Diagnostic and management dilemmas in pulmonary hypertension.

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Introduction

Although current international guidelines provide comprehensive evidence-based guidance for the management of pulmonary hypertension (PH), clinicians are still regularly faced with uncertainty regarding correct diagnosis and optimal treatment.

Methods

A European Respiratory Society webinar series “Diagnostic and management dilemmas in PH” was developed by a panel of expert PH physicians during 2024–2025. Ten challenging scenarios or disease areas encountered in clinical practice were identified. For each, a PubMed literature search was performed using appropriate keywords and a suggested approach was drafted based on the search, clinical guidelines and on expert clinical experience. These draft approaches were reviewed and revised by the writing group to achieve consensus.

Diagnostic and management dilemmas

What are the possible causes of PH with a high cardiac output and which features on noninvasive and invasive investigation point towards the diagnosis?

PH may develop as a result of increased pulmonary blood flow in association with a number of conditions ( table 1 ) [ 1 ]. First, several common conditions such as pregnancy, liver disease, anaemia and obesity (as well as less common diseases such as beriberi) are characterised by systemic vasodilation and reduced systemic vascular resistance (SVR). Haemolytic anaemia associated with sickle cell disease is particularly associated with a high output picture (often with elevated left atrial pressure) [ 2 , 3 ]. Of note, tricuspid regurgitant velocity has a tendency to overestimate true pulmonary arterial pressure in this disease group [ 2 ]. In addition, over-dilatation of the systemic and/or pulmonary circulation by therapies for systemic hypertension or PH can result in a high cardiac output picture. This may occasionally be a particular issue with over-escalation of parenteral prostanoid therapies. Second, low SVR may also develop in response to systemic arteriovenous malformations, which may be iatrogenic (arteriovenous fistula for dialysis), congenital ( e.g. hereditary haemorrhagic telangiectasia) or microscopic ( e.g. multiple myeloma and Paget's disease of the bone) [ 1 , 4 , 5 ]. Congenital intra- or extra-hepatic portosystemic venous shunts may also result in a similar picture [ 6 ]. Physiological responses to a low SVR (including sympathetic activation with tachycardia and activation of the renin–angiotensin–aldosterone system with resultant salt and fluid retention) result in increased cardiac output. Third, increased metabolic demand, most notably due to thyrotoxicosis, also results in a hyperdynamic state [ 7 ]. Finally, increased pulmonary blood flow may develop due to congenital systemic to pulmonary shunt (atrial and ventricular septal defect, anomalous pulmonary venous drainage and patent ductus arteriosus) [ 8 ]. More than one of the above processes may occur in a given clinical state, e.g. elevated cardiac output in patients with myelofibrosis may relate to not only anaemia but also increased metabolic demands of extramedullary haematopoiesis [ 9 ]. In addition to elevated pulmonary pressure occurring purely as a result of increased pulmonary blood flow, increased sheer stress ( e.g. congenital systemic to pulmonary shunt) or unprocessed vasoactive agents ( e.g. portal hypertension) acting on the pulmonary vasculature may lead to a secondary pulmonary vasculopathy with elevation of pulmonary vascular resistance (PVR) and further increase in pressure [ 10 ]. Other causes of PH may also coexist in the setting of high pulmonary blood flow, including elevated left atrial pressure and hypoventilation.

Clinicians should therefore be alert to the possibility of high cardiac output in patients with suspected PH. Although tricuspid regurgitant velocity obtained at transthoracic echocardiography may suggest elevated pulmonary arterial pressure, normal right ventricular size with visually hyperdynamic function or the identification of an intracardiac shunt with left-to-right shunting raise the possibility of high cardiac output. A normal, or especially a supranormal, diffusing capacity of the lung for carbon monoxide ( D LCO ) may suggest increased pulmonary blood flow [ 11 ]. Computed tomography (CT) imaging should be carefully interrogated; significant dilatation of the main pulmonary artery in the absence of right ventricular hypertrophy suggests increased flow, while pulmonary venous drainage, interatrial and interventricular septa and the aorta and pulmonary artery should be systematically reviewed for evidence of possible shunting [ 12 ]. In addition, the infra-diaphragmatic area should be examined for evidence of liver disease, portal hypertension and, depending on the contrast phase, hepatic vascular anatomy. Laboratory investigations including full blood count and thyroid function should be routinely performed. Right heart catheterisation (RHC) characteristics include elevated mean pulmonary arterial pressure with an elevated cardiac index (>4 L·min −1 ·m −2 ) and normal or mildly elevated PVR [ 1 ]. In such situations, a more extensive saturation run (including at least samples from the superior and inferior vena cava and pulmonary artery) should be performed. In a high output picture of uncertain cause, plasma electrophoresis (to assess for multiple myeloma) and alkaline phosphatase (to assess for Paget's disease) should also be assessed and an abdominal ultrasound performed to assess vascular anatomy [ 13 ]. Particularly in patients with obesity, an arterial blood gas and sleep study should be performed to exclude type 2 respiratory failure and obesity hypoventilation syndrome. Management of PH associated with high cardiac output should focus on identification and treatment of the underlying cause [ 1 ]. Pulmonary vasodilator therapies will generally worsen the situation although may have a role in selected patients who have developed true pulmonary arterial hypertension (PAH).

