INTRODUCTION — Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis (PVOD/PCH) are now considered the same disease. PVOD/PCH is a rare condition that represents a small subgroup of adult patients with pulmonary hypertension (PH) (table 1) [1-3]. The terms "isolated pulmonary venous sclerosis," "obstructive disease of the pulmonary veins," and "venous form of primary pulmonary hypertension" were previously used to describe the syndrome [4-7]. Compared with pulmonary arterial hypertension (eg, idiopathic or heritable PAH), PVOD/PCH-associated PH has a grim prognosis and serious adverse effects can occur when pulmonary hypertension-specific advanced therapy is administered. Thus, the suspicion for and early identification of PVOD/PCH is critical to its management. For the purposes of this topic, the term PVOD will be used.
The epidemiology, pathogenesis, clinical features, and diagnosis of PVOD are reviewed here. The treatment of PVOD-associated PH as well as the clinical features and diagnosis of other forms of pulmonary hypertension are discussed separately. (See "Treatment and prognosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)
TERMINOLOGY — The World Health Organization (WHO) has classified pulmonary hypertension (PH) based upon etiology and mechanism into the five groups listed below (table 1) . Pulmonary arterial hypertension (PAH) refers to group 1 PAH. Pulmonary hypertension (PH) refers to any of group 2 through group 5 PH, and is also used when referring to all five groups collectively.
●Group 1 – PAH (PVOD is a subgroup of this type of PAH)
●Group 2 – PH due to left heart disease
●Group 3 – PH due to chronic lung disease and/or hypoxemia
●Group 4 – Chronic thromboembolic pulmonary hypertension (CTEPH)
●Group 5 – PH due to unclear multifactorial mechanisms
PVOD and PCH are classified as a subgroup of PAH since they share diagnostic hemodynamic similarities with PAH (see 'Right heart catheterization' below). However, while PAH causes pre-capillary pulmonary hypertension (ie, pulmonary "arteriolar" hypertension, which overall includes those in groups 1, 3, 4, and some patients in group 5 PH), PVOD and PCH are forms of mixed pre-capillary, capillary, and post-capillary pulmonary hypertension (ie, pulmonary "venous" hypertension) similar in this manner to patients with group 2 PH (table 2).
EPIDEMIOLOGY — The true incidence of PVOD is unknown, primarily because many cases are probably misclassified as idiopathic PAH (IPAH) or chronic thromboembolic pulmonary arterial hypertension (CTEPH) (table 1) [9,10]. However, estimates from a pooled analysis of seven case series (465 patients) suggest that PVOD accounts for 10 percent of cases of PAH (range 5 to 25 percent) [11-18]. Thus, the annual incidence of PVOD is estimated to be 0.1 to 0.2 cases per million persons in the general population .
Many cases of PVOD are detected in children and young adults. More recently, however, a bimodal age distribution has been demonstrated, with a separate population affected in later life (ages 60 to 80) . Age at diagnosis has ranged from eight weeks to the ninth decade of life .
Unlike classic IPAH, which has a female preponderance, PVOD affects males and females equally [2,22,23]. However, among non-familial cases of PVOD, another series suggested a male predominance in the condition .
The epidemiology of other forms of pulmonary hypertension is discussed separately.
PATHOGENESIS AND RISK FACTORS — Most cases of PVOD are idiopathic. The pathogenesis is unknown and likely multifactorial. It has been postulated that PVOD may represent a common aberrant response to an inciting event of endothelial injury that leads to widespread fibrosis of pulmonary venules . A familial form of PVOD and several risk factors have been reported, the details of which are discussed in the sections below. (See 'Genetic factors' below and 'Drugs and toxins' below and 'Autoimmune disorders' below and 'Miscellaneous' below.)
The pathogenesis of other forms of pulmonary hypertension (PH) is provided separately. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Pathogenetic mechanisms'.)
Genetic factors — Families with multiple members affected by PVOD have been identified, suggesting a genetic basis for some with this disease [7,17,25-27]. The age at which the disease presented in such families has ranged from eight weeks to age 50 .
Genetic mutations of the following have been identified:
●Eukaryotic translation initiation factor 2-alpha kinase (EIF2AK4) gene – One study of 13 families with PVOD detected recessive and biallelic mutations in the EIF2AK4 gene . Biallelic mutations have also been described in 25 percent sporadic cases of PVOD [27,28]. In a registry of patients with suspected PVOD, those with biallelic mutations of EIF2AK4 presented at a younger age but disease severity was similar to those without mutations . Two brothers with PCH (thought to be a variant of PVOD), were also identified to have biallelic mutations in EIF2AK4, as were 2 out of 10 patients with sporadic PCH . This kinase, EIF2AK4 (also called GCN2), phosphorylates the protein, EIF2, to down regulate protein synthesis necessary for cell growth and replication. Thus, mutations potentially result in uncontrolled cell growth. We generally test patients with suspected PVOD for mutations in this gene, particularly among patients <40 years of age. (See 'Evaluation and approach to clinical diagnosis' below.)
