456 (100%)
`268 (59%)
`63 (14%)
`7·1 (6·6–7·6)
`26·5 (24·7–28·4)
`117 (114–120)
`17·05 (16·63–17·48)
`0·93 (0·88–0·97)
`454 (100%)
`302 (67%)
`14 (3%)
`107 (24%)
`15 (3%)
`16 (4%)
`17 (15–20)
`6 (2–19)
`24·0 (21·7–26·4)
`13·7 (1·7–39·8)
`398 (87%)
`212 (53%)
`160 (40%)
`150 (38%)
`91 (23%)
`57 (14%)
`12 (3%)
`7 (2%)
`10 (3%)
`4 (1%)
`0 (0%)
`0 (0%)
`2 (1%)
`2 (1%)
`3 (1%)
`6 (2%)
`5 (1%)
`
`362 (79%)
`214 (59%)
`47 (13%)
`7·5 (7·0–8·1)
`28·0 (25·9–30·1)
`119 (116–123)
`17·21 (16·74–17·68)
`0·94 (0·90–0·99)
`362 (100%)
`229 (63%)
`8 (2%)
`99 (27%)
`13 (4%)
`13 (4%)
`17 (14–20)
`6 (2–19)
`24·4 (21·8–27·1)
`14·1 (2·3–39·8)
`317 (88%)
`182 (57%)
`115 (36%)
`107 (34%)
`61 (19%)
`45 (14%)
`9 (3%)
`7 (2%)
`9 (3%)
`2 (1%)
`0 (0%)
`0 (0%)
`1 (<1%)
`1 (<1%)
`3 (1%)
`6 (2%)
`3 (1%)
`
`102 (28%)
`58 (57%)
`16 (16%)
`8·5 (7·5–9·5)
`30·8 (26·7–35·0)
`124 (118–131)
`17·68 (16·67–18·69)
`1·02 (0·93–1·11)
`102 (100%)
`57 (56%)
`5 (5%)
`33 (32%)
`5 (5%)
`2 (2%)
`24 (16–31)
`6 (3–38)
`0·7 (0·5–0·9)
`0·2 (0·0–1·1)
`88 (86%)
`55 (63%)
`26 (30%)
`25 (28%)
`14 (16%)
`10 (11%)
`2 (2%)
`1 (1%)
`1 (1%)
`0 (0%)
`0 (0%)
`0 (0%)
`1 (1%)
`0 (0%)
`0 (0%)
`4 (5%)
`2 (2%)
`
`260 (72%)
`156 (60%)
`31 (12%)
`7·2 (6·5–7·8)
`26·8 (24·4–29·3)
`117 (113–121)
`17·02 (16·50–17·54)
`0·91 (0·86–0·97)
`260 (100)
`172 (66%)
`3 (1%)
`66 (25%)
`8 (3%)
`11 (4%)
`15 (12–18)
`5 (1–17)
`33·7 (30·7–36·7)
`28·5 (12·6–48·9)
`229 (88%)
`127 (55%)
`89 (39%)
`82 (36%)
`47 (21%)
`35 (15%)
`7 (3%)
`6 (3%)
`8 (3%)
`2 (1%)
`0 (0%)
`0 (0%)
`0 (0%)
`1 (<1%)
`3 (1%)
`2 (1%)
`1 (<1%)
`(Continues on next page)
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`(Continued from previous page)
`Group 3*
`Bronchopulmonary dysplasia
`Interstititial lung disease
`High altitude
`Congenital diaphragmatic hernia
`Congenital pulmonary hypoplasia
`Disordered breathing or OSAS
`Kyphoscoliosis
`Other
`Groups 4 or 5*
`WHO Functional Class
`I
`II
`III
`IV
`6 min walk test
`Metres (mean [95% CI])
`
`All patients
`
`Patients with confi rmed pulmonary hypertension
`
`All
`
`Incident
`
`Prevalent
`
`52 (11%)
`17 (33%)
`12 (23%)
`7 (13%)
`6 (12%)
`7 (13%)
`5 (10%)
`2 (4%)
`2 (4%)
`4 (1%)
`449 (98%)
`54 (12%)
`212 (47%)
`146 (33%)
`37 (8%)
`175 (38%)
`407 (389–426)
`
`42 (12%)
`11 (26%)
`10 (24%)
`7 (17%)
`4 (10%)
`5 (12%)
`5 (12%)
`2 (5%)
`2 (5%)
`3 (1%)
`362 (100%)
`45 (12%)
`185 (51%)
`108 (30%)
`24 (7%)
`153 (42%)
`417 (398–436)
`
`13 (13%)
`3 (23%)
`4 (31%)
`3 (23%)
`1 (8%)
`2 (15%)
`0 (0%)
`0 (0%)
`1 (8%)
`1 (1%)
`102 (100%)
`11 (11%)
`52 (51%)
`28 (27%)
`11 (11%)
`46 (45%)
`445 (414–476)
`
`29 (11%)
`8 (28%)
`6 (21%)
`4 (14%)
`3 (10%)
`3 (10%)
`5 (17%)
`2 (7%)
`1 (3%)
`2 (1%)
`260 (100%)
`34 (13%)
`133 (51%)
`80 (31%)
`13 (5%)
`107 (41%)
`405 (381–429)
`
`Data are n (%) or mean (95% CI) unless otherwise specifi ed. Incident cases were those diagnosed within 3 months of enrolment. Prevalent cases were those diagnosed more
`than 3 months before enrolment. Two patients are missing for pulmonary hypertension classifi cation because of missing data. Patients could be counted in more than one