Suggested approach

Multiple conditions including those causing systemic vasodilation, systemic arteriovenous shunting, high metabolic demands or congenital left-to-right shunts may present with PH and a high cardiac output picture. Features such as a high D LCO , hyperdynamic ventricular function and pulmonary arterial and right ventricular dilatation in the absence of hypertrophy should raise clinical suspicion.

A 65-year-old man with a significant past smoking history, normal spirometry and D LCO of 35% predicted has previously been diagnosed with idiopathic PAH (IPAH). High-resolution CT shows minimal upper-lobe emphysema. Which PH classification group should the patient be in? What effect do cardiopulmonary comorbidities have on outcomes and response to therapy in IPAH?

Differentiating Group 1 PH (PAH) from Group 2 PH (PH associated with left heart disease) and Group 3 PH (PH associated with chronic lung disease or hypoxia) can be difficult [ 13 , 14 ]. Traditionally, IPAH was described in younger, predominantly female patients without significant comorbidities [ 15 ]. Recent data from the COMPERA registry suggest a demographic shift [ 16 ]. Of 861 patients with a diagnosis of IPAH in the COMPERA registry, only 12.6% had this classical IPAH phenotype while 35.8% had features of left heart disease (left heart phenotype) and 51.6% had features of lung disease (lung phenotype). 5-year survival in the classical, left heart and lung phenotypes was 85%, 59% and 42%, respectively [ 16 ]. Patients with a left heart phenotype tended to be older women with cardiovascular risk factors such as systemic hypertension, diabetes mellitus, coronary artery disease, obesity and atrial fibrillation [ 16 ]. Although patients with an IPAH and left heart phenotype have a normal resting pulmonary arterial wedge pressure (PAWP), they may have left ventricular diastolic impairment resulting in increased right ventricular afterload and reduced right ventricular reserve [ 17 ]. Clinical likelihood tools such as the H 2 FPEF score may identify patients with higher risk of having heart failure with preserved ejection fraction (HFpEF) in whom provocation tests such as fluid challenge or straight-leg raise may be considered [ 18 – 20 ]. Patients with a lung phenotype also tend to be older but are more likely to be male, have a significant smoking history and hypoxaemia, and may have minor parenchymal lung disease on CT imaging. Although these patients have preserved spirometry, they invariably have low D LCO , at <45% of predicted. Recent data describing severe arteriolar and venular remodelling with microvascular rarefaction, absence of plexiform lesions and alveolar tissue destruction as part of early diffuse emphysema in patients with IPAH and a lung phenotype suggest shared pathogenic mechanisms with Group 3 PH [ 21 , 22 ].

Current guidelines suggest an individualised approach in patients with IPAH who have cardiopulmonary comorbidities, including initial oral monotherapy; registry data show that phosphodiesterase-5 inhibitors (PDE5i) are most widely used [ 13 , 16 ]. Cautious administration and close follow-up of these patients is important because PAH medication may cause a decline in oxygen saturation [ 23 ]. An analysis of 1120 patients with IPAH from the COMPERA registry demonstrated that 6-min walk distance (6MWD), World Health Organization functional class (WHO-FC) and N-terminal pro-brain natriuretic peptide (NT-proBNP) did improve in those patients with cardiac comorbidities, but to a lesser degree than patients with no comorbidities [ 24 ]. A recent analysis of 1088 patients with IPAH and at least one cardiovascular comorbidity from the French registry demonstrated superior improvements in 6MWD, haemodynamic parameters and risk score in patients treated with initial dual combination therapy as opposed to monotherapy [ 25 ]. Analysis of randomised controlled trial (RCT) data from the AMBITION study demonstrated lower clinical response and tolerability in patients with multiple cardiac comorbidities [ 26 ]. However, RCT data for other PAH therapies, including macitentan, tadalafil, treprostinil and selexipag, failed to demonstrate worse outcomes in patients with cardiac comorbidities [ 27 – 29 ]. Although real-world observational data suggest that the use of sotatercept in patients with PAH and cardiopulmonary comorbidities is associated with improvements in risk score and exercise capacity, further post hoc RCT and open label extension data are awaited [ 30 ].

