The Epidemiology Disclosures of At Risk groups for Pediatric PH - - PowerPoint PPT Presentation

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The Epidemiology Disclosures of At Risk groups for Pediatric PH - - PowerPoint PPT Presentation

3/10/2017 The Epidemiology Disclosures of At Risk groups for Pediatric PH The University Medical Center Groningen has received fees for advisory board and steering committee activities of Prof. Berger from: - Actelion, R.M.F. Berger -


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University Medical Center Groningen The Netherlands

10th International Conference Neonatal and Childhood Pulmonary Vascular Disease San Francisco 2017

The Epidemiology

  • f At Risk groups

for Pediatric PH

R.M.F. Berger

University Medical Center Groningen The Netherlands

Disclosures

The University Medical Center Groningen has received fees for advisory board and steering committee activities of Prof. Berger from:

  • Actelion,
  • Bayer,
  • Glaxo-Smith-Kline,
  • Lilly

University Medical Center Groningen The Netherlands

The Epidemiology

  • f At Risk groups

for Pediatric PH

University Medical Center Groningen The Netherlands

Modified classification of PH: 5th WSPH (Nice 2013)

  • 1. Pulmonary arterial hypertension

1.1 Idiopathic PAH 1.2 Heritable PAH

1.2.1 BMPR2 1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3 1.2.3 Unknown

1.3 Drug- and toxin-induced 1.4 Associated with:

1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1’ Pulmonary veno-occlusive disease &/or pulmonary capillary haemangiomatosis 1’’ Persistent PH of the newborn (PPHN)

  • 2. PH due to LHD

2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow obstruction

  • 3. PH due to lung diseases and/or hypoxia

3.1 COPD 3.2 Interstitial lung disease 3.3 mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases

3.7.1 Congenital diaphragmatic hernia 3.7.2 Bronchopulmonary dysplasia

  • 4. CTEPH
  • 5. PH with unclear multifactorial mechanisms

5.1 Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: segmental PH, tumoural obstruction, fibrosing mediastinitis, chronic renal failure

Simonneau G, et al. J Am Coll Cardiol 2013;

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University Medical Center Groningen The Netherlands

Epidemiology of Pediatric PAH

data from large registries

TOPP 1 Reveal-children 2 Patients, n 362 216 Age (yrs), median 7.5 7 Female, % 59 64 Group 1: PAH 317 (88) 216 (100) IPAH/HPAH 212 (53) 122 (56) CHD 160 (40) 23 (36) CTD 9 (3) 10 (5) Portopulmonary 2 (1) 3 (1) Other 14 (4) 4 (2) Group 3: Lung disease 42 (12) NE Other 3 (1) NE

5

  • 1. Berger et al; Lancet 2012.
  • 2. Barst et al; Circulation 2012

Values given are n (%) unless otherwise indicated

University Medical Center Groningen The Netherlands

Genetics in Pediatric iPAH/HPAH

known PAH-genes

BMPR2 ACVRL1 ENG TBX4 Total Levy et al.

Eur Resp J 2016

5 14% 4 11% NT 3 8% 37 100% Harrison et al

Circulation 2005

2 13% 1 7% 1 7% NT 16 100% Kerstjens et al

J Med Genet 2013

NT NT NT 3 15% 20 100%

Rosenzweig et al JHLT 2008

8 10% NT NT NT 78 100%

Pfarr Respir Res 2013

4 14% 2 7% 1 (VUS) 4% NT 29 100%

Compared to adult PAH, the genetic architecture of pediatric PAH seems enriched in ACVRL1 and TBX4 mutations (Levy et al, 2016)

NT=Not Tested

University Medical Center Groningen The Netherlands

Pediatric PAH in Hereditary Hemorrhagic Telangiectasia (HHT)

  • HHT presents at all ages
  • 50% ACVRL1 mutation
  • Of these 16% PAH
  • ACVRL1 mutation carriers are younger at PAH diagnosis, but have

worse prognosis

Smoot et al, Arch Dis Child 2009

University Medical Center Groningen The Netherlands

Congenital Heart Disease

Cumulative incidence of PH after shunt closure

Dutch ConCor registry

Van Riel et al. JACC 2016

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University Medical Center Groningen The Netherlands

Cumulative incidence of PH after shunt closure

specified per age at closure

Van Riel et al. JACC 2016

University Medical Center Groningen The Netherlands

Prevalence of PAH-CHD

per clinical subclassification ConCor Dutch National Registry for adults with CHD, 2014

PAH No PAH Total %

  • D. Post-operative PAH

17 1112 1129 1,5 (Age at repair: median 0.6 yrs, range 0.2-7.6 yrs)

Van Riel , Int J Cardiol 2014

Children, Epidemiological survey 1991-2005 in the Netherlands

Van Loon, Circulation 2010

University Medical Center Groningen The Netherlands

Pediatric PAH associated with CTD

  • Juvenile systemic sclerosis (rare)
  • Prevalence of PAH is < 10%
  • Systemic juvenile idiopathic arthritis (JIA)
  • PAH and ILD rare, underestimated?
  • Systemic Lupus Erythematosus
  • Sporadic cases
  • Case reports and small series, in line with registry data
  • Screening?

Rabinovich CE; Nat Rev Rheumatol 2011 Kimura et al; Arthr Care Res 2013

University Medical Center Groningen The Netherlands

Pediatric PortoPulmonary Hypertension

  • POPH chilldren, single center study
  • PAH in 0.5% of the children with portal hypertension,
  • and in 0.9% of the children with end-stage liver disease

awaiting transplantation

  • Portosystemic shunts
  • Hepatopulmonary syndrome
  • pulmovary AV malformations more frequent (6-20%)
  • Median survival: 3 months untreated
  • 80% 5-year probability of survival whentreated

(CPSS closure, pulmonary vasodilators, and/or liver Tx).

