Version October 2024
INTRODUCTION — Patients with pulmonary hypertension (PH) due to diffuse 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 prevalence, pathogenesis, and diagnosis of PH due to lung disease and/or hypoxemia are presented here. The treatment and prognosis of patients with group 3 PH are reviewed separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis".)
CLASSIFICATION AND DEFINITIONS — The classification and definitions of PH and cor pulmonale are discussed below:
●Classification – Patients with PH are classified into five groups based upon etiology [1]. Patients in group 1 are considered to have pulmonary arterial hypertension (PAH; also sometimes referred to as pre-capillary PH), whereas patients in group 2 (due to left-sided heart disease), group 3 (due to chronic lung disorders and hypoxemia), group 4 (due to pulmonary artery obstructions), and group 5 (due to unidentified or mixed mechanisms) are considered to have PH (table 1). When all five groups are discussed collectively, the term PH is used. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)
●Pulmonary hypertension – PH is defined as a mean pulmonary artery pressure (mPAP) >20 mmHg at rest, measured by right heart catheterization [1]. PH is considered severe if mPAP is ≥35 mmHg or the mPAP is >20 mmHg with an elevated right atrial pressure (>14 mmHg) and/or the cardiac index is <2 L/min/m2 [2]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis'.)
●Cor pulmonale – Cor pulmonale is a complication of PH. Cor pulmonale refers to PH-induced altered structure (eg, hypertrophy or dilatation) and/or impaired function of the right ventricle (RV) that is associated with chronic lung disease and/or hypoxemia (ie, group 3 PH). While some experts disagree on the inclusion of RV dysfunction due to pulmonary vascular disease (ie, group 1 PAH), most agree that RV dysfunction due to left-sided heart disease or congenital heart disease is not considered cor pulmonale [3].
PREVALENCE — Accurate estimations of PH in patients with chronic lung disease and/or hypoxemia have been difficult to ascertain due to heterogeneity in the type and severity of underlying lung disease and study differences in the definitions of PH (eg, mean pulmonary artery pressure [mPAP] >20 mmHg or ≥25mmHg) as well as techniques (echocardiography or right heart catheterization [RHC]) used to assess PH. In general, most patients in group 3 PH have mild to moderate elevations in mPAP (20 to 35 mmHg). Less than 5 percent have severe PH, which is typical of group 1 pulmonary arterial hypertension (PAH).
Group 3 PH appears to be more prevalent in older adults. In one series of patients ≥65 years with PH, group 3 PH occurred in 14 percent, while 28 percent had group 2 PH and 17 percent had mixed group 2/3 PH [4].
Group 3 PH can be due to obstructive lung disease, restrictive lung disease, lung disorders with mixed restriction and obstruction, hypoventilation syndromes (eg, sleep apnea), hypoxia without lung disease (eg, high altitude), and developmental lung disorders. The prevalence in individual disorders is discussed in the sections below.
Chronic obstructive pulmonary disease — Several studies report that PH is generally mild in patients with chronic obstructive pulmonary disease (COPD) and has a prevalence that ranges from 25 to 90 percent [3,5-20]. However, data are biased since they are derived from patients with severe COPD undergoing lung transplant evaluation (right heart catheterization [RHC] data, which are more accurate than echocardiography, are more readily available and justified in this population). As examples:
●In one study of 374 patients with advanced lung disease (transplant candidates), most of whom had COPD, the prevalence of PH was 25 percent by RHC [7]. Almost half of the study population were misclassified as having PH by echocardiography (sensitivity and specificity of 85 and 55 percent, respectively) suggesting that echocardiography may be less useful diagnostically in those with severe lung disease.
●One retrospective review of 156 patients with advanced lung disease, most of whom had COPD, reported that two-thirds had right ventricle (RV) dysfunction [9]. PH was in the mild range with a mean mPAP of 25 mmHg, but was markedly lower than that seen in those with group 1 PAH (table 1), in whom the mean mPAP was 50 mmHg.