In patients with a lung phenotype, improvements in 6MWD, WHO-FC and NT-proBNP at first follow-up in an analysis of COMPERA patients were smaller than in those with classical IPAH but similar to those with a diagnosis of Group 3 PH [ 31 ]. An analysis of 493 patients from the ASPIRE registry demonstrated significant improvements in exercise capacity and quality of life at first follow-up in patients with classical IPAH but not in those with a lung phenotype [ 32 ].

Suggested approach

Although current guidelines would class this patient as having IPAH with cardiopulmonary comorbidities, there are increasing data that such patients share more characteristics with patients with Group 3 PH. An individualised approach to therapy should be undertaken with optimisation of cardiopulmonary disease. Initial monotherapy, most likely with a PDE5i, may be considered with close monitoring and subsequent reassessment.

What features on echocardiography suggest post-capillary PH and when should you proceed to RHC?

Independent of the aetiology of PH, echocardiography is a critical tool to estimate pulmonary pressure, giving noninvasive haemodynamic insights and providing information on cardiac morphology, valvular diseases and congenital heart defects [ 13 ]. However, it is sufficient neither to confirm the diagnosis of PH nor to identify the underlying aetiology. Nevertheless, a comprehensive multiparametric evaluation may detect some features helpful in distinguishing post- versus pre-capillary PH.

Driven by the backwards transmission of increased left heart chamber pressures to the pulmonary venous component, post-capillary PH can be suspected in the presence of an increase in left atrium volume index and the bowing of the interatrial septum from left to right atrium, both being predictive of increased left heart filling pressure and PAWP [ 33 ]. Similarly, echocardiographic evidence of left ventricle hypertrophy (increased left ventricular wall thickness) and restrictive filling pattern (estimated by restrictive trans-mitral pattern or increased E/e′ ratio, where E is the early wave velocity of passive blood flow from the left atrium to the left ventricle, and e′ represents the mitral annular velocity of the same phase assessed by tissue Doppler imaging) suggest a diagnosis of HFpEF and post-capillary PH, as does the evidence of significant mitral or aortic valve disease [ 34 ].

Nonetheless, patients with cardiovascular comorbidities or established HFpEF may develop a predominant pre-capillary component, which might be suggested on echocardiography by the presence of right atrium enlargement with bowing of the interatrial septum from right to left, severe dilatation of the right ventricle with a D-shaped left ventricle, and detection of systolic notching on the right ventricle outflow tract (predictive of increased PVR). When a significant pre-capillary component is suspected on echocardiographic and clinical basis, RHC is recommended to confirm the diagnosis and to properly treat the underlying condition [ 13 ]. In addition to patients with post-capillary PH developing a pre-capillary component to their disease (combined post- and pre-capillary PH (CpcPH)), some patients who initially present with pre-capillary PH may subsequently develop a CpcPH phenotype. It is also important to appreciate that elevated left ventricular filling pressure may coexist with chronic thromboembolic disease and so echocardiographic features of post-capillary PH should not always preclude further diagnostic evaluation for potential chronic thromboembolic pulmonary hypertension (CTEPH) [ 35 ].

Suggested approach

Echocardiographic features of left ventricular diastolic dysfunction ( e.g. left atrium dilatation, left ventricular hypertrophy, abnormal E/A and elevated E/e′), left ventricular systolic dysfunction or significant left-sided valvular disease may suggest post-capillary PH. RHC may be indicated in the presence of features suggestive of additional significant pre-capillary disease.

What is the evidence for PAH therapies in PH associated with left heart disease?

The 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines give a strong recommendation against the use of PAH-specific drugs in PH associated with left heart disease, based on a high level of evidence (class III-A) [ 13 ]. The results of the recently published PASSION trial further support this recommendation [ 36 ]. This trial, exploring safety and efficacy of oral tadalafil in CpcPH associated with HFpEF, was terminated early owing to disruption in the supply of study medication. In the population included in the trial, there was no significant difference in hospitalisation due to heart failure (the primary end-point) and there was a safety concern due to increased all-cause mortality in the treatment arm [ 36 ].

