Pulmonary Hypertension Due to Lung Disease or Hypoxia

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Continuing Education Activity

Pulmonary hypertension (PH) is the elevated pressure in the pulmonary vascular system. Chronic obstructive pulmonary disease (COPD) and diffuse pulmonary lung disease (DPLD), including idiopathic pulmonary fibrosis (IPF) and combined pulmonary fibrosis and emphysema (CPFE), are the most common disease-causing chronic hypoxia and are associated with the highest incidence of pulmonary hypertension in this group. PH is classified according to the underlying pathophysiology of the disease. PH that develops due to advanced lung diseases and prolonged events of hypoxia is included in group 3. PH is a progressive condition with grave consequences if not recognized and optimized early in the disease. This activity reviews the evaluation for early recognition and optimization of PH and highlights the role of the interprofessional team in evaluating and managing patients with this condition.

Objectives:

  • Identify different causes of group 3 pulmonary hypertension.
  • Describe the pathophysiology of pulmonary hypertension due to hypoxia.
  • Review the diagnostic workup to identify the presence of pulmonary hypertension.
  • Identify the adverse events associated with uncontrolled pulmonary hypertension.

Introduction

Pulmonary hypertension (PH) is a progressive disease that, if left untreated, can be life-threatening and lead to failure of the right ventricle. The 6th world symposium on pulmonary hypertension (WSPH), held in 2019, defined PH as mean pulmonary artery pressure (mPAP) > 20 mmHg.[1] European society of cardiology and European respiratory society updated guidelines in 2022 and further classified PH as pre-capillary PH with pulmonary vascular resistance > 2 wood units and pulmonary wedge pressures less than or equal to 15 and post-capillary PH with pulmonary wedge pressures greater than 15 mmHg.[2] Furthermore, the World Health Organization (WHO) divided PH into five groups based on differences in pathophysiology and therapeutic options.[3] PH associated with respiratory system disorders due to chronic lung disease with or without hypoxemia is included in group 3. This article discusses etiology, epidemiology, clinical and physician manifestation, evaluation, and management.

Other groups of pulmonary hypertension include pulmonary arterial hypertension (group 1), PH due to left heart disease (group 2), PH due to chronic thromboembolic pulmonary hypertension (CTEPH) (group 4), and other miscellaneous disorders causing PH (group 5) will be discussed separately.

Etiology

Chronic obstructive pulmonary disease (COPD) and diffuse pulmonary lung disease (DPLD), including idiopathic pulmonary fibrosis (IPF) and combined pulmonary fibrosis and emphysema (CPFE), are the most common disease-causing chronic hypoxia and are associated with the highest incidence of pulmonary hypertension in this group.[4] Pulmonary hypertension in this group varies with the severity of the disease. Most patients with COPD have mild to moderate PH, but a small group of patients with advanced COPD develops severe PH. The development of PH in this group of lung diseases is associated with a poor functional status, impaired quality of life, need for supplemental oxygen, and worse prognosis.

Other conditions that PH may also develop are cystic fibrosis, chronic hypersensitivity pneumonitis, lung cancer, and other less common chronic lung diseases, including pulmonary Langerhans histiocytosis and lymphangioleiomyomatosis (LAM). The severity of PH is reported to be proportional to the extent of illness and parenchymal involvement.[5] A small percentage of PH is also reported in developmental lung disorders like bronchopulmonary dysplasia and congenital diaphragmatic hernia.[6]

Other causes include pulmonary hypertension associated with hypoxia at high altitudes, which develops in people living over 2500 meters above sea level.[7] PH is reported more frequently in obesity hypoventilation syndrome (OHS) and overlap syndrome than in obstructive sleep apnea.[8] Due to associated nocturnal desaturation and worsening lung function, these patients with OHS usually present with more severe PH and poor prognosis.[9]

Epidemiology

Group 3 PH (associated with chronic lung diseases and hypoxia) has a higher incidence of PH than group 2 PH (due to left heart disease).[4] The prevalence of pulmonary hypertension in COPD is not known precisely, but it is estimated that approximately 10-30% of patients with mild to moderate COPD have PH.[10] The global initiative for chronic obstructive lung disease (GOLD) estimates that almost 90% of patients with COPD stage IV develop PH with mPAP > 20 mmHg.[11] PH is common in patients with IPF, and the prevalence of PH in IPF has been reported to be between 37-41%. The prevalence of PH in IPF may be higher as most of the reports come from patients evaluated for lung transplants with advanced IPF.[12]

