WHO Group 3 Pulmonary Hypertension: Causes and Treatment
WHO Group 3 pulmonary hypertension is caused by chronic lung diseases and/or hypoxemia, with the primary treatment being optimization of the underlying lung disease, supplemental oxygen to maintain saturations >90%, and avoidance of pulmonary vasodilators except in highly selected cases. 1
Primary Causes of Group 3 PH
Pediatric Population
- Bronchopulmonary dysplasia (BPD) is the most common cause in children, accounting for up to one-third of pediatric PH cases 1
- Congenital diaphragmatic hernia and other causes of pulmonary hypoplasia commonly result in Group 3 PH 1
- Severe obstructive sleep apnea with recurrent hypoxemia 1
- Advanced diffuse lung disease in children 1
Adult Population
- Chronic obstructive pulmonary disease (COPD) is one of the most common causes in the United States 2
- Interstitial lung disease (ILD), which carries the worst prognosis among Group 3 PH subtypes 3
- Sleep-disordered breathing and hypoventilation syndromes 3, 4
- High altitude exposure 3
Pathophysiology
The mechanisms driving Group 3 PH are multifactorial and include 4:
- Hypoxic vasoconstriction as the primary driver
- Parenchymal lung and vascular bed destruction reducing the pulmonary vascular bed
- Vascular remodeling with smooth muscle proliferation
- Chronic inflammation affecting pulmonary vessels
- Comorbid left heart dysfunction and thromboembolic disease can compound the severity 4
Treatment Approach for WHO Functional Class III
Foundation of Management
The cornerstone of Group 3 PH treatment is optimizing the underlying lung disease, not pulmonary vasodilators. 1
Specific Interventions
Oxygen Therapy:
- Supplemental oxygen should be used to maintain oxygen saturations >90% at all times 1
- Long-term oxygen therapy is recommended for chronic hypoxemia 1, 4
Underlying Lung Disease Optimization:
- Treat the specific lung pathology aggressively (bronchodilators for COPD, antifibrotics for ILD, etc.) 1
- Minimize further lung insults 1
- Avoid atelectasis 1
- Normalize ventilation when possible 1
Pulmonary Vasodilator Therapy - Critical Caveats:
The use of PAH-specific drugs in Group 3 PH is NOT recommended as standard therapy 1. However, there are specific exceptions:
- Sildenafil is often successfully used in infants with BPD and congenital diaphragmatic hernia, despite theoretical concerns about worsening V/Q mismatch 1
- Inhaled treprostinil showed efficacy in the INCREASE trial for PH-ILD in adults, providing the first evidence-based treatment option for this subset 3
- Patients with "out of proportion" PH (severe PH relative to lung disease severity) should be enrolled in randomized controlled trials targeting PAH-specific drugs 1
Common Pitfall: Indiscriminate use of pulmonary vasodilators in Group 3 PH can worsen V/Q mismatch and clinical outcomes 1. These agents should only be used after careful consideration and ideally in consultation with a PH specialist center 1.
Advanced Interventions
Lung Transplantation:
- Accepted treatment option for children and adults with Group 3 PH who have progressive disease despite optimal therapy 1
- Important caveat: Long-term outcomes after transplantation are less favorable for Group 3 PH compared to Group 1 PAH 1
Monitoring and Referral
Screening and Diagnosis:
- Echocardiography is recommended as a screening tool for infants with severe BPD, children with advanced diffuse lung disease, and adults with severe lung disease 1
- Right heart catheterization is required for definitive diagnosis 1, 4
Specialist Referral Indications:
- Suspected severe PH 4
- Pulmonary vascular phenotype (PH severity out of proportion to lung disease) 4
- Uncertainty regarding further management 4
- Referral to centers following ≥50 PAH/CTEPH patients is recommended 1