●In another retrospective study of 215 patients with COPD undergoing transplant evaluation, half had PH, with a mean mPAP of 27 mmHg [10]. Only 10 percent of patients had a mPAP >35 mmHg and less than 4 percent had a mPAP >45 mmHg. Data from the Organ Procurement and Tissue Network database showed a similar prevalence of mild and severe PH [12].
●In contrast, in those undergoing evaluation for lung reduction surgery for emphysema, a higher prevalence of 91 percent was reported but the prevalence of severe PH was similar [11].
The prevalence is likely lower in those with mild to moderate COPD but RHC data are less readily available in this population and most estimates are derived from echocardiography [13-19]. Resting PH ranges from 20 to 60 percent in those with moderate COPD [16-18] with the higher end of this range consistently noted during exercise [18,19]. PH can develop over time with one study reporting that 25 percent of patients with moderate COPD and normal resting mPAP developed PH (defined as mPAP >20 mmHg on RHC) over a seven year period [20].
The severity of PH appears to correlate with the magnitude of hypoxemia, hypercapnia, and airflow obstruction, as suggested by a study that found right RV hypertrophy in 40 percent of patients with a forced expiratory volume in one second (FEV1) <1 L and 70 percent of patients with a FEV1 <0.6 L [3].
Interstitial lung disease — The reported prevalence of interstitial lung disease (ILD)-associated PH ranges from 30 to 90 percent and similar to patients with COPD, PH is generally mild to moderate and rarely severe. Rates vary depending upon the population studied:
●Idiopathic pulmonary fibrosis (IPF) – An mPAP of ≥25 mmHg is present in 8 to 15 percent at initial evaluation of IPF, in 30 to 50 percent of advanced cases, and in over 60 percent of end-stage IPF patients (mPAP mostly assessed by RHC) [21-24]. In the largest of these studies, 46 percent of patients with advanced ILD had mPAP ≥25 mmHg but only 9 percent had mPAP >40 mmHg (ie, severe PH) [23]. A decreased diffusing capacity may predict PH [25], although spirometric abnormalities correlate poorly [26,27]. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis".)
●Connective tissue diseases (CTDs) – The prevalence of PH alone or PH in combination with ILD varies widely among CTDs [28-37]. Most data come from studies in patients with systemic sclerosis [36,38]. The prevalence of PH in patients with systemic sclerosis is estimated on average to range from 10 to 15 percent, the details of which are discussed separately. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Epidemiology'.)
●Pneumoconioses – PH can complicate pneumoconioses, including asbestosis, coal worker's pneumoconiosis, silicosis, and unspecified pneumoconiosis [39-41]. In general, although rates are unknown, the severity of the parenchymal disease may correlate with severity of the PH [40,41]. (See "Asbestos-related pleuropulmonary disease".)
●Combined pulmonary fibrosis and emphysema (CPFE) – CPFE is a syndrome where clinical, radiologic, and pathologic features of both fibrosis and emphysema exist in the same patient [42]. PH in CPFE is a common complication that is thought to be more frequent and severe when compared with COPD and ILD alone. In an observational cohort of 110 patients with IPF, compared with those with IPF alone, the systolic pulmonary artery pressure was higher in the 31 patients who had CPFE (82 versus 57 mmHg) [43]. Another study of 40 patients with CPFE with PH reported a mPAP in this population that was in the severe range (40 mmHg) [44]. These patients are often characterized by a severe reduction in their diffusing capacity (DLCO) in the setting of a normal or near normal forced expiratory volume in one second and forced vital capacity.
●Lymphangioleiomyomatosis (LAM) – LAM was originally classified as group 5 but is now classified as group 3. Rare case reports describe low rates of PH in patients with lymphangioleiomyomatosis (typically <7 percent), the details of which are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Other'.)