`APAH disease category and in more than one associated disease category for group 3. BMI=body-mass index. BSA=body surface area. IPAH=idiopathic pulmonary arterial
`hypertension. FPAH=familial pulmonary arterial hypertension. APAH=pulmonary arterial hypertension associated with other disorders. HHT=hereditary haemorrhagic
`teleangiectasia. PVOD=pulmonary veno-occlusive disease. PCH=pulmonary capillary haemangiomatosis. OSAS=obstructive sleep apnoea syndrome. *Classifi ed according to
`(3rd World Pulmonary Hypertension Symposium11).
`
`Table 1: Demographic and clinical characteristics at diagnosis in all patients and in patients with confi rmed pulmonary hypertension
`
`the study and had fi nal responsibility for the decision to
`submit for publication.
`
`Results
`From Jan 31, 2008, to Feb 15, 2010, 456 patients were
`enrolled. Enrolment of prevalent and incident patients
`was stopped at one site on Feb 10 and Aug 19, of 2009,
`respectively, to prevent overrepresentation of that site.
`Enrolment of prevalent patients at all other sites was
`stopped on May 22, 2009, to prevent such patients
`accounting for more than two-thirds of the total. No
`further predefi ned restriction rules were required.
`Of the 456 patients in the all-patients cohort, 362 (79%)
`met all enrolment criteria for confi rmed pulmonary
`hypertension, with 357 (99%) diagnoses based on right-
`heart catheterisation and fi ve (1%) based on independently
`reviewed echocardiography and clinical records—of these
`fi ve cases, three were further confi rmed by histo-
`pathological fi ndings. Of the confi rmed pulmonary
`hypertension cases, about 30% were incident and about
`70% were prevalent (table 1). The distribution of the all-
`patients cohort (456) was: Europe 157, Turkey 33, China 70,
`Japan 14, Australia 15, Brazil one, Mexico 21, USA 135,
`Canada ten. Of the 94 patients excluded from the
`confi rmed pulmonary hypertension cohort, 11 did not
`meet haemodynamic criteria (six with mPAP<25 mm Hg
`or PVRI<3 WU/m–²; fi ve with mPCWP>12 mm Hg), and
`
`83 did not have suffi cient data to adequately calculate
`PVRi. Table 1 shows patient characteristics of each cohort.
`We recorded no apparent diff erences between patients in
`the confi rmed pulmonary hypertension cohort and those
`excluded from that cohort.
`In those with confi rmed disease, the median age at
`diagnostic right-heart catheterisation was 7·0 years
`(IQR 3–12) with 61 patients (17%) diagnosed between
`3 and 24 months of age, 111 (31%) between 2 and 6 years,
`89 (25%) between 7 and 11 years, and 101 (28%) between
`12 and 18 years. The average time from diagnostic right-
`heart catheterisation to enrolment was about 34 months
`in prevalent cases, and less than a month in incident
`cases (table 1). The mean time from onset of symptoms
`to diagnosis did not seem to diff er between incident and
`prevalent cases, but tended to be longer when PAH was
`associated with congenital heart disease with unrepaired
`or residual systemic-to-pulmonary shunt and shorter in
`APAH not associated with congenital heart disease than
`in other subgroups (table 2).
