Review
Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
Enfermedad venooclusiva pulmonar y hemangiomatosis capilar pulmonar
Carlos Ortiz-Bautista
, Ignacio Hernández-González, Pilar Escribano-Subías
Corresponding author
Unidad de Hipertensión Pulmonar, Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain
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Under simple polarized light (middle image), the glass shows strong birefringence which, after applying the first order red compensator (below), is confirmed as negative birefringence–as it is yellow in colour and is positioned parallel to the compensator's axis (arrow)–. 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(A) Mediastinal lymph nodes (red arrows). (B) Pulmonary window showing septal thickening.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pulmonary hypertension (PH) is a haemodynamic status of the pulmonary circulation defined by a mean pulmonary artery pressure ≥25<span class="elsevierStyleHsp" style=""></span>mmHg diagnosed by right heart catheterization.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">1</span></a> Pulmonary veno-occlusive disease (PVOD) represents a rare form of pulmonary hypertension characterized by the primary involvement of the pulmonary venous system.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">2</span></a> The characteristic pathological lesion of PVOD is the obliteration of small pulmonary veins by fibrous intimal thickening (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) and irregular capillary proliferation,<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">3</span></a> which causes a progressive increase in pulmonary vascular resistance and ultimately can lead to right heart failure and death.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">In recent years there have been advances in the knowledge of PVOD, such as the discovery that mutations in the <span class="elsevierStyleItalic">eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4)</span> gene are responsible for inherited forms of PVOD.<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">4,5</span></a> Despite advances in the understanding of the genetic, cellular and molecular basis of PVOD in the last decade, it is still a rare lung disease with no approved effective pharmacological treatment, with lung transplantation being the treatment of choice for candidate patients.</p><p id="par0015" class="elsevierStylePara elsevierViewall">PVOD is part of group 1 PH according to the latest classification of the PH World Symposium,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">6</span></a> and forms part, together with pulmonary capillary hemangiomatosis (PCH) of a special designation (subgroup 1′) within the same group, in order to highlight the important differences with pulmonary arterial hypertension (PAH). Although they were considered different clinical entities in the past, recent clinical and pathological studies support the concept that both entities (PVOD and PCH) are actually different clinical expressions of the same disorder.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">7</span></a> This concept has been reinforced by the recent discovery that mutations in the EIF<span class="elsevierStyleItalic">2AK4</span> gene are responsible for hereditary cases of both entities.<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">4,8</span></a> The latest guidelines published jointly by the ESC/ERS also distinguish various types of PVOD/PCH: idiopathic, hereditary, drugs, induced by toxin-drug-radiation and forms associated with HIV-connective tissue diseases.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology and risk factors</span><p id="par0020" class="elsevierStylePara elsevierViewall">According to the literature, it is estimated that the prevalence of idiopathic or heritable PVOD is approximately 1–2 cases per million inhabitants with an annual incidence of 0.1–0.5 per million inhabitants.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">9</span></a> However, these data come from indirect estimates. Since the diagnosis of PVOD is difficult without histological or genetic confirmation and many cases still remain misclassified as PAH, knowing the exact prevalence and incidence of PVOD is not easy. Several pathological studies in patients with pulmonary hypertension suggest that between 3 and 12% of cases initially labelled as idiopathic PAH are actually PVOD.</p><p id="par0025" class="elsevierStylePara elsevierViewall">As in PAH, PVOD has been described in all age groups, from the first weeks of life until the seventh decade of life. With regard to gender distribution, unlike PAH, which predominantly affects women, PVOD has equal gender distribution. While hereditary cases develop at an earlier age (27<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10 years), sporadic cases predominantly affect older women.</p><p id="par0030" class="elsevierStylePara elsevierViewall">More and more data is available about potential risk factors associated with PVOD, among which we highlight tobacco smoke and organic solvents exposure, autoimmunity and inflammatory processes and certain chemotherapeutic agents. Although initial studies showed that smoking in patients with PVOD was higher compared to patients with PAH, the relationship between tobacco smoke exposure and PVOD is not entirely clear. A recent study shows that exposure to organic solvents, such as trichlorethylene, plays an important role in the development of PVOD.