●Others – Other ILDs associated with PH are actually classified in group 5 PH:
•Sarcoidosis – PH can exist in any patient with sarcoidosis, but is most common among patients with advanced disease [45-50]. In a prospective study of 212 patients with sarcoidosis, 6 percent had PH (estimated sPAP ≥40 mmHg on echocardiography) [46]. In contrast, another prospective study that included 363 patients with severe sarcoidosis (lung transplantation candidates), PH was detected in 74 percent [45]. One large European cohort suggested a prevalence of only 3 percent in White individuals with sarcoidosis [51]. PH correlated with the need for supplemental oxygen, but not spirometric results or treatment with glucocorticoids. Mechanisms involved include fibrotic obliteration of pulmonary vessels, extrinsic compression of pulmonary vessels by lymphadenopathy, granulomatous involvement of small pulmonary vessels, and pulmonary veno-occlusive-like lesions, left ventricular dysfunction, or portopulmonary hypertension from liver disease [52]. (See "Clinical manifestations and diagnosis of sarcoidosis".)
•Pulmonary Langerhans cell histiocytosis (PLCH) – PH associated with PLCH tends to be more common and may be more severe than PH associated with other lung diseases (eg, emphysema, IPF) [26]. A retrospective study of 17 patients with PLCH reported that 89 percent had an estimated sPAP on echocardiography >35 mmHg and 53 percent had an estimated sPAP >50 mmHg; PH correlated with the severity of lung function [53]. (See "Pulmonary Langerhans cell histiocytosis".)
•Others – PH may complicate cystic fibrosis, bronchopulmonary dysplasia, hypersensitivity pneumonitis, and possibly lung cancer [54-57]. (See "Cystic fibrosis: Clinical manifestations of pulmonary disease", section on 'Pulmonary hypertension' and "Pulmonary hypertension associated with bronchopulmonary dysplasia" and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)
Sleep disordered breathing — Most studies suggest PH rates of 20 to 30 percent in patients with obstructive sleep apnea (OSA) [58-61], although estimates may be inaccurate since many patients also have COPD and/or left-sided heart disease, which can also contribute to the development of PH. In most cases PH is mild. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Complications'.)
One large review of eight studies reported prevalence rates of PH in OSA that ranged from 17 to 70 percent, and an average mPAP level of 30 mmHg [58]. However, in one study that reported the highest rates of PH (70 percent), most patients had a component of left-sided pulmonary venous hypertension (ie, group 2 PH (table 1)) and when this study was removed from the analysis, the prevalence of PH decreased to 22 percent. These lower rates are similarly reflected in other studies [60].
Rates may be higher in those with coexistent obesity hypoventilation syndrome with one study reporting a prevalence of 58 percent [61]. (See "Clinical manifestations and diagnosis of obesity hypoventilation syndrome", section on 'Assess complications'.)
High altitude — High altitude is defined as an elevation of >2500 meters above sea level. There are a paucity of data on prevalence of high-altitude PH, defined as mean pulmonary artery pressure PAP ≥30 mmHg by the International Society for Mountain Medicine with some reports suggesting rates of 5 percent or higher [62,63].
Miscellaneous — Pulmonary developmental disorders are rare causes of PH.
PATHOGENESIS — Among the etiologies of group 3 PH, the strongest evidence favors hypoxic pulmonary vasoconstriction (HPVC) with remodeling of the pulmonary vascular bed. Most of the data are derived from patients with chronic obstructive pulmonary disease (COPD), but these mechanisms are likely common among all patients with group 3 PH. However, other disease-specific mechanisms are likely also involved in the development of PH.
●Hypoxic pulmonary vasoconstriction – HPVC is a normal regulatory mechanism designed to limit blood flow to hypoxic alveoli and preserve ventilation-perfusion matching. Both alveolar hypoxia and peripheral arterial hypoxemia may contribute to HPVC, particularly high altitude PH. Its effect on pulmonary vascular pressure depends on the duration of the hypoxia.
•Short-term hypoxia (hours to days) causes immediate precapillary arteriole vasoconstriction, which appears to be mediated by mitochondrial signaling and ion channels in smooth muscle cells and can be fully reversed with oxygen therapy [64-66]. This type of HPVC can be seen in patients who develop intermittent hypoxemia (eg, obstructive sleep apnea) or acute hypoxemic respiratory failure; in the latter, the acute rise in pulmonary pressures can be misconstrued as due to underlying PH but they frequently resolve to baseline after treatment of the underlying cause of hypoxemia.
