Disclosures No relevant disclosures Guidelines For Screening - - PowerPoint PPT Presentation

3/10/2017 1

Guidelines For Screening Those at Risk of PH

Eric D. Austin, MD, MSCI Director, Vanderbilt Pediatric PH Program Vanderbilt University Medical Center

Disclosures

• No relevant disclosures
• Although, worth mentioning:

– Limited evidence exists from formal studies on Screening in pediatric population

Screening

• The process of detecting disease early, with

the intention of intervening to halt its progression. As Yogi Berra said: “You can observe a lot by just watching.”

Screen Secondary Prevention

• Detect a disease in its earliest stages, before

symptoms appear

• Intervene to slow or stop disease progression
• Key Assumption:

– Earlier detection & intervention is helpful

U.S. Department of Health & Human Services. https://www.ahrq.gov/professionals/quality-patient-safety/quality-resources/tools/ppip/ppipslides/ppiplongsl10.html

3/10/2017 2

Screening To Facilitate Prevention

“Secondary Prevention”

Symptomatic PH is a Late Finding

Austin, Kawut, Gladwin, Abman. Pulmonary Hypertension: NHLBI Workshop on the Primary Prevention

• f Chronic Lung Diseases. Ann Am Thorac Soc 2014 Apr; 11(Suppl 3): S178–S185.

‘Development’ ‘Peak’

Current Approach

Austin, Kawut, Gladwin, Abman. Pulmonary Hypertension: NHLBI Workshop on the Primary Prevention

• f Chronic Lung Diseases. Ann Am Thorac Soc 2014 Apr; 11(Suppl 3): S178–S185.

‘Development’ ‘Peak’

Secondary Prevention

Austin, Kawut, Gladwin, Abman. Pulmonary Hypertension: NHLBI Workshop on the Primary Prevention

• f Chronic Lung Diseases. Ann Am Thorac Soc 2014 Apr; 11(Suppl 3): S178–S185.

‘Development’ ‘Peak’

3/10/2017 3

Issues for Screening for a Rare Condition (e.g., PH)

• A. Employ low risk, high yield method(s)
• B. Target high risk individuals
• A. Potential Screening Methods
• Noninvasive Studies

– Genetic testing

• BMPR2, ALK1, ENG, EIF2AK4, TBX4, etc…

– Blood or Urine studies (e.g., NT-proBNP) – ‘-Omics’: independent or integrated

• Noninvasive Measures of ‘Function’

– Echocardiogram (ECHO), ECG – cMRI, PET/CT, Metabolic imaging (e.g., FDG-PET)

• Invasive Measures

– Cath +/- Pulmonary Angiography, Lung Bx, RV Bx

• A. Potential Screening Methods
• Noninvasive Studies

– Genetic testing

• BMPR2, ALK1, ENG, EIF2AK4, TBX4, etc…

– Blood or Urine studies (e.g., NT-proBNP) – ‘-Omics’: independent or integrated

• Noninvasive Measures of ‘Function’

– Echocardiogram (ECHO), ECG – cMRI, PET/CT, Metabolic imaging (e.g., FDG-PET)

• Invasive Measures

– Cath +/- Pulmonary Angiography, Lung Bx, RV Bx

• B. Target high risk individuals

3/10/2017 4

Developmental Lung Diseases

• Congenital diaphragmatic hernia (CDH)
• Alveolar Capillary Dysplasia with MPV
• Lung Hypoplasia
• Surfactant Protein Abnormalities
• Pulmonary Alveolar Proteinosis
• Pulmonary Lymphangiectasia

Developmental Lung Diseases

• Premature / Bronchopulmonary dysplasia (BPD)
• Congenital diaphragmatic hernia (CDH)
• Alveolar Capillary Dysplasia with MPV
• Lung Hypoplasia
• Surfactant Protein Abnormalities
• Pulmonary Alveolar Proteinosis
• Pulmonary Lymphangiectasia

Reasonable Approach: Screening ECHO (& BNP) at time of Lung Disease Dx Serial Screening: q1-2 yrs and as clinically indicated

Prematurity and PH

316 enrolled 316 enrolled 7 day PH, n=115 (42%) 7 day PH, n=115 (42%) 36 wks PH 21% 36 wks PH 21% 36 wks No PH 79% 36 wks No PH 79% 7 day No PH, n=162 (58%) 7 day No PH, n=162 (58%) 36 wks PH 9% 36 wks PH 9% 36 wks No PH 90% 36 wks No PH 90% 20 died, 17 LTF, 2 w/draw 20 died, 17 LTF, 2 w/draw

• Criteria:

– < 34 wks – 500–1,250 g

• ECHOs performed

– 7 days of age – 36 weeks PMAge

Mourani PM et al. Am J Respir Crit Care Med. 2015;191:87-95.