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">10</span></a> Furthermore, all patients exposed to trichlorethylene had tobacco smoke exposure, suggesting that the tobacco smoke can have a potentiating role in the development of PVOD.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Although initially the association between chemotherapy and PVOD has been suggested in isolated case reports, recent series have confirmed these data, mainly after exposure to alkylating agents. In a French registry study, almost 85% of cases associated with chemotherapy had received chemotherapy with alkylating agents, mainly cyclophosphamide (43%).<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">11</span></a> On the other hand, the same group has recently published that mitomycin-C alone or in combination with 5-fluorouracil is a potent inducer of PVOD, both in humans and rats.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">12</span></a> Chemotherapy-induced PVOD has also been described in the context of hematologic cancers, particularly after bone marrow transplantation.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Finally, an autoimmune substrate has been described in PVOD. In a retrospective study with 24 patients, Montani et al. describe the presence of autoantibodies in 30% of patients in the series, mainly ANA and antiphospholipid agents.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">2</span></a> Also, an association between PVOD and various autoimmune disorders has been described, such as sarcoidosis, granulomatosis of Langerhans, connective tissue disease, Hasimoto's thyroiditis and more rarely with HIV.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">13</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The recent discovery of biallelic mutations in the <span class="elsevierStyleItalic">EIF2AK4</span> gene as responsible for cases of heritable PVOD (autosomal recessive inheritance) has allowed to know more about the molecular mechanism of this disease's pathogenesis.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">2,5,14</span></a> The <span class="elsevierStyleItalic">EIF2AK4</span> gene encodes the protein <span class="elsevierStyleItalic">general control nonderepressible</span> 2 (GCN2), a kinase that phosphorylates the subunit-α of the <span class="elsevierStyleItalic">eukaryotic translation initiation factor 2</span> (EIF2). Phosphorylation of eIF2-α protects cells against oxidative stress, inflammation, cell survival or angiogenesis. GCN2's role and expression in the pulmonary vasculature is still unknown, so more studies are needed. However, the hypothesis is raised concerning the fact that a GCN2 reduction due to mutations in the <span class="elsevierStyleItalic">EIF2AK4</span> gene could cause greater cell susceptibility to oxidative stress and inflammation.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Diagnosis</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical manifestations</span><p id="par0050" class="elsevierStylePara elsevierViewall">The clinical presentation in PVOD is generally nonspecific and difficult to distinguish from PAH, with which it shares many similarities. The main symptom is exertional dyspnoea. In many cases, the patient does not recognize the symptoms, leading to a delay in diagnosis, having advanced functional class at the time of diagnosis. Pressure overload maintained over time causes right ventricular dysfunction and right heart failure in advanced stages of the disease, which, along with presyncopal/syncopal symptoms result in poor prognosis. Haemoptysis has been described in the context of PVOD, although infrequent.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Cardiac auscultation shows signs of pulmonary hypertension such as splitting and strengthening of the second sound, tricuspid regurgitation murmur and sometimes third sound of the right ventricle. Regarding the respiratory system, lung crackles may occur in patients with pulmonary infiltrates.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Other specific signs that may occur are “<span class="elsevierStyleItalic">clubbing</span>” (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>)<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">15</span></a> and Raynaud syndrome, although infrequent.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Electrocardiogram</span><p id="par0065" class="elsevierStylePara elsevierViewall">Electrocardiographic changes are also non-specific and often show signs of PH such as axis deviation to the right, right atrial enlargement, signs of hypertrophy and right ventricular overload (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Transthoracic echocardiography</span><p id="par0070" class="elsevierStylePara elsevierViewall">Transthoracic echocardiography is the non-invasive diagnostic tool of choice in the initial evaluation of all patients with suspected PH, although there are no echocardiographic parameters that distinguish PVOD from other forms of PAH. However, it does allow us to rule out a left cause of PH and gives us prognostic information (right ventricular function, pericardial effusion) (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Radiography</span><p id="par0075" class="elsevierStylePara elsevierViewall">Chest radiography offers little diagnostic information in PVOD. Usually, dilation of the right cavities and enlarged pulmonary trunks are found, unspecific data of pulmonary hypertension aetiology. Sometimes, signs of pulmonary oedema may appear, especially after initiating specific vasodilator treatment.