Overview | Epidemiology | Pathophysiology | Diagnostic Evaluation | Treatment
Patients with pulmonary hypertension (PH) fall into World Health Organization (WHO) Group 3 when their PH (defined by a mean pulmonary artery pressure [mPAP] ≥ 25mmHg and pulmonary artery occlusion pressure [PAOP] ≤ 15mmHg) is associated with chronic lung diseases including:
- Chronic obstructive pulmonary disease (COPD)
- Diffuse parenchymal lung diseases (DPLD), which encompasses:
- Idiopathic pulmonary fibrosis (IPF)
- Combined pulmonary fibrosis and emphysema (CPFE)
- Sleep disordered breathing
- Chronic exposure to high altitudes
- Developmental abnormalities
Although mildly elevated pulmonary artery pressures may be seen in these lung diseases, the presence of even moderate PH requires close attention by the care team and almost always a referral to a PH center for further management is warranted.
PH is considered to be severe in these patients if:
- Cardiac output is reduced
- Mean pulmonary artery pressure (mPAP) ≥ 35mmHg.
Common challenges clinicians often face in the initial diagnosis and workup of the disease are:
- Does the severity of lung disease explain the presence and degree of PH?
- Are the patient’s symptoms (dyspnea, fatigue, exercise impairment) best explained by PH, chronic lung diseases, or a combination of both?
- Because COPD is such a common disease, PH secondary to COPD is one of the most frequent causes of PH
- Greater than 90% of patients with severe COPD (GOLD Stage IV) have been estimated to have abnormally high pulmonary pressures, with 3 - 5% of these patients having severe PH.2
- PH is prevalent in 8-15% of patients upon their diagnosis of IPF but will affect >50% in advanced disease
- Approximately 9% of IPF patients will have severe PH.3
- The severity of the lung disease as measured by breathing tests or radiographic appearance does not correlate well with the degree of PH.3, 4
- Combined pulmonary fibrosis and emphysema (CPFE)
- The combination of both fibrotic and emphysematous lung disease puts patients at significantly higher risk of developing PH with estimated prevalence of 30-50%, and many of these patients (almost one-half) will have severe PH with poor prognosis. 5
- Other lung diseases (sleep disordered breathing, developmental diseases)
- Less is known about the prevalence of PH in these diseases, but as our level of suspicion increases an increasing number of patients with these lung diseases have been diagnosed with PH.
- Sleep disordered breathing-associated PH in particular can range from mild/moderate, as in isolated obstructive sleep apnea (OSA), to severe (when obstructive sleep apnea is combined with obesity hypoventilation syndrome or another cause for hypoxemia). The severity of obstructive sleep apnea correlates with severity of pulmonary hypertension. 6
PH due to chronic lung diseases is due to an increase in pulmonary vascular resistance (PVR) that occurs from years of pulmonary vasculature remodeling in response to inflammation of lung tissue and airways, fibrotic lung changes, and/or hypoxic vasoconstriction with poor gas exchange associated with the underlying lung disease. As opposed to marked intimal proliferation of the pulmonary blood vessels in PAH, the changes in WHO Group III PH are also characterized by medial thickening, likely as a result of hypoxia.2 The end result is higher pulmonary artery pressures, reduced distensibility of the blood vessels, and inability to recruit more pulmonary blood vessels for gas exchange in the setting of exercise.
As is the case in pulmonary arterial hypertension (WHO Group 1 PH), WHO Group 3 PH also strains the relationship between the pulmonary vasculature and the right side of the heart (right ventricle, RV). Normally, the right ventricle pumps blood into a high capacitance pulmonary circuit and the total resistance it faces is equivalent to the pulmonary vascular resistance (PVR).7 In PH, not only is the RV pumping against higher resistance (PVR), but there is also an increased pulsatile component requiring more effort from the RV. The ability of the RV to adapt to these high-pressure conditions and its coupled relationship (or lack thereof) with the pulmonary vasculature essentially determines the overall course.
Tests that are often performed to help answer these questions and may be repeated for interval monitoring:
- Echocardiography is the initial screening test in these patients
- Right heart catheterization should be performed if one or more of the following conditions exists1:
- Evaluation of lung transplantation
- Worsening clinical status or gas exchange disproportionate to ventilatory impairment
- Need to understand prognosis
- Severe PH is suspected and further therapy is being considered
- Suspicion of left heart dysfunction contributing to PH (WHO Group 2)
- Pulmonary function tests to characterize lung disease and gas exchange
- Imaging of lungs (including CT scan)
- 6 minute walk distance test
- Laboratory tests
Treatment in PH associated with lung disease is aimed first and foremost at the underlying lung disease when possible and, when appropriate, consideration for lung transplantation that could cure the PH. Therefore it is critical in these situations (when transplantation is an option) that the patient’s care involve not only a PH center but also access to an experienced lung transplant team.