Among endothelin receptor antagonists, bosentan and macitentan were tested in heart failure in the studies BADDHY and MELODY-1, respectively, the latter specifically targeting patients with CpcPH [ 37 , 38 ]. Neither showed any significant benefit on outcome, and both reported fluid retention and worsening oedema in the treatment arm. The SERENADE study of macitentan in patients with heart failure and preserved or mildly reduced ejection fraction employed a novel study design incorporating a single-blinded run-in period prior to randomisation to identify patients likely to better tolerate treatment [ 39 ]. Despite this, treatment with macitentan did not improve NT-proBNP but was associated with increased adverse events.

Finally, the soluble guanylate cyclase stimulator riociguat has been tested in patients with PH associated with HFpEF in the DYNAMIC trial [ 40 ]. The study met the primary end-point of cardiac output increase, but no significant improvement in symptoms was reported in the treatment arm, while riociguat was more frequently discontinued due to drug-related adverse events.

In view of these findings, the latest recommendations from the World Symposium on Pulmonary Hypertension confirmed those of the ESC/ERS guidelines, and advised against the use of PAH-specific drugs in PH associated with left heart disease [ 33 ].

Suggested approach

Based on current evidence, PAH-specific therapies are not recommended in patients with confirmed PH associated with left heart disease. Further studies of other potential therapies in well-phenotyped patients with a significant pre-capillary component are needed.

What forms of PH may be associated with obesity?

All forms of PH may be present in patients with obesity, but some may be of special relevance. An obvious example is PH associated with hypoventilation syndromes. In patients with obesity hypoventilation syndrome, nocturnal respiratory events contribute to the development of PH, which is often severe [ 41 ]. Noninvasive ventilation frequently leads to haemodynamic improvement in this condition [ 42 , 43 ].

Another important example is PH associated with HFpEF. Epidemiological studies have identified a strong, independent relationship between obesity and the development of HFpEF [ 44 ], and approximately 80% of patients with HFpEF have overweight or obesity and exhibit manifestations of metabolic syndrome [ 45 ]. In PH associated with HFpEF, optimisation of cardiac therapy is recommended. Currently, no PH drugs are approved for this condition.

Obesity has been also observed in up to 40% of patients with PAH in recent epidemiological studies. Interestingly, obesity appears to exert a protective effect in PAH, with its presence being associated with a lower mortality risk compared with patients with normal weight [ 46 , 47 ]. This so-called obesity paradox underlines that the specific needs of patients with obesity and PH should be clarified by future studies and recommendations [ 48 ].

Suggested approach

Alternative forms of PH (including PH associated with obesity hypoventilation syndrome and left heart disease) should be excluded in patients with obesity and suspected PAH.

A patient with obesity has a PAWP of 18 mmHg at RHC but a normal-sized left atrium and no other features of left heart disease on echocardiography. How does obesity affect normal reference ranges of pulmonary haemodynamics?

The haemodynamic criteria for PH were revised in the 2022 ESC/ERS PH guidelines [ 13 , 14 ] and these recommendations were confirmed by the Seventh World Symposium on PH [ 49 ]. Accordingly, a PAWP ≤15 mmHg characterises pre-capillary PH and a PAWP >15 mmHg characterises post-capillary PH. A patient with a PAWP of 18 mmHg RHC has post-capillary PH using haemodynamic criteria, which is typically associated with left heart disease.

Nevertheless, both documents emphasise that PAWP should always be considered within the clinical context for appropriate classification of PH and for optimal decision-making regarding the management of patients [ 49 ]. PAWP may be influenced by several factors, including the applied zero-reference level (ZRL), the influence of the transmitted intrathoracic pressure on all pulmonary pressure values, the effects of the respiratory cycle, the use of breath-arrest manoeuvres, the effects of the cardiac cycle, the potential presence of large V-waves and the patient's volume status [ 50 ]. In patients with obesity, the first three factors may be of special relevance.

Current guidelines suggest the use of the mid-thoracic level for the ZRL [ 13 , 14 ]. Of note, each centimetre difference between ZRLs leads to a pressure difference of 0.78 mmHg [ 51 ]. This may become particularly relevant in patients with obesity. Not properly adjusting the transducer after a previous RHC performed in a patient with smaller thoracic diameter may lead to the recording of falsely elevated pressures.

