physiologic clinical and hemodynamic similarities of these conditions. However, special attention should be taken in these patients presenting with AVMs. Indeed, PAH speci c medications, because of their vasodilator properties can major the risk of systemic bleeding (systemic AVMs), hypoxemia worsening, by increasing the intrapulmonary shunt through pulmonary AVMs, or acute right afterload increase and thus right heart failure.

In conclusion, the absence of HHT clinical manifestation in PAH patients should not exclude the diagnosis of PAH associated with ACVRL1 or endoglin mutation and a detailed familial history and a careful examination of PAH patients and rst-degree relatives for signs of HHT may help detect these patients.

Pulmonary Veno-Occlusive Disease (Group 1.5)

Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are uncommon forms of PH whose diagnosis, as dif cult it is to differentiate from that of PAH, is of paramount importance for an appropriate management of these patients [165, 166]. In view of the dif-culty to accurately diagnose PVOD, these true prevalence and incidence appreciations are arduous. However, it has been suggested that PVOD represents 3–12% of histological forms of cases initially considered as idiopathic PAH [167, 168]. Whereas idiopathic PAH shows a distinct female preponderance, PVOD is characterized by a male/female ratio around 1 [5, 169]. Although initially considered to be two different conditions, it is now well-admitted that PVOD and PCH are two presentations of the same disease, with respect to numerous common traits and overlapping features [166]. Indeed, histological examination of lung samples shows extensive and diffuse occlusion of pulmonary veins bybrous tissue and intimal thickening involving preferentially venules and small veins in lobular septa in PVOD (Fig. 41.4), and localized capillary proliferations which could obstruct veins and venular walls in PCH [4, 8, 167, 170]. Indeed, a clinicopathologic study analyzing specimens from 35 patients diagnosed as having either PVOD or PCH concluded that lesions of capillaries were present in 3/4 of cases diagnosed as PVOD and that signi cant venous involvement was present in 4/5 cases initially diagnosed as PCH [8]. It has been hypothesized that capillary hemangiomatosis may result from an angioproliferative process associated with venous obstruction, as observed in PVOD. Furthermore, the discovery of a common genetic background in PVOD or PCH families con rmed that the terms “PVOD” and “PCH” described the same entity [7, 171]. According to these observations PVOD/PCH was grouped in a subgroup of group 1, entitled “group 1.5: PAH with features of venous/capillaries

(PVOD/PCH) involvement” in the current classi cation of PH (Table 41.1) [1].

In 2014, biallelic mutations of the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) gene were identi ed in 100% of familial form of PVOD/PCH and 25% of sporadic PVOD/PCH [7, 171, 172]. Thereby, EIF2AK4 is now recognized as the major genetic risk factor for PVOD/PCH. Heritable PVOD/PCH is an autosomal recessive disease, characterized by a male/female ratio of 1:1, and by a lower age at PVOD/PCH diagnosis compared to non-­heritable PVOD/PCH patients [7]. In sporadic, nongenetic forms of PVOD/PCH, some risk factors and associated conditions have been highlighted. Indeed, cases of PVOD/PCH are diagnosed in the context of treatment with a number of chemotherapeutic regimens, notably alkylating agents such as cyclophosphamide and mitomycin [173– 175]. PVOD/PCH has also been reported as a complication of hematologic or solid organ malignancies, peripheral blood stem cell transplantation, bone marrow transplantation, and radiotherapy. Of note, occupational exposure to solvent with trichloroethylene is also frequently described [176]. Moreover, a higher tobacco exposure and an increased proportion of smokers in PVOD/PCH as compared to PAH were reported [5]. This difference was not explained by the difference in the male/female ratio, since the increased tobacco exposure was observed in both genders. This relationship is also supported by the described association between PVOD/PCH and pulmonary Langerhans cell histiocytosis, a pulmonary disease occurring almost exclusively in smokers. Finally, it is increasingly described that a certain number of disease-­associated PH exhibit signi cant degree of venular involvement. It is mainly shown in connective tissue diseases, especially, systemic sclerosis [177, 178], infammatory diseases such sarcoidosis [179], or Langerhans cell histiocytosis [68]. However, the relative infrequency of these different associations highlights the dif culty in establishing whether it is the disease or its associated treatment that is responsible for the onset of PVOD/PCH.

PVOD/PCH is associated with a poor prognosis and require speci c management, justifying the diagnosis of the subgroup of PVOD/PCH patients among PAH patients early in the course of the disease. A de nitive diagnosis of PVOD/ PCH requires histological examination of lung samples or identi cation of bi-allelic mutations in EIF2AK4 gene, in particular in familial form of PVOD/PCH. However, lung biopsies are associated with a signi cant mortality risk in patients with established pulmonary vasculopathy and thus is contraindicated. Thereby, pathological con rmation is usually obtained from autopsy or lung explants, and treatment decisions are usually based on clinic-radiological grounds. Distinguishing PVOD/PCH from PAH on clinical grounds alone is dif cult since physical ndings are often identical.