•Chronic hypoxia (days to weeks), in contrast, causes pulmonary vasoconstriction by a variety of mechanisms and is often only partially reversible [67,68]. As an example, correction of hypoxemia with supplemental oxygen in one study decreased the pulmonary vascular resistance and mean pulmonary artery pressure, but only by a small amount [69]. Mechanisms by which chronic hypoxia induce vasoconstriction include:
-The endogenous vasodilator, nitric oxide, decreases due to diminished endothelial nitric oxide synthase (eNOS) production and increased hemoglobin-mediated inactivation [70,71].
-Production of the voltage-gated potassium channel's alpha subunit or activity of the full transmembrane protein decrease, causing the resting membrane potential to change. As a result, intracellular free calcium increases and pulmonary artery smooth muscles contract (ie, vasoconstriction) [72-75].
-Cytosolic phospholipase A2 (cPLA2) activity increases, which releases arachidonic acid from phospholipid membranes. Arachidonic acid can then be metabolized by cyclooxygenases and lipoxygenases into a number of different vasoactive eicosanoids, including prostaglandins, thromboxanes, and leukotrienes.
-Increased expression of endothelin-1 resulting in vasoconstriction, smooth muscle cell proliferation and matrix deposition (figure 1) [76-84].
●Vascular remodeling – Evidence of vascular remodeling over time can be seen pathologically. Initial changes include distal neomuscularization of the arterioles, intimal thickening, and medial hypertrophy. Abnormal collagen matrix is deposited within the adventitia later [85,86]. Eventually it is thought that this obliterative remodeling leads to fewer peripheral blood vessels and consequently increased peripheral vascular resistance seen in PH [18-20]. The varying degree to which each individual's disease is reversible may explain, in part, why the progression to severe PH is unpredictable in patients with COPD [87-91].
●Other mechanisms – Genetic polymorphisms may explain the significant variability in the prevalence of PH among patients with COPD. As an example, patients with hypoxemic COPD that carry the LL serotonin transporter gene polymorphism had higher mean pulmonary artery pressure (mPAP) than those with the LS or SS variant (34 mmHg versus 23 mmHg and 22 mmHg, respectively) [92].
Nitric oxide, prostacyclin, thromboxane, C-reactive protein, tumor necrosis factor alpha, transforming growth factor-beta, and vascular endothelial growth factor may also play important roles in PH associated with COPD or interstitial lung disease (ILD) [79,80,93-96].
Additional mechanisms underlying ILD-associated PH include [77,97-99]:
•Vascular destruction due to progressive parenchymal fibrosis
•Vascular inflammation
•Perivascular fibrosis
•Thrombotic angiopathy
•Endothelial dysfunction
Among the different ILDs, additional abnormalities may also exist:
•Patients with PH associated with idiopathic pulmonary fibrosis (IPF) may have an abnormal vascular phenotype, characterized by aberrant gene expression profiles that promote vascular remodeling [100].
•Anti-endothelial antibodies and other autoimmune processes have been implicated in the development of PH associated with connective tissue diseases (CTD; eg, systemic sclerosis) [34].
•Although classified as group 5 PH, in sarcoidosis-associated PH purported mechanisms include vasculature compression by enlarged lymph nodes, sarcoidosis-related arteritis, and pulmonary veno-occlusive disease [101-108]. PH associated with pulmonary Langerhans cell histiocytosis (PLCH) has been associated with a proliferative pulmonary vasculopathy involving the muscular arteries and veins has been reported in patients with PLCH [109] which may explain why PH in this population tends to be more severe than predicted by the degree of hypoxemia or spirometric abnormality [53,110].
The mechanism of PH in patients with sleep-related breathing disorders is presumed to be due to HPVC from nocturnal events but HPVC is less well studied in this population than in patients with COPD. Daytime hypoxemia from coexistent chronic lung disease or diastolic heart failure may also contribute to the development of PH in patients with sleep-related breathing disorders [3,91,111,112]. (See "Obstructive sleep apnea and cardiovascular disease in adults", section on 'Pulmonary hypertension'.)
