Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial disease of unknown origin and characterized by the pathological changes of universal interstitial pneumonia (UIP), mainly manifested by diffuse alveolitis, disorganization of alveolar units and pulmonary fibrosis. The disease is progressive, with cyanosis, pulmonary hypertension, pulmonary heart disease, and right heart insufficiency in advanced stages.
Pulmonary arterial hypertension (PAH) is a disease state characterized by vasospasm, intimal hyperplasia and remodeling of the small pulmonary arteries. The proliferation and remodeling of small pulmonary artery vessels leads to a progressive increase in pulmonary vascular resistance (PVR). According to the WHO 2003 classification criteria for PAH [1], PAH due to IPF is classified as “pulmonary hypertension associated with respiratory disease and/or hypoxemia”, which is one of the traditional categories of “secondary pulmonary hypertension”. It is one of the traditional “secondary pulmonary hypertension”. In the past, PAH in patients with IPF was not given sufficient attention and targeted treatment was not advocated, mainly because it was thought that pulmonary vasodilator drugs might lower systemic blood pressure and provide limited benefit to patients [2]. However, recent studies have found that PAH is closely related to the prevalence and mortality of IPF [3,4], and PAH is one of the important factors affecting the prognosis and mortality of patients with interstitial lung disease, especially IPF patients [5-7]. Early detection of PAH and timely intervention have an important impact on the improvement of prognosis and survival quality of IPF patients, so PAH in IPF patients has attracted academic attention again in recent years.
I. Incidence of PAH in IPF patients.
The incidence of PAH in IPF patients is limited by a variety of factors, and precise statistics are not yet available. The few studies with right heart catheterization data have focused on IPF patients awaiting lung transplantation. Lettieri et al [3] counted 32% of IPF patients awaiting lung transplantation between 1998 and 2004 with PAH confirmed by right heart catheterization (95% confidence interval 21%-42%); Nathan et al [8] reported 41% of 118 IPF patients with PAH in 2007 (95% confidence interval 32%-50%); Lederer et al [9] reported 41% with PAH in 2007 (95% confidence interval -50 -(95% confidence interval 32%); Lederer et al [9] reported that 20% (95% confidence interval 7%-32%) of 41 patients with IPF who underwent right heart catheterization had PAH; Lederer et al [10] evaluated 376 patients with IPF who underwent right heart catheterization between 2004 and 2005 and found that 28% (95% confidence interval) had PAH. These foreign data show that about 20-40% of patients with IPF have pulmonary hypertension [11]. There are no precise epidemiological data on the incidence of IPF in China, right heart catheterization is limited, and no data are available to date on the incidence of PAH in Chinese patients with IPF.
II. Pathological changes and pathogenesis of PAH due to IPF
1.Pathological changes
(1) Lesions associated with hypoxia and fibrosis: lesions of the pulmonary vasculature due to IPF involve arteries, small arteries, veins, and capillary beds. A series of lesions can be seen such as thickening of the vessel wall, hypertrophy and proliferation of small muscular pulmonary artery smooth muscle, deposition of collagen fibers, and myelination of small distal pulmonary arteries. Associated with deposition of fibroblasts, myofibroblasts and extracellular matrix. These changes are consistent with those exhibited by other pulmonary diseases associated with hypoxia [11].
(2) Extensive intimal hyperplasia: small muscular pulmonary arteries in IPF patients have extensive intimal hyperplasia, fibrosis, and thickening of the elastic lamina, distributed in areas of dense or sparse fibrosis [12], changes that are uncommon in other pulmonary diseases and animal models associated with hypoxia [12,13]; pulmonary veins also have proliferation and fibrosis of the intima [12].
(3) Thrombosis: thrombosis can be seen in small myocardial pulmonary arteries in the lung tissue of IPF patients [14], which is associated with increased resistance to the pulmonary circulation.