`PAH (group 1) and pulmonary hypertension associated
`with respiratory disorders or hypoxaemia (group 3) made
`up 88% (317) and 12% (42), respectively, of the confi rmed
`pulmonary hypertension cohort (362). Only three patients
`(<1%) were in pulmonary hypertension group 4 or 5.
`There was an overall female preponderance (1·4 to 1) that
`was unchanged when stratifi ed by incident or prevalent
`
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`case, pulmonary hypertension group, PAH subgroup, or
`age. Of the 317 PAH patients, 57% had IPAH or FPAH
`and 36% had APAH associated with congenital heart
`disease (table 2). Most congenital heart disease cases
`(106 out 115, 93%) included systemic-to-pulmonary shunts.
`APAH associated with disorders other than congenital
`heart disease was reported in 6% of PAH patients (table 2).
`Bronchopulmonary dysplasia was the most frequent
`disorder associated with pulmonary hypertension group 3,
`present in 11 of 42 patients (26%). We recorded a signifi cant
`association between the number of patients in each
`pulmonary hypertension group and age (p=0·01), with
`pulmonary hypertension group 3 disorders occurring
`more frequently in patients aged 3–24 months at diagnosis
`than
`in older age-at-diagnosis cohorts
`(15 aged
`3–24 months, 25%; 12 aged 2–6 years, 11%; six aged
`7–11 years, 7%; and nine aged 12–18 years, 9%).
`We recorded comorbid disorders in 86 of 362 (24%)
`patients with confi rmed pulmonary hypertension.
`Chromosomal disorder was most frequent (47, 13%)
`with 42 patients having trisomy 21. There was a
`
`trisomy 21 and
`signifi cant association between
`pulmonary hypertension group (p=0·02). Trisomy 21
`was present more often in patients with group 3 disorders
`(nine of 42, 21%) than in those with PAH (group 1,
`32 of 317, 10%). Within the PAH cohort (317), trisomy 21
`was present in 26 of 115 (23%) patients with APAH
`associated with congenital heart disease, fi ve of 182 (3%)
`patients with IPAH or FPAH, and one of 20 (5%) patients
`with APAH not associated with congenital heart disease.
`In the remaining 44 patients, we recorded a spectrum of
`other chromosomal abnormalities, syndromes, and non-
`chromosomal anomalies.
`Of
`the 362 patients with confi rmed pulmonary
`hypertension, 21 (6%) had lived at an altitude greater than
`2000 m for more than 6 months, 47 (13%) were premature
`(gestation <37 weeks), and eight (2%) had a history of
`persistent pulmonary hypertension of the newborn. In
`fi ve of these eight, pulmonary hypertension seemed to
`persist and was confi rmed by right-heart catheterisation
`(done at >3 months of age), whereas in the other three, the
`disorder was thought to have resolved during the neonatal
`
`All PH confi rmed PH group 3
`
`PH group 1
`
`IPAH or FPAH
`
`APAH with CHD
`
`APAH excluding
`APAH with CHD
`
`Patients
`Female
`Preterm
`Age at diagnosis (years)
`(mean [95% CI])
`Incident patients
`Ethnicity
`White or Hispanic
`Black
`Asian
`Other
`Unknown
`Time from onset symptoms to
`diagnosis (months) (mean [95% CI])
`Median (IQR)
`Time from diagnosis to enrolment
`(months) (mean [95% CI])
`Median (IQR)
`WHO functional class
`I
`II
`III
`IV
`6 min walk test
`Metres (mean [95% CI])
`
`All CHD
`
`Unrepaired shunt*
`
`Repaired shunt
`
`Never shunt
`
`362 (100%)
`214 (59%)
`47 (13%)
`7·5 (7·0–8·1)
`
`42 (100%)
`26 (62%)
`18 (43%)
`5·5 (3·7–7·3)
`
`182 (100%)
`109 (60%)
`14 (8%)
`7·6 (6·9–8·3)
`
`115 (100%)
`66 (57%)
`11 (10%)
`7·7 (6·7–8·8)
`
`61 (100%)
`38 (62%)
`5 (8%)
`8·4 (6·9–9·9)