</p><p id="par0080" class="elsevierStylePara elsevierViewall">By contrast, high resolution computed tomography (HRCT) has become the non-invasive diagnostic tool of choice in recent years. There are several radiographic signs described in the HRCT of patients with PVOD; among them, the presence of mediastinal lymph nodes, enlarged lobular septa and infiltrates with centrilobular ground-glass pattern stand out (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>).<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">16</span></a> Recently, in a series of 24 patients, Montani et al. have described that 75% of these patients have at least two of these radiographic signs on HRCT,<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">2</span></a> indicating that the absence of these radiographic signs does not definitively rule out the possibility of PVOD.</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Respiratory function tests and functional capacity</span><p id="par0085" class="elsevierStylePara elsevierViewall">One of the predominant clinical data on the progression of PVOD is marked respiratory failure at rest assessed by pulse oximetry and blood gas analysis. This reduction in arterial oxygenation is justified not only by the presence of interstitial oedema but also by a reduced cardiac output in advanced stages of the disease.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Usually spirometry and lung volumes are preserved. However, it has been reported that patients with PVOD have a reduced diffusing capacity for lung CO (DLCOc) with values usually lower than 50% regarding the predicted value.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">2</span></a> This parameter is important because it differentiates PVOD from PAH, since in the latter the DLCOc is relatively preserved. This reduction in DLCOc may be justified by the presence of interstitial oedema and reduced capillary blood flow.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Data on functional capacity in patients with PVOD were scarce until Laveneziana et al. recently published data on the physiological response to exercise in patients with PVOD compared to patients with PAH with the same haemodynamic characteristics and pulmonary function at rest. This paper demonstrates that patients with PVOD have an increased ventilatory demand, which may justify their higher degree of dyspnoea. Other important data from this study are lower peak oxygen consumption, higher desaturation with effort and higher ventilatory inefficiency in patients with PVOD.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right heart catheterization</span><p id="par0100" class="elsevierStylePara elsevierViewall">Hemodynamically, PVOD is defined as pre-capillary PH (mean pulmonary artery pressure ≥25<span class="elsevierStyleHsp" style=""></span>mmHg and PCWP <15<span class="elsevierStyleHsp" style=""></span>mmHg). From a pathophysiological point of view, it is important to know that in the context of PVOD, PCWP does not reflect the true pulmonary capillary wedge pressure. On one hand, PCWP is obtained during the occlusion of one pulmonary arterial branch with the distal balloon of the Swan-Ganz catheter, which causes a flow interruption distal to the balloon, producing a static column of blood reflecting the pressure in one diameter pulmonary vein similar to the branch of the occluded artery. In other words, the PCWP is a measure of the pressure in a relatively large calibre pulmonary vein. Furthermore, the pathological lesion in PVOD is found in small venules behind the pulmonary capillary bed, reason why the PCWP calculated by right heart catheterization in PVOD is normal (≤15<span class="elsevierStyleHsp" style=""></span>mmHg). However, the obstruction of small postcapillary venules produces a retrograde increase in pressure, causing pulmonary capillary pressure to increase, resulting in fluid extravasation and pulmonary oedema. By this same mechanism, specific vasodilator therapy and acute vasodilator test in patients with PVOD can cause acute pulmonary oedema.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Bronchoscopy and bronchoalveolar lavage</span><p id="par0105" class="elsevierStylePara elsevierViewall">In the study of PH, performing a bronchoscopy is not usually necessary unless the patient has haemoptysis. However, the usefulness of bronchoscopy and bronquioloalverolar lavage (BAL) have been described as additional diagnostic tools in the work-up for PVOD after occult alveolar haemorrhage was detected.</p><p id="par0110" class="elsevierStylePara elsevierViewall">Inspection of the airways may reveal intense hyperaemia of the lobar and segmental bronchi since elevated pulmonary venous pressure chronically produces vascular engorgement of venous plexus.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">18,19</span></a> On the other hand, a small retrospective study published a few years ago, identified a higher percentage of hemosiderin-laden macrophages in the BAL of eight patients with PVOD compared to eleven patients with PAH (40 versus 3%).