Fig. 41.4  Pathologic assessment and high-resolution CT of a patient with pulmonary veno-occlusive disease. (a) Fibrous obstruction of a septal vein (*) associated with capillary proliferation. Magni cation 400, hematoxylin-eosin staining. (b) High-resolution CT of the chest

showing diffuse poorly-de ned centrilobular nodular opacities with associated septal line thickening. (c) High-resolution CT of the chest showing mediastinal lymph node enlargement

As in PAH, the installation of symptoms is usually insidious, marked by progressive dyspnea, asthenia and symptoms related to right heart failure in more advanced disease. Because of the non-speci c aspect of this symptomatology, PVOD/PCH diagnosis is frequently made later in the course of the disease, when symptoms are already well established. Digital clubbing and Raynaud phenomenon have been asso-

ciated with PVOD/PCH but are observed no more frequently than in idiopathic PAH [5]. Auscultatory crackles and pleural effusions may be indicative of acute pulmonary edema, occurring particularly after initiation of PAH speci c therapy. In PVOD/PCH, measured values of the pulmonary artery wedge pressure (PAWP), formerly called pulmonary capillary wedge pressure (PCWP), a misleading term, are

characteristically in the normal range despite the involvement of pulmonary venules. In fact, in the context of PVOD/ PCH, pressure measurements that are recorded when a catheter is wedged in a branch of the pulmonary artery refect pressures in the larger veins which are typically unaffected by the disease process. Thus, pulmonary artery wedge pressure measured in PVOD/PCH do not refect the true capillary pressure, making obsolete the term of PCWP [5, 180]. Obviously, due to the site of vascular involvement in PVOD/ PCH, the true pulmonary capillary pressure is increased, explaining the frequent occurrence of pulmonary edema especially when vasodilator drugs are applied on the pulmonary circulation. As a result, PVOD/PCH is characterized by a pattern of precapillary PH on RHC even though the anatomic obstruction is predominantly post-capillary. Interestingly, PVOD/PCH is associated with a similar proportion (12%) of acute vasodilator responders as idiopathic PAH. In contrast to idiopathic PAH, however, an acute response in PVOD/PCH is not associated with a better prognosis and a long-term response to calcium channel blockers has never been observed [181].

A non-invasive approach has been proposed to screen PH patients with a high clinical suspicion of PVOD/PCH [165, 180, 182]. These include high-resolution computed tomography of the chest, arterial blood gases, DLCO, and more rarely bronchoalveolar lavage. On HRCT of the chest, the triad of diffuse ground glass opaci cation in a centrilobular distribution, septal thickening, and mediastinal lymph node enlargement is common and highly suggestive of PVOD/ PCH in patients with precapillary PH [183, 184] (Fig. 41.4). Indeed, PVOD/PCH patients are characterized by signi - cantly lower resting partial pressure of arterial oxygen and DLCO compared to those with idiopathic PAH [169, 180]. Finally, PVOD/PCH patients have signi cantly increased numbers of hemosiderin-laden macrophages and relatively high average Golde score (yet usually <100) on bronchoalveolar lavage [185].

The response to medical therapy and prognosis of PVOD/ PCH are poor. An important clinical hallmark of PVOD/PCH is that about 50% of the patients may experience potentially life-threatening deterioration due to severe pulmonary edema after initiation of speci c PAH therapy [5, 180], which is the result of an increased pulmonary blood fow against a post-­ capillary xed obstruction. Although pulmonary edema has been reported with all speci c PAH therapies [5], it has been reported clinical, functional, and hemodynamic improvements in PVOD patients with cautious use of intravenous epoprostenol used as a bridge therapy to lung transplantation in selected patients [180]. Furthermore, some very moderate clinical and hemodynamic improvement have been reported in some isolated cases or small case series [186–191]. In addition, the existence of an infammatory background in PVOD/PCH patients could prompt some physicians to introduce immunosuppressive agents in these patients.

Nonetheless, data relative to this subject in the literature are scarce and such therapies are currently not recommended by the last international guidelines [1]. Recently, a series of three cases of idiopathic or heritable PVOD with features of undetermined immune diseases who experienced clinical and hemodynamic stabilization or improvement under immunosuppressive therapies including glucocorticoids and mycophenolate mofetil was reported [192]. However, because of the dysregulated immunity presented by these patients, it is not clear whether and how frequently immunosuppressants could improve this condition even in the absence of immune dysregulation.

Nevertheless, because of the overall poor response to speci c PAH therapy and poor outcomes, lung transplantation remains the treatment of choice of PVOD/PCH.

Small Patella Syndrome (Group 1.2)

TBX4 syndrome is an autosomal dominant syndrome affecting at diverse degrees and depending on the patients, the lower limbs, the pulmonary parenchyma, and the pulmonary vasculature. The TBX4 gene is a member of the T-box gene family, transcription factors playing dominant roles in the development of numerous organs [193–195].

Historically, TBX4 syndrome has been described as a dysplasia of the lower limbs, characterized by hypoplasia or aplasia of the patella, ossi cation defects of the ischia, and inferior pubic rami and anomalies of the feet dominated by the existence of a large gap between the rst and the second toes and fat feet, explaining why this syndrome was classically named small patella syndrome (SPS) or coxo-podo-­ patellar syndrome [196]. It was not until 2013 that the involvement of mutations in the TBX4 gene in the development of a pulmonary vasculopathy has been highlighted [197]. Indeed, TBX4 plays a major role in the development and branching of the lungs, and its mutations may result in bronchial, parenchymal, and pulmonary vascular abnormalities such as tracheal and bronchial diverticula, thickened and irregular bronchial walls, peri-bronchial cysts or emphysematous-­like lesions (Fig. 41.5) [198, 199].

TBX4 mutations can sometimes result in the development of PAH, classi ed in the group 1.2: “heritable PAH” of the updated classi cation of PH (Table 41.1) [1]. Its clinical presentation is close to that seen in idiopathic PAH and the classical female predominance is also a constant [199]. PAH in these patients occurs with a bimodal distribution mode with arst peak during early childhood [197–200] and a second peak in late adulthood [199]. To date, TBX4 mutations are considered to represent about 6% of pediatric PAH and 3% of adult-onset PAH [199, 201]. However, with respect to its implication in the growth of the lungs and the lower limbs, TBX4-related PAH patients can also present anomalies typical of small patella syndrome and/or parenchymal abnormali-

Fig. 41.5  Pathologic assessment and high-resolution CT of a patient with TBX4-related PAH with lung parenchymal involvement. (a) Interstitial brosis with remodeled vessels and cholesterol cleft depos-

its (*). (b) 3-mm thick transverse CT section of the upper lobes. Presence of multiple tracheal and bronchial diverticula (arrow), associated with the presence of emphysema in both lungs

ties [198, 199, 202].At diagnosis, PH is classically precapillary with severe hemodynamic involvement. Features of SPS are found in most of cases but can frequently be missed if the examination of the lower limbs is not rigorous, and HRCT of the chest, whose examination must be meticulous, reveals bronchial lesions and parenchymal lesions in about 60% and 90% of cases, respectively [199]. However, penetrance of SPS, lung anomalies, and PAH is incomplete, and a same mutation in subjects, from a same family or not, can result in different phenotypes of expression, from a totally asymptomatic clinical picture, to a subject combining PAH, SPS, and lung parenchymal anomalies [199, 203, 204].

Pathological assessment of the lungs of TBX4-related PAH patients con rms the existence of a typical vasculopathy, and reveals distal lung development abnormalities associated with the presence of cholesterol cleft inclusions located in the perivascular connective tissue, the pathophysiological signi cance of which is currently unknown (Fig. 41.5) [198, 199].

As classically observed in other heritable PAH, initiation of PAH speci c therapies allows clinical and, to a lesser extent, hemodynamic improvement. The prognosis remains severe and lung transplantation remains, to date, the only curative option [199].

Conclusion

In conclusion, PH can occur in several orphan lung diseases, including sarcoidosis, Langerhans cells histiocytosis, neuro bromatosis, lymphangioleiomyomatosis, and combined pulmonary brosis and emphysema. As classically observed in end-stage chronic lung diseases, PH may be a conse-

quence of hypoxic vasoconstriction and vascular bed restriction, and thus appears proportionate with the severity of the parenchymal involvement. However, a speci c pulmonary vascular involvement (in particular in sarcoidosis, neuro - bromatosis, and pulmonary Langerhans cell histiocytosis) may also develop, associated with severe “out-of-­proportion” precapillary PH, usually associated with a poor prognosis. During the last 20 years, mutations in ACVRL1 or TBX4, 2 genes well-known to be responsible for the HHT syndrome and the SPS, respectively, were identi ed as genes of interest in heritable PAH. In these patients, PAH is usually (but not always) accompanied by characteristic phenotypic traits related to these syndromes. PVOD represents a rare pulmonary vascular disease, with a clinical presentation close to idiopathic PAH, but with important differences in diagnosis, management, and outcome (Box 41.1).

Clinical Vignette

A 71-year-old man was referred for progressive exertional dyspnea. The patient had a history of atrialbrillation with pacemaker implantation few years ago, obstructive apnea syndrome treated with continuous positive pressure, abdominal aortic aneurysm, and he was a former smoker (50 pack-year). He presented a combined pulmonary brosis and emphysema syndrome with typical HRCT of the chest features (Fig. 41.6). PFTs revealed an obstructive pattern on spirometry, a nearly normal plethysmography measurement and a markedly reduced DLCO (Table 41.2). During the 6 months period preceding his admission, he presented a respiratory worsening with an increased