`
`45 (100%)
`25 (56%)
`6 (13%)
`7·4 (5·8–8·9)
`
`9 (100%)
`3 (33%)
`0 (0%%)
`4·8 (0·6–9·0)
`
`20 (100%)
`11 (55%)
`4 (20%)
`10·0 (7·5–12·4)
`
`102 (28%)
`362 (100)
`229 (63%)
`8 (2%)
`99 (27%)
`13 (4%)
`13 (4%)
`17 (14–20)
`
`6 (2–19)
`24 (22–27)
`
`13 (31%)
`42 (100)
`35 (83%)
`0 (0%)
`3 (7%)
`2 (5%)
`2 (5%)
`16 (7–25)
`
`55 (30%)
`182 (100)
`118 (65%)
`5 (3%)
`48 (26%)
`5 (3%)
`6 (3%)
`15 (11–19)
`
`26 (23%)
`115 (100)
`65 (57%)
`2 (2%)
`40 (35%)
`3 (3%)
`5 (4%)
`24 (17–32)
`
`4 (1–20)
`25 (18–32)
`
`5 (1–17)
`25 (21–29)
`
`9 (4–29)
`24 (19–28)
`
`14 (23%)
`61 (100)
`35 (57%)
`2 (3%)
`23 (38%)
`1 (2%)
`0
`30 (16–44)
`
`10 (3–28)
`23 (16–29)
`
`10 (22%)
`45 (100)
`28 (62%)
`0 (0%)
`12 (27%)
`2 (4%)
`3 (7%)
`19 (11–26)
`
`8 (4–25)
`25 (18–32)
`
`2 (22%)
`9 (100)
`2 (22%)
`0 (0%)
`5 (56%)
`0 (0%)
`2 (22%)
`22 (4–40)
`
`9 (7–45)
`24 (3–46)
`
`7 (35%)
`20 (100)
`8 (40%)
`1 (5%)
`8 (40%)
`3 (15%)
`0 (0%)
`5 (1–8)
`
`3 (1–4)
`16 (6–27)
`
`14 (2–40)
`362 (100%)
`45 (12%)
`185 (51%)
`108 (30%)
`24 (7%)
`153 (42%)
`417 (398–436)
`
`22 (2–40)
`42 (100%)
`8 (19%)
`20 (48%)
`13 (31%)
`1 (2%)
`10 (24%)
`466 (352–580)
`
`15 (1–43)
`182 (100%)
`28 (15%)
`84 (46%)
`55 (30%)
`15 (8%)
`83 (46%)
`407 (379–434)
`
`14 (4–41)
`115 (100%)
`8 (7%)
`72 (63%)
`31 (27%)
`4 (3%)
`50 (43%)
`422 (393–452)
`
`13 (4–36)
`61 (100%)
`2 (3%)
`40 (66%)
`18 (30%)
`1 (2%)
`30 (49%)
`420 (385–456)
`
`19 (6–45)
`45 (100%)
`4 (9%)
`28 (62%)
`13 (29%)
`0 (0%)
`19 (42%)
`429 (370–488)
`
`20 (4–26)
`9 (100%)
`2 (22%)
`4 (44%)
`0 (0%)
`3 (33%)
`1 (11%)
`355 (NC)
`
`8 (1–23)
`20 (100%)
`1 (5%)
`8 (40%)
`7 (35%)
`4 (20%)
`9 (45%)
`427 (330–525)
`
`Patients from pulmonary hypertension groups 4 and 5 (n=3), included in all patients with confi rmed pulmonary hypertension, are not depicted separately in this table. APAH=pulmonary arterial hypertension
`associated with other disorders. IPAH=idiopathic pulmonary arterial hypertension. FPAH=familial pulmonary arterial hypertension. CHD=congenital heart disease. NC=not calculated. *Or partial repair.
`
`Table 2: Demographic and clinical characteristics at diagnosis in patients with confi rmed pulmonary hypertension (PH confi rmed) diagnosis according to pulmonary hypertension
`groups and subgroups
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`
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`
`period with PAH subsequently diagnosed by right-heart
`catheterisation. A history of bronchopulmonary dysplasia
`was reported in 17 of 362 patients (5%) and was regarded
`as the cause of the pulmonary hypertension by the treating
`physician in 11. Of the 362 patients, 34 (9%) had reactive
`airway disease, 23 (6%) had sleep disordered breathing or
`obstructive apnoeas (with obstructive sleep apnoea judged
`causative for the pulmonary hypertension in fi ve), and
`168 (46%) had a history of congenital heart disease, which
`was deemed causative for pulmonary hypertension in 115.
`Family history was available in 320 of 362 patients with
`confi rmed pulmonary hypertension. Family history for
`PAH was present in 21 of 182 patients with PAH without
`an associated disorder (12% FPAH) and in two of
`20 patients with APAH not associated with congenital
`heart disease (10%).Genetic testing was done for 56 of
`the 317 patients with PAH, eight of whom (14%) had
`abnormal results—ie, four of the 29 IPAH (14%), two of
`the nine FPAH (22%), and two of the 18 APAH (11%)
`patients. Because of patient-privacy regulations, the
`abnormality cannot be disclosed in the registry.