Pulmonary pressures may be assessed either at end-expiration or by averaging pressure measurements over several respiratory cycles [ 49 ]. Patients with obesity frequently present with large respiratory swings and even positive intrathoracic pressures at end-expiration. For this reason, in these subjects, the assessment of pulmonary vascular pressures averaged over three to four respiratory cycles is recommended, because it is more reliable and avoids significant overestimation.

Finally, obesity is associated with lower chest wall compliance and therefore higher intrathoracic pressures [ 52 – 54 ]. In a recent study in patients with obesity, the placement of an oesophageal balloon and the adjustment of pulmonary vascular pressures for oesophageal pressure led to a decrease in PAWP and reduced the rate of patients with post-capillary PH from 75% to 19% of the study population [ 52 ]. This suggests that, in a large proportion of patients with obesity, the elevation of pulmonary pressures is not directly associated with pulmonary vascular or left heart conditions.

Of note, patients with obesity may frequently present with cardiovascular comorbidities and therefore have a good reason for elevated PAWP [ 44 , 45 ]. However, in the absence of signs of left heart disease on echocardiography, one of the mentioned factors may lead to increased PAWP.

Suggested approach

RHC findings should be interpreted in the context of other investigations, including echocardiography and cross-sectional imaging. An elevated PAWP in a patient with obesity in the absence of other features suggestive of left heart disease does not necessarily exclude pre-capillary PH.

What conditions may mimic CTEPH and what features on CT pulmonary angiography should make me consider them?

Chronic thromboembolic pulmonary disease is diagnosed in symptomatic patients with signs of chronic, organised, fibrotic clots on radiological imaging, such as mural thrombus, webs and/or bands, and chronic total occlusions (pouch lesions or tapered lesions), after at least 3 months of therapeutic anticoagulation [ 13 ]. PH in this setting is a consequence of pulmonary artery obstruction due to these organised fibrotic clots and the associated microvasculopathy [ 55 ]. Within the clinical classification of PH, CTEPH is placed in classification Group 4 (PH associated with pulmonary artery obstructions) [ 13 ]. CTEPH is a relatively common and important cause of PH, with a distinct management strategy and potentially curative treatment options, which makes early and correct diagnosis essential.

During diagnostic work-up of CTEPH, a differential diagnosis of other diseases causing pulmonary artery obstruction or compression should be considered. Malignant intraluminal tumours ( e.g. pulmonary artery sarcoma), large vessel vasculitis, congenital or acquired abnormalities of the pulmonary artery (including (congenital) peripheral pulmonary artery stenosis), sarcoidosis, silicosis and fibrosing mediastinitis (FM) can also cause pulmonary artery obstruction with subsequent development of PH, and are the most well-known CTEPH mimics [ 3 ]. High-quality computed tomography pulmonary angiography (CTPA) and careful radiological evaluation are essential in this crucial differential diagnosis. In some cases, additional invasive pulmonary angiography may also be useful. For an accurate diagnosis of CTEPH, several key pitfalls must be recognised.

The first pitfall is to not perform CTPA when the ventilation/perfusion (V̇/Q̇) scan is abnormal and suggestive for CTEPH in the work-up for PH. Compression or involvement of the pulmonary arteries can be seen in conditions such as FM (see dilemma 8), sarcoidosis (see dilemma 9) and silicosis [ 56 ]. Stenosis or thrombosis of the pulmonary veins also results in (mismatched) perfusion defects on V̇/Q̇ scanning. A rare, but well-known example of this is ring-like stenosis or total occlusion of the pulmonary veins after pulmonary vein isolation for atrial fibrillation ( supplementary figure ). Currently this serious complication occurs less frequently owing to new ablation techniques (0.5%) [ 56 – 58 ].