(4) Disruption and proliferation of pulmonary capillary beds: there are two different types of pulmonary capillary lesions, one is the destruction of capillary beds, which can be seen in areas where fibrosis is more concentrated and is closely associated with increased pulmonary circulatory resistance [12]; the other is the proliferation of capillary beds, which is mainly seen in normal lung tissue sites around fibrotic lesions, and its role in the formation of pulmonary hypertension is unclear [ 15].
2, Pathogenesis.
The pathogenesis of pulmonary hypertension due to IPF is still not well understood, and it is currently believed that it may be the result of a combination of factors, mainly including the following.
(1) Hypoxic pulmonary vasoconstriction and pulmonary vascular remodeling.
Hypoxic pulmonary vasoconstriction refers to the contraction of small muscular pulmonary arteries with an internal diameter of between 200-600 μm caused by hypoxia, resulting in a rapid but mostly reversible increase in pulmonary vascular resistance. This response is a physiological protective response of the body and is a function of the pulmonary vasculature itself. The main effect is to reduce local blood flow in poorly ventilated alveoli by vasoconstriction, thus achieving a more appropriate ventilation/blood flow distribution and improving ventilation efficiency. Localized pulmonary vasoconstriction has little effect on pulmonary artery pressure, whereas widespread pulmonary vasoconstriction can cause an increase in pulmonary vascular resistance and pulmonary artery pressure. This pulmonary hypertension due solely to vasoconstriction is theoretically reversible, and some degree of relief can be achieved with pulmonary vasodilator drugs.
However, IPF is a chronic, progressive, fibrotic, partially cellulitic lung disease in which chronic hypoxemia, combined with chronic inflammation and the interaction of various vasoactive substances and growth factors, leads to structural changes in the pulmonary vasculature, or pulmonary vascular remodeling, resulting in persistent pulmonary hypertension. This vascular remodeling often involves the entire wall, including intimal hyperplasia, mid-layer hypertrophy, arterial myelination, increased whole-layer stroma, loss of blood vessels in some areas and neovascularization in other areas [16-18], which eventually leads to narrowing of the vascular lumen, reduced vascular compliance and increased resistance. one of the features of IPF is abnormal collagen deposition, and prolonged hypoxic pulmonary hypertension, which stimulates collagen synthesis, increases the collagen content of the pulmonary artery wall and contributes to the remodeling of the pulmonary vasculature. Studies have demonstrated [19] that the amount of collagen content in the pulmonary artery wall is closely related to the reduced compliance or expandability of the pulmonary vasculature. Therefore, many scholars believe that pulmonary hypertension due to IPF is related to pulmonary artery vasoconstriction or pulmonary artery remodeling due to hypoxemia [4]. This pulmonary hypertension due to vascular remodeling is difficult to be improved by drugs.
There are numerous cytokines involved in pulmonary vascular remodeling in IPF, including, endothelin (ET)-1, serotonin, prostacyclin (PGIS) and thromboxane, platelet differentiation growth factor (PDGF) and transforming growth factor (TGF)-β [4,11,15]. Fibroblasts and epithelial cells can release factors that lead to vascular remodeling, such as alveolar epithelial cells highly expressing ET-1, which can promote pulmonary vasoconstriction and smooth muscle cell division.
(2) Impaired pulmonary vascular endothelium and functional abnormalities.
Damage to pulmonary vascular endothelial cells (PAECs) is associated with hypoxia, inflammation, mechanical shear injury, and exposure to certain toxicants or drugs in genetically susceptible individuals. When primitive PAECs are activated to proliferate, clusters of PAECs accumulate in the lumen of the vessel, narrowing the pulmonary artery and affecting blood flow. non-myelinated vascular myelination and collagen synthesis, resulting in disruption of the pulmonary vascular bed and structural remodeling and distortion of the vessel wall.
