2. Pulmonary Hypertension in the Setting of CF: Secondary vs Idiopathic
Pulmonary Hypertension in the Setting of CF: Secondary vs Idiopathic? Heather M. Staples, M.D. Baylor College of Medicine Houston, TX

3. Presenter Disclosure
Heather M. Staples, M.D. There are no relationships to disclose related to this presentation.

4. Pakistani female with cystic fibrosis (A1319E homozygous) RG
Pakistani female with cystic fibrosis (A1319E homozygous)
At 10 yo - new onset dyspnea on exertion while an avid soccer player
FEV1: 64% predicted
Micro: PA/MSSA/Stenotrophomonas, intermittent use of oral antibiotics, no admissions in >2 yr
CXR: prominent pulmonary artery
Echo: indicators of pulmonary hypertension
Mildly dilated right atrium and ventricle
Flattened interventricular septum

5. At 11yo- elective right heart catheterization
WHO Classification of Pulmonary Hypertension 1
idiopathic, heritable, drug/toxin induced, asso. w/other disease, PVOD, PPHN 2
Due to left sided heart disease 3
Due to lung disease or hypoxia 4
Chronic thromboembolic disease 5
Unclear or multifactorial mechanisms
At 11yo- elective right heart catheterization
severe PAH with PVR 29 Woods units (normal <3WU)
Started on PH pharmacotherapy which has been escalated over the last 5 years
Diagnosed as idiopathic PAH (WHO Group 1) and not considered secondary to her lung disease (WHO Group 3)

6. Diagnosis of Pulmonary Hypertension
Pharmacotherapy for Pulmonary Hypertension
PDE5 Inhibitor
sildenafil, tadalafil
Endothelin Receptor Antagonist
bosentan, ambrisentan, macitentan
Prostacyclins
epoprostenol, treprostinil, iloprost
CCBs
nifedipine, amlodipine, diltiazem
Other Agents
digoxin, diuretics, O2, anticoagulants
Diagnosis of Pulmonary Hypertension
Gold standard: cardiac catheterization
mPAP > 25mmHg and/or PVRi > 3WU x m2
Estimates of PAP and PVR via echocardiography
TR jet velocity, Interventricular septal position, RV function and dilation

7. Since PH diagnosis
Negative institutional PAH genetic panel
Worsening CF-related lung disease: FEV1 down to 32% predicted, no significant change to microbiology or frequency of exacerbations
Worsening hypoxemia out of proportion to lung disease
3 LPM O2 continuously

8. Currently on triple PH therapy 
sildenafil
ambrisentan
treprostinil
Currently on triple PH therapy
tadalafil 40 mg qd, treprostinil ER 2.5 mg BID oral route, ambrisentan 10 mg qd
6 minute walk distance has declined, most recently 462 yards (<3%ile predicted) with SaO2 nadir of 82% despite oxygen

9. Discussion Points
When is PH considered secondary to lung disease in CF and when idiopathic or primary?
What is impact of PH and its treatment on the clinical course of CF?
What is the role of hypoxemia in increasing morbidity of both PH and CF?

10. When is PH considered secondary to lung disease vs idiopathic or primary?
Typically seen in late stage lung disease
Hypoxic vasoconstriction, pulmonary hyperinflation, inflammation, loss of pulmonary vasculature
Patients not considered late stage (FEV1 >40% predicted) unlikely to have CF-related/2o PH
Most CF patients with PH have mild increase in PVR

11. Impact of PH therapy on the clinical course of CF
Increase in V/Q mismatch due to interference with hypoxic pulmonary vasoconstriction
Adds to the complexity and burden of therapy
Increases opportunity for and likelihood of non- adherence
Potentially worsens prognosis for CF survival

12. Role of hypoxemia in morbidity of PH and CF
Hypoxemia in the absence of alveolar hypoxia does not contribute to PH
Hypoxemia and CF
Increased alveolar hypoxia due to end stage lung disease
V/Q mismatch due to mucus plugging and heterogeneous lung disease

13. Take Home Points
Severe PH in cystic fibrosis is rare in children and adolescents, even in end stage lung disease
Uncommon diseases sometimes occur together, in this case, CF and IPAH
PH therapy not only adds to the burden of care intrinsic to CF, but likely through intended physiological changes may accelerate CF lung disease progression

14. References
Abman, Steven H., et al. “Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society.” Circulation. Vol 135, Nov pp
Aneskey.com/physiology-of-the-airway/
Dormer, RL, et al. “Sildenafil (Viagra) corrects F508del-CFTR location in nasal epithelial cells from patients with cystic fibrosis.” Thorax. 2005; 60:55-59.
Fraser, Kristin L., et al. “Pulmonary Hypertension and Cardiac Function in Adult Cystic Fibrosis.” Chest. Vol 115, No. 5, May 1999, pp
Galie, Nazzareno, et al. “2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.” European Heart Journal. (2016) 37,
Hayes, Don Jr., et al. “Pulmonary Hypertension in Cystic Fibrosis with Advanced Lung Disease.” Amer J of Resp and Clin Care Med. Vol 190, No 8, Oct pp
Mongomery, Gregory S. “Effects of Sildenafil on Pulmonary Hypertension and Exercise Tolerance in Severe Cystic Fibrosis-Related Lung Disease.” Pediatric Pulmonology. 41: (2006).
Poschet, Jens F., et al. “Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis.” Am J Physiol Lung Cell Mol. 293: L712-L719, June 2007.
Ronelli, Adriano R., et al. “ Prevalence of pulmonary hypertension in end-stage cystic fibrosis and correlation with survival.” The Journal of Heart and Lung Transplantation. Vol 29, No 8, August pp
Schrijver, Iris, et al. “ The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients.” Jnl of Molecular Diagnostics. Vol 18, No 1, Jan 2016, pp
Stecenko, Arlene A., et al. “Predicting Arterial Oxygen Tension From Maximum Expiratory Flow Volume Curves in Cystic Fibrosis.” Pediatric Pulmonology. 6:27-30 (1989).
Ziegler, Bruna, et al. “Pulmonary hypertension as estimated by Doppler echocardiography in adolescent and adult patients with cystic fibrosis and their relationship with clinical, lung function and sleep findings.” Clin Respr J

15. Acknowledgements NACFC
- Marie Egan and Felix Ratjen
The Cystic Fibrosis Center at Texas Children’s Hospital
- George B. Mallory, Jr, Fadel Ruiz, Marianna Sockrider