CLINICAL EVALUATION
Suspecting group 3 pulmonary hypertension — A high index of suspicion is needed for the detection of PH in patients with pulmonary disorders since many of the symptoms of the lung disease itself mimic those of PH (eg, exertional dyspnea, fatigue, lethargy). Features that prompt a diagnosis of PH in patients with lung disease are discussed in this section while the general signs and symptoms of PH are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults".)
During the routine evaluation of chronic lung disease or hypoxemia, patients undergo a history and physical examination, and typically also undergo imaging with chest radiography and/or computed tomography (CT), pulmonary function testing (PFT; including spirometry, lung volumes, and diffusing capacity), and occasionally lung biopsy. Other than lung biopsy, most of these tests are also routinely performed during the evaluation of patients with PH of unclear etiology, the details of which are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)
Importantly, evaluation should occur when patients are stable, rather than during an exacerbation of their underlying lung disease, which can temporarily increase pulmonary pressures due to hypoxic vasoconstriction.
Specific to patients with lung disease and/or hypoxemia, the following findings should prompt consideration of PH [2,113]:
●Exertional dyspnea or hypoxemia that is not fully explained by the degree of parenchymal lung disease or severity of the underlying sleep disorder.
●Rapid decline of arterial oxygenation upon exercise.
●Any of the clinical features suggestive of right-sided heart failure including: exertional chest pain (eg, atypical or non-anginal chest pain), syncope or near-syncope, increased intensity of or a palpable pulmonic component of the second heart sound, a widened split second heart sound, elevated jugular venous pressure, peripheral edema, and/or electrocardiogram that demonstrates right-axis deviation, right atrial enlargement and/or right ventricular hypertrophy. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)
●Imaging, particularly, high resolution CT (HRCT) of the chest that demonstrates enlarged pulmonary arteries, attenuation of peripheral pulmonary vasculature, or right ventricular enlargement is suggestive of PH. Although the exact cutoff is unclear, a main pulmonary artery diameter of >29 mm has been shown to have a sensitivity and specificity of 89 and 83 percent, respectively, for diagnosing PH [114].
●PFTs revealing severe reductions in diffusing capacity (eg, <30 percent predicted), but in particular, a diffusing capacity that is decreased out of proportion to the severity of the restrictive or obstructive defect. (See "Overview of pulmonary function testing in adults".)
●Lung biopsy, (if done during the diagnostic evaluation of interstitial lung disease [ILD]) may incidentally reveal PH. However, this is rare and lung biopsy is not required or advisable in the setting of suspected PH.
Doppler echocardiography — While investigating patients with suspected PH of unknown etiology for underlying lung disease and/or sleep disordered breathing is routine, there are minimal guidelines for clinicians for the investigation of PH in those who have known underlying lung disease, hypoxemia, and/or OSA. Nonetheless, most experts agree that it is prudent to perform an initial echocardiogram in the following:
●Patients suspected to have PH based upon any of the features listed above. (See 'Suspecting group 3 pulmonary hypertension' above.)
●Patients with at least moderate obstructive disease on PFTs or patients with interstitial lung disease who need supplemental oxygen [115]. (See "Overview of pulmonary function testing in adults".)
●Patients suspected as having coexistent left-sided heart disease. (See "Tissue Doppler echocardiography".)
Echocardiography is used to detect elevated pulmonary artery systolic pressures (ePASP) as well as altered right-sided ventricle structure or dysfunction and evidence of left-sided heart disease. However, the definition of mild, moderate, and severe PH on echocardiography is ill-defined (and the cut-offs are somewhat arbitrary). In addition, echocardiography can be misleading, particularly in those with advanced lung disease [7,116,117] (see 'Prevalence' above). With these caveats in mind, we suggest the following (table 2):
●If echocardiogram is supportive of mild PH (eg, ePASP 20 to 39 mmHg) in the absence of any other etiology for PH, then most clinicians do not proceed with right heart catheterization (RHC), but rather observe patients for progressive symptoms over time. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis", section on 'Nonsevere pulmonary hypertension'.)