Prematurity and PH

316 enrolled 316 enrolled 7 day PH, n=115 (42%) 7 day PH, n=115 (42%) 36 wks PH 21% 36 wks PH 21% 36 wks No PH 79% 36 wks No PH 79% 7 day No PH, n=162 (58%) 7 day No PH, n=162 (58%) 36 wks PH 9% 36 wks PH 9% 36 wks No PH 90% 36 wks No PH 90% 20 died, 17 LTF, 2 w/draw 20 died, 17 LTF, 2 w/draw

• Criteria:

– < 34 wks – 500–1,250 g

• ECHOs performed

– 7 days of age – 36 weeks PMAge

Mourani PM et al. Am J Respir Crit Care Med. 2015;191:87-95.

3/10/2017 5

p<0.001

ECHO-determined PH @ 36 weeks Babies: < 34 wks & 500–1,250 g

Mourani PM et al. Am J Respir Crit Care Med. 2015;191:87-95.

Infants w/ PH @ 36 Wks

50% 40% 30% 25% 20%

All Subjects (n=277) None (n=50) Mild (n=100) Moderate (n=62) Severe (n=65)

BPD Severity

Approach to Premature Lung Dz

• Early ECHO (& BNP) for Premature with:

– <28 weeks – High Vent and/or Oxygen support – Oligohydramnios, IUGR – Slow improvement

• Consider repeat q2-4 wks

Abman SH et al. Circulation. 2015;132:2037-99. Kim DH et al. Neonatology. 2012;101:40-46.

Established BPD Prevalence 12-28%

• Screen @ 36 weeks PMA, via 2 approaches:
• 1. All BPD patients @ 36 weeks
• 2. Severity-based
• O2 need
• PPV
• Poor growth
• Recurrent episodes
• IVH, NEC
• ASD
• etc…

Abman SH et al. Neoreviews. 2011;12:e645-e651. Abman SH et al. Circulation. 2015;132:2037-99. Weismann CG et al. J Perinatol. Epub Feb 2017.

Established BPD: screening over time

• Serial ECHO (& BNP) q 4-6 months and prn
• Caveats

– ECHO may underestimate presence or severity

• Consider adding ECG

– ‘Unmask’ PVD during times of stress

• Bronchiolitis

Abman SH et al. Circulation. 2015;132:2037-99. Mourani PM et al. Pediatrics. 2008;121:317–325.

3/10/2017 6

Some Additional Conditions

Condition Recommendation Pediatric Evidence Chronic Hemolytic Anemia (e.g., SCD) 8 y/o; q1-2 yrs and prn limited HHT (ACVRL1, ENG) Yearly; and prn limited Down Syndrome post CHD 8 y/o; prn limited Liver disease @ Dx and @ Liver Tx eval; Yearly screen for both POPH and HPS limited CTD, including SSc Yearly; and prn limited ECHO, BNP, +/- ECG Consider additional studies for some Conditions; e.g.: DLCO & Lung Volumes in CTD and Chronic Hemolytic Anemia

Abman SH et al. Circulation. 2015;132:2037-99. Chaudry RA et al. Arch Dis Child. 2011;96:131–136. Schwaiger JP et al. European Respiratory Review. 2011; 22: 515–525

Healthy Pediatric Relatives, At Risk

• 1° relative of idiopathic PAH (IPAH)

– No known ‘causative’ PH gene

• Relative of heritable PAH (HPAH)
• 1. Familial disease
• 2. Known ‘causative’ PH gene
• Relative of PVOD & PCH, HHT-PAH cases

follow same approaches

1° relative of idiopathic PAH (IPAH)

• Disease & Genetic counseling
• Approach:

– Physical Exam and ECHO q1-3 years

Soubrier F et al. Resp Res. J Am Coll Cardiol 2013;62:D13–21.

