Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis

INTRODUCTION — Patients with pulmonary hypertension (PH) due to chronic lung disease (eg, chronic obstructive pulmonary disease, interstitial lung disease, or overlap syndromes) or conditions that cause hypoxemia (eg, obstructive sleep apnea, alveolar hypoventilation disorders) are classified as having group 3 PH (table 1).

The treatment and prognosis of patients with group 3 PH are reviewed here. The prevalence, pathogenesis, and diagnostic evaluation of patients with suspected group 3 PH are presented separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)

Our approach is for the most part similar to that outlined in several society guidelines [1].

CLASSIFICATION — The World Health Organization (WHO) classifies patients with PH into five groups based upon etiology [2]. Patients in group 1 are considered to have pulmonary arterial hypertension (also sometimes referred to as precapillary PH), whereas patients in group 2 (due to left-sided heart disease), group 3 (due to lung disorders and hypoxemia), group 4 (due to pulmonary artery obstructions), and group 5 (associated with different or mixed mechanisms) are considered to have PH (table 1). When all five groups are discussed collectively, the term PH is generally used. Classification of PH is discussed in detail separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

Group 3 PH can be caused by several lung disorders including:

●Obstructive lung disease (eg, chronic obstructive pulmonary disease or bronchiectasis)

●Restrictive lung disease (eg, interstitial lung disease, kyphoscoliosis)

●Other lung disease with mixed obstruction and restriction (eg, pulmonary fibrosis with emphysema)

●Hypoxia without lung disease (eg, high altitude, sleep-disordered breathing, obesity hypoventilation)

●Developmental lung disorders (eg, bronchopulmonary dysplasia, congenital lobar emphysema)

GENERAL MEASURES

Treatment of underlying condition — Treatment of the underlying condition (eg, chronic obstructive pulmonary disease [COPD], interstitial lung disease, sleep-disordered breathing) is indicated in all patients with group 3 PH. However, while some strategies (eg, continuous positive airway pressure) modestly reduce pulmonary artery pressures (PAP), evidence to suggest significant reductions in PH or improved clinically impactful outcomes (eg, reduced mortality, improved exercise capacity, delayed progression) is lacking [3-5]. Nonetheless, disease-specific therapies are assumed to result in improved alveolar hypoxia, which is thought to contribute to the pathogenesis of PH and to progression of PH. For patients with high altitude PH, re-exposure to normal inspired oxygen tension is appropriate. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults", section on 'Pathogenesis'.)

Treatment of the underlying conditions are discussed separately. (See "Treatment of idiopathic pulmonary fibrosis" and "Stable COPD: Initial pharmacologic management" and "Obstructive sleep apnea: Overview of management in adults" and "Obstructive sleep apnea and cardiovascular disease in adults", section on 'Impact of treatment'.)

Conventional and supportive therapies — Similar to patients with group 1 pulmonary arterial hypertension (PAH), all patients with group 3 PH should exercise as tolerated, receive routine vaccinations (figure 1), be counselled against smoking, and be treated with supportive measures including oxygen and diuretics, when indicated. With the exception of oxygen, evidence to support the use of these therapies is typically extrapolated from patients with other forms of PH, the details of which are discussed separately. (See "Standard immunizations for nonpregnant adults" and "Pneumococcal vaccination in adults" and "The benefits and risks of aerobic exercise" and "Pulmonary rehabilitation" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

Details regarding the care of select PH populations including patients who are considering pregnancy or who are pregnant, patients who are planning to travel or be exposed to high altitude, and patients requiring surgery are also discussed separately. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'Special populations'.)

●Exercise, cessation of smoking, vaccination – The importance of regular exercise, cessation of smoking, and vaccination are discussed separately. (See "Standard immunizations for nonpregnant adults" and "Pneumococcal vaccination in adults" and "The benefits and risks of aerobic exercise" and "Pulmonary rehabilitation" and "Overview of smoking cessation management in adults" and "Pharmacotherapy for smoking cessation in adults" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

●Oxygen – Supplemental oxygen is typically prescribed for patients in group 3 PH who have hypoxemia (at rest or during exercise or sleep) with a goal of maintaining a peripheral oxygen saturation between 90 and 96 percent [6]. Supplemental oxygen, however, has only been documented to improve survival (figure 2 and figure 3) and pulmonary vascular resistance in patients with COPD-associated PH who also have documented hypoxemia (ie, a partial arterial pressure of oxygen [PaO₂] below 60 mmHg) [7-12]. In contrast, oxygen appears not to benefit those who are normoxemic [13]. Indications for supplemental oxygen are described in the table (table 2). Evidence that describes benefit from supplemental oxygen in COPD are discussed separately. (See "Long-term supplemental oxygen therapy", section on 'Benefits'.)

