Introduction

In the ERS/ESC guidelines for the diagnosis and the treatment of pulmonary hypertension, pulmonary hypertension (PH) has been de ned as an increase in mean pulmonary arterial pressure (mPAP) >20 mmHg at rest as assessed by right heart catheterization (RHC) [1]. This new hemodynamic de nition was proposed during the 6th world symposium on pulmonary hypertension (WSPH), bringing back the threshold to consider mPAP as pathologic from ≥25 mmHg (historical hemodynamic de nition of PH) to >20 mmHg, corresponding to the mean of mPAP in the general population (14 mmHg) plus two standard deviations (3.3 mmHg) as the upper limit of normal [2]. Precapillary PH, de ned by normal pulmonary arterial wedge pressure (PAWP) and increased pulmonary vascular resistances (PVR) ≥2 Wood

Units (WU), includes different subgroups of PH, including pulmonary arterial hypertension (PAH) (which itself has orphan disease status), PH due to chronic lung diseases, chronic thromboembolic pulmonary hypertension and PH with unclear and/or multifactorial mechanisms (Table 41.1). PH associated with parenchymal lung diseases is characterized in the vast majority of cases by a modest increase of pulmonary arterial pressure, resulting from pulmonary vasoconstriction and mild vascular remodeling due to chronic hypoxemia [3]. However, the increase in pulmonary arterial pressure may seldomly be out-of-proportion to the severity of the underlying lung disease, refecting a speci c pulmonary vascular involvement. Unfortunately, there is no consensus on the hemodynamic or functional de nition of the “out-of-proportion PH” occurring in the context of chronic lung diseases.

Table 41.1  Updated clinical classi cation of pulmonary hypertension (adapted from [1])

1. Pulmonary Arterial Hypertension (PAH)

1.1. Idiopathic

1.1.1.Non-responders at vasoreactivity testing

1.1.2.Acute responders at vasoreactivity testing 1.2. Heritable

1.3. Associated with drugs and toxins 1.4. Associated with:

1.4.1.Connective tissue disease

1.4.2.HIV infection

1.4.3.Portal hypertension

1.4.4.Congenital heart diseases

1.4.5.Schistosomiasis

1.5. PAH with features of venous/capillaries (PVOD/PCH) involvement

1.6. Persistent pulmonary hypertension of the newborn

2.Pulmonary hypertension associated with left heart disease

2.1.Heart failure:

2.1.1.with preserved ejection fraction

2.1.2.with reduced or mildly reduced ejection fraction

2.2.Valvular heart disease

2.3.Congenital/acquired cardiovascular conditions leading to post-capillary pulmonary hypertension

3.Pulmonary hypertension associated with lung diseases and/or hypoxia

3.1.Obstructive lung disease or emphysema

3.2.Restrictive lung disease

3.3.Lung disease with mixed restrictive/obstructive pattern

3.4.Hypoventilation syndromes

3.5.Hypoxia without lung disease

3.6.Developmental lung disorders

4.PH associated with pulmonary artery obstructions

4.1.Chronic thromboembolic pulmonary hypertension

4.2.Other pulmonary artery obstructions

5.PH with unclear and/or multifactorial mechanisms

5.1.Hematologic disorders

5.2.Systemic disorders 5.3 Metabolic disorders

5.4.Chronic renal failure with or without hemodialysis

5.5.Pulmonary tumour thrombotic microangiopathy

5.6.Fibrosing mediastinitis

PAH pulmonary arterial hypertension, PCH pulmonary capillary hemangiomatosis, PVOD pulmonary veno-occlusive disease

Classifcation of Pulmonary Hypertension

The current classi cation of PH revised during the 2022 ESC/ERS Guidelines on pulmonary hypertension is presented in Table 41.1 [1]. The group 1 corresponds to all forms of PAH, including idiopathic PAH, heritable PAH, drugs and toxins induced PAH, and PAH associated with different conditions (connective tissue disease, HIV infection, portal hypertension, congenital heart disease, schistosomiasis or chronic hemolytic anemia). A subgroup 1.5 includes a rare entity characterized by a predominant pulmonary venous or capillary involvement: pulmonary veno-occlusive disease

(PVOD) and/or pulmonary capillary hemangiomatosis (PCH). Pathologic and genetic studies have demonstrated that PVOD and PCH represents distinct naming of the same entity [4–8]. Group 2 includes post-capillary PH associated with left heart diseases, de ned by an increased PAWP (above or equal to 15 mmHg, or above) and normal PVR [9]. Group 3 was de ned as “PH associated with lung diseases and/or hypoxia.” In this group, the predominant cause of PH is hypoxemia as a result of either chronic lung disease, impaired control of breathing, or residence at high altitude; however, the precise prevalence of PH in all these conditions remains unknown [10]. In this group, combined pulmonarybrosis and emphysema represents a category of lung disease characterized by a mixed obstructive and restrictive pattern frequently associated with severe PH [11, 12]. Group 4 de ned chronic thromboembolic pulmonary hypertension (CTEPH) [13]. Group 5 corresponds to heterogeneous conditions with unclear or multifactorial etiologies. This group includes hematological disorders (5.1), systemic disorders (5.2), metabolic disorders (5.3), chronic renal failure (5.4) orbrosing mediastinitis (5.6).