●In contrast, if PH is moderate (eg, ePASP ≥40 and <60 mmHg) or severe (ePASP ≥60 mmHg, tricuspid regurgitant jet velocity >3 meters/second, RV dilatation or dysfunction), then most experts refer to a center with expertise in PH to proceed with RHC to confirm the diagnosis.
●If echocardiography does not reveal PH (eg, PASP <20 mmHg), no RHC is generally done, unless the suspicion for PH is high (eg, unexplained symptoms or hypoxemia). Similarly, for those with an inadequate study in whom the suspicion is high, then many experts proceed with RHC.
Further details regarding features suggestive of PH on echocardiography are discussed separately. (See "Echocardiographic assessment of the right heart" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)
Additional testing — Several additional diagnostic tests may be performed as part of the evaluation of patients with suspected PH to identify specific pulmonary etiologies as well as exclude other etiologies of PH. Additional tests include overnight oximetry (to detect nocturnal hypoxemia), polysomnography (to detect obstructive sleep apnea (OSA) only if suspected), ventilation/perfusion (V/Q) scanning and/or CT pulmonary arteriography (to detect thromboembolic disease or pulmonary artery obstructions; group 4 PH), the six-minute walk test (6MWT; to determine the World Health Organization functional class (table 3)), cardiopulmonary exercise testing (may help distinguish group 3 from group 2 PH), and laboratory studies (eg, arterial blood gas, N-terminal pro-brain natriuretic peptide level, HIV serology, liver function tests, and connective tissue disease screening). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial diagnostic evaluation (noninvasive testing)'.)
Although cardiac magnetic resonance imaging (MRI) is an alternative and may be superior to echocardiography for assessment of right ventricular size, pressures, and function (ie, contractility, ejection fraction, wall motion abnormalities) [118], it is not universally available. In addition, if echocardiographic imaging was adequate, MRI is not typically performed as the result does not alter the decision to proceed with confirmatory RHC. (See "Clinical utility of cardiovascular magnetic resonance imaging".)
PATIENT SELECTION FOR RIGHT HEART CATHETERIZATION — Although right heart catheterization (RHC) is the gold standard test to confirm the diagnosis of PH, not every patient requires this procedure. The choice depends upon factors including the suspected severity of PH, the potential for pulmonary arterial hypertension (PAH)-specific therapy (which is often limited in group 3 PH), the values and life expectancy of the patient, candidacy for lung transplantation or trial inclusion, suspected component of group 2 (or other) PH, and potential prognostic information. Patients in whom RHC is being considered should be referred to a center with expertise in PH.
Hemodynamic values for normal adults can be found in the table (table 4). Due to exaggerated changes in intrathoracic pressure with breathing in those with significant lung disease, mean pressures should be averaged over several breaths and not during a breath hold. The definitions of PH by RHC (mean pulmonary arterial pressure [mPAP] ≥20 mmHg) and technical details regarding RHC are provided separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization' and "Pulmonary artery catheterization: Indications, contraindications, and complications in adults" and "Pulmonary artery catheterization: Interpretation of hemodynamic values and waveforms in adults" and "Pulmonary artery catheters: Insertion technique in adults".)
Right heart catheterization not indicated
Suspected mild pulmonary hypertension — In patients with suspected group 3 PH, most experts will not proceed with RHC when PH is assessed as mild (table 2). This may be defined as an estimated pulmonary artery systolic pressure (ePASP) 20 to 39 mmHg on echocardiography without signs of right ventricular dysfunction (see 'Doppler echocardiography' above). In such cases, a clinical diagnosis of group 3 PH can be made based upon clinical assessment and noninvasive testing. The rationale for this approach is that no additional diagnostic or therapeutic decisions would be gained from RHC, which is a procedure that carries risk. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis", section on 'Nonsevere pulmonary hypertension'.)
Patients with contraindications — It is unusual that a RHC cannot be placed but contraindications include infection (particularly at the insertion site or the presence of bacteremia) and the presence of right ventricle assist device as well as irreversible coagulopathy, electrolyte disturbances and other conditions which are discussed separately. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults", section on 'Contraindications'.)