Pathophysiology

The pathophysiology of PH group 3 is multifactorial and depends on the underlying disease processes. Pulmonary vasoconstriction in response to hypoxia plays a prominent role in the early phase of the disease process in both obstructive and restrictive lung disease. Prolonged hypoxemia impairs the release of endothelin-derived vasodilators like nitric oxide and prostaglandins. Also, it promotes the release of pulmonary vasoconstrictors like endothelin, increasing pulmonary vascular resistance (PVR).[13] 

In the late phase, remodeling of pulmonary microvessels with smooth muscle hyperplasia and constriction of intima leads to vascular lumen obliteration.[14] Other mechanical factors include vessel distortion due to the destruction of alveolar space in COPD and fibrosis in IPF elevates the pressure in the pulmonary vascular bed.[15]

History and Physical

Symptoms of pulmonary hypertension significantly overlap with the underlying disease. For group 3 PH, it mimics the clinical manifestations of other groups except for clinical history of chronic lung disease and hypoxia during the day or nighttime. Although unexplained dyspnea is a ubiquitous presentation, in a recent survey of experts, it was not found to be very specific. Instead, the expert panel identified syncope, dizziness, and palpitations as highly predictive of PH.[16] 

Physical exam findings are not specific and cannot accurately predict the disease's progression. Poor oxygen saturation, jugular venous distension, peripheral edema, ascites, altered heart sounds (especially loud P2 or S2), right ventricular heave, and right-sided heart failure signs such as hepatomegaly are helpful but present later in the disease process.[17][18]

Evaluation

Due to the lack of sensitivity and specificity of physical examination, prompt screening and testing are required to establish the diagnosis. Pulmonary function tests (PFT) help to distinguish between restrictive and obstructive impairment. An out-of-proportion decrease in diffusing capacity for carbon monoxide (DLCO) may predict the development of pulmonary hypertension and the need for further investigation. In general, a low DLCO (<40% of predicted) or rapid decline in DLCO (≥ 15%), and a DLCO disproportionate to lung volumes (i.e., FVC/DLCO ratio > 1.6), is a trigger for a low threshold for suspicion for PH.[16] It is also associated with high PVR and is a predictor of increased mortality in patients with interstitial lung disease.[19] Therefore, a screening method was proposed for PH in patients with advanced IPF, which shows that using the ratio of FVC /DLCO when combined with SpO2 in linear regression formula has high sensitivity and negative predictive value to screen patients with mPAP > 21 mmHg.[20]

Six-minute walk test (6MWT) and oxygen saturation on exertion also give insight into the underlying presence of PH. A worsening six-minute walk distance (6MWD) despite stable PFT, need for oxygen supplementation on exertion, and slow heart rate recovery in one minute can predict underlying PH.[21][22] However, there is no specific threshold identified to date for 6MWD or desaturation to predict the presence of PH.

When there is high clinical suspicion of pulmonary hypertension, the consensus from experts recommends obtaining echocardiography and Brain natriuretic peptide (BNP) or NT-proBNP. Transthoracic echocardiography (TTE) is considered the most useful non-invasive screening test for PH. Right ventricular systolic pressure (RVSP) can be estimated using the peak tricuspid regurgitation velocity, and systolic pulmonary artery pressures (sPAP) can be predicted using inferior vena cava (IVC) dilatation and collapsibility as a surrogate marker for right atrial pressures. TTE also helps to distinguish between pre-capillary and post-capillary hypertension by measuring left-sided parameters such as left atrial dilation and elevated diastolic filling pressures. Several studies, however, have shown that estimation of pressure through TTE can significantly overestimate the RVSP in chronic lung disease and lead to overdiagnosis of group 3 PH.[23][5] A study looked into adding other factors, including right ventricular outflow tract (RVOT) diameter and tricuspid annular plane systolic excursion (TAPSE) with RVSP, showed improved sensitivity and negative predictive value to predict PH in patients with advanced lung disease.[24]