In the evaluation of PH occurring in the context of orphan lung diseases, physicians should rule out other types of PH (in particular post-capillary PH and CTEPH) and screen for other risk factors of PAH (connective tissue disease, portal hypertension, HIV infection). Of note, precapillary PH associated with orphan lung diseases may be observed in different subgroups of this classi cation: in group 1 (1.2: small patella syndrome and hereditary hemorrhagic telangiectasia, 1.6: PVOD/PCH), group 3 (syndrome of combined pulmonary brosis/emphysema, lymphangioleiomyomatosis), and group 5 (sarcoidosis, pulmonary Langerhans cell histiocytosis, neuro bromatosis).

Pulmonary Hypertension Associated with Sarcoidosis (Group 5.2)

Sarcoidosis is a multisystem disease characterized by granulomatous infammation of unknown cause, with pulmonary involvement being one of the commonest disease manifestations [14–16].

PH may complicate sarcoidosis with an estimated prevalence of 2.5–15% in unselected patients [17–21] but this prevalence can vary largely according to the population studied. PH has been estimated to be between 47% and 53.8% in patients with persistent dyspnea [22–24] and as high as 74% in patients with advanced parenchymal lung disease on transplantation waiting list [25, 26]. In addition, PH emerge more commonly in radiologic stage 4 pulmonary sarcoidosis, accounting for up to 66–74% of all sarcoidosis-­ associated PH (SaPH) [17, 27–29]. Nevertheless, interpretation of the true prevalence of PH in sarcoidosis is limited because right heart catheterization was not performed

in many studies, despite the low accuracy of echocardiography to detect PH and con rm its mechanism [19, 22, 30].

Pathological processes underlying SaPH are complex and multiple, and may fall under different groups according to the current clinical classi cation of PH [1]. Parenchymal lung disease related to sarcoidosis can result in extensive interstitial brosis with destruction of the pulmonary vascular bed, and together with alveolar hypoxia, may promote the development of mild or moderate precapillary PH [16, 20, 31, 32]. Although PH is frequently associated with advancedbrotic lung disease in sarcoidosis [22, 32, 33], there is occasionally a signi cant discrepancy between the severity of lung disease with the severity of PH. This suggests that alternate mechanisms, other than direct obliteration of the vascular bed by the brotic process, may participate to the development of PH [20, 34]. In the absence of parenchymal involvement, a true vascular involvement should be suspected [16, 34–37]. In fact, distal arterial or venous in­ ltration by granulomas may occur. Notably, pulmonary venular lesions have been frequently reported, mimicking PVOD (Fig. 41.1) [32, 34, 35, 38]. A post-capillary component may induce SaPH mainly through direct myocardial involvement by cardiac sarcoidosis causing heart failure with preserved left ventricular ejection fraction, or through ischemic or hypertensive heart disease secondary to cortico-induced arterial hypertension or diabetes mellitus [22, 31, 39]. Furthermore, hepatic involvement may exceptionally result in porto-pulmonary hypertension [40]. Finally, enlargement of intrathoracic lymph nodes or brosing mediastinitis can lead to extrinsic compression of the proximal pulmonary vasculature [27, 34, 41–43]. In summary, the often multifac-

Fig. 41.1  Pathologic assessment of a patient with pulmonary hypertension associated with sarcoidosis. Pulmonary venous involvement is frequently observed in pulmonary hypertension associated with sarcoidosis. Epitheloid giant-cell granulomas (*) can be observed in the vicinity of veins, and may lead to their obstruction. Magni cation 100, hematoxylin-eosin staining

torial nature of SaPH is best considered under a speci c subgroup in the classi cation of PH: “unclear and/or multifactorial mechanisms” [1] (Table 41.1).

Several studies have demonstrated a correlation between severity of the disease and PH occurrence, in particular for mild or moderate PH [20, 22, 25, 33]. Moreover, PH in sarcoidosis has been associated with oxygen desaturation during 6 min walking test and low DLCO [28, 29, 31, 33]. Interestingly, others biomarkers of PH such as NT-proBNP have failed to predict PH occurrence in sarcoidosis, although it has been demonstrated to be increased in cardiac involvement [44]. However, PH may be present in all stages of sarcoidosis [20, 34] and referral for formal RHC is mandatory if PH is suspected [31].

It is recognized that patients with SaPH have a worse prognosis compared to those without precapillary PH [22, 45, 46]. Five-year survival in SaPH has been estimated to be 55% [27]. Risk factors associated with mortality include high level of mPAP, African American ethnicity and chronic respiratory failure requiring oxygen therapy [45].

Oxygen therapy should be prescribed if chronic hypoxemia is present to prevent hypoxic vasoconstriction. The ef - cacy of immunosuppressive therapy on pulmonary vascular disease in sarcoidosis is not clear because these treatments have not demonstrated consistent bene ts [16, 23, 47]. However, immunosuppressant use could bene t to a speci c SaPH subpopulation: indeed, a signi cant effect has been described in a speci c population where PH was related to extrinsic compression pulmonary vessels by mediastinal metabolically active lymph nodes [27].