Right heart catheterization is indicated
Suspected moderate or severe pulmonary hypertension — The value of RHC is controversial in this group, particularly in those with suspected moderate PH since many patients are not eligible for PAH-specific therapy (table 2). One trial reporting some success of the PAH-specific agent, inhaled treprostinil, in patients with PH due to interstitial lung disease (PH-ILD) has increased the use of RHC in this population [119]. This trial is discussed separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis", section on 'Interstitial lung disease'.)
Typically, we have a low threshold to perform RHC in the Group 3 PH population since RHC provides diagnostic and prognostic information for potential transplant candidacy and life expectancy. In our experience, most clinicians perform RHC in patients with suspected severe group 3 PH (ePASP ≥60 mmHg), while RHC may be performed on a case-by-case basis for those with suspected moderate group 3 PH (eg, estimated PASP 40 to 59 mmHg). RHC is also often performed in those with a high suspicion for severe PH in whom echocardiography is inadequate. (See 'Doppler echocardiography' above and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis", section on 'Severe pulmonary hypertension'.)
Suspected alternate etiologies for pulmonary hypertension — Patients in whom contributions from alternate etiologies for PH are suspected, should undergo RHC. In particular, those with suspected left-sided heart disease (group 2 PH (table 1 and table 5)) or patients in whom a strong vascular component (eg, group 1 PAH) is suspected (eg, mild lung disease but suspected severe PH or underlying connective tissue disease); in such cases therapeutic decisions are affected by RHC data, namely addressing heart failure or candidacy for treatment or entering a clinical trial for PAH-directed therapy.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of chronic dyspnea and of the signs and symptoms of PH are discussed separately. (See "Approach to the patient with dyspnea" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial differential diagnosis'.)
The causes of right ventricle dilation and/or dysfunction are shown in the tables (table 6 and table 7) and can generally be distinguished on clinical assessment or are evident on echocardiography itself.
DIAGNOSIS — A patient is considered to have group 3 PH when PH exists in an individual who has chronic lung disease (CLD) and/or hypoxemia, and no alternative cause of the PH can be identified. For some patients, a clinical diagnosis of group 3 PH can be made based upon clinical assessment and echocardiographic findings of PH. For others, PH can be definitively confirmed on right heart catheterization (RHC; mean pulmonary arterial pressure [mPAP] >20 mmHg). The extent of investigations needed to be done to sufficiently exclude other etiologies should depend upon clinical suspicion. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization' and 'Patient selection for right heart catheterization' above and 'Differential diagnosis' above.)
The 6th World Symposium on Pulmonary Hypertension modified their hemodynamic definition of group 3 PH with the following [1]:
●CLD and/or hypoxia without PH – mPAP <21 mmHg, or mPAP 21 to 24 mmHg with pulmonary vascular resistance (PVR) <2 Wood units (WU)
●CLD and/or hypoxia with PH – mPAP 21 to 24 mmHg with PVR ≥3 WU, or mPAP 25 to 34 mmHg
●CLD and/or hypoxia with severe PH – mPAP ≥35 mmHg, or mPAP ≥25 mmHg with low cardiac index (<2.0 L·min−1·m−2) or PVR >5 WU [120-122]
FINALIZING THE CLASSIFICATION — Importantly, in order to classify PH as group 3, other etiologies in the differential of PH (table 1) need to be excluded, particularly evidence of significant left heart failure. In general, features that distinguish group 3 PH from others include:
●The presence of moderate to severe impairment (eg, forced expiratory volume in one second [FEV1] <60 percent in patients with chronic obstructive pulmonary disease [COPD] and forced vital capacity [FVC] <70 percent in patients with pulmonary fibrosis). (See "Overview of pulmonary function testing in adults".)
●Characteristic imaging (of a lung disorder) or polysomnographic findings of (a sleep-related breathing disorder) to explain PH.
●Reduced breathing reserve, normal oxygen pulse, mixed venous oxygen saturation above the lower limit of normal, and an increase in the partial arterial pressure of carbon dioxide during exercise testing (particularly relevant in COPD). (See "Cardiopulmonary exercise testing in cardiovascular disease".)