<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">20</span></a> Based on this study, BAL has been proposed as another diagnostic tool, with the presence of alveolar haemorrhage being highly suggestive of PVOD, while its absence does not definitively exclude the diagnosis. However, given the methodological limitations of this study, more studies are still needed for determining the usefulness of this technique in this clinical setting.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Finally, it is important to stress that transbronchial lung biopsy is not indicated in patients with suspected PVOD since the probability of reaching a diagnosis is low and is associated with an unacceptably high rate of complications, mainly due to bleeding.</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Prognosis</span><p id="par0120" class="elsevierStylePara elsevierViewall">It is difficult to know exactly the prognosis of patients with PVOD due to the shortage of published data in this regard and biases inherent to publications from tertiary centres. Despite the above, published data suggest that PVOD is one of the aetiologies of PH with worse prognosis. The latest and largest series published to date in this regard is that of Montani et al. in which 24 patients with PVOD are retrospectively analyzed in comparison to 24 patients with PAH. In this series, the time from diagnosis to death or lung transplantation and time from first symptoms to death or lung transplantation are significantly lower in patients with PVOD (11.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>16.4 versus 42.3<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>29.9, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0001 and 24.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>22.2 versus 57.9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>38.2, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001, respectively).<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">2</span></a> This poor prognosis is also confirmed in a recently published series of patients with PVOD on a waiting list for lung transplantation, which, compared to PAH patients, mortality of patients with PVOD after 6 months on the waiting list was significantly higher (22.6 vs 11%; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.03).<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">21</span></a> For these reasons, once the diagnosis has been made, and in the absence of contraindications, patients with PVOD should be referred to early lung transplantation.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Treatment</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">General measures</span><p id="par0125" class="elsevierStylePara elsevierViewall">As it occurs in other PH groups, hypoxaemia is an aggravating factor in the progression of PVOD because it induces pulmonary vasoconstriction. Therefore, oxygen therapy is indicated in patients with baseline or exercise-induced hypoxaemia. Patients with PVOD have oxygen partial pressure figures in arterial blood significantly lower than patients with PAH, suggesting that these patients may require oxygen therapy in earlier stages of progression.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">2</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Anticoagulation has traditionally been part of the treatment of patients with PAH as it improved its prognosis by reducing thrombotic events in situ. However, in recent years, it has been found that this clinical benefit is not so significant and only occurs in certain groups of PAH. Thus, the latest European guidelines for PH only recommend anticoagulation therapy in patients with idiopathic and heritable PAH or that induced by anorectic drugs.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">1</span></a> Regarding PVOD, there are no prognostic data regarding anticoagulation in these patients and therefore no explicit recommendations in this regard. However, since these patients have occult alveolar haemorrhage, it seems logical that the risk of bleeding (haemoptysis) in these patients outweighs the still unclarified prognosis benefits. Therefore, until more data is available and in the absence of another long-term anticoagulation indication, anticoagulant therapy should not be started in patients with PVOD.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Infections are other possible factors associated with clinical deterioration in these patients, therefore, annual vaccination is recommended against pneumococcus and influenza virus. Since exposure to tobacco smoke has been described as an etiologic factor in PVOD, smoking cessation is a measure of particular importance.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Diuretic therapy provides symptomatic relief and can improve oxygenation in patients showing signs of right heart failure or pulmonary oedema.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Finally, as with PAH, pregnancy is associated with clinical deterioration and increased mortality in these patients. In addition, PH treatments have potential teratogenic effects, so gestational age patients should be informed, placing special emphasis on reliable contraceptive measures.