Pulmonary Hypertension Grading and Classification
Pulmonary hypertension is graded functionally using the WHO Functional Classification (Classes I-IV), which stratifies patients based on physical activity limitations and symptoms, with Class I representing no limitation and Class IV representing inability to perform any activity without symptoms. 1
Hemodynamic Definition
- Pulmonary hypertension is defined as mean pulmonary arterial pressure ≥25 mmHg at rest measured by right heart catheterization 1, 2, 3
- Pre-capillary PH requires pulmonary artery wedge pressure ≤15 mmHg and pulmonary vascular resistance >3 Wood units 1, 2
- Post-capillary PH is defined by pulmonary artery wedge pressure >15 mmHg 1, 4
WHO Functional Classification System
The functional grading system directly impacts treatment decisions and prognosis assessment 1:
Class I
- No limitation of physical activity 1
- Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope 1
Class II
- Slight limitation of physical activity 1
- Comfortable at rest 1
- Ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope 1
Class III
- Marked limitation of physical activity 1
- Comfortable at rest 1
- Less than ordinary activity causes undue dyspnea, fatigue, chest pain, or near syncope 1
Class IV
- Inability to carry out any physical activity without symptoms 1
- Signs of right heart failure present 1
- Dyspnea and/or fatigue may be present at rest 1
- Discomfort increased by any physical activity 1
Clinical Classification Groups
The European Respiratory Society defines five clinical groups of pulmonary hypertension 1, 2:
Group 1: Pulmonary Arterial Hypertension (PAH)
- Idiopathic PAH (formerly primary pulmonary hypertension) 1
- Heritable PAH (BMPR2 mutations) 1, 2
- Drug and toxin-induced PAH 1, 2
- Associated PAH: connective tissue disease, HIV infection, portal hypertension, congenital heart disease, schistosomiasis 1, 2
- Characterized by pre-capillary PH with PVR >3 Wood units 1, 2
Group 2: PH Due to Left Heart Disease
- Most common form of PH in clinical practice 5, 3
- Left ventricular systolic or diastolic dysfunction 1, 2
- Valvular disease 1, 2
- Congenital/acquired left heart inflow/outflow obstruction 1, 2
Group 3: PH Due to Lung Diseases and/or Hypoxia
- Chronic obstructive pulmonary disease 1, 2
- Interstitial lung disease 1, 2
- Sleep-disordered breathing 1, 2
- Alveolar hypoventilation disorders 1, 2
- Chronic high altitude exposure 1, 2
Group 4: Chronic Thromboembolic PH (CTEPH)
- Organized thrombi obstructing pulmonary arteries 1, 2
- Other pulmonary artery obstructions: angiosarcoma, arteritis, congenital stenoses 1, 2
- Ventilation/perfusion lung scan is mandatory to exclude CTEPH in all unexplained PH 1
Group 5: PH with Unclear/Multifactorial Mechanisms
- Hematological disorders: chronic hemolytic anemia, myeloproliferative disorders, post-splenectomy 1, 2, 6
- Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 1, 2, 6
- Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 1, 2, 6
- Chronic renal failure, fibrosing mediastinitis, pulmonary tumoral thrombotic microangiopathy 1, 2, 6
Prognostic Assessment Parameters
The European Respiratory Society identifies specific parameters that determine better versus worse prognosis 1:
Better Prognosis Indicators:
- No clinical evidence of right ventricular failure 1
- Slow rate of symptom progression 1
- No syncope 1
- WHO Functional Class I-II 1
- 6-minute walk test distance >500 meters 1
- Peak oxygen consumption >15 mL/min/kg 1
- Normal or near-normal BNP/proBNP levels 1
- No pericardial effusion on echocardiography 1
- TAPSE >2.0 cm and cardiac index >2.5 L/min/m² 1
- Right atrial pressure <8 mmHg 1
Worse Prognosis Indicators:
- Clinical evidence of right ventricular failure present 1
- Rapid symptom progression 1
- Syncope present 1
- WHO Functional Class III-IV 1
- 6-minute walk test distance <300 meters 1
- Peak oxygen consumption <12 mL/min/kg 1
- Very elevated and rising BNP/proBNP 1
- Pericardial effusion present 1
- Cardiac index <2.0 L/min/m² 1
- Right atrial pressure >15 mmHg 1
Treatment Approach by Classification
Group 1 PAH Treatment
- Epoprostenol (IV prostacyclin) is FDA-approved for WHO Group 1 PAH to improve exercise capacity, predominantly for NYHA Class III-IV patients 7
- Sildenafil is FDA-approved for WHO Group 1 PAH to improve exercise ability and delay clinical worsening 8
- Targeted therapies include phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostacyclin analogues, and soluble guanylate cyclase stimulators 5
- All patients with confirmed PAH must be referred to a specialist center 5
Group 2 PH Treatment
- Management primarily targets the underlying left heart disease 5, 3
- PAH-specific therapies are not indicated and may be harmful 5
Group 3 PH Treatment
- Treatment focuses on optimizing the underlying lung disease 5, 3
- Long-term oxygen therapy is indicated when arterial oxygen pressure is consistently <8 kPa (60 mmHg) 1
Group 4 CTEPH Treatment
- Surgical pulmonary endarterectomy is the treatment of choice for eligible patients 5
- Riociguat is the only licensed targeted therapy for inoperable or persistent/recurrent CTEPH 5
- All CTEPH patients must be referred to a specialist center 5
Group 5 PH Treatment
- Right heart catheterization is mandatory to confirm diagnosis and exclude other PH groups 6
- Disease-specific therapy is recommended: enzyme replacement for Gaucher disease, thyroid hormone optimization, immunosuppression for sarcoidosis when indicated 6
- For chronic renal failure, optimize volume status through careful fluid management 6
Diagnostic Algorithm
Right heart catheterization is essential for accurate diagnosis and classification of all PH 1, 5:
- Echocardiographic diagnosis of "PH likely" with symptoms requires right heart catheterization (Class I recommendation) 1
- Routine biochemistry, hematology, immunology, and thyroid function tests are indicated in all PAH patients 1
- Ventilation/perfusion lung scan is recommended in all unexplained PH to exclude CTEPH (Class I recommendation) 1
- Contrast CT angiography is indicated in CTEPH workup 1
- Abdominal ultrasound is indicated for screening portal hypertension 1
- Open or thoracoscopic lung biopsy is not recommended in PAH patients (Class III recommendation) 1
Follow-Up Assessment
The European Respiratory Society recommends specific assessments at baseline and every 3-6 months 1: