(PGI), mainly used in monotherapy regimen [72–79]. However, there have not been yet prospective randomized controlled trials to assess the effectiveness and safety of PAH speci c therapies in PLCH related PH.

In a retrospective study of 29 patients with PLCH related PH, Le Pavec et al. demonstrated severe hemodynamic impairment with 66% of subjects displaying a mPAP ≥40 mmHg [80]. In 23 of the 29 patients from this cohort, PH was diagnosed with a mean delay of 11 years after the initial diagnosis of PLCH. In this retrospective study, PAH speci c therapies improved hemodynamics (mPAP and pulmonary vascular resistance) associated with an improvement in functional class in 2/3 of the patients and an increase of 6MWD >10% in 45% of patients. Functional class was the only predictor of death and the use of PAH speci c therapy was not associated with improvement in survival [80].

PAH speci c therapies appeared to be relatively safe in this context, nor signi cant worsening of gas exchange nor pulmonary edema related to potential venular involvement were reported in PLCH related PH. However, severe acute pulmonary edema has been reported by other authors during initiation of intravenous epoprostenol therapy [63, 67, 68].

Effects of cladribine, a cytotoxic agent used in progressive PLCH, on PLCH related PH are not known. Nevertheless, it was reported to improve hemodynamic in one patient previously treated with bosentan, in parallel to improvement in clinical status, lung function, 6MWD and lung parenchymal impairment on high-resolution computed tomography (HRCT) [81].

Recently, mutations in the mitogen-activated protein kinase (MAPK) pathway including the well-known of dermatologic-­ oncologists BRAFV600E mutation, have been highlighted in up to 50% of LCH [82–84]. This important step forward opens the door to new treatment possibilities with targeted therapies directed against MAPK pathway. To date, there are no data concerning the use of such therapies in PLCH and their potential impact on pulmonary vascular involvement.

Lungs or heart-lung transplantation remains the treatment of choice for end-stage PLCH and/or for severe PLCH related PH [64]. Of note, recurrence of PLCH in lung allografts has been reported and risk of recurrence was associated with the presence of extrapulmonary disease prior to transplantation [64, 85, 86].

PH in Combined Pulmonary Fibrosis and Emphysema (Group 3.3)

Combined pulmonary brosis and emphysema (CPFE) wasrst described as a distinct entity characterized by diffuse destruction of the lung parenchyma in 2005 [11]. This syndrome,­ typically occurring in male smokers, results from

the combined effects of centrilobular or paraseptal emphysema in the upper lobes and lung brosis in the lower lobes [11, 87–90]. Despite extensive parenchymal involvement, pulmonary function tests are often well preserved in this condition, but associated with marked reduction in the DLCO and severe hypoxemia [11, 90, 91]. Precapillary PH frequently complicates the course of CPFE with a prevalence ranging from 47% to 90%, depending on the method of detection (i.e., echocardiography or RHC), which is more frequent than in COPD or IPF alone [11, 12, 92]. Hemodynamic impairment develops early after the diagnosis of CPFE, is usually severe, and appears correlated with the degree of emphysema on HRCT [12, 91, 92].

CPFE related PH is classi ed in subgroup 3.3 “Lung disease with mixed restrictive/obstructive pattern” (Table 41.1) [1]. The main assumption regarding the mechanism of PH in this context, is the association of alveolar destruction from emphysema and alveolar membrane thickening frombrosis, leading to reduced lung perfusion and obliteration of the pulmonary vascular bed [10, 93]. However, a true pulmonary vasculopathy, in some extent similar to what is classically observed in PAH, was described in histologic studies of CPFE related PH patients. Vascular remodeling usually associates intimal brosis, medial hypertrophy of small pulmonary arteries, and in situ thrombosis, but without plexiform lesions [94–96]. In addition, a certain degree of venular involvement can sometimes be observed, but without major capillary impairment [95]. Interestingly, some vascular lesions can develop in areas of normal lung [94].

A retrospective study reported the hemodynamic, functional, and survival characteristics of 40 patients displaying PH associated with CPFE [92]. At the time of diagnosis, RHC revealed moderate to severe PH (mPAP of 40 ± 9 mmHg, PVR of 6.5 ± 2.6 WU, and cardiac index of 2.5 ± 0.7 L/min/m2). Furthermore, 85% of the patients were in either functional class III or IV, with a mean 6MWD of only 244 ± 126 m. Moreover, univariate analysis found that DLCO <22%, PVR > 6.1 WU, and cardiac index <2.4 L/ min/m2 were predictive factors of death [92].

Prognosis of CPFE is highly affected from the development of PH with a 1-year survival of CPFE related PH patients estimated at 60 ± 10% [92].

Interestingly, CPFE could also be present in connective tissue diseases, with a similar prevalence of PH [97].

Although some published case reports suggest an improvement in hemodynamics of CPFE related PH under PAH speci c therapy [92, 98–100], PAH speci c therapies are not recommended due to the lack of published evidence and the potential risk of aggravating hypoxemia by worsening ventilation/perfusion mismatch [10, 58]. Finally, lung transplantation should be considered in selected patients and

supportive care for chronic respiratory failure, especially oxygen therapy, is required.

PH Associated with Neurofbromatosis Type 1 (Group 5.2)

Neuro bromatosis type 1 (NF1), also known as von Recklinghausen disease, is one of the most common genetic diseases with a prevalence of 1/3000 to 1/6000, an incidence of 1/2000 to 1/3000 and almost complete penetrance before the age of 5 [101]. This disease is caused by mutations in the neuro bromin 1 (NF1) gene, which codes for a cytoplasmic protein involved in tumor suppression called neuro bromin. Neuro bromin is a guanosine triphosphatase (GTPase)- activating protein (GAP) that acts as a negative regulator of signal transmitted by Ras [102]. Its loss is associated with constitutive activation of transcription pathways: the mitogen-­activated protein (MAP) kinase pathway ending by ERK activation and the mammalian target of rapamycin (mTOR) pathway, mediated by activation of the PI3kinase-­ AKT pathway and by the TSC1-TSC2 complex. The diagnosis of NF1 is clinical, based on the presence of at least two out of seven clinical criteria (café au lait spots, cutaneous or subcutaneous neuro bromas plexiform neuro bromas, axillary or groin freckles, glioma of the optic pathways, Lisch nodules on the iris, bone dysplasia, rst-degree family history) [103]. The characteristics of the disease vary widely from patient to patient, and some may develop respiratory complications such as airway plexiform neuro bromas, intrathoracic meningoceles, cysts, bullae, or interstitial in l- trates that can go up to pulmonary brosis and also PH [101]. Initially PH has been described as a consequence to an

a

advanced parenchymal disease, but then several case reports and a series of eight cases of PH associated with NF1 (PH-­ NF1) published by our team showed that patients with mild or absent lung parenchymal abnormalities can develop PH (Fig. 41.3) [104]. Using data from the French Pulmonary Hypertension Network, our team then reported in 2020 the clinical, functional, hemodynamic, and radiographic characteristics as well as the responses to speci c treatments for PAH in 49 patients with a combination of PH and NF1 [105]. Thus, it has been shown that PH-NF1 mainly affects women (female/male sex ratio of 3.9) whereas, due to its autosomal dominant transmission with full penetrance, NF1 is equally distributed between men and women. The onset of PH was late in history with a median age at diagnosis of 62 years (min-max 18–82). At diagnosis, PH was hemodynamically severe (mPAP of 45 mmHg and PVR of 10.7 WU) and was accompanied by major dyspnea with >90% of patients in NYHA functional class III or IV. The pulmonary function tests showed the existence of a major diffusion impairment (median DLCO: 30% of theoretical) associated with severe hypoxemia (median PaO2 in ambient air: 56 mmHg). Systematic analysis of chest scans showed associated pulmonary parenchymal lesions in most patients (cysts, ground glass opacities, emphysema and reticulations) most often moderate, not explaining the severity of PH. Histological data available in some of these patients revealed non-speci c interstitial pneumonia (NSIP) and intense pulmonary vascular remodeling. The response to speci c treatments for PAH is generally disappointing and the prognosis poor, with a 5-year transplant-free survival of 42%. Transplantation is an option to be evaluated early, despite the risks of complications under immunosuppressants in these patients at risk of cancer. Thus, four patients were transplanted, 3 of whom

b

Fig. 41.3  Pathologic assessment and high-resolution CT of a patient with NF1-associated pulmonary hypertension. (a) Interstitial brosis with partial loss of parenchymal architecture associated with pro-

nounced arterial remodeling complete occlusion by intimal brosis. Magni cation 40, hematoxylin-eosin staining. (b) High-resolution CT of the chest showing diffuse small rounded lung cysts

were still alive at the time of the study. The severity of PH “disproportionate” to the radiological abnormalities, the predominance of women and the observed pulmonary vascular remodeling, suggest the existence of a pulmonary microvascular disease associated with NF1. Research is needed to elucidate how the mutation of NF1 and its action on the Ras and mTOR signaling pathway may participate in the development of vascular remodeling and PH.

As a consequence, NF1 related PH was classi ed in group 5 in the updated clinical classi cation of pulmonary hypertension, among other forms of PH with unclear/multifactorial mechanisms [1]. PH represents a rare but severe complication of NF1 that is characterized by a late onset, with female predominance, severe functional and ­hemodynamic impairment, and poor outcome. Speci c PAH therapy seems to have only modest effect in these patients and these patients should be referred for lung transplantation if eligible.

PH Associated with Lymphangioleiomyomatosis (Group 3)

Lymphangioleiomyomatosis (LAM) is a rare multisystem metastasizing neoplasm predominantly affecting women in their reproductive years, with an estimated prevalence of 1–9/1,000,000 people [106–108]. It may occur sporadically or, in about 30% of patients, in the setting of tuberous sclerosis complex (TSC) with mutations in the TSC1 and TSC2 genes, coding for hamartin and tuberin respectively [109– 111]. The current accepted model for LAM is consistent with Knudson’s “two-hit” hypothesis of tumor development: an initial mutation in either TSC1 or TSC2 is followed by a second hit represented by loss of heterozygosity, causing the loss of function of either TSC1 or TSC2 gene products [112]. A major role of the complex hamartin-tuberin is to inhibit the mammalian target of rapamycin (mTOR) pathway. Thus, LAM is the consequence of a dysregulation of the mTOR pathway, leading to an abnormal proliferation of smooth muscle like cells (also called LAM cells) along lymphatics in the lungs and abdomen that leads to diffuse cystic lung disease, recurrent pneumothoraces, benign renal tumors, pleural and peritoneal chylous effusions, and abdominal lymphangioleiomyomas [111, 113]. At the pulmonary level, metalloprotease secretion by the LAM cells leads to the formation and progression of thin wall cysts, which in turn are responsible for airfow obstruction, low DLCO, and chronic respiratory insuf ciency [114–116]. In addition, serum levels of vascular endothelial growth factor-D (VEGF-D), which promotes the lymphatic vessels expansion, have been shown to be higher in LAM patients than in healthy controls and than in patients with other cystic lung diseases [117]. Sirolimus, an mTOR inhibitor has been shown to slow the

rate of lung function decline, to decrease VEGF-D serum levels, to be effective on extra-thoracic lesions of LAM and to improve quality of life [118, 119]. However, lung transplantation remains the only option for patients with advanced respiratory disease [120–126].