●Presence of mild to moderate PH on echocardiography or right heart catheterization (RHC; mean pulmonary artery pressure [mPAP] <35 mmHg). (See 'Doppler echocardiography' above.)
Since overlap syndromes are not uncommon, distinguishing group 3 from other groups is challenging (table 5) [4]. For example, many patients with COPD also have left-sided heart disease (group 2/3) and some patients have components of pre-capillary disease (group 1/3; eg, systemic sclerosis). These cases are best evaluated in a center with expertise in PH where RHC (table 5) is typically performed to help define contribution of select etiologies to PH as well as the contribution of PH to symptoms. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Pulmonary hypertension'.)
Whether similar values should be taken into account for those with high altitude PH is unclear although PH has been defined by other as mPAP ≥30mmHg [62].
SUMMARY AND RECOMMENDATIONS
●Classification – Patients with pulmonary hypertension (PH) due to chronic lung disease (eg, chronic obstructive pulmonary disease, interstitial lung disease, combined fibrosis and emphysema) or conditions that cause hypoxemia (eg, obstructive sleep apnea, hypoventilation syndromes) are classified as having group 3 PH (table 1). (See 'Classification and definitions' above.)
●Epidemiology – The prevalence of group 3 PH varies depending upon the underlying disease and its severity with rates ranging from 20 to 90 percent. Most patients in group 3 PH have mild to moderate elevations in mean pulmonary artery pressure (eg, mPAP 25 to 34 mmHg) (table 2). In contrast, to patients with group 1 pulmonary arterial hypertension (PAH), few patients in group 3 PH (<5 percent) have severe PH (mPAP ≥35 mmHg or mPAP ≥25 mmHg, and elevated right atrial pressure and/or a cardiac index <2 L/min/m2). The severity of PH appears to correlate with the severity of the underlying disorder. (See 'Prevalence' above.)
●Pathogenesis – Hypoxic pulmonary vasoconstriction with remodeling of the pulmonary vascular bed are common mechanisms that underlie the development of PH in patients with chronic lung disorders and/or hypoxemia. However, other mechanisms are likely also involved. (See 'Pathogenesis' above.)
●Clinical evaluation – A high index of suspicion for PH should be maintained and Doppler echocardiography performed in patients with chronic lung disorders and/or hypoxemia who have the following (See 'Clinical evaluation' above and 'Suspecting group 3 pulmonary hypertension' above.):
•Exertional dyspnea or hypoxemia disproportionate to the severity of the underlying lung or sleep disorder
•Features suggestive of right-sided heart failure
•Enlarged pulmonary artery or right ventricle on imaging
•Severe reduction in diffusing capacity (especially one that is decreased out of proportion to the severity of the restrictive or obstructive defect)
Echocardiography should also be performed in patients with at least moderate obstructive disease and patients with interstitial lung disease who need supplemental oxygen as well as in patients suspected as having coexistent left-sided heart disease. Additional testing may be performed to rule out other competing or contributing etiologies or to help narrow the differential. (See 'Doppler echocardiography' above and 'Additional testing' above.)
●Right heart catheter indications – Selecting patients for right heart catheterization (RHC) depends upon factors including the suspected severity of PH, the potential for PAH-specific therapy, the values and life expectancy of the patient, candidacy for lung transplantation or trial inclusion, suspected component of group 2 (or other) PH, and potential prognostic information. (See 'Patient selection for right heart catheterization' above.)
In general, patients suspected to have severe group 3 PH or an alternate class should undergo RHC, while patients suspected to have mild PH or who have contraindications do not need RHC until PH progresses or the contraindication resolves; RHC in patients with suspected moderate PH should be considered on a case-by-case basis. Patients in whom RHC is being considered should be referred to a center with expertise in PH.
●Diagnosis – A patient is considered to be in group 3 when PH exists in an individual who has chronic lung disease and/or hypoxemia, and no alternative cause of the PH can be identified. For some patients, a clinical diagnosis can be made based upon clinical assessment and echocardiographic findings. For others, PH can be definitively confirmed on RHC (mPAP >20 mmHg). The extent of investigations needed to be done to sufficiently exclude other etiologies should be depend upon clinical suspicion. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization'.)
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