The use of PAH speci c therapy in SaPH is currently not recommended, but in clinical practice, patients with severe precapillary PH are often treated with one or a combination of these off-label drugs [48]. Such treatments have predominantly been assessed in open-label observational studies [23, 24, 27, 28, 49–54]. However, a multicenter, double-blind, randomized trial comparing bosentan versus placebo in 35 patients with sarcoidosis and concomitant precapillary PH showed improvements in hemodynamics (mPAP and PVR), but no effect on exercise capacity (6-min walking distance (6MWD) or functional class) in patients treated with bosentan [55]. A meta-analysis of available studies on speci c therapies in SaPH, a recent retrospective study of SaPH patients registered within the French Pulmonary Hypertension Registry between 2004 and 2015 and a large retrospective cohort study con rmed these data showing that hemodynamic improvement under PAH speci c therapy regimen often does not result in an improvement in NYHA functional class, exercise capacity of quality of life [27, 28, 56]. However, a randomized pla- cebo-controlled trial evaluating the ef cacy of oral prostacyclin analogue selexipag in SaPH is running [57].

Gas exchange deterioration may also occur following vasodilator therapy via uncoupling of hypoxic pulmonary

vasoconstriction, resulting in worsening of ventilation/perfusion mismatch [58]. Furthermore, potential risk of pulmonary edema can occur in cases with predominant venular involvement in a manner similar to PVOD [24, 59]. Thus, current guidelines do not support the use of PAH speci c therapy in SaPH and off-label use of these therapies should only be considered in experienced PH centers.

Finally, because of the poor prognosis of SaPH and the lack of ef cacy of speci c PAH therapy, lung transplantation should be considered early in the course of the disease, despite the fact that the presence of PH prior to lung transplantation represents a risk factor of peri-transplant mortality [45] and primary graft dysfunction [60].

PH Associated with Pulmonary Langerhans Cell Histiocytosis (Group 5.2)

Langerhans cell histiocytosis is an infammatory myeloid neoplasia characterized by clonal expansion of myeloid precursors in ltrating organs and differentiating into Langerhans cells [61]. Pulmonary involvement usually occurs as a single-­ system disease but can, in scarce cases, be associated with extrapulmonary manifestations [62]. Pulmonary Langerhans cell histiocytosis (PLCH) predominantly affect young smoker adults and constitutes a rare cause of diffuse parenchymal lung disease [62]. PH can complicate the course of PLCH and severe PH is frequently reported in advanced disease [62–65]. Prevalence of severe PH (formerly de ned by mPAP ≥35 mmHg) in PLCH patients referred for lung transplantation assessment has been reported to range from 44% to 100% [63, 64] signi cantly higher than other chronic lung diseases such as COPD or IPF [63].

a

In contrast with PH related with classic interstitial lung diseases, despite lung parenchymal impairment, PLCH related PH is not classi ed in group 3 PH but in group 5 “unclear and/or multifactorial mechanisms” [1]. Indeed, discrepancy between hemodynamic severity and lung parenchymal involvement is frequently observed in PLCH related PH. In fact, hemodynamic parameters and pulmonary function tests are not correlated, suggesting that a speci c pulmonary vascular involvement occurs independently of parenchymal lesions [63, 64].

Histopathological studies have shown a speci c and diffuse pulmonary vasculopathy which is usually characterized by a proliferative vasculopathy with intimal brosis and medial hypertrophy involving the small to medium-sized pulmonary arteries and septal veins. This vascular involvement predominantly affects the pulmonary veins and, to a lesser extent, the muscular pulmonary arteries (Fig. 41.2) [63, 66, 67]. Notably, a signi cant venous involvement with a “veno-occlusive pattern” is present in up to one third of patients [63, 68]. Uncommonly, vascular lesions are due to direct in ltration by Langerhans cells [63, 67]. Finally, vascular lesions may be observed in areas free from parenchymal lesions [63, 67] and, interestingly, vascular lesions adjacent to areas of parenchymal involvement appeared less severe [67].

Exercise limitation in PLCH patients looks multifactorial (i.e., ventilatory and cardiocirculatory) [69, 70] although hemodynamic impairment appears to be the main source in PLCH related PH [71].

There are few data about the use of PAH speci c therapies in PLCH related PH. Some case reports describe improvement in functional class, hemodynamic and 6MWD, without deterioration of gas exchange or occurrence of pulmonary edema under endothelin receptor antagonists (ERA), phosphodiesterase type 5 inhibitors (PDE5i) or prostaglandins

b

Fig. 41.2  Pathologic assessment and high-resolution CT of the chest of a patient with pulmonary hypertension associated with pulmonary Langerhans cell histiocytosis. (a) Diffuse pulmonary vasculopathy which predominantly involves the pulmonary veins and, to a lesser

extent, the muscular pulmonary arteries. See intimal brosis of a septal vein with partial obliteration. Magni cation 100, hematoxylin-eosin staining. (b) High-resolution CT of the chest showing multiple small cysts and nodules