It was shown that the emergence of PH can complicate the evolution of LAM in about 7% and 45% of patients with LAM, whatever the stage of the disease, and at time of lung transplantation, respectively [116, 124, 127, 128]. Thereby, the European Respiratory Society guidelines for the diagnosis and management of LAM has underlined that PH has not been reported frequently in LAM patients and that screening for PH is not recommended in patients with non-severe LAM [120]. However, it was suggested that estimation of PAP should be performed in patients considered for lung transplantation [122]. In the updated classi cation of PH, PH associated with LAM has been switched from group 5 to group 3 [1, 2]. Indeed, it was shown that PH is usually mild in LAM, and is associated with severely altered pulmonary function [127, 129, 130]. There are two major hypotheses that can explain PH in LAM patients. The rst is the classic hypoxic vasoconstriction mechanism which occurs in the context of severe parenchymal distortions caused by cysts [116, 128]. This is supported by several studies reporting a signi cant correlation between hemodynamic severity in one hand, lung function and PaO2 level in the other hand [127– 130]. In addition, it was shown that sirolimus is effective in improving pulmonary hemodynamics, in parallel with signi cant improvements of FVC, FEV1, and PaO2 [128, 130]. The second is related to an up regulated mTOR secretion by the LAM cells, activation of mTOR complexes 1 and 2 in the context of hypoxia which in the end lead to vascular smooth cell proliferation and PH [129, 131, 132].

In a retrospective multicenter study, Cottin et al. reported 20 patients with LAM and precapillary PH con rmed by right heart catheterization [129]. The mean age at diagnosis of PH was 49 years with a mean time interval between LAM and PH diagnosis of 9.2 years. Hemodynamics showed moderate PH with a mPAP of 32 ± 6 mmHg, a cardiac index of 3.5 ± 1.1 L/min/m2, and PVR of 4.7 ± 2.3 WU, with only four patients (20%) having a mPAP >35 mmHg. These hemodynamic results suggested that in the majority of cases, PH was mild or moderate and related to the severity of pulmonary involvement [129]. Pulmonary function tests showed a decreased FEV1 at 42 ± 25% and DLCO at 29 ± 13% with blood gases showing mild hypoxemia (PaO2 of 55.5 ± 9.8 mmHg in room air) [129]. Only six patients received oral PAH speci c therapy and showed a decrease in mPAP and PVR from baseline. The authors showed that the overall probability of survival at 2 years was 94% [129].

In conclusion, mild to moderate PH is relatively a common nding in LAM patients with severe lung involvement. Chronic hypoxemia and pulmonary capillary destruction

caused by cystic lung lesions may represent the predominant mechanism of PH in this setting. Sirolimus, by improving lung function and hypoxemia, might improve pulmonary hemodynamics in these patients. Nevertheless, some patients may have speci c pulmonary vascular involvement, and one potential mechanism may be the activation of mTOR, as proposed in patients with NF1-associated PH. These patients may be candidates for speci c PAH therapies, but further studies are needed in order to assess this possibility.

Hereditary Hemorrhagic Telangiectasia (Group 1.2)

Hereditary hemorrhagic telangiectasia (HHT), also called Rendu–Osler–Weber syndrome, is a vascular disorder with an estimated prevalence of 1/6000 people. It is characterized by mucocutaneous telangiectasias, recurrent epistaxis, macroscopic arteriovenous malformations (particularly in the pulmonary, hepatic, and cerebral circulations), and more rarely PH [133, 134]. Diagnosis of HHT is clinical and considered de nite in the presence of at least 3 of the 4 Curaçao criteria, including (1) spontaneous and recurrent epistaxis,