Impairment of PAECs leads to imbalance of pulmonary vasodilator function, which on the one hand decreases prostacyclin (PGI2) synthase and nitric oxide (NO) synthase in PAECs, resulting in decreased synthesis of endogenous vasodilators PGI2 and NO. aggregation of platelets, activated neutrophils and macrophages. On the other hand, abnormally activated platelets in the pulmonary circulation can release endothelin (ET)-1, 5-HT, thromboxane A2 (TXA2) and other pulmonary vasoconstrictor substances to increase, causing an imbalance of diastolic and vasoconstrictor substances, resulting in pulmonary vasoconstriction and reduced pulmonary blood flow, causing reactive PAH.
(3) Coagulation and autoimmune abnormalities: platelet activation and coagulation, abnormalities in the thrombomodulin/protein C system and fibrinolytic system cause in situ thrombosis in the pulmonary arteries. 10-30% of patients with IPAH have positive antinuclear antibodies (less than 1:160), increased serum IL-1, IL-6 and monocyte chemokines, and inflammatory cell infiltration in pulmonary artery lesions. Some patients may have Raynaud’s phenomenon or concomitant immune disorders such as thyroid. All of these affect the formation of PAH to varying degrees.
III. Diagnosis and differential diagnosis of pulmonary arterial hypertension due to IPF
1.Diagnostic criteria.
In 2003, the World Health Organization (WHO) defined the criteria for PAH [1]: the mean pulmonary artery pressure (mPAP) ≥ 25 mmHg measured by right heart catheterization at rest at sea level or mPAP ≥ 30 mmHg during exercise. if there is no right heart catheterization data, Doppler ultrasonography suggests pulmonary artery systolic pressure (PASP) ≥ 40 mmHg (equivalent to tricuspid blood regurgitation) The diagnosis of PAH can also be made on the basis of the level of mPAP at rest, which can be classified as mild (26-35 mmHg), moderate (36-45 mmHg) and severe (>45 mmHg).
2. Clinical manifestations.
The symptoms of PAH in patients with IPF are not specific, including dyspnea after exercise, weakness, lower limb edema, palpitations, chest discomfort, chest pain, hemoptysis, etc. Physical examination: In mild PAH, there are often no abnormal signs, but in moderate PAH, there may be increased respiratory rate, rapid pulse, cyanosis, pestle finger, jugular vein filling or anger, lifting-like pulsation at the lower sternal border, systolic murmur and hyperinflation and splitting of the second pulmonary valve sound, regurgitant murmur in the tricuspid region, and the fourth right heart sound; in severe PAH, the pulmonary artery is significantly dilated. In severe PAH, the pulmonary artery is significantly dilated, and there is GrahamSteel murmur, swelling of both lower limbs, hepatomegaly, ascites and other signs of right heart insufficiency.
3. Diagnostic methods.
Non-invasive tests for PAH.
(1) Electrocardiogram: The electrocardiogram of patients with PAH suggests a right-sided cardiac axis, right ventricular and right atrial hypertrophy, etc.
(2) Color echocardiography: It is the most valuable test for noninvasive estimation of PAH. It can reveal the enlarged right atrium and right ventricle chambers, reduced wall motion, dilatation of the pulmonary artery and its main branches, etc. Based on these data, the pressure of the pulmonary artery can be estimated, and the diagnosis of PAH can be initially determined. The current criteria for determining PAH by color echocardiography is PASP>40mmHg.
(3) Chest X-ray: X-ray signs of PAH include widening of the right lower pulmonary artery by ≥15 mm, the ratio of its transverse diameter to the transverse diameter of the trachea ≥1.07, increased hilar width, conical projection of the pulmonary artery by ≥7 mm, baseline lengthening of the pulmonary artery segment, projection of the pulmonary artery segment by ≥3 mm, dilatation of the central pulmonary artery with slender or stump-like peripheral vessels.
(4) Spiral CT pulmonary arteriography (CTPA) and magnetic resonance imaging (MRI): both can clearly show the morphological features of the pulmonary arteries and their branches, and the widening of the pulmonary arteries and their branches in patients with PAH, and can clarify pulmonary fibrosis, which can provide more information for IPF-PAH diagnosis.