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Specific pulmonary vasodilator therapy</span><p id="par0150" class="elsevierStylePara elsevierViewall">In recent decades, a multitude of vasodilators have been developed and approved to treat pulmonary hypertension, such as prostacyclin, endothelin-1 receptor antagonists, inhibitors of phosphodiesterase-5 and guanylate cyclase soluble inhibitors. Evidence of these drugs in the treatment of PAH and other PH groups is very wide. However, none of these drugs have proven effective in the treatment of PVOD and there are no randomized studies in this subgroup of patients. The little information we have about the use of specific pulmonary vasodilator therapy in patients with PVOD comes from case reports or case series publications. In addition, special care must be exercised with these therapies, as their use in patients with PVOD can induce pulmonary oedema in a high percentage of patients (50%).<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">9</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">To date, the largest series published on specific pulmonary vasodilator therapy in patients with PVOD has been published by Montani et al., in which 12 patients on the waiting list for lung transplantation treated with intravenous epoprostenol were retrospectively analyzed.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">22</span></a> After 3–4 months of treatment with a mean maximum dose of 13<span class="elsevierStyleHsp" style=""></span>ng/kg/min a significant benefit was observed both in functional class and haemodynamics with improvement in cardiac index (1.99<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.68 to 2.94<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.89<span class="elsevierStyleHsp" style=""></span>L/min/m<span class="elsevierStyleSup">2</span>; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.002) and indexed pulmonary vascular resistance (28.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.4 to 17<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.2<span class="elsevierStyleHsp" style=""></span>Wood/m<span class="elsevierStyleHsp" style=""></span>units<span class="elsevierStyleSup">2</span>; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>0.0001). Of the 12 patients, 9 received a lung transplant. All patients were under diuretic therapy at baseline and one third of them needed to increase the dose of diuretics to minimize the risk of pulmonary oedema.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Lung transplantation</span><p id="par0160" class="elsevierStylePara elsevierViewall">To date, lung transplantation remains the only definitive treatment in patients with PVOD. As stated above, given the poor prognosis of this disease, candidate patients should be referred for early lung transplantation. There are few data on long-term follow-up in PVOD patients undergoing lung transplantation, however, so far, recurrences of the disease have not been described after lung transplantation.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">New therapies</span><p id="par0165" class="elsevierStylePara elsevierViewall">In recent years, new treatment strategies have been developed for PAH based on immunosuppressive therapies. However, clinical evidence to date is limited and these therapies are not without side effects, that is why clinical guidelines do not recommend their use at present.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">1</span></a> Similarly, the use of immunosuppressive therapy is not recommended in patients with PVOD. Recently published data on the use of imatinib in PAH patients show a high rate of serious adverse events and discontinuation of treatment. These risks are greater than any possible improvements in haemodynamics and exercise capacity in patients able to remain under treatment with imatinib, which limits its usefulness in the treatment of PAH.<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">23,24</span></a></p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conclusions</span><p id="par0170" class="elsevierStylePara elsevierViewall">PVOD is a rare cause of PH that shares many clinical similarities with PAH, but unlike the latter, it has a poor short-term prognosis. Despite advances in non-invasive imaging techniques in recent years, the diagnosis remains difficult in many cases. Because of these difficulties, the genetic test will acquire a determining role in the diagnosis of these patients in the coming years. Given the poor prognosis implied by this disease, once diagnosed and in the absence of contraindications, candidate patients should be referred without delay to lung transplantation.</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Funding</span><p id="par0175" class="elsevierStylePara elsevierViewall">Funding for this work was provided by the Carlos III Institute of Health and the Ministry of Economy and Competitiveness of Spain through the Cardiovascular Research Network.