Serum biomarkers such as BNP or N terminal-pro-BNP concentrations are useful screening tools for assessing patients with ILD-related-PH. Serum BNP levels are an independent prognostic marker used for risk evaluation. BNP, however, loses sensitivity when PH is cofounded by left heart disease.[25][26]

Pulmonary hypertension can be multifactorial and present as a spectrum of diseases due to the right and left heart disease. Right heart catheterization (RHC) is the gold standard for confirming the diagnosis of PH due to chronic lung disease and hypoxia. RHC can be valuable in distinguishing between pre- and post-capillary disease or the presence of combined pre-capillary and post-capillary disease. RHC is recommended for patients with exaggerated symptoms not explained by the extent of the underlying condition, patients undergoing evaluation for treatment with vasodilators, and patients being considered for a lung transplant. However, a low threshold for RHC is appropriate to confirm a PH diagnosis, particularly in those with high clinical suspicion of PH and right ventricular abnormalities on echocardiography (including dilation or enlargement and a low tricuspid annular plane systolic excursion) and in those with autoimmune ILD.

In addition to PFT and 6MWD, other useful testing modalities are chest Computed Tomography (CT) scans which can be very useful to evaluate ILD stability or progression when symptoms are disproportionate to the severity of the underlying ILD.

CT scan of the chest is commonly obtained in patients with COPD and ILD to measure the disease's extent and screen for lung cancer. There is no significant correlation between the extent of parenchymal changes seen on high-resolution CT imaging and the presence and degree of PH.[27]

The ratio of the main pulmonary artery to ascending aorta greater than 0.9 in IPF predicted PH and worse outcomes.[28][29]

Treatment / Management

The goal of the management of PH in group 3 is to optimize the underlying disease and improve the functional status. This includes guideline-directed therapy using appropriate bronchodilators in obstructive lung disease, antifibrotics in patients with fibrotic lung disease, and immunosuppressive agents in connective tissue disease-induced ILD to slow disease progression.

Patients with obesity hypoventilation syndrome (OHS) should be encouraged to use noninvasive mechanical ventilation (NIV).[30] Long-term use of NIV in OHS has been shown to improve pulmonary hemodynamics.[31]

In patients with advanced disease with hypoxemia, long-term oxygen therapy (LTOT) in patients with COPD has shown a decrease in the progression of PH when used for >15 hours and improvement in PAP when used for >18 hours.[32][33] However, there is no direct evidence to support that the use of LTOT in pulmonary fibrosis slows PH progression. Still, supplementary oxygen should be prescribed to avoid prolonged episodes of hypoxia which can potentially further worsen pulmonary hypertension.

Systemic vasodilators have been associated with concerns regarding the theoretical risk of worsening gas exchange due to hypoxic vasoconstriction and subsequent ventilation-perfusion mismatch.[34] Although this has not been observed in the multiple trials conducted to investigate the potential use of vasodilators in patients with ILD.[4] Trials with endothelin receptor antagonists, including Bosentan, Macitentan, and Ambrisentan, have shown no benefit but may be harmful.[35][36][37] A trial with Riociguat, a soluble guanylate cyclase stimulator, was stopped early due to increased adverse events and mortality.[38] Phosphodiesterase-type 5 inhibitors (PDE5i) have been studied in multiple trials in patients with chronic lung disease with no significant improvement in 6MWD or quality of life.[39][40]

The most recent use of inhaled treprostinil in the INCREASE trial showed an improved six-minute walk distance compared to patients who received a placebo. This supports the idea that inhaled vasodilators may cause less ventilation-perfusion mismatch than systemic use of vasodilators.[41]

While most vasodilator therapies are not effective and may be harmful, inhaled treprostinil is approved in group 3 PH. Based on the INCREASE trial, the US FDA approved inhaled treprostinil as the first and only treatment for group 3 PH associated with ILD. When supportive therapy and inhaled vasodilator therapy fail to control the disease progression, systemic vasodilators can be cautiously trialed on a case-by-case basis in tertiary pulmonary hypertension centers. 