(5) 6-minute walking distance (6MWT): the distance walked in 6 minutes is one of the diagnostic tools for estimating pulmonary function and disease severity in patients with chronic lung disease. 6MWT distance is significantly shorter in patients with PAH due to IPF. Hanno et al [20] studied 39 patients with IPF, and the mean 6MWT was 303.93±21.92m in those without PH elevation (n=28). 21.92m, and the mean 6MWT for those with increased PH (n=11) was 185.45±41.12m.
(6) Pulmonary function tests: carbon monoxide diffusion (DLco) has an important value in predicting PAH in patients with IPF [21]. steven et al [22] found a 2-fold increase in the incidence of PH when the carbon monoxide diffusion rate (DLco%) was <30 compared to DLco% ≥30.
(7) Brain natriuretic peptide (BNP) assay: BNP is the main representative of the natriuretic peptide system, which is mainly secreted by the ventricular muscle and has been used in studies of left ventricular failure. The normal level of plasma BNP is <18 pg/ml .Leuchte et al [20] tested BNP in patients with IPF and found that BNP levels were significantly higher in patients with combined PAH, with a sensitivity of 100% and specificity of 89%.
Invasive tests for PAH.
(1) Right heart catheterization and cardiovascular angiography: It is the gold standard for the diagnosis of PAH, which can most accurately measure the pulmonary artery pressure and calculate the right heart displacement, pulmonary circulation resistance and other indicators, and can provide a reliable basis for the diagnosis and classification of PAH.
(2) Lung biopsy: It can detect the pathological changes of secondary PAH caused by IPF (as described above).
4.Differential diagnosis
The diagnosis of IPF combined with PAH should be based on two main points: first, whether the patient’s diagnosis of IPF is established; second, whether PAH is present, both of which have corresponding diagnostic criteria and are relatively easy. However, there are some cases that need to be differentiated in the diagnosis, mainly including the following.
(1) PAH due to connective tissue disease: Most have a history of connective tissue disease and its specific manifestations, some develop PAH after the development of interstitial lung disease, and some directly cause PAH. identification is mainly based on extra-pulmonary manifestations and related autoimmune detection indexes, such as rheumatoid factor, antinuclear antibody, and anti-granulocyte cytoplasmic antibody (ANCA).
(2) COPD-associated pulmonary hypertension: These patients are differentiated from IPF-PAH by history, physical examination and various tests to confirm the presence of COPD.
(3) PAH due to pulmonary artery thromboembolism: pulmonary embolism has various clinical manifestations, mostly occurs suddenly, mostly without evidence of pulmonary fibrosis, and CTPA helps to differentiate. However, there are also cases of IPF combined with pulmonary embolism, and PAH is related to both at this time, which needs to be distinguished.
(4) PAH caused by other diseases: such as portal hypertension, congenital heart disease, HIV infection, etc. can cause PAH. The diagnosis can be considered based on the characteristics of the underlying disease, which often involves extra-pulmonary organs, such as the liver, heart, etc., while the clinical manifestations of IPF-PAH mainly focus on the lungs.
The differential diagnosis of these diseases is not difficult when they exist alone, but it is not easy when they are combined with pulmonary fibrosis.
IV. Treatment of pulmonary arterial hypertension due to IPF
As mentioned above, PAH due to IPF develops gradually after IPF, therefore, the treatment should first be directed at IPF; on the basis of this, relevant anti-PAH drugs should be administered, with the main purpose of controlling the progression of the disease and reducing the death rate.
The treatment for PAH due to IPF includes the following aspects.