The second pitfall is to miss the radiological mimickers of (chronic) venous thromboembolism in the pulmonary vascular bed on imaging [ 59 ]. On CTPA, lobulated finger-like contrast defects mostly centrally located with heterogenous attenuation, complete vessel occlusion, expansile masses, extraluminal extension, involvement of the pulmonary valve and right outflow tract, and pulmonary nodules in the lung parenchyma are highly suspect for malignancy, especially pulmonary artery sarcomas ( figure 1 ) [ 56 , 59 ]. Another important clue for intravascular malignancy is an increase of the assumed thrombus despite anticoagulation therapy. Pulmonary artery sarcomas might show 2-fluoro-2-deoxy- d -glucose (FDG)-positron emission tomography (PET) avidity; however, variation is seen between different sarcoma types [ 56 ]. Large vessel vasculitis ( e.g. Takayasu arteritis ( figure 2 ), Behçet disease, Hughes–Stovin syndrome and, rarely, giant cell arteritis) can cause extrinsic compression and endoluminal obstruction of the pulmonary arteries. Findings suggestive for large vessel vasculitis on CTPA are an abnormal aortic and/or pulmonary artery contour with mural thickening and decreased size of the vessel lumen with the absence of intraluminal thrombus [ 56 , 60 ]. In late-stage disease, pulmonary aneurysms (especially in Beçhet and Hughes–Stovin) and transmural arterial calcification may be seen. FDG-PET is very useful in the active phase of vasculitis, during which the wall of the vessel shows FDG uptake [ 60 ]. Of note, isolated involvement of the pulmonary arteries in Takayasu arteritis has been described [ 61 ].

A third pitfall is ascribing a diagnosis of CTEPH to all patients with pulmonary arterial thrombosis and PH. For example, the vasculopathy of IPAH or Eisenmenger syndrome might be accompanied by in situ thrombosis, especially in the context of dilated proximal pulmonary arteries. Registry data show that the mean age of patients with CTEPH is around 63 years and that CTEPH is very rare in very young patients [ 62 ]. In young patients presenting with severe pre-capillary hypertension and radiological evidence of pulmonary arterial thrombus, causes of PH other than chronic venous thromboembolism must be considered.

Suggested approach

CTEPH mimics include causes of extrinsic pulmonary arterial or venous compression ( e.g. FM, sarcoidosis), pulmonary venous stenosis ( e.g. post-pulmonary vein isolation) and pulmonary arterial obstruction secondary to acquired conditions ( e.g. sarcoma and vasculitis) or congenital stenoses. Patients with V̇/Q̇ scans consistent with CTEPH should proceed to CTPA, which should be carefully assessed for features of these alternative conditions.

What are the causes of PH associated with FM and how should it be managed?

FM is a rare, benign, but potentially serious disorder caused by proliferation of fibrous tissue in the mediastinum with compression of mediastinal bronchovascular structures ( figure 3 ) [ 63 ]. Pulmonary complications are frequent and may include PH, which can be severe and challenging to manage [ 64 ]. V̇/Q̇ scanning in FM typically reveals segmental perfusion defect, mimicking the pattern observed in CTEPH and potentially leading to misdiagnosis (see dilemma 7). CTPA and, in some cases, formal pulmonary angiography are critical for diagnosis because they highlight extravascular compression rather than intravascular obstruction, differentiating FM from CTEPH.

In a French PH registry case series, 27 patients with PH associated with FM were identified, with a median age of 60 years [ 64 ]. Unlike historical series from North America, where histoplasmosis was the predominant aetiology, causes of FM in this cohort included sarcoidosis, tuberculosis (confirmed or suspected) and prior mediastinal irradiation [ 65 ]. Almost two thirds of the patients were in WHO-FC III and IV with a reduced 6MWD. RHC confirmed moderate to severe PH, which could be pre-capillary, post-capillary or CpcPH, depending on the anatomical level and site of vascular compression. Severe extrinsic compression of pulmonary arteries and/or bronchi was observed at various levels, including main, lobar or segmental levels. In addition, pulmonary venous compression led to associated pleural effusions in the respective territories.

There are currently no specific treatment guidelines for PH associated with FM. FDG-PET may reveal signs of disease activity, prompting intermittent corticosteroid use in selected cases. Observational data from North America have reported response to rituximab in populations with mainly histoplasmosis-associated disease [ 66 ]. Off-label use of PAH-targeted therapies can be tempting, based on haemodynamic severity, but should be discontinued if no clinical benefit is observed. The risk of pulmonary arterial thrombosis is high because of the obstructive flow, but careful anticoagulant management is required owing to hypertrophied bronchial arteries and risk of haemoptysis. Balloon pulmonary angioplasty and lung transplantation should be discussed on a case-by-case basis, with rare situations reported so far [ 67 , 68 ]. Survival rates in a French series were 88%, 73% and 56% at 1, 3 and 5 years, respectively, emphasising the progressive nature of the disease [ 69 ].