It is inferred that supplemental oxygen may benefit other groups of patients with group 3 PH and hypoxemia, based upon data derived from patients with COPD and the rationale that oxygen may be beneficial by reducing hypoxic vasoconstriction, right ventricle (RV) afterload and/or pulmonary vascular remodeling. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults", section on 'Pathogenesis'.)

In our experience, some patients with chronic hypoxemia demonstrate a marked reduction in PAP with continuous oxygen therapy while others have mild or moderate reductions. Predictors of a long-term response to supplemental oxygen include a decrease of the mean PAP greater than 5 mmHg and a high peak oxygen consumption (VO₂) during exercise (>6.5 cc/kg per minute) [14].

For patients with high altitude PH, re-exposure to normal inspired oxygen tension is appropriate, ie, administration of supplemental oxygen and/or descent to lower altitude.

●Diuretics – Patients with fluid retention from PH-related RV failure may benefit from diuretics. However, their administration is associated with some risk in patients with PH, the details of which are discussed separately. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

●Anticoagulation – Anticoagulation is not typically administered to those with group 3 PH, although practice varies among centers and there are no data specific to this group that suggest benefit or harm associated with anticoagulation. Anticoagulation (typically with warfarin) in other PH populations (eg, group 4) is discussed separately. (See "Chronic thromboembolic pulmonary hypertension: Initial management and evaluation for pulmonary artery thromboendarterectomy", section on 'Anticoagulant therapy (indefinite)' and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

●Inotropic agents – Digoxin is an oral cardiac glycoside with inotropic effects that provides symptomatic benefit to patients with left ventricle (LV) systolic dysfunction; however, it is not typically indicated for the treatment of group 3 PH in the absence of coexisting atrial fibrillation or LV dysfunction based upon the rationale that outside of these indications, it has unproven benefit and may have adverse effects [15-17]. Among the potential detrimental effects, digoxin may induce pulmonary vasoconstriction and worsening PH [18]. In addition, the risk of digoxin toxicity is increased in the setting of hypoxemia and diuretic-induced hypokalemia. The administration of other inotropic agents in the acute setting is discussed separately. (See "Use of vasopressors and inotropes" and "Inotropic agents in heart failure with reduced ejection fraction".)

OUR APPROACH — The treatment approach used by most experts is based upon data derived from small case series of patients with group 3 PH and data extrapolated from larger randomized trials performed in patients with group 1 pulmonary arterial hypertension (PAH). Unlike patients with PAH, we do not use the World Health Organization (WHO) functional classes to stratify patients (table 3) for therapy since functional class may be affected by both PH and the underlying lung disorder. Rather, we stratify patients based upon the severity of associated PH and severity of right ventricular (RV) failure (eg, elevated right atrial pressure, low cardiac index) and echocardiographic findings of impaired RV function. Among patients with chronic lung disease, PH is categorized as nonsevere (pulmonary vascular resistance [PVR] ≤5 Wood units [WU]) or severe (PVR >5 WU) based on pulmonary hemodynamic findings from right heart catheterization (RHC) since this threshold has prognostic significance [1]. While there is a consensus definition for severe PH on RHC [1], definitions for mild or moderate PH on RHC and severity of PH on echocardiography are less well defined. Values used in the sections below are based upon our clinical experience and society guidelines.

Nonsevere pulmonary hypertension — Patients in this category include those with mild to moderate PH as estimated by echocardiography (eg, estimated systolic pulmonary artery pressure [sPAP] between approximately 35 and 60 mmHg), those with PVR ≤5 WU on RHC, and those without symptoms of RV failure [1].

Observation — Patients with lung disorders and/or hypoxemia who have nonsevere PH typically require general supportive measures only (see 'General measures' above). All patients with nonsevere PH should be closely monitored every 6 to 12 months for the signs and symptoms of progressive PH. Clinical and echocardiographic findings indicative of development of RV failure are particularly important since these patients have a worse prognosis and may be more likely to respond to PH-specific therapy. It is sometimes challenging to distinguish progressive symptoms due to underlying lung disease from symptoms due to PH such that referral to a center with PH expertise should be performed where additional investigations can be done to help with this distinction. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)

Severe pulmonary hypertension — Patients in this category include those with severe PH as estimated by echocardiography (eg, estimated sPAP ≥50 mmHg) or by RHC (PVR >5 WU or patients with elevated mean PAP ≥25 mmHg with elevated right atrial pressure and/or low cardiac index <2 liters/minute/meter²) [1,19]. Most patients in this category are treated with general measures (see 'General measures' above) and, unlike patients with group 1 PAH, are not typically treated with PAH-directed therapy with the exception of PH associated with interstitial lung disease (ILD). Patients with severe PH should be referred to a specialized center for further evaluation and management and for potential inclusion in clinical trials. (See 'Pulmonary arterial hypertension-directed therapy' below.)