●Bone morphogenetic protein receptor type II (BMPR2) – Mutations in several loci of the BMPR2 gene have been reported in patients with PVOD [2,31,32]. BMPR2 mutations are responsible for up to one-half of all cases of familial pulmonary arterial hypertension (PAH), and as many as 25 percent of cases of nonfamilial PAH. The true incidence in PVOD is unknown but mutations appear to be significantly less common than in those with typical PAH (ie, pre-capillary PAH) . The bone morphogenetic protein family of proteins is related to TGF-beta and consists of at least 10 peptides that are produced by many different cells and have multiple actions on growth and development. Centers with expertise in PH test patients with a family history for mutations in this gene, regardless of the suspicion for PVOD, the details of which are provided separately. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Genetic mutations'.)
While the occurrence of a rare disease in two members of the same family may indicate an exclusively genetic component, common exposures to food, drugs, environmental agents, or infectious diseases could also play a role.
Epigenetic or immunomodulatory factors — Epigenetic factors may also be important in the pathogenesis of PVOD. Granulysin (GNLY) is a proinflammatory molecule present in cytotoxic granules of T cells that has been implicated in many disease processes. One study reported reduction in the demethylation of the GNLY gene in the lungs and blood of patients with PVOD compared with idiopathic or heritable PAH patients and normal controls who do not have PAH . This was associated with a decrease in circulating cytotoxic and natural killer T cells and an increase of natural killer cells.
Drugs and toxins — Exposures to chemotherapeutic agents are more commonly encountered in patients with PVOD than in patients with typical group 1 PAH (ie, pre-capillary PAH) (table 1). In contrast, anorexigen exposure, which is a risk factor for the development of group 1 PAH, is rare in PVOD.
The following drugs and toxins have been reported to be associated with PVOD:
●Chemotherapeutic regimens – Recognition of hepatic veno-occlusive disease (HVOD) as a complication of antineoplastic chemotherapy was followed by reports of a similar association between PVOD and a variety of chemotherapy regimens . A definitive association with specific medications has been difficult to identify because many patients are exposed to multiple chemotherapy regimens over several years. However, bleomycin, mitomycin (also known as Mitomycin-C), carmustine (BCNU), cisplatin, mechlorethamine (no longer systemically available), vincristine, procarbazine, and cyclophosphamide are thought to confer the greatest risk [34-39]. PVOD may be a consequence of the toxic metabolites of antineoplastic chemotherapy damaging pulmonary venule endothelium.
●Chemicals – Chemical exposures also contribute to the development of PVOD. In a case-control study of 33 patients with PVOD, occupational exposure to organic solvents (especially trichlorethylene) was associated with an eight-fold risk in the development of PVOD . In a separate case report, a 14 year-old boy who had a two-year history of ingesting and sniffing a powdered cleaning product developed PVOD . The cleaning product contained silica, soda ash, dodecyl benzyl sulfonate, and trichloro-s-triazinetriome.
●Cigarette smoking – As compared with patients with other forms of PAH (eg, pre-capillary PAH), patients with PVOD have greater previous smoking exposure .
Drugs that are risk factors for PAH (eg, cocaine and anorectic agents such as fenfluramine) or HVOD (eg, bush teas containing pyrrolizidine alkaloids) have not been associated with PVOD [26,41-43]. Toxins associated with the development of PAH and HVOD are discussed separately. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Drugs and toxins' and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults".)
Hematopoietic stem cell transplant — PVOD appears to be more common after hematopoietic stem cell transplantation (allogeneic or autologous) than following routine cytoreductive chemotherapy, but this impression is anecdotal and has not been confirmed with empirical evidence [24,44-47]. An autopsy series of 35 patients who died more than one year following allogenic stem cell transplant revealed PVOD in 12 patients (34.3 percent); as only one subject was clinically diagnosed prior to death, it is not clear if the diagnosis was clinically significant in all cases . Proposed mechanisms include chemotherapy- or radiation-induced injury as well as factors related to the transplant itself. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Pulmonary veno-occlusive disease'.)
Autoimmune disorders — Most patients with PVOD lack features of systemic autoimmune disease. However, case reports have described PVOD in association with the following autoimmune disorders [49-66]:
●Rheumatoid arthritis and Felty syndrome
●Systemic lupus erythematosus
●Langerhans cell histiocytosis
●Mixed connective tissue disease
●Chronic active hepatitis
●Focal or systemic granulomatous venulitis
Although supportive of a possible immunologic basis for PVOD, there has been insufficient evidence to support a clear mechanism underlying the development of PVOD in patients with autoimmune disorders. In addition, the presence of connective tissue or autoimmune disorders does not distinguish PAH from PVOD as many of these disorders are encountered in typical PAH (ie, pre-capillary PAH). In patients with PAH and systemic sclerosis, where PVOD is of particular concern, imaging and pathologic features of PVOD occur frequently, although data regarding the clinical significance on prognosis and treatment response has been mixed [61,67,68].