</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflict of interests</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres827197" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec823521" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres827196" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec823520" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Epidemiology and risk factors" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Diagnosis" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical manifestations" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Electrocardiogram" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Transthoracic echocardiography" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Radiography" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Respiratory function tests and functional capacity" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Right heart catheterization" ] 6 => array:2 [ "identificador" => "sec0050" "titulo" => "Bronchoscopy and bronchoalveolar lavage" ] ] ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Prognosis" ] 8 => array:3 [ "identificador" => "sec0060" "titulo" => "Treatment" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "General measures" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "Specific pulmonary vasodilator therapy" ] 2 => array:2 [ "identificador" => "sec0075" "titulo" => "Lung transplantation" ] 3 => array:2 [ "identificador" => "sec0080" "titulo" => "New therapies" ] ] ] 9 => array:2 [ "identificador" => "sec0085" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0090" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflict of interests" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-10-17" "fechaAceptado" => "2016-11-07" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec823521" "palabras" => array:4 [ 0 => "Pulmonary hypertension" 1 => "Pulmonary veno-occlusive disease" 2 => "Prostacyclins" 3 => "Lung transplantation" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec823520" "palabras" => array:4 [ 0 => "Hipertensión pulmonar" 1 => "Enfermedad venooclusiva pulmonar" 2 => "Prostaciclinas" 3 => "Trasplante pulmonar" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pulmonary veno-occlusive disease is a rare cause of pulmonary hypertension which is part, together with pulmonary capillary hemangiomatosis, of the special designation (subgroup 1′) within pulmonary hypertension group 1 in the latest classification of the pulmonary hypertension World Symposium. Recent discovery that gene mutations in eukaryotic translation initiation factor 2 alpha kinase 4 (<span class="elsevierStyleItalic">EIF2AK4</span>) are responsible for inherited forms of pulmonary veno-occlusive disease has changed the role of genetic testing, acquiring relevant importance in the diagnosis of these patients. Despite the advances in genetic, cellular and molecular basis knowledge in the last decade, pulmonary veno-occlusive disease remains as a rare aetiology of pulmonary hypertension without any effective medical treatment approved and poor outcomes. This document aims to review the advances occurred in the understanding of pulmonary veno-occlusive disease in the last years.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad venooclusiva pulmonar es una causa rara de hipertensión pulmonar que forma junto a la hemangiomatosis capilar pulmonar una designación especial (subgrupo 1′) dentro del grupo 1 de hipertensión pulmonar en la última clasificación del Simposio Mundial sobre Hipertensión Pulmonar. El reciente descubrimiento de que las mutaciones del gen <span class="elsevierStyleItalic">eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4)</span> son responsables de las formas hereditarias de la enfermedad venooclusiva pulmonar, ha provocado que el test genético adquiera un papel determinante en el diagnóstico de estos pacientes. A pesar de los avances en el conocimiento de las bases genéticas, celulares y moleculares de la enfermedad venooclusiva pulmonar en la última década, sigue siendo clásicamente una enfermedad pulmonar rara sin ningún tratamiento farmacológico eficaz aprobado y con un pronóstico muy pobre. El presente documento pretende revisar los avances que se han producido en el conocimiento de esta enfermedad en los últimos años.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Ortiz-Bautista C, Hernández-González I, Escribano-Subías P. Enfermedad venooclusiva pulmonar y hemangiomatosis capilar pulmonar. Med Clin (Barc). 2017;148:265–270.</p>" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 674 "Ancho" => 901 "Tamanyo" => 96270 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Pathological study in patient with pulmonary veno-occlusive disease who underwent lung transplantation. Note fibrous intimal thickening of small pulmonary veins (arrows).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1036 "Ancho" => 1500 "Tamanyo" => 249227 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Clubbed fingers in patient diagnosed with pulmonary veno-occlusive disease.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 849 "Ancho" => 1701 "Tamanyo" => 534939 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Electrocardiogram in patient with pulmonary veno-occlusive disease in which right axis is observed with signs of overload and right ventricular hypertrophy.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 603 "Ancho" => 1500 "Tamanyo" => 84991 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Transthoracic echocardiography in patient with pulmonary veno-occlusive disease showing severe dilatation of right cavities and severe pulmonary hypertension (tricuspid regurgitation velocity 4.8<span class="elsevierStyleHsp" style=""></span>cm/s, estimated SPPA 91<span class="elsevierStyleHsp" style=""></span>mmHg). (A) Apical 4-chamber view. (B) Continuous Doppler at tricuspid valve in apical 4-chamber view.</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 545 "Ancho" => 1500 "Tamanyo" => 106234 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">High-resolution CT-scan in patient diagnosed with pulmonary veno-occlusive disease. (A) Mediastinal lymph nodes (red arrows). 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