Suggested approach

Unlike in North America where histoplasmosis is the major cause, FM in Europe develops in association with conditions such as sarcoidosis, tuberculosis and previous irradiation. PH may develop due to compression of pre-capillary or post-capillary vessels and so PH associated with FM sits in classification Group 5. Treatment involves comprehensive diagnostic assessment and individualised management in expert PH centres.

A patient with known sarcoidosis is referred with suspected PH. What are the possible mechanisms for the development of PH and how should it be treated?

Sarcoidosis-associated pulmonary hypertension (SAPH) is an important complication of sarcoidosis that has a severe impact on patient outcomes. The different phenotypes of PH in sarcoidosis are primarily classified according to haemodynamic characteristics (pre-capillary/post-capillary) and underlying pathophysiological mechanisms.

There are at least five mechanisms that can lead to PH in sarcoidosis [ 70 , 71 ]: 1) hypoxic vasoconstriction and pulmonary vascular rarefaction, commonly seen in the fibrosing forms of sarcoidosis [ 72 , 73 ]; 2) granulomatous pulmonary vasculopathy, which can result in significant impairment of the D LCO ; 3) a result of left heart disease, in which left ventricular dysfunction (either systolic or diastolic) leads to post-capillary PH; 4) although less common, portal hypertension from liver involvement in sarcoidosis can contribute to PH; and 5) FM or compressive lymphadenopathies: this phenotype involves extrinsic compression of the pulmonary arteries or veins by fibrotic mediastinal tissue or enlarged lymph nodes, leading to obstructive PH (see dilemmas 7 and 8) [ 64 ].

In addition, other forms of PH such as CTEPH may coexist with pulmonary sarcoidosis [ 74 ].

The management of SAPH remains challenging because of its heterogeneous nature and the multifaceted pathophysiological underpinnings. Several key findings have emerged from recent studies. PAH-targeted therapies, such as endothelin receptor antagonists, PDE5i and prostanoids, have been employed in patients with pre-capillary forms of PH; however, their efficacy appears limited. While these agents may improve haemodynamic parameters, their impact on exercise capacity in patients with severe SAPH has been modest [ 73 ]. Immunosuppressive therapy has shown promise, especially in patients with obstructive PH due to metabolically active lymphadenopathies or mediastinal fibrosis, as evidenced by increased 18F-FDG uptake on PET imaging. Haemodynamic improvements in such cases suggest potential for targeting of the inflammatory component of sarcoidosis [4]. Anticoagulation remains an important treatment to consider in obstructive forms of SAPH. In select cases of obstructive PH secondary to mediastinal fibrosis, endovascular interventions such as balloon angioplasty and stenting of the pulmonary arteries may be considered. This therapeutic option is considered when FM leads to significant compression of the pulmonary arteries, impairing blood flow [ 75 ].

Evidence supports a tailored approach, in which treatment is highly customised based on the specific PH phenotype and underlying sarcoidosis-related complications. Further research is crucial to better understand these relationships and develop more effective targeted therapies.

Suggested approach

Different pathophysiological mechanisms may lead to the development of SAPH. Treatment should involve an individualised approach involving optimal management of the underlying sarcoidosis with trials of PAH therapies and/or interventional techniques in selected patients.

Should PH associated with pulmonary Langerhans cell histiocytosis and neurofibromatosis type 1 sit within PH classification Group 3 or 5?

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease affecting one in 3000 individuals, with full penetrance [ 76 ]. Pulmonary complications are recognised in NF1, including PH, a rare but severe manifestation. In a French PH registry case series, 49 patients were identified with PH associated with NF1 (PH-NF1), with a mean age at PH diagnosis of 62 years and a female predominance [ 77 ]. These patients exhibited marked functional and haemodynamic impairments. Interestingly, respiratory volumes were generally preserved, but a marked reduction in D LCO and frequent hypoxaemia were reported. High-resolution chest CT scans revealed parenchymal abnormalities in 75% of cases, typically cysts and ground-glass opacities. Pathological analysis in three patients who underwent lung transplantation showed pulmonary arterial remodelling, venular involvement and nonspecific interstitial pneumonia ( figure 4 ) [ 77 ]. These findings justify the classification of PH-NF1 within Group 5 of the clinical classification of PH, which includes disorders with unclear or multifactorial mechanisms. Treatment with PAH-approved drugs provided modest clinical and haemodynamic benefits, but prognosis remained poor, with a 5-year survival rate of 42%. Given the limited therapeutic options and frequent disease progression, early referral to specialised PH centres is advised and lung transplantation assessment should be considered in advanced cases, with specific precautions during pre-transplant evaluation owing to the increased risk of malignancy in this population. This strategy is feasible in clinical practice, as demonstrated by the four patients who successfully underwent transplantation in the French cohort [ 77 ]. Currently, no disease-specific guidelines exist for PH-NF1, and management must be individualised on a case-by-case basis. This underscores the urgent need for consensus-based recommendations and targeted research to guide clinical decision-making.

