Session V – Chronic Obstructive Pulmonary Disease and Interstitial Lung Disease

Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease

The presence of both pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) is associated with increased morbidity, including reduced exercise capacity and worse dyspnea scores, and mortality. The correlation between lung function and the severity of PH is not linear. Regardless of severity of the disease, PH in COPD is usually mild to moderate with a mean pulmonary artery pressure generally below 35 to 45 mm Hg. Some patients, however, have severe PH, and they are considered a different group of patients with concomitant COPD and PH.

In the National Emphysema Treatment Trial (NETT), patients with PH on right heart catheterization had a mean forced expiratory volume in 1 second (FEV1) of 27%. Although 91% of those patients had a mean PA pressure of more than 20 mmHg, only 5% had a mean PA pressure above 35 mm Hg. Interestingly, there was no correlation between the severity of PH and emphysema scores, severity of hyperinflation, or the diffusion capacity. Two-thirds of these patients, however, had left ventricular diastolic dysfunction, which probably reflects that the risk factors for COPD are the same risk factors for the development of cardiovascular disease.

Historically, PH in COPD was thought of as hypoxia driven due to chronic hypoxic vasoconstriction. But the modern view is that it reflects more of a multifactorial etiology, including vascular destruction, mechanical stress, and inflammation due to the proximity of the bronchus to the blood vessel.

Supplemental oxygen remains the first-line therapy. Trials of long-term oxygen therapy and nocturnal oxygen therapy have clearly demonstrated that oxygen improves survival in these patients but without necessarily having a consistent effect on hemodynamics. Pulmonary rehabilitation (similar to COPD patients without PH) also improves skeletal muscle function, quality of life, and exercise capacity.

Drugs specific to PH may lower pulmonary vascular resistance in COPD patients with PH, but they can also make them more hypoxemic because of worsening ventilation-perfusion (V/Q) mismatch. Thus, the current approach is based on the severity of COPD and the severity of PH.

• For mild to moderate COPD disease (FEV1 around 60% or higher) and a mean PA pressure between 25 to 35 mm Hg, it is unclear which disease is predominant, and practitioners may consider vasodilator therapy under close monitoring at a referral center.
• For severe COPD (FEV1 less than 60%) with a mean PA between 25 and 35 mm Hg, leave them alone because there are no data to support any benefit from PH drugs.
• For severe COPD (FEV1 less than 60%) with a mean PA more than 35 mm Hg, consider referral to a specialized center for clinical trials or for trying vasodilators under very close monitoring.

Key points for PH in COPD

• Pulmonary arterial hypertension in patients with COPD is associated with worse morbidity and mortality.
• The correlation between lung function and the severity of PH is not linear.
• Regardless of the disease severity, PH in COPD is usually mild to moderate (mean pulmonary artery pressure below 35 to 45 mm Hg).
• The etiology of PAH in COPD is multifactorial and includes chronic hypoxia, vascular destruction, mechanical factors, and vascular inflammation.
• The best initial management approach is to treat the underlying disease with oxygen supplementation and pulmonary rehabilitation.
• Using vasodilators for PH-targeted therapy can worsen oxygenation and should only be considered in special situations under close monitoring at a specialized center.

Pulmonary Hypertension in Interstitial Lung Disease

Currently, no drug is FDA approved to treat PH in patients with interstitial lung disease (ILD). Many patients with ILD and PH do not clearly fit into a WHO group. Approximately 40% of patients with interstitial lung disease develop PH, either idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), or nonspecific interstitial pneumonia (NSIP). Having PH in the setting of ILD is associated with poor survival, and it gives these patients a higher lung allocation score when being considered for lung transplant.