Miscellaneous — Several additional mechanisms have been proposed but are not likely to be causative:
●Infection – Previous infection is a frequently cited risk factor for PVOD but there is insufficient evidence to support it as a plausible cause [69,70]. Observations that have suggested infection as a risk factor for PVOD include: an influenza-like illness often precedes the development of PVOD, serological tests performed around the time of diagnosis have suggested recent infection with Toxoplasma gondii or measles [4,5,71], features suggestive of Epstein-Barr or cytomegalovirus infection (eg, lymphadenopathy, fever, and erythrophagocytosis) have been reported around the time of diagnosis , and two cases have been reported in association with human immunodeficiency virus (HIV) infection [73,74].
●Thrombotic diathesis – A number of researchers have theorized that a thrombotic diathesis (ie, a predisposition toward thrombosis or a defect in fibrinolysis) may play a role in the pathogenesis of PVOD. The theory is supported by early reports of increased platelet adhesiveness in patients with PVOD [4,75], as well as cases in which PVOD occurred in conjunction with risk factors for hypercoagulability (eg, oral contraceptive use, pregnancy, myeloproliferative disorders) [76-79]. Arguing against the theory, documented venous or arterial thrombi are rare in the extrapulmonary circulation of patients with PVOD and many patients do not have evidence of pulmonary venous thrombi on histopathologic examination .
●Congenital – Rare cases of PVOD have been described in infants with hypoplastic left heart syndrome, scimitar syndrome, and partial anomalous pulmonary vein connection [81-84].
●Hormonal – PVOD has been reported in patients taking oral contraceptives and during pregnancy which is considered by most experts as an incidental association only, although a causative role cannot be ruled out [76-78].
EVALUATION AND APPROACH TO CLINICAL DIAGNOSIS
Overview — There has been a paradigm shift in the diagnosis of patients with PVOD. In the past, many patients required a surgical lung biopsy for definitive histopathologic diagnosis. However, most experts now believe that a clinical diagnosis of PVOD can be made in most patients following an integrated assessment for pulmonary hypertension using a constellation of clinical, computed tomographic (contrast-enhanced CT), physiologic, and hemodynamic findings (table 3) [85-87]. We and other experts prefer this noninvasive approach to the diagnosis since the risk of biopsy in patients with pulmonary vasculopathy is considerably high (hemorrhage, hemodynamic collapse).
During the evaluation of patients for pulmonary hypertension (PH), PVOD should be suspected in those with manifestations of pulmonary arterial hypertension who have evidence of pulmonary venous congestion in the absence of left-sided heart disease. Importantly, the following should be kept in mind:
●With the exception of patients with biallelic mutations in the EIF2AK4 gene, the diagnosis of PVOD cannot be made unless right heart catheterization has demonstrated findings consistent with pulmonary arterial hypertension (PAH; ie, an elevated mean pulmonary artery pressure >20 mmHg and a normal pulmonary artery occlusion pressure ≤15 mmHg, and an elevated pulmonary vascular resistance ≥3 Wood Units). The major diagnostic challenge for clinicians is to distinguish PVOD-associated PH from other forms of group 1 PAH (table 1) since there is considerable clinical and hemodynamic overlap between these two entities. (See 'Hemodynamic findings of PAH' below.)
●It is the interpretation of additional clinical findings in this context, that a confident clinical diagnosis of PVOD is generally made:
•Common supportive features include the CT findings of pulmonary capillary hypertension (eg, septal thickening, diffuse ground glass opacities and lymphadenopathy). These and other supportive radiographic findings are discussed below. (See 'Venous congestion on chest imaging' below.)
•Physiologic abnormalities of low diffusion and poor oxygenation provide additional evidence to support the diagnosis. However, these features are generally not specific. (See 'Low diffusing capacity and poor oxygenation' below.)
•The diagnosis of PVOD is highly suggested when pulmonary edema develops following vasoreactivity testing or PAH-specific advanced therapy.
The evaluation of patients with suspected PH is provided separately (algorithm 1). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)
Clinical manifestations of pulmonary hypertension — Most patients with PVOD present with prominent symptoms of pulmonary hypertension (PH), none of which are specific for PVOD [2,89-93]. Data that describe the clinical manifestations of PVOD are discussed in this section, while a detailed discussion of the clinical presentation of PH is provided separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)
Two of the largest case series of patients with PVOD report a similar profile of symptoms to that in patients with PH including the following [2,90]:
●Dyspnea on exertion and lethargy (>95 percent)
●Symptoms of right heart failure (55 percent; eg, leg edema, right upper quadrant pain secondary to hepatic congestion)
●Exertional syncope (45 percent)
●Chronic cough (36 percent)
●Atypical chest pain (18 percent)
●Orthopnea (18 percent)
●Hemoptysis (8 percent)
Two-thirds of patients presented with World Health Organization (WHO) class III, with fewer cases presenting with functional class II (17 percent) or IV (20 percent) . While one case series reported a higher incidence of patients presenting with hemoptysis in those with PVOD compared with patients who have other forms of PAH (8 versus 4 percent) (table 1), this was not significant. When it occurs, hemoptysis is typically minimal and rarely massive or life threatening, although diffuse alveolar hemorrhage and sudden death are uncommonly described presentations of PVOD.