The goal of treating the underlying lung disease is to prevent the insult from worsening the disease.
Predicting reversibility of the elevated resistance is not well understood but likely depends on chronicity and extent of fibrotic changes in the pulmonary vasculature as well as involvement of the pulmonary vasculature by the disease process.
- OSA should be treated with regular CPAP/BiPAP use and if the patient is not tolerating the treatment, all attempts should be made to facilitate as much regular use of the CPAP as possible (re-fit or change mask, re-titrating the pressure, etc). Treatment of OSA has been shown to improve pulmonary artery pressures6.
- In COPD, oxygen use also may reverse hypoxia-driven medial thickening contributing to elevated PVR.2
None of the treatments for underlying lung diseases target pulmonary vasculature specifically (except long-term oxygen to oxygen saturations above a minimum level) and have not been studied in PH populations specifically.1
- PH-specific therapy for fibrosis and/or COPD. There are currently no PAH-specific drugs that are approved for use in WHO Group 3 PH. Several small trials have been completed in these patients showing safety and possible benefit in functional capacity, but none of the studies have been designed or powered to show improvement in survival. However, if PH in fibrosis or COPD is severe and thought to be developing alongside the lung disease (WHO Group 1 PAH) rather than caused by it (WHO Group 3), consideration for treatment with PAH-targeted therapies is made carefully on a case-by-case basis with general considerations as outlined below.
- Treating PH associated with either fibrosis or COPD with PH vasodilators is truly analogous to a balancing act. Although the overall goal is to improve flow in the pulmonary vasculature, special caution must be taken to watch for interference with ongoing hypoxic vasoconstriction that could potentially worsen gas exchange. Another issue that can cause problems with PAH-targeted therapy is especially relevant in COPD patients: lung areas with low ratio of ventilation to perfusion. Gas exchange can also worsen in patients with this problem and therefore treatment must be initiated and titrated with close monitoring.8 Inhaled vasodilators (inhaled prostacyclins, nitric oxide) may be considered in an attempt to try to avoid these complications. Each patient’s therapeutic plan thus is created on a case-by-case basis with regards to these matters.
See Treatment section in PAH for detailed information about classes of PAH-specific therapies (prostacyclins, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators).
- Prostanoids: Prostanoids can be administered through multiple routes. While preliminary data suggest that inhaled prostanoid (i.e., iloprost or inhaled treprostinil9) improves hemodynamics in patients with lung disease, long-term data are not yet available. The use of intravenous or oral prostanoids has not been studied in this population.
- Endothelin receptor antagonists (ERAs): ERAs are another class of oral vasodilators, and have been studied in fibrosis with negative results (macitentan, bosentan10) or stopped early because of a signal for harm (ambrisentan11), although these studies have included all patients with fibrosis, not PH patients only. In patients with severe COPD, a small randomized trial with bosentan showed no improvement in 6MWD but deteriorated gas exchange.12
- Phosphodiesterase-5 inhibitors (sildenafil, tadalafil) and the soluble guanylate cyclase stimulators (riociguat): These oral vasodilators have been examined in small trials of IPF and COPD with neutral results.13,14 Again, patients with severe PH related to these diseases have not been studied separately in large, randomized trials for these drugs.
- WHO Group 3 PH- World Health Organization (WHO) category for pulmonary hypertension due to lung disease
- COPD- chronic obstructive pulmonary diseaseDPLD- diffuse parenchymal lung disease, when the lung disease affects the lung airways and blood vessels
- CPFE- combined pulmonary fibrosis and emphysema, a condition characterized by having both COPD and DPLD that significantly increases risk for PH
- PVR- pulmonary vascular resistance, defined as the pressure gradient across the pulmonary vasculature divided by the pulmonary blood flow
- Hypoxic vasoconstriction- constriction of blood vessels in response to sensing low amounts of oxygen; can occur in varying degrees in fibrosis and COPD
- Obesity hypoventilation syndrome- an incompletely understood condition found in some obese people characterized by improper gas exchange that can lead to pulmonary hypertension
Kishan Parikh, MD
April 29, 2015
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