Patients with advanced lung disease should be referred to centers with expertise in advanced lung disease and pulmonary hypertension for early evaluation of the lung transplant.[4] The international society for heart and lung transplant Guidelines recommends that patients with IPF should be referred to the transplant center when FVC < 80% and DLCO < 40% predicted or progressive decline in FVC and DLCO of 10% and 15% of predicted, respectively. Similarly, patients with COPD should be referred with FEV1< 25% of predicted and a BODE score >5.[42]

Differential Diagnosis

Suspected patients with group 3 PH should undergo diagnostic workup to exclude other causes of PH, including valvular heart disease and decompensated left heart disease (group 2), chronic thromboembolism, venous thromboembolism (group 4), and infection. It is essential to distinguish and understand the driving etiology of PH as it changes the management options and prognosis.

Group 3 PH in patients with lung disease can co-exist with group 1 PH, particularly in connective tissue – ILD cases. PH in these patients can be a continuum, contributed by hypoxia and other disease factors. These patients should be referred to a center with PH expertise for individualized management. Patients with group 3 lung disease, particularly ILD patients, can have simultaneous pre-capillary and post-capillary PH due to the prevalence of coronary artery disease.[43]

Prognosis

Pulmonary hypertension in COPD is usually mild to moderate in severity, with mPAP between 20 and 35 mmHg with the progression of pulmonary artery pressures at approximately < 0.5 mmHg/year.[44] A small subgroup of patients (5%) with advanced COPD exhibits a severe progression of PH with pulmonary artery pressures (mPAP > 35 mmHg) with poor circulatory reserves more than the ventilatory reserves expected for the respiratory impairment seen in the pulmonary function test. PH in COPD is a strong predictor of survival and is associated with poor outcomes and high mortality.[4][45]

Pulmonary hypertension associated with IPF is recognized to have a worse prognosis and poor quality of life.[21] Patients with IPF were found to have higher 1-year mortality compared to a cohort of lung transplant patients without PH. Similarly, patients with combined pulmonary fibrosis and emphysema develop severe PH and fear a worse prognosis than patients with IPF without emphysema.[46]

Complications

Elevated pressures in the pulmonary artery secondary to hypoxia from untreated and progressively worsening chronic lung disease increase right ventricular afterload. Due to the slow progression of pulmonary vascular resistance (PVR)in the setting of group 3 PH, RV adapts and hypertrophy to compensate for the high afterload. This subsequently causes RV diastolic dysfunction and paves the way to right ventricular and pulmonary artery (RV-PA) uncoupling. In one study, RV dysfunction was seen as worse in group 3 PH compared to patients in group 1 PH despite less severe PVR. Worse outcomes were also observed in the male gender. [46] In addition, lung hyperinflation and an increase in intrapleural pressures decrease the preload and venous return to RV. Under the persistently high afterload, RV eventually fails with reduced systolic function, and cor pulmonale ensues.[47]

Deterrence and Patient Education

Patients with group 3 PH should be educated on adherence to therapy for the underlying disease resulting in pulmonary hypertension. Patients with advanced restrictive and obstructive lung disease requiring oxygen supplementation should be counseled on the continued use of oxygen therapy to avoid periods of prolonged hypoxia. Good compliance with inhalers for patients with COPD and consideration for anti-fibrotic treatment in pulmonary fibrosis may prove to be vital to slow PH progression.

Close follow-up with pulmonologists and early referral to PH experts are crucial to detect the early disease progression and initiation of therapy. Patients should be screened and referred for evaluation of lung transplants.

Enhancing Healthcare Team Outcomes

Group 3 PH onset is silent due to signs and symptoms similar to the underlying lung disease and long-standing hypoxia. Progression of pulmonary hypertension can affect the patient’s quality of life and worsen mortality. Thus, it is imperative to recognize the development of PH in the early stage of the disease, which may improve long-term patient outcomes and survival.

Managing pulmonary hypertension requires an interprofessional team of clinicians, including a primary physician, pulmonologist, PH expert, specialty pharmacist, radiologist, and echocardiography expert. Patients with PH require close follow-up with regular lab work, echocardiography, 6MWD, and oxygen saturation on exertion to track the progression of the disease. Shared decision-making between the multiple specialties is required to plan and advance the treatment. Group 3 PH can overlap with group 1 (PAH) and group 2 PH (left heart disease) and requires referral to centers with expertise in treating PH with ongoing clinical trials.[48] [Class IC recommendation] Due to the progressive nature of some lung diseases causing PH, patients may need evaluation and referral to a center for a lung transplant.


Details

Updated:

6/11/2023 10:41:22 PM

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