(1) Oxygen therapy. Hypoxia can cause pulmonary vasoconstriction and pulmonary vascular reconstruction, which play an important role in PAH, so oxygenation can be one of the effective treatments for hypoxic pulmonary hypertension. However, there is no data to prove that oxygen therapy can prolong the survival of patients [11]
(2) Vasoactive drugs: vasoactive drugs reduce pulmonary vascular resistance by dilating myocardial pulmonary arteries. However, dilating the pulmonary vasculature may exacerbate shunting and hypoxia at sites with reduced ventilation/blood flow ratios. Therefore, finding drugs that selectively dilate damaged vessels at sites of good ventilation is an ideal way to improve the prognosis of patients with PAH associated with IPF [4,23,24]. There are four specific targeted vasoactive drugs, including: (i) calcium channel blockers: effective in idiopathic pulmonary hypertension but not in PAH due to other causes [25]; and (ii) endothelin (ET-1) receptor antagonists. Patients with pulmonary hypertension have varying degrees of elevated vascular endothelial cell endothelin expression and plasma endothelin levels, so blocking endothelin receptors is one of the important treatments for pulmonary hypertension. Although this drug is effective in PAH, the only study of IPF treated with an ET-1 receptor antagonist did not include patients with combined PAH, so its effect on PAH is unknown [26]. (iii) Prostacyclin (PGI2), which acts by activating adenylate cyclase and inhibits platelet aggregation and vascular smooth muscle proliferation. Clinical trials have shown that intravenous administration of epoprostenol reduces mean pulmonary artery pressure but increases pulmonary blood shunting [27], and therefore is not recommended for routine use. ④Phosphodiesterase inhibitors: sildenafil can increase the concentration of cGMP by inhibiting phosphodiesterase 5, making the effect of endogenous NO more persistent. cGMP reduces pulmonary arterial pressure by activating protein kinase G, increasing K+ channel opening, supercharging cell membranes, decreasing intracellular Ca2+ concentration, and diastole of pulmonary vascular smooth muscle. ghofrani et al [28] showed that a single dose of sildenafil in patients with IPF-PAH decreased mean pulmonary artery pressure, reduced shunting, and increased arterial partial pressure of oxygen.Collard et al [28] observed 14 patients with IPF who used sildenafil for 3 months and found that it prolonged the walking distance of 6MWD in patients with IPF. However, randomized controlled studies are needed to confirm their efficacy.
(3) Other vasodilator drugs [4,23,24]: Nitric oxide has antiplatelet activity, anti-inflammatory, and antioxidant effects. Clinical trials have demonstrated its efficacy on all types of PAH with relatively high safety. Inhalation of NO and administration of L-arginine can significantly reduce pulmonary artery pressure and pulmonary vascular resistance.
(4) Anticoagulation therapy: intravascular thrombosis in the lungs of IPF patients is related to PAH, and long-term anticoagulation therapy should be of some benefit. A recent randomized controlled study [29] suggests that patients with IPF may benefit from anticoagulation therapy
(5) Single lung transplantation: it is one of the effective methods to treat IPF combined with PAH.
In conclusion, many drugs are currently being tried for the treatment of PAH in patients with IPF, but there is a lack of convincing randomized double-blind placebo-controlled studies to confirm their effectiveness. Therefore, the only effective treatment for PAH in patients with IPF is still oxygen therapy [11].
V. Problems and research directions in the study of PAH due to IPF
PAH is one of the important factors affecting the disease development, prognosis, and survival rate of IPF, and many scholars have devoted themselves to the research of early detection and prediction of PAH due to IPF, and have proposed many examination tools and related parameters [30, 31], which have greatly reduced the difficulty of diagnosis. However, the pathogenesis of PAH due to IPF is not well understood, and the specific treatment after the diagnosis of PAH remains a challenge. Many drugs, although effective in treating PAH, are still not promising for prolonging survival. Therefore, effective treatment for IPF itself is the fundamental way to solve PAH due to IPF. The investigation of the mechanism and treatment of PAH due to IPF is also crucial to improve the survival and quality of life of these patients, which is called “treating both the symptoms and the root cause”.