Pulmonary arterial hypertension-directed therapy — Pharmacologic agents used for PAH-directed therapy include prostacyclin pathway agents (eg, epoprostenol, treprostinil, iloprost, selexipag), phosphodiesterase-5 (PDE-5) inhibitors (eg, sildenafil, tadalafil), nitric oxide-cyclic guanosine monophosphate enhancers including soluble guanylate cyclase stimulators (riociguat), and endothelin receptor antagonists (eg, bosentan, ambrisentan, macitentan). While these agents have efficacy in the treatment of patients with group 1 PAH (table 1) (see "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Definition'), their efficacy in group 3 PH is limited and in some cases, may be harmful [20]. With the exception of inhaled treprostinil for PH associated with ILD, none of these agents have been approved for use in group 3 PH. The poor performance of PAH-directed therapy in this population may be partially explained by vasodilatory effects of these agents that may exacerbate ventilation-perfusion abnormalities and worsen gas exchange in patients with lung disease [21-25].

However, exceptions to this general rule exist. In rare circumstances PAH-directed therapy is considered for patients who are in RV failure with advanced WHO functional class III or IV symptoms (table 3) in whom general measures have failed and in whom a strong component of PH is thought to be unrelated to their lung disease (eg, severe PH and mild lung disease). This is particularly true for select patients with systemic sclerosis (SSc), in whom a vasculopathy similar to other forms of PAH is known to occur. In such cases, patients should be evaluated in the setting of a center with expertise in PH where extensive investigations can be conducted to distinguish patients with PAH (ie, group 1) who happen to have concomitant lung disease from patients with PH due to their lung disease (ie, true group 3 PH); such centers are also likely to be involved in suitable clinical trials for both of these populations. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis".)

Chronic obstructive disease — Several trials in patients with chronic obstructive pulmonary disease (COPD) have shown mixed effects of PAH-directed therapy on resting and exercise-induced pulmonary hemodynamics, six-minute walk distance (6MWD), and many have shown worsening oxygenation parameters and quality of life (QOL) [26-37]. Data have been described for the following agents:

●Prostacyclin pathway agents including prostacyclin and inhaled iloprost [33-35]

●PDE-5 inhibitors including sildenafil [26-29]

●Endothelin receptor antagonists including bosentan [31] and ambrisentan [32]

●Nitric oxide-cyclic guanosine monophosphate enhancers including riociguat [37] and inhaled nitric oxide [36]

Interstitial lung disease — There have been mixed results from PAH-directed therapy clinical trials in patients with ILD-related PH with some agents demonstrating benefit and others either no benefit or an increase in serious adverse events:

●Pulmonary fibrosis:

•Parenteral prostanoids – Twelve weeks of parenteral treprostinil has been shown to improve right atrial pressure, cardiac index, RV function, QOL, brain natriuretic peptide (BNP), and 6MWD in a case series of patients with pulmonary fibrosis and severe PH without any adverse effects on oxygenation [38].

•Inhaled treprostinil – Inhaled delivery of prostanoids is attractive since there may be less potential for worsening of ventilation/perfusion mismatch than with oral or parenteral agents. In one multicenter randomized controlled trial (INCREASE) of 326 patients with ILD-related PH (mostly idiopathic pulmonary fibrosis [IPF], connective tissue disease (CTD), and combined pulmonary fibrosis and emphysema [CPFE]), 16 weeks of inhaled treprostinil resulted in a small improvement in the 6MWD compared with placebo (mean difference was 31 meters) [39]. In addition, inhaled treprostinil resulted in a reduction in N-terminal pro-BNP (15 percent reduction versus 46 percent increase in NT-proBNP levels) and reduced the proportion of patients who clinically deteriorated during the period of the trial (23 versus 33 percent).

Higher doses were also associated with increased benefit [40]. In a post-hoc analysis of the INCREASE study, inhaled treprostinil was also associated with improvements in forced vital capacity compared with placebo, particularly among patients with IPF [41]. The impact of treprostinil on the subgroup with CPFE was less robust than that on patients with IPF- and CTD-related ILD. Adverse effects were mild and included headache, cough, dyspnea, dizziness, nausea, fatigue, and diarrhea. Inhaled treprostinil has received regulatory approval for this indication [42]. Further studies are needed to help define patient subgroups who are most likely to respond.