Relative of heritable PAH (HPAH) case

IPAH

Age at diagnosis (years) NS NS Females n=188 Females n=81 Males n=79 Males n=34 100 80 60 40 20

BMPR2-PAH

BMPR2-PAH is more Severe

Austin ED et al. Resp Res. 2009; 10 :87 doi:10.1186/1465-9921-10-87Elliott CG et al. Circulation. 2006; 113: 2509-2515. Rosenzweig EB et al. J Heart Lung Transplant. 2008; 27:668-674. Sztrymf B et al. Am J Respir Crit Care Med. 2008. 177:1377-83. Pfarr N et al. Resp Res. 2011;12:99http://respiratory-research.com/content/12/1/99. Brittain CHEST 2013.

3/10/2017 7 + + + +

Red = Mutation Carrier

• +

+ + +

• Austin, Ma et al Circ Cardiovasc Genetics, 2012

BMPR2 is more severe. But, only ~20% BMPR2 mutation carriers develop PAH in their lifetime + + + +

Red = Mutation Carrier

• +

+ + +

• Austin, Ma et al Circ Cardiovasc Genetics, 2012

+

Relative of heritable PAH (HPAH) case

** Disease & Genetic counseling **

Gene Mutation Known? Yes (e.g., BMPR2) No PE & ECHO q 1-3 yrs Counsel & Genetic Testing PE & ECHO yearly Mutation detected No Mutation: No special Monitoring

Soubrier F et al. Resp Res. J Am Coll Cardiol 2013;62:D13–21.

Conclusions

• Screening for PH

– Noninvasive methods: ECHO, BNP, ECG

• Goal is to provide Secondary Prevention

3/10/2017 8

Conclusions Conclusions

Needs:

• When to

Screen?

• Can we

impact

• utcome?

Eric.austin@vanderbilt.edu

Conclusions

• Screening for PH

– Noninvasive methods: ECHO, BNP, ECG

• Goal is to provide Secondary Prevention
• Lack of Pediatric data to dictate how and

when to Screen for most conditions

• Paucity of Pediatric data to convincingly

demonstrate benefit from earlier diagnosis

3/10/2017 9

Panama PVRI Classification Scheme

Adapted from Jesus del Cerro M et al. Pulm Circ. 2011;1:286-298.

• 1. Prenatal or Developmental Lung Diseases

Example: Congenital diaphragmatic hernia (CDH)

• 2. Perinatal Pulmonary Vascular Maladaptation

Example: PPHN

• 3. Bronchopulmonary Dysplasia (BPD)/Premature-associated Lung Disease
• 4. Congenital Heart Disease
• 5. Isolated Pediatric PH Vascular Disease (PHVD) or Isolated PAH

Example: idiopathic PAH, familial BMPR2-PAH, PVOD, PCH

• 6. Congenital Abnormalities or Malformations With Multifactorial Disease Entities

Example: Trisomy 21

• 7. Pediatric Lung Disease

Example: ILD of childhood, sleep-disordered breathing, CF

• 8. Thromboembolic Disease
• 9. Hypobaric Hypoxic Exposure
• 10. Associated With Other System Disorders

Example: hemolytic anemia, metabolic disorders, portal hypertension

PAH With BMPR2 Mutation: More Severe Disease

• Younger at Diagnosis
• Worse cardiac performance
• +/- Shorter survival

Elliott CG et al. Circulation. 2006; 113: 2509-2515. Rosenzweig EB et al. J Heart Lung Transplant. 2008; 27:668-674. Sztrymf B et al. Am J Respir Crit Care Med. 2008. 177:1377-83. Pfarr N et al. Resp Res. 2011;12:99http://respiratory-research.com/content/12/1/99. Brittain CHEST 2013.

BMPR2-PAH IPAH

Vasodilator Responsiveness

p=0.003

1/27 14/40

Percent Vasoreactive

50 40 30 20 10

Nonsynonymous BMPR2 variation No nonsynonymous BMPR2 mutation

Chronic Hemolytic Anemia (e.g. SCD)

• Adults: 6-11% with SCH with PH by cath

– Associated with high morbidity and mortality – TRJV ≥ 2.5 m/s 10-fold increased risk death

• Children: definitive data lacking

– TRJV ≥ 2.5 m/s reduced 6MWTD over time

• TRJV ≠ high PVR
• Approach:

– Screening ECHO & BNP at 8 yrs and q1-2 yrs

• Earlier and more frequent depending severity

Abman SH et al. Circulation. 2015;132:2037-99. Chaudry RA et al. Arch Dis Child. 2011;96:131–136.