Exposure to toxins or the presence of conditions classically associated with PVOD (eg, mitomycin, trichloroethylene, systemic sclerosis, hematopoietic stem cell transplantation) should raise the suspicion for PVOD. (See 'Drugs and toxins' above and 'Hematopoietic stem cell transplant' above and 'Autoimmune disorders' above.)
The signs of PVOD are generally those of progressive PH, including cyanosis, a loud pulmonic component of the second heart sound, a split-second heart sound, right-sided cardiac murmurs (eg, tricuspid regurgitation), a third or fourth heart sound (ie, gallop), a left parasternal heave, a downward subxiphoid thrust, a pulmonary artery tap, elevated jugular venous pressure, an enlarged liver, and peripheral edema. Auscultatory crackles may occur in patients who have prominent chronic pulmonary infiltrates and decreased breath sounds with dullness to percussion may exist in patients with pleural effusions.
Since these symptoms are shared with PAH and sometimes mistaken for a respiratory infection, the initial suspicion for PVOD is frequently low, resulting in a delayed diagnosis. (See 'Diagnostic delay' below.)
Venous congestion on chest imaging — Similar to patients with other forms of PAH (table 1), patients with PVOD commonly have imaging features of pulmonary hypertension including enlargement of central pulmonary arteries and the right ventricle (image 1 and image 2). Importantly, many patients with PVOD additionally have findings of capillary congestion and lymphadenopathy, but with a normal-sized left atrium and normal-sized major pulmonary veins (66 to 100 percent).
The triad of diffuse ground glass opacification (particularly centrilobular distribution), septal thickening, and mediastinal lymphadenopathy in patients with PAH, is thought to be highly suggestive of PVOD [2,91]. One study reported a diagnostic sensitivity and specificity of over 80 and 67 percent, respectively, when one or more of these findings were present . In this study, CT scans of 15 patients with histologically confirmed PVOD were compared with those from pathologically confirmed idiopathic PAH. Ground-glass opacities were significantly more frequent in PVOD (87 versus 33 percent) as were subpleural septal lines (93 versus 13 percent), and lymphadenopathy (80 versus 0 percent). In a review of the CT manifestations in 25 consecutive patients with PVOD, all had at least one of the three findings (ground glass opacities, septal lines, lymphadenopathy) and 92 percent of patients had at least two of the findings, the most common one being septal thickening seen in 23 (92 percent) of the 25 patients .
However, clinicians should be aware many of these features are non-specific, and their absence does not exclude a diagnosis of PVOD.
The presence of venous congestion and lymphadenopathy with a normal-sized left atrium and normal-sized major pulmonary veins are features that may help distinguish PH due to PVOD from other causes of post-capillary PH, namely that due to left-sided heart disease (ie, group 2 PH (table 1)). These features are likely due to chronic pulmonary capillary hypertension, transudation of fluid into the interstitium, and enlargement of pulmonary lymphatic channels. However, in general, these features are not highly specific since they may be seen in many other pulmonary disorders including pulmonary hemorrhage, infarction, infection, and sarcoidosis; thus their presence or absence neither confirms nor precludes a diagnosis of PVOD.
Chest radiography — Similar to patients with other forms of PAH, chest radiographs may demonstrate enlargement of the central pulmonary arteries (ie, signs of pulmonary arterial hypertension). In contrast, additional radiographic signs of venous congestion including scattered patchy parenchymal opacities, Kerley B lines, and lymphadenopathy with a normal left atrium may be suggestive of PVOD (image 3) [23,95-98]. Pleural effusion (from elevated pulmonary capillary and visceral pleural capillary hydrostatic pressure) is a frequently cited chest radiograph finding in patients with PVOD [2,61,90,95,98]. While pleural effusions were thought to be more frequent in patients with PVOD than typical PAH (table 1), studies using CT do not support this distinction [2,91,99-101].
Details regarding the utility of chest radiography in the evaluation of patients with suspected PH are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Imaging'.)
Computed tomography — CT scans usually show features of venous congestion similar to those seen on chest radiography but with improved resolution (image 4). Retrospective reports suggest that over two-thirds of patients with PVOD have evidence of CT abnormalities (ranges from 66 to 100 percent) with some reports suggesting that the diagnostic sensitivity of the classic PVOD triad of patchy ground glass opacities, septal lines, and mediastinal adenopathy is greater than 80 percent. (See 'Venous congestion on chest imaging' above.)