Ecochard-Dugelay et al; J Pediatr Gastroenterol Nutr. 2015

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Congenital portosystemic shunts

Abernethy malformation

University Medical Center Groningen The Netherlands

Other congenital AV shunts

  • Vein of Galen malformation (cerebral)
  • presenting features: severe PH and high-output cardiac failure in

the newborn period

  • The natural history mortality of 42–91% if untreated.

University Medical Center Groningen The Netherlands

Pediatric PAH associated with HIV

  • HIV in Africa

The prevalence of PH in a pooled sample of 664 (adult) patients was 14% (95% CI 6%-23%) Prevalence reduced (eliminated) with early and adequate treatment of HIV? Non/hardly-existing in children in developed countries?

Bigna JJR, et al. BMJ 2016

University Medical Center Groningen The Netherlands

PH in preterm infants

Arjaans et al, in preparation

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University Medical Center Groningen The Netherlands

PH in preterm infants

0.0 0.2 0.4 0.6 0.8 1.0 Proportion PH No BPD Mild BPD Moderate BPD Severe BPD Bronchopulmonary Dysplasia Classification

  • Heterogeneity
  • Bias
  • Presence of PH associated with increased mortality
  • Lack of data on longer term follow up

Arjaans et al, in preparation

University Medical Center Groningen The Netherlands

PH in childhood interstitial lung disease chILD

Incidence reported as

  • 3.6 cases per million in Ireland and the UK (2002)
  • 1.3 cases per million in Germany (2009)

University Medical Center Groningen The Netherlands

chILD

Occurrence of Pulmonary Hypertension

  • Only observational case series, mainly retrospective
  • No clinical trials or population-based observational studies.
  • 10 availble studies:

frequencies of PH ranged from 1% to 64%.

  • nly 50% of the studies described the investigative tests used to

diagnose pulmonary hypertension (cardiac cath and/or echo and/or ECG)

  • In these latter studies:

frequencies of PH ranging from 25% to 64%.

Bromley et al. Pediatr Pulmonol 2016

University Medical Center Groningen The Netherlands

chILD Survival

10 20 30 40 50 60 70 80 90 100 2 4 5

Fan et al AJRCCM 1997

Years survival

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chILD

Risk factors for Mortality

OR CI Female sex 1.75 0.73-4.20 CHD 0.49 0.17-1.37 Prematurity 3.60 1.18-10.96 Pulmonary Hypertension 6.84 2.57-18.20

Deutsch et al AJRCCM 2007

5-year survival Children with DLD (1 month to 18 yrs) 64% Those who presented with PH 38%

Fan et al AJRCCM 1997,

University Medical Center Groningen The Netherlands

Pediatric PAH, Comorbidities

TOPP Patients, n 362 Age (yrs), median 8.9 Comorbidities 86 (24) T risomy 21 42 (12) Other 44 (12)

chromosomal, non-chromosomal, syndromes

History of PPHN 8 (2*) ≥ 10 times normal; ≥ 2.5 times higher controlling for trisomy 21

Berger et al. Lancet 2012

University Medical Center Groningen The Netherlands

PH in children with Down Syndrome

  • Increased frequency of PH in tris 21, accelerated PVD
  • Risk factors:
  • PPHN (prevalence 5%)
  • CHD (prevalence 40-50%)
  • Obstructive upper airway (OSAS)
  • Airway infections / immune system
  • Developmental lung anomalies
  • Alveolar rarefaction
  • Vascular anomalies

University Medical Center Groningen The Netherlands

PAH with abnormal pulmonary vasculature

  • Congenital Diaphragmatic Hernia
  • Early PH

~100%

  • Late PH

~ 20-30%?

  • Lung hypoplasia
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University Medical Center Groningen The Netherlands

PAH with abnormal pulmonary vasculature

  • Scimitar syndrome (1-3 in every 100,000 live births)
  • Isolated unilateral absence of PA (~1 in 200.000 pers)

PH in 40% over time

University Medical Center Groningen The Netherlands

Pediatric CTEPH

  • Extremely rare or non-existing?
  • Mostly, thromboembolic processes proximal in PA and associated

with indwelling lines, procedures etc

  • “Pediatric CTEPH”: Ventriculo-atrial drain

University Medical Center Groningen The Netherlands

Ped PH associated with Sickle Cell Disease

  • Prevalence of PH (TR Vmax >2,5m/s) in children with SCD was 21

% (95 % CI 16--26)

  • PH is confirmed in about 10% of patients with elevated TRVmax
  • Prevalence of elevated TRJV declined to 11 % (95 % CI 9–13) when

using cutoff of ≥3 m/s.

  • Fourfold higher risk of death among persons with SCD who have

increased TR Vmax

Musa et al Ann Hematol 2016 Gladwin et al NEJM 2004

University Medical Center Groningen The Netherlands

Other risk groups

  • Heterotaxia
  • Metabolic diseases

(e.g cobalamin C deficiency)

  • Syndromes
  • Schistosomiasis

“100 years of neglect in paediatric schistosomiasis”

Bustinduy et al Parasitology 2017

  • Pulmonary venous diseases
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University Medical Center Groningen The Netherlands

Conclusions

  • Pediatric PH is a rare disease
  • Pediatric PH may complicate many neonatal and pediatric disease

conditions

  • Epidemiological data often insufficient
  • The occurrence of PH is often associated with a dramatic worsening
  • f outcome (mortality)
  • It is important to know the risks of complicating PH in neonatal and

pediatric conditions

  • Early detection and treatment is required in order to strive for

improved oucome