Bronchopulmonary Dysplasia (BPD)

• NIH definition:

– infant < 32 wks – O2 requirement at 28 days PMA

• Prevalence: 15-25%
• Aggravating/comorbid factors:

– cardiac shunt(s) – cardiac dysfunction – aspiration

Jobe AH, Bancalari E. Am J Respir Crit Care Med. 2001;163:1723-9. Abman SH et al. Circulation. 2015;132:2037-99.

3/10/2017 10

Connective Tissue Disease

• Adults

– CTD-PAH most prevalent in Scleroderma (SSc)

• 5-12% adult studies
• 19%: DLCO < 60% predicted & SSc duration > 3 yrs
• Children

– Lower prevalence but full data lacking – High morbidity

Abman SH et al. Circulation. 2015;132:2037-99. Schwaiger JP et al. European Respiratory Review. 2011; 22: 515–525

Connective Tissue Disease

• Adults

– CTD-PAH most prevalent in Scleroderma (SSc)

• 5-12% adult studies
• 19%: DLCO < 60% predicted & SSc duration > 3 yrs
• Children

– Lower prevalence but full data lacking – High morbidity

Abman SH et al. Circulation. 2015;132:2037-99. Schwaiger JP et al. European Respiratory Review. 2011; 22: 515–525

Reasonable Approach: At CTD Diagnosis: ECHO, BNP, Lung Volumes, DLCO Serial Screening: Yearly and as clinically indicated

Hereditary Hemorrhagic Telangiectasia (HHT) and PAH

• Autosomal dominant vascular disease

– Mucocutaneous telangiectasias – Multiorgan AVMs – PAH rare, may proceed HHT dx

• ALK1: TGFβ type I receptor (≤ 10% PAH)
• endoglin: accessory TGFβ receptor (< 1% PAH)

Trembath NEJM 2001 Johnson Nat Gen 1994

HHT-PAH

• Shorter survival
• Vasodilator

unresponsive

• Younger Dx & Death

< BMPR2 mutation

• Less severe hemodynamics

Girerd B et al. Am J Respir Crit Care Med. 2010;181:851-61.

BMPR2/ACVRLI- 227 225 193 166 134 114 99 84 73 56 40 33 26 BMPR2+ 91 82 70 63 50 44 37 30 25 23 18 13 9 ACVRLI+ 9 5 4 4 3 1 1

Cumulative Survival (%)

Time to death (months) BMPR2/AVCRLI- BMPR2/+ AVCRLI+ p=<0.01

1 .8 .6 .4 .2

12 24 36 48 60 72 84 96 108 120 132 144

ACVRL1 mutation Endoglin mutation

3/10/2017 11

HHT-PAH

• Shorter survival
• Vasodilator

unresponsive

• Younger Dx & Death

< BMPR2 mutation

• Less severe hemodynamics

Girerd B et al. Am J Respir Crit Care Med. 2010;181:851-61.

BMPR2/ACVRLI- 227 225 193 166 134 114 99 84 73 56 40 33 26 BMPR2+ 91 82 70 63 50 44 37 30 25 23 18 13 9 ACVRLI+ 9 5 4 4 3 1 1

Cumulative Survival (%)

Time to death (months) BMPR2/AVCRLI- BMPR2/+ AVCRLI+ p=<0.01

1 .8 .6 .4 .2

12 24 36 48 60 72 84 96 108 120 132 144

HHT-PAH More Severe

• Shorter survival
• Vasodilator

unresponsive

• Younger Dx & Death

< BMPR2 mutation

• Less severe hemodynamics

Girerd B et al. Am J Respir Crit Care Med. 2010;181:851-61.

BMPR2/ACVRLI- 227 225 193 166 134 114 99 84 73 56 40 33 26 BMPR2+ 91 82 70 63 50 44 37 30 25 23 18 13 9 ACVRLI+ 9 5 4 4 3 1 1

Cumulative Survival (%)

Time to death (months) BMPR2/AVCRLI- BMPR2/+ AVCRLI+ p=<0.01

1 .8 .6 .4 .2

12 24 36 48 60 72 84 96 108 120 132 144

Reasonable Approach: At HHT Diagnosis: ECHO, BNP, Lung Volumes, DLCO Serial Screening: Yearly and as clinically indicated