CT findings include the following [91,99,101-107]:
●Evidence of PH itself (eg, central pulmonary artery enlargement, right ventricle dilation or hypertrophy, intraventricular septal bowing)
●Signs of post capillary venous congestion including smooth septal thickening, diffuse or mosaic ground glass opacities, multiple small nodules, pleural effusions, pericardial effusions, or areas of alveolar consolidation (often in a centrilobular distribution) (image 5)
●Mediastinal lymphadenopathy, which may be a consequence of venolymphatic shunts and circulating angiogenic factors
●Normal-sized pulmonary veins and left atrium
One study has reported that centrilobular ground glass opacities tend to be smaller in patients with PVOD than in those with PCH (2.5 mm versus 5.6 mm), although the diagnostic value of this observation is unclear .
Ventilation perfusion scanning — Ventilation-perfusion (V/Q) images are frequently performed in the evaluation of patients with suspected PAH. However, for patients with suspected PVOD, they are of limited diagnostic value because they are often normal or lead to misdiagnosis [98,108-110]. As an example, a small proportion of patients with PVOD (approximately 7 percent) have normal ventilation with focal areas of hypoperfusion (ie, unmatched perfusion defects), which are classically associated with chronic thromboembolic pulmonary hypertension (CTEPH). Thus, the finding of an unmatched defect in PVOD may lead to a misdiagnosis of CTEPH. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Features specific to thromboembolism'.)
Low diffusing capacity and poor oxygenation — A severely reduced single breath diffusing capacity for carbon monoxide (DLCO), partial pressure for arterial oxygen (PaO2), and oxygen saturation nadir on six-minute walk testing (6MWT) should raise the suspicion for PVOD. While the optimal cutoff values are not standardized, we consider a DLCO <55 percent predicted, a PaO2 <65 mmHg (8.7 kPa), and O2 saturation (<85 percent) during 6MWT as severe. However, although suggestive of PVOD, clinicians should be aware that these features are not pathognomonic and can be found in other etiologies.
Best illustrating this feature as suggestive of PVOD is a retrospective analysis that compared 24 patients with histologically proven PVOD with 24 patients who had IPAH . Patients with PVOD had lower DLCO (52 versus 70 percent predicted), PaO2 (61 versus 75 mmHg) and nadir on 6MWT (80 versus 87 percent).
Pulmonary function tests — Pulmonary function testing (PFTs) are indicated during the evaluation of patients with suspected PH. PFT findings in patients with PVOD include the following [2,85,90,97]:
●Spirometry – In patients with PVOD spirometric values are frequently normal or show a mild restrictive pattern but obstructive ventilatory deficits have also been described.
●Lung volumes – Lung volumes are typically in the normal or slightly reduced range.
●DLCO – The single breath DLCO is typically reduced.
Notably, a reduced DLCO can be found in many other conditions as well as in severe PAH. Conversely, a normal or mildly reduced value does not exclude the diagnosis and it may be falsely overestimated when occult alveolar hemorrhage occurs as a complication of PVOD. (See "Overview of pulmonary function testing in adults" and "Selecting reference values for pulmonary function tests".)
Arterial blood gas — The finding of severe hypoxemia and low nadir on 6MWT is also nonspecific and most experts consider that, although suggestive of PVOD, such parameters of oxygenation do not definitively distinguish between these etiologies. (See "Measures of oxygenation and mechanisms of hypoxemia" and "Overview of pulmonary function testing in adults", section on 'Six-minute walk test'.)
Cardiopulmonary exercise testing — Data regarding cardiopulmonary exercise testing (CPET) utility in suspected PVOD are still limited and suspicious cutoff values have not yet been established. Nonetheless, some findings in CPET may be helpful. CPET can objectively measure exercise performance and provide insight into etiology of limitation. As compared with patients with other forms of PAH, those with PVOD demonstrate lower peak oxygen uptake (VO2), lower resting and exercise oxygen saturations, and more ventilatory inefficiency with increased ratio of minute ventilation to carbon dioxide production (VE/VCO2) and lower end-tidal carbon dioxide during exercise [111,112].
Hemodynamic findings of PAH
Right heart catheterization — A diagnosis of PVOD cannot be inferred until a diagnosis of pulmonary hypertension is made on right heart catheterization (RHC). Patients with PVOD have the typical hemodynamic features of PAH (elevated mean pulmonary artery pressure [>20 mmHg] and a normal pulmonary artery wedge pressure [pawp; ≤15 mmHg]; occasionally, the pawp is a little elevated), and a pulmonary vascular resistance ≥3 Woods units (table 4) [2,90]. It is the pre-capillary hemodynamic pattern on RHC (elevated mean pulmonary arterial pressure [mPAP] and normal pawp) together with similar symptomatology that lead to the misdiagnosis of PVOD as typical PAH. Details regarding RHC and findings in PAH are discussed separately (table 2). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization' and "Pulmonary artery catheterization: Indications, contraindications, and complications in adults" and "Pulmonary artery catheterization: Interpretation of hemodynamic values and waveforms in adults" and "Pulmonary artery catheters: Insertion technique in adults".)