`The most frequently reported symptoms at presentation
`were dyspnoea on exertion and fatigue (table 3). Syncope
`was reported in 73 of 298 (25%) patients without shunt
`defi ned as either no history of a congenital systemic-to-
`pulmonary shunt, or a repaired congenital systemic-to-
`pulmonary shunt without a residual shunt (in about 30%
`with IPAH or FPAH and in roughly 20% without shunt),
`but was not reported in any child with an unrepaired or
`
`residual congenital systemic-to-pulmonary shunt. A
`history of syncope was less frequent in the youngest age
`group at diagnosis (two aged 3–24 months; 3%) than in
`older age groups at diagnosis: 24 aged 2–6 years, 22%;
`24 aged 7–11 years, 27%; and 23 aged 12–18 years, 23%
`(p=0·0006).
`We recorded functional class at diagnosis for all
`patients. Irrespective of pulmonary hypertension group,
`most (230 [64%] of 362 patients with confi rmed
`pulmonary hypertension) were in functional class I
`or II at diagnosis. The 6 min-walk test was reported in
`about
`150 patients with confi rmed pulmonary
`hypertension with a mean distance of roughly 420 m
`(table 2). This test was not done in children in the
`youngest age group (3–24 months), but was done in
`23% (25) of children aged 2–6 years, 58% (52) of those
`aged 7–11 years, and 75% (76) of those aged 12–18 years
`at diagnosis.
`Table 4 shows haemodynamic indices at diagnosis. Of
`362 patients with confi rmed pulmonary hypertension,
`76 (21%) had cardiac index (ie, systemic blood fl ow)
`<2·5 L/min per m² (normal 2·5–4·0 L/min per m²);
`34 (9%) had mean right atrial pressure >12 mm Hg.
`Haemodynamics diff ered signifi cantly between patients
`with PAH (group 1) and patients with pulmonary
`hypertension associated with respiratory disorders or
`hypoxaemia (group 3). mPAP, mean systemic arterial
`pressure (mSAP), mPAP to mSAP ratio, PVRi, systemic
`vascular resistance index (SVRi), PVRi to SVRi ratio, and
`
`All PH
`confi rmed
`
`PH group 3
`
`PH group 1
`
`IPAH or FPAH APAH with congenital heart disease
`
`APAH excluding
`APAH with CHD
`
`All CHD
`
`Unrepaired
`shunt*
`
`Repaired
`shunt
`
`Never shunt
`
`Patients
`Dyspnoea with exertion
`Fatigue
`Syncope
`Cyanosis with exertion
`Cough
`Cyanosis with rest
`Dyspnoea with rest
`Chest pain or discomfort
`Near-syncope
`Dizziness
`Palpitations
`Pallor with exertion
`Irritability
`
`362 (100%)
`235 (65%)
`149 (41%)
`73 (20%)
`64 (18%)
`48 (13%)
`44 (12%)
`39 (11%)
`39 (11%)
`28 (8%)
`25 (7%)
`22 (6%)
`17 (5%)
`17 (5%)
`
`42 (100%)
`22 (52%)
`12 (29%)
`3 (7%)
`10 (24%)
`6 (14%)
`11 (26%)
`12 (29%)
`3 (7%)
`1 (2%)
`2 (5%)
`0 (0%)
`3 (7%)
`5 (12%)
`
`182 (100%)
`121 (66%)
`82 (45%)
`57 (31%)
`24 (13%)
`32 (18%)
`7 (4%)
`13 (7%)
`24 (13%)
`21 (12%)
`14 (8%)
`12 (7%)
`8 (4%)
`8 (4%)
`
`115 (100%)
`77 (67%)
`47 (41%)
`10 (9%)
`27 (23%)
`8 (7%)
`22 (19%)
`11 (10%)
`7 (6%)
`5 (4%)
`6 (5%)
`6 (5%)
`5 (4%)
`3 (3%)
`
`61 (100%)
`48 (79%)
`29 (48%)
`0 (0%)
`22 (36%)
`1 (2%)
`15 (25%)
`3 (5%)
`4 (7%)
`1 (2%)
`4 (7%)
`6 (10%)
`5 (8%)
`2 (3%)
`
`45 (100%)
`24 (53%)
`13 (29%)
`8 (18%)
`5 (11%)
`7 (16%)
`4 (9%)
`6 (13%)
`2 (4%)
`4 (9%)
`2 (4%)
`0 (0%)
`0 (0%)
`1 (2%)
`
`9 (100%)
`5 (56%)
`5 (56%)
`2 (22%)
`0 (0%)
`0 (0%)
`3 (33%)
`2 (22%)
`1 (11%)
`0 (0%)
`0 (0%)
`0 (0%)
`0 (0%)
`0 (0%)
`
`20 (100%)
`14 (70%)
`6 (30%)
`3 (15%)
`3 (15%)
`2 (10%)
`4 (20%)
`3 (15%)
`4 (20%)
`1 (5%)
`2 (10%)
`3 (15%)
`0 (0%)
`1 (5%)
`
`Data are number (%). Patients from pulmonary hypertension groups 4 and 5 (n=3), included in all patients with confi rmed pulmonary hypertension, are not depicted
`separately in this table. Full details are provided in the webappendix. APAH=pulmonary arterial hypertension associated with other disorders. IPAH=idiopathic pulmonary
`arterial hypertension. FPAH=familial pulmonary arterial hypertension. CHD=congenital heart disease. *Or partial repair.