(2) multiple mucocutaneous telangiectasia at characteristics sites, (3) visceral involvement with pulmonary, liver, cerebral, spinal or gastrointestinal arteriovenous malformations (AVMs), and (4) a family history [135]. HHT is inherited in an autosomal dominant fashion with late-onset penetrance and nearly complete penetrance (97%) at the age of 60 years. Several genes have been implicated in the pathogenesis of HHT, including endoglin (ENG) on chromosome 9, encoding endoglin (HHT type 1) activin receptor-like kinase-1 (ACVRL1) located on chromosome 12, encoding ALK-1 (HHT type 2), and, far less frequently, mother against decapentaplegic homolog 4 (MADH4) on chromosome 18, encoding SMAD4 (combined syndrome of HHT and juvenile polyposis) [136–138]. These genes are involved in the transforming growth factor-β (TGF-β) signaling pathway: homo and/or heterodimers of BMP9 and BMP10 are high in nity ligands of a receptor complex formed by the association of ALK-1, endoglin and bone morphogenetic protein-­ receptor type II (BMPRII), which, once activated, induces the phosphorylation and thus the activation of the SMAD proteins (including SMAD4), transcription factors implicated in the growth and the proliferation of endothelial cells [139–143]. Thereby, HHT causing genes are involved in the same signaling pathway than the BMPR2 gene, the main predisposing gene of heritable PAH.

Main pulmonary vascular involvement in HHT is characterized by the development of AVMs which may responsible of the creation of clinically signi cant right-to-left shunts, causing hypoxemia, paradoxical embolism, stroke, and cerebral abscesses [144]. In addition, PH can complicate the

course of about 8% of HHT patients and several mechanisms may be involved in the genesis of high pulmonary pressures [145].

Most commonly, the presence of systemic shunts through AVMs, mostly located in the liver, creates a high pulmonary fow and increased cardiac output, resulting in hyperkinetic pulmonary hypertension, hemodynamically characterized by elevated mPAP, high cardiac output and low to normal PVR. Recently, antiangiogenic therapy with bevacizumab (anti-VEGF antibodies) showed promising results in reducing the size of hepatic AVMs and thus decreasing cardiac output and pulmonary pressures [146, 147]. However, the potential deleterious impact of VEGF pathway inhibition on pulmonary vasculature remains a matter of debate [148]. Other drugs such anti-angiopoietin antibodies, or immunosuppressive drugs (i.e., tacrolimus and sirolimus) have been investigated during the last years, mostly in preclinical models and induced signi cant effects in reducing systemic AVMs. However, their effects on pulmonary pressure and high cardiac output were not assessed [149–152]. Interventional strategies, including ligation, banding or embolization of the hepatic arteries are not recommended anymore, because of the important morbidity and mortality associated with these procedures in this population [153]. Finally, liver transplantation is being considered in patients with refractory high outfow heart failure despite optimal medical management and induces in the majority of cases a dramatic improvement in pulmonary hemodynamics [154–156].

However, HHT is also associated, in a restricted population, with PAH characterized by remodeling of small pulmonary arteries, with broadly similar histologic lesions than observed in idiopathic PAH [157–159]. The prevalence of PAH (in the absence of liver AVMs) is currently estimated to be lower than 5% in HHT patients [160]. Many case series have reported the association of ACVRL1 mutations and PAH in HHT patients without any other cause of PH [157– 159, 161–163]. At the opposite, only few cases of PAH in endoglin mutants have been reported, although endoglin and ACVRL1 mutations are present in a comparable proportion in the population, suggesting a less potent association between endoglin and PAH [158, 162, 164]. We previously demonstrated that PAH patients carriers of an ACVRL1 mutation are signi cantly younger (21.8 ± 16.7 years) at PAH diagnosis, as compared to BMPR2 mutation carriers (35.7 ± 14.9 years) and non-carriers (47.6 ± 16.3 years) with a more rapid disease evolution [161]. Interestingly, ACVRL1 mutation carriers may develop severe PAH without any clinical evidence of HHT because of the early development of PAH in these patients and the late-onset penetrance of ACVRL1 mutations for HHT manifestations [161]. PAH speci c therapies are currently approved in these patients, by analogy with idiopathic PAH and other heritable PAH in view of the patho-