The pre-capillary pattern on RHC may appear somewhat discrepant with the post-capillary pathology in PVOD. However, wedging of the balloon-tipped vascular catheter creates a static column of blood between the transducer and the left atrium so that pawp reflects the left atrial pressure; while this is typically elevated in patients with post-capillary pulmonary hypertension from left-sided heart failure, left atrial and large pulmonary venous pressures remain normal in PVOD [113,114].
Several findings during RHC may help support the presence of PVOD as an etiology for PAH:
●Atypical pawp tracing during flushing – Reliable occlusion pressure ("wedge") tracings can be difficult to obtain in patients with PVOD and they can have an unusual appearance during flushing. To document successful wedging of the catheter, an oxygen tension similar to arterial blood may need to be demonstrated using blood slowly aspirated from the distal port of the pulmonary artery catheter. Ideally, the pawp should be measured in several different locations to ensure that a given measurement is not spurious or the result of a local phenomenon. During flushing, the distal port of the wedged catheter causes the infused saline to become trapped between the catheter tip and narrowed pulmonary veins; as a result, the pressure rises disproportionately and falls extremely slowly to baseline [4,115,116].
●The development of pulmonary edema during vasoreactivity testing – A vasodilator trial (with short-acting pulmonary arterial vasodilators such as inhaled nitric oxide, intravenous epoprostenol, or adenosine) is typically performed for select patients with PAH to safely predict those who may exhibit a favorable response to calcium channel blockade. The development of pulmonary edema in response to a pulmonary vasodilator is strongly suggestive of PVOD, but not pathognomonic [2,90,117,118]. Details regarding vasoreactivity testing in patients with PVOD as well as in patients with PAH are provided separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'Vasoreactive patients' and "Treatment and prognosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Assessing vasoreactivity'.)
Echocardiography — Transthoracic echocardiography is a useful tool in the evaluation of patients with suspected PAH. In patients with PVOD, the major value of echocardiography is to establish the absence of significant left-sided heart disease and to evaluate the right ventricle for the typical findings of right ventricular strain due to pulmonary hypertension. (See "Echocardiographic assessment of the right heart" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)
Family history or EIF2AK4 mutation — In the context of patients who have hemodynamic findings consistent with PAH, patients who also have a family history of PVOD or a mutation in the EIF2AK4 gene, are considered by most experts as likely having PVOD such that serum for mutational analysis should be sent. While hemodynamic measurements are useful in assessing progression and response to therapy in individual patients, they are not required for diagnosis in patients who are homozygous for EIF2AK4 mutations. (See 'Genetic factors' above.)
Pulmonary edema from pulmonary vasodilators — The development of acute pulmonary edema on vasoreactivity testing or during the administration of PH-specific medications is also considered by experts as highly suggestive of PVOD when the diagnosis has not been previously suspected, or supportive of the diagnosis when it is suspected. Detailed discussion of vasoreactivity testing and the risks of treating PVOD patients with PH-specific advanced therapy is provided separately. (See "Treatment and prognosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Assessing vasoreactivity'.)
Others — Additional features that support the diagnosis of PVOD include evidence of occult hemorrhage on bronchoscopy. Laboratory tests are generally unhelpful.
●Bronchoscopy and bronchoalveolar lavage – Bronchoscopy is not routinely performed in patients undergoing an evaluation for pulmonary hypertension unless there is an alternate diagnostic indication (eg, parenchymal abnormality or airway inspection for cancer in those with hemoptysis).
Similarly, in patients with suspected or known PVOD, we do not routinely perform bronchoscopy. However, some experts routinely perform bronchoscopy in patients with suspected PVOD to identify occult alveolar hemorrhage. This latter practice is based upon one small study that identified a higher percentage of hemosiderin-laden macrophages in bronchoalveolar lavage fluid in eight patients with PVOD compared with eleven patients with idiopathic PAH (40 versus 3 percent) . Given the methodological limitations of this study, it remains unclear whether or not this feature can sufficiently distinguish PVOD from other forms of PH or whether it predicts an increased risk of clinically significant hemorrhage in this population. (See "Flexible bronchoscopy in adults: Overview" and "Flexible bronchoscopy in adults: Indications and contraindications" and "The diffuse alveolar hemorrhage syndromes".)
In patients with PVOD in whom bronchoscopy is performed, airway inspection may reveal intense hyperemia of the lobar and segmental bronchi (which drain to the pulmonary veins), with vascular engorgement in the form of bright red longitudinal streaks . In contrast, these findings are not present in the trachea and main bronchi, presumably because the venous drainage of central airways is into nonoccluded bronchial veins.