`
`Table 3: Clinical symptoms at diagnosis, reported for 5% or more of all patients with confi rmed pulmonary hypertension (PH confi rmed), according to
`pulmonary hypertension groups and subgroups
`
`542
`
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`All patients with
`PH confi rmed
`
`PH group 3
`
`PH group 1
`
`IPAH or FPAH
`
`APAH with CHD
`
`All CHD
`
`357 (99%)
`
`42 (100%)
`
`178 (98%)
`
`115 (100%)
`
`APAH excluding
`APAH with CHD
`
`Unrepaired
`shunt*
`
`61 (100%)
`
`Repaired
`shunt
`
`45 (100%)
`
`Never shunt
`
`9 (100%)
`
`19 (95%)
`
`345 (95%)
`7 (7–8)
`··
`357 (99%)
`58 (56–59)
`··
`357 (99%)
`8 (8–9)
`··
`353 (98%)
`68 (66–69)
`··
`348 (96%)
`3·7 (3·5–3·8)
`··
`357 (99%)
`1·00 (1·0–1·0)
`··
`353 (98%)
`0·86 (0·7–1·0)
`··
`357 (99%)
`16·0 (14·9–17·0)
`··
`340 (94%)
`19·7 (18·7–20·8)
`··
`340 (94%)
`0·80 (0·6–1·0)
`··
`202 (56%)
`66% (65–67)
`··
`214 (59%)
`91% (90–92)
`··
`117 (36)
`206 (64)
`
`41 (98%)
`7 (6–8)
`··
`42 (100%)
`44 (39–48)
`··
`42 (100%)
`9 (8–9)
`··
`42 (100%)
`62 (58–67)
`··
`41 (98%)
`4·2 (3·6–4·8)
`··
`42 (100%)
`1·00 (1·0–1·0)
`··
`42 (100%)
`0·69 (0·6–1·0)
`··
`42 (100%)
`9·8 (8·1–11·5)
`··
`41 (98%)
`15·8 (13·2–18·3)
`··
`41 (98%)
`0·66 (0·5–1·0)
`··
`30 (71%)
`66% (63–70)
`··
`32 (76%)
`86% (81–91)
`··
`21 (51)
`20 (49)
`
`172 (95%)
`7 (6–8)
`0·73
`178 (98%)
`59 (57–62)§
`<0·0001
`178 (98%)
`8 (8–9)
`0·99
`176 (97%)
`68 (66–70)§
`0·04
`175 (96%)
`3·4 (3·2–3·6)§
`0·02
`182 (100%)
`1·00 (1·0–1·0)
`0·92
`176 (97%)
`0·87 (0·7–1·0)§
`0·0001
`178 (98%)
`17·2 (15·8–18·6)§
`<0·001
`169 (93%)
`20·5 (19·2–21·8)§
`0·002
`169 (93%)
`0·82 (0·6–1·0)§
`0·02
`72 (40%)
`66% (64–68)
`0·96
`78 (43%)
`94% (93–95)§
`<0·0001
`61 (38)
`100 (62)
`
`110 (96%)
`7 (7–8)
`··
`115 (100%)
`61 (57–64)§
`··
`115 (100%)
`9 (8–9)
`··
`113 (98%)
`68 (65–70)§