The presence of PH should be suspected in patients with ILD who have more shortness of breath than expected based on the severity of their ILD, have loud heart sounds in the pulmonary area (P2) or signs of right heart failure, or a diffusing capacity of carbon monoxide (DLCO) that is less than 40%. This is particularly true in patients with scleroderma-associated ILD in whom the DLCO is highly correlated with PH as well as worsening survival. We often use the forced vital capacity (FVC) to DLCO ratio to detect PH. When the ratio is above 1.8, we can almost certainly say there is a degree of PH. When the ratio is less than 1.4, it is probably fibrosis. A ratio between 1.4 and 1.8 is considered a gray zone. Unfortunately, there is no significant correlation between mean pulmonary artery pressure and FVC or fibrosis scores on chest CT scans.

Initial treatment efforts should focus on treating the interstitial lung disease itself, primarily with oxygen. Regarding PH-specific therapies for ILD, the preponderance of evidence suggests that we might be causing more harm than good or just not providing any real benefit. We need to question whether it is the lung disease or the PH that is driving outcomes. And we still need longer term mortality (or other relevant endpoints) studies to help us make decisions.

Meanwhile, one management approach is to consider PH-specific vasodilator therapy in patients with very high pressures, RV dysfunction, and low cardiac index. Other factors favoring therapy include a diagnosis of scleroderma or anorexigen or if the patient has limited parenchymal lung disease and no major comorbidities. However, we have to carefully weigh the benefits and risks, especially as worsening V/Q mismatch may result in worsening hypoxemia and increased oxygen needs. It is important to manage patient expectations before starting therapy, and to warn them that they may feel worse. Close follow-up is needed to determine if therapy is ineffective or harmful. These patients should also be referred early for consideration of lung transplant. It is also important to address end-of-life palliative care with these patients.

Key points for PH in ILD

• There are currently no FDA-approved drugs for the treatment of PH in ILD.
• Having PH in the setting of ILD is associated with poor survival.
• An FVC to DLCO ratio above 1.8 in patients with ILD suggests the presence of PH; a ratio less than 1.4 makes it less likely.
• Management efforts should focus on treating the ILD itself, including use of supplemental oxygen
.
• Evidence suggests that PH-specific therapies may cause more harm than benefit when used to treat ILD.
• Until more evidence is available, PH-specific vasodilator therapy can be considered in patients with very high pressures, RV dysfunction, and low cardiac index.
• Close follow-up is needed to stop therapy if it is ineffective or harmful.
• Consider early referral for lung transplant, if indicated.
• Address end-of-life palliative care with appropriate patients.

Session V – Chronic Obstructive Pulmonary Disease and Interstitial Lung Disease References

Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease Related References

1. Boerrigter BG, Bogaard HJ, Trip P, et al. Ventilatory and cardiocirculatory exercise profiles in COPD: the role of pulmonary hypertension. Chest. 2012;142(5):1166-74.
2. Fein DG, Zaidi AN, Sulica R. Pulmonary hypertension due to common respiratory conditions: classification, evaluation and management strategies. J Clin Med. 2016;5(9).
3. Joppa P, Petrasova D, Stancak B, Tkacova R. Systemic inflammation in patients with COPD and pulmonary hypertension. Chest. 2006;130(2):326-33.
4. Seeger W, Adir Y, Barberà JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62(25 Suppl):D109-16.

Pulmonary Hypertension in Interstitial Lung Disease Related References

1. Hoeper MM, Behr J, Held M, et al. Pulmonary hypertension in patients with chronic fibrosing idiopathic interstitial pneumonias. PLoS One. 2015;10(12):e0141911.
2. Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, Anstrom KJ, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010;363(7):620-8.
3. Shin S, King CS, Puri N, et al. Pulmonary artery size as a predictor of outcomes in idiopathic pulmonary fibrosis. Eur Respir J. 2016;47(5):1445-51.
4. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D34-41.
5. Teramachi R, Taniguchi H, Kondoh Y, et al. Progression of mean pulmonary arterial pressure in idiopathic pulmonary fibrosis with mild to moderate restriction. Respirology. 2017;22(5):986-90.