•PDE-5 inhibitors – While sildenafil is of limited or no benefit in patients with IPF who do not have PH [43,44], some studies suggest possible benefit in those with RV dysfunction [45,46].

•Endothelin receptor antagonists and nitric oxide-cyclic guanosine monophosphate enhancers – Ambrisentan has been shown in major trials to be ineffective and associated with adverse effects (eg, worsening oxygenation, disease progression, increased hospitalizations) in patients with PH due to IPF or other etiologies and IPF (without PH) [32,47,48]. Bosentan and macitentan are also ineffective in IPF but have not been tested in IPF-associated PH [49-51]. Although early studies suggested some benefit from riociguat [52-54], a phase II study in patients with idiopathic interstitial pneumonia-associated PH was terminated early due to an increase in drug-related adverse events and mortality [48,55].

●SSc – Data describing the use of PAH-directed therapy in patients with SSc are discussed separately. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis".)

●Others – PH in lymphangioleiomyomatosis is now also classified as group 3 PH given similarities to other chronic lung disease [1]. (See "Sporadic lymphangioleiomyomatosis: Treatment and prognosis".)

Although classified as belonging to group 5 PH, only case reports describe individual responses to therapy in rare ILDs, such as pulmonary Langerhans histiocytosis [56-58]. (See "Pulmonary Langerhans cell histiocytosis".)

Similarly, retrospective case series suggest some patients with sarcoidosis-associated PH (typically classified as group 5 PH) may experience improved functional class and hemodynamic parameters with the use of inhaled iloprost, inhaled nitric oxide, sildenafil, ambrisentan, bosentan, or combination therapy [21,25,59-67]. Most studies suggest marginal improvements in pulmonary hemodynamics with minimal or no effect on 6MWD, and some even reporting pulmonary edema, although the latter may have been due to the coexistence of pulmonary veno-occlusive disease. (See "Sarcoidosis-associated pulmonary hypertension: Diagnostic evaluation in adults" and "Sarcoidosis-associated pulmonary hypertension: Treatment and prognosis in adults".)

Sleep-disordered breathing and hypoxia — Only case reports describe individual responses to therapy in rare diseases including kyphoscoliosis and obesity hypoventilation [68,69].

Overlap syndromes — Despite the poor prognosis of PH associated with overlap syndromes (eg, combined vascular and ILD, combined COPD and ILD), data are limited regarding the use of PAH-directed therapy in this population. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis" and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening".)

Patients who fail therapy — Patients with severe group 3 PH who fail therapy should be considered for lung transplantation. Other surgical measures have not been evaluated in this population (eg, atrial septostomy). (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Right-to-left shunt' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Lung transplantation'.)

In patients who fail therapy and are not candidates for lung transplantation, consideration of palliative care for assistance with symptom management is appropriate. (See "Palliative care for adults with nonmalignant chronic lung disease".)

Lung transplantation — Lung transplantation may be an option in patients with group 3 PH who progress despite therapy [70].

The effect of PH on lung transplantation outcome is uncertain [71-76]. Several studies suggest that PH does not adversely impact the survival of patients with ILD who undergo lung transplantation [71-73]. But registry data suggests that PH is a risk factor for 90-day mortality after single lung transplantation [75] and the presence of PH may confer a higher risk of primary graft dysfunction in patients undergoing transplantation for ILD [77].

While single lung transplantation without cardiopulmonary bypass is an option for most patients with chronic lung disease without PH [72,73,78,79] it may be less suitable for those with severe PH [80-83], where bilateral lung transplantation is usually preferred. Living lobar lung transplantation is also an option for a small number of patients [78,84]. (See "Lung transplantation: An overview" and "Lung transplantation: Disease-based choice of procedure" and "Noninfectious complications following lung transplantation" and "Lung transplantation: General guidelines for recipient selection".)

PROGNOSIS — PH from underlying lung disease and/or hypoxemia is typically progressive and is generally associated with increased morbidity and mortality.

●Chronic obstructive pulmonary disease (COPD) – Numerous trials have shown that PH negatively affects survival in COPD and that survival worsens with increasing PH severity [85-91].

As an example, four-year survival is roughly 75 percent among patients with COPD of varying severity [85], but <50 percent among patients whose COPD is complicated by PH [86]. Survival for longer than three years is rare among patients with COPD who have a pulmonary vascular resistance (PVR) >550 dynes-sec-cm⁵ (6.875 Wood units [WU]) [87].