Importantly, transbronchial biopsy should not be performed in patients with PVOD since it is unlikely to establish the diagnosis and it is associated with an unacceptably high complication rate (typically hemorrhage).
●Laboratory tests and flow cytometry – Laboratory tests are generally unremarkable, although microangiopathic hemolytic anemia , heavy proteinuria , and elevations in serum IgG and IgM concentrations  have been described in isolated cases. While an alteration in cytotoxic T cell populations has been reported, there is no role for the routine evaluation of flow cytometry in the evaluation of patients suspected as having PVOD .
Diagnostic delay — Delays in the diagnosis of PVOD are common since the condition is rare, the presentation is nonspecific, and not every patient presents with classic features. Many patients are initially presumed to have heart failure (due to the abnormalities on chest radiographs and CT scans), CTEPH (due to abnormalities on V/Q scans), or parenchymal lung disease, such as sarcoidosis, cystic fibrosis, or pneumoconiosis (due to chronic interstitial changes on chest radiographs) . Thus, the diagnosis can be missed and is sometimes only made retrospectively at autopsy or on examination of explanted tissue. Rarely is PVOD found incidentally on lung biopsy material performed during the evaluation of interstitial lung disease. (See 'Histopathology' below.)
LUNG BIOPSY — On the rare occasion that lung biopsy is pursued for definitive diagnosis (eg, in patients without classic clinical and radiologic findings who have only mild pulmonary hypertension and hypoxemia for whom biopsy risk is sufficiently low), surgical lung biopsy is preferred over transbronchial biopsy (TBBx) since the latter is typically insufficient to diagnose PVOD and the risk of uncontrolled hemorrhage is thought to be higher with TBBx. (See "Overview of minimally invasive thoracic surgery".)
HISTOPATHOLOGY — A definitive diagnosis of PVOD requires histological examination of lung tissue. While in the past, the diagnosis was typically made on surgical lung biopsy, the diagnosis is now frequently made on clinical grounds and histological confirmation is often obtained only in explanted lung or at autopsy. (See 'Evaluation and approach to clinical diagnosis' above.)
PVOD is a fibroproliferative disease primarily affecting the small pulmonary veins with relative sparing of the larger veins. The pathologic hallmark of PVOD is extensive and diffuse occlusion of the pulmonary veins due to smooth muscle hypertrophy and collagen matrix deposition (ie, fibrous tissue). The fibrous tissue may be loose and edematous (perhaps reflecting an earlier stage of development), or dense and sclerotic (perhaps reflecting a later stage of development) (figure 1) [11,124-126]. While uncommon, luminal narrowing of the pulmonary veins from acute thrombus is also seen.
In addition, to these features, the media of the pulmonary veins may become "arterialized" with an increase in elastic fibers; when "arterialization" is extensive, these features may be mistaken for pulmonary arterial hypertension (PAH). Recanalization of completely occluded vessels occurs over time, and calcium may encrust the elastic fibers in the walls of the veins or alveoli. Intimal thickening tends to be eccentric and usually involves the venules and small veins in the interlobular septa which may help to distinguish PVOD from PAH.
Long-standing PVOD can result in the deposition of collagen fibers within lobular septae and, to a lesser degree, alveolar walls. These changes are similar to those noted in long-standing mitral stenosis . Fibrosis may be sufficiently extensive that the differential diagnosis includes idiopathic pulmonary fibrosis (picture 1). (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis".)
Pulmonary arterioles may also be involved, with moderate to severe medial hypertrophy in approximately one-half of cases . Arteritis and arterial plexiform lesions, classic features of PAH, are usually absent. Such cases may represent mixed pre-capillary and post-capillary pulmonary hypertension (table 2).
Alveolar capillaries may be engorged and tortuous, consistent with PCH [95,129,130]. In a retrospective cohort study, 73 percent of patients with PVOD had coexisting PCH, and venous changes were seen in most patients receiving histologic diagnosis of PCH . This observation has led to the agreement among experts that, for most patients, PVOD and PCH represent the same diagnosis. PCH may be caused by PVOD; specifically, PCH may be a proliferative response to pulmonary venous hypertension. Supporting this hypothesis, PCH can complicate other diseases characterized by pulmonary venous hypertension [131-133].
Additional findings include dilated pulmonary lymphatics, dilated pleural lymphatics, and interstitial edema that is most notable in lobular septa (picture 2) [80,107]. Concomitant type II pneumocyte hyperplasia and focal lymphocytic infiltrates occur in many patients and can be extensive [125,134].