PH has also been shown to predict increased hospitalization in patients with COPD [92].

Among different hemodynamic variables and thresholds, PVR >5 WU was the strongest predictor of prognosis [93]. Severe reduction in the diffusing capacity for carbon monoxide (DLCO) is also associated with a high mortality [94], with one study reporting a 4 percent increase in the risk of death for every 1 percent reduction in DLCO percent predicted [95]. Other risk factors for death include male sex, poor exercise capacity, and high PVR [91]. Survival also appears to be worse in patients with COPD compared with patients with idiopathic pulmonary arterial hypertension (ie, group 1 disease) [91].

●Interstitial lung disease (ILD) – Similarly, patients with ILD-related PH have a poorer prognosis than patients with ILD alone [96-104].

In a retrospective study of 131 patients with idiopathic pulmonary fibrosis (IPF), patients with PH had a shorter median survival than patients without PH (11 versus 23 months) [105]. Moreover, mortality increases as the severity of the PH increases [96,98]. In another retrospective study of IPF patients survival correlated with PH severity with median survival estimates of 4.8 years in those with a systolic pulmonary artery pressure (sPAP) ≤35 mmHg, 4.1 years in those with a sPAP 36 to 50 mmHg, and 0.7 years in those with a sPAP >50 mmHg [98]. Similar trends have been reported in those with sarcoidosis [60,106]. (See "Sarcoidosis-associated pulmonary hypertension: Treatment and prognosis in adults".)

●Sleep-disordered breathing – The presence of PH may also have prognostic importance in patients with obstructive sleep apnea, the details of which are discussed separately. (See "Obstructive sleep apnea and cardiovascular disease in adults", section on 'Clinical evidence'.)

Similar poor outcomes in obesity hypoventilation have been reported where the presence of PH is associated with reduced exercise capacity, greater daytime sleepiness, and worse health-related quality of life [4,107].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)

SUMMARY AND RECOMMENDATIONS

●Classification – Patients with pulmonary hypertension (PH) associated with chronic lung disease (eg, chronic obstructive pulmonary disease, interstitial lung disease, or overlap syndromes) or conditions that cause hypoxemia (eg, obstructive sleep apnea, alveolar hypoventilation disorders) are classified as having group 3 PH (table 1). (See 'Introduction' above and 'Classification' above.)

●General measures – While considerable variation exists among centers, we suggest that all patients be treated for their underlying lung disease, receive routine conventional therapies (eg, vaccination, counselled against smoking, exercise), and supportive therapies (when indicated; eg, oxygen, diuretics). Supplemental oxygen is typically prescribed for those with hypoxemia (at rest or during exercise or sleep) with a goal of maintaining a peripheral oxygen saturation greater than 90 percent. (See 'General measures' above and "Long-term supplemental oxygen therapy" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)", section on 'General measures and supportive therapy'.)

●Our approach – Most patients with group 3 PH should be referred to a specialized center for evaluation. Our general approach is the following:

•Most patients – For most patients with group 3 PH, we recommend against treatment with pulmonary arterial hypertension (PAH)-directed therapy since it has not been shown to result in significant benefit and may be associated with harm (Grade 1B).

•Nonsevere PH – Patients with group 3 PH who have nonsevere PH should be closely monitored every 6 to 12 months for the signs and symptoms of progressive PH and right ventricular failure. (See 'Nonsevere pulmonary hypertension' above.)

•Severe PH – Most patients with group 3 PH who have severe PH should be referred to a specialized center for potential inclusion in clinical trials. (See 'Severe pulmonary hypertension' above.)

•Suspected component of PAH – Patients with a suspected component of group 1 PAH whose underlying lung disease does not explain the severity of PH, and some patients with severe right heart failure, may be eligible for PAH-directed therapies on a case-by-case basis, but caution is required due to the possibility of worsening oxygenation. All patients who receive PAH-directed therapy should be closely monitored for a treatment response.

•Patients who fail therapy – Patients with group 3 PH who progress despite therapy should be evaluated for lung transplantation. Other surgical measures have not been evaluated in this population (eg, atrial septostomy). (See 'Lung transplantation' above.)

●Prognosis – PH associated with underlying lung disease and/or hypoxemia is typically progressive and is generally associated with increased morbidity and mortality. Mortality generally increases with the severity of PH. (See 'Prognosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Michael McGoon, MD, and Jay H Ryu, MD, who contributed to earlier versions of this topic review.