A slightly less common finding is hemosiderin in alveolar macrophages or the interstitium, thought to be due to passive congestion or occult hemorrhage. Hemorrhage may also be present, but it is difficult to distinguish blood due to disease from blood due to the biopsy procedure. Occasionally, hemosiderin or blood is sufficiently prominent that the diagnosis of idiopathic pulmonary hemosiderosis or a healed vasculitis such as granulomatosis with polyangiitis is entertained. While PVOD may be suggested if hemosiderosis and one or more sclerosed venules are identified in a biopsy specimen, this is not diagnostic because intimal sclerosis can be a normal consequence of aging. The presence of an occasional sclerosed pulmonary vein is not sufficient for diagnosis and must be interpreted in conjunction with clinical and radiographic features. (See "Idiopathic pulmonary hemosiderosis".)
In our experience, autopsy or explanted lungs findings usually reveal components of mixed precapillary pulmonary hypertension (picture 3) and PVOD (ie, post capillary pulmonary hypertension) in various proportions suggesting that both forms of pulmonary hypertension may coexist and are not necessarily mutually exclusive . Details regarding the pathology of arterial hypertension are described separately. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Idiopathic and heritable'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)
SUMMARY AND RECOMMENDATIONS
●Terminology – Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH) is a rare condition that represents a small subgroup of adult patients with pulmonary hypertension (table 1). (See 'Introduction' above and 'Terminology' above.)
●Epidemiology – The true incidence of PVOD is unknown. However, the annual incidence is estimated to be 0.1 to 0.2 cases per million persons in the general population. It is more common in children and young adults but affects males and females equally. (See 'Epidemiology' above.)
●Pathogenesis – Most cases of PVOD are idiopathic. The pathogenesis is unknown and likely multifactorial. Genetic mutations in the eukaryotic translation initiation factor 2-alpha kinase (EIF2AK4) gene have been described in the familial form of PVOD. In addition, several risk factors have been reported, including chemotherapeutic agents, hematopoietic stem cell transplantation, and autoimmune disorders. (See 'Pathogenesis and risk factors' above.)
●Initial evaluation – We believe that a clinical diagnosis of PVOD can be made in most patients following an integrated assessment for pulmonary hypertension using a constellation of clinical, CT (usually contrast-enhanced) (image 4), physiologic, and hemodynamic findings (table 3). A clinical diagnosis of PVOD is typically made in those who have hemodynamic findings of pulmonary arterial hypertension (PAH; especially severe PAH) and the CT findings of venous congestion (eg, septal thickening, diffuse ground glass opacities and lymphadenopathy (image 5)). (See 'Evaluation and approach to clinical diagnosis' above and 'Overview' above.)
•Clinical features – Most patients have nonspecific signs and symptoms of pulmonary hypertension. (See 'Clinical manifestations of pulmonary hypertension' above.)
•Right heart catheterization and echocardiography – In most patients with PVOD, right heart catheterization findings are similar to those in patients with other forms of PAH (table 1); the mean pulmonary artery pressure is >20 mmHg while the pulmonary artery wedge pressure is typically normal (≤15 mmHg) and pulmonary vascular resistance ≥3 Wood Units (table 4). In keeping with these findings, echocardiographic evidence of left-sided heart disease is absent. (See 'Overview' above and 'Right heart catheterization' above and 'Echocardiography' above.)
•Chest CT – Additional CT findings include multiple small nodules, pleural and pericardial effusions, alveolar consolidation, and normal-sized left atrium and major pulmonary veins. Ventilation perfusion scans are of limited diagnostic value because they are often normal or lead to misdiagnosis. (See 'Overview' above and 'Venous congestion on chest imaging' above.)
•Pulmonary function – A severely low single breath diffusing capacity for carbon monoxide (DLCO; <55 percent predicted) and severe hypoxemia (<65 mmHg) are suggestive of PVOD but are considered by most experts as nonspecific. (See 'Overview' above and 'Low diffusing capacity and poor oxygenation' above.)
•Family history – A family history of PVOD and mutations in the EIF2AK4 gene are strongly supportive of a diagnosis of PVOD, although rarely present. Similarly, the development of acute pulmonary edema on vasoreactivity testing or during the administration of PH-specific advanced therapy is also highly suggestive of PVOD. (See 'Family history or EIF2AK4 mutation' above and 'Pulmonary edema from pulmonary vasodilators' above.)
•Diagnostic delay – Delays in the diagnosis of PVOD are common since the condition is rare, the presentation is nonspecific, and not every patient presents with classic features. Thus, the diagnosis is sometimes only made retrospectively at autopsy or on explanted tissue. Rarely is PVOD found incidentally on lung biopsy material performed during the evaluation of interstitial lung disease. (See 'Diagnostic delay' above and 'Lung biopsy' above.)
●Histopathology – The pathologic hallmark of PVOD is extensive and diffuse occlusion of the pulmonary veins due to smooth muscle hypertrophy and collagen matrix deposition (ie, fibrous tissue) (picture 1). Additional pathologic features include arterialization of pulmonary veins, engorged and tortuous alveolar capillaries similar to those seen in PCH, dilated lymphatics, and hemosiderin-laden macrophages. (See 'Histopathology' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Clardy, MD, who contributed to earlier versions of this topic review.
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