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare smoking-related interstitial lung disease associated with the clonal expansion of myeloid precursors that infiltrate organs and differentiate into Langerhans cells [ 78 ]. Imaging typically reveals multiple bilateral cysts with upper-lobe predominance. PH is highly prevalent in PLCH, affecting 41% of patients in a recent cohort [ 79 ]. While PH in PLCH is typically moderate and correlates with the degree of parenchymal lung involvement, it may also present in a disproportionately severe form or arise in patients with preserved pulmonary function and lung volumes [ 80 ]. Beyond the mechanical consequences of cystic lung destruction, additional mechanisms may contribute to PH, including proliferative vasculopathy involving the small-to-medium-sized pulmonary vessels, especially pulmonary veins and direct infiltration with Langerhans cells [ 80 , 81 ]. As with PH-NF1, evidence for the efficacy of PAH-targeted therapies remains limited to retrospective series and case reports, which have documented clinical and haemodynamic benefits, most often with monotherapy [ 82 ]. In advanced disease, lung transplantation has to be considered.

Suggested approach

PH associated with both NF-1 and PLCH belong in Group 5 of PH classification, underscoring the need for specialised care in expert PH centres, early transplant consideration and research into targeted therapies addressing the underlying mechanisms (especially mitogen-activated protein kinase and Akt-mechanistic target of rapamycin pathways, which are activated in both diseases).

Points for clinical practice

Multiple possible mechanisms exist for PH in the presence of high cardiac output. These should be suspected in patients with features such as high D LCO and dilated pulmonary arteries in the absence of right ventricular hypertrophy.

There are increasing data that PH in patients with a significant smoking history, D LCO <45% predicted and with or without mild parenchymal lung disease shares more characteristics with Group 3 PH. An individualised approach to therapy should be undertaken with optimisation of cardiopulmonary disease. Initial monotherapy, most likely with a PDE5i, may be considered with close monitoring and subsequent reassessment.

Echocardiographic features of significant left ventricular diastolic dysfunction, systolic dysfunction or left-sided valvular disease may suggest post-capillary PH. RHC may be indicated in the presence of features suggestive of additional significant pre-capillary disease.

Based on current evidence, PAH-specific therapies are not recommended in patients with confirmed PH associated with left heart disease.

Alternative forms of PH (including PH associated with obesity hypoventilation syndrome and left heart disease) should be excluded in patients with obesity and suspected PAH. An elevated PAWP in a patient with obesity, in the absence of other features suggestive of left heart disease, does not necessarily exclude pre-capillary PH.

CTEPH mimics include causes of extrinsic pulmonary arterial or venous compression ( e.g. FM, sarcoidosis), pulmonary venous stenosis ( e.g . post-pulmonary vein isolation) and pulmonary arterial obstruction secondary to acquired conditions ( e.g. sarcoma and vasculitis) or congenital stenoses. Patients with V̇/Q̇ scans consistent with CTEPH should proceed to CTPA, which should be carefully assessed for features of these alternative conditions.

In Europe, FM develops in association with conditions such as sarcoidosis, tuberculosis and previous irradiation. PH may develop owing to compression of pre-capillary or post-capillary vessels.

Different pathophysiological mechanisms may lead to the development of SAPH. An individualised approach to treatment should involve optimal management of the underlying sarcoidosis with trials of PAH therapies and/or interventional techniques in selected patients.

PH-NF1 and PH associated with PLCH belong in Group 5 of PH classification, underscoring the need for specialised care in expert PH centres and early transplant consideration.

Footnotes

Provenance: Submitted article, peer reviewed.

Conflict of interest: R. Condliffe reports no conflicts of interest related to this manuscript. J. Aman reports no conflicts of interest related to this manuscript. A. Boucly reports institutional grants from MSD and Janssen; speaker fees from Janssen, Merck, AOP Orphan, Ferrer, Gossamer, AstraZeneca and United Therapeutics; and support to attend meetings from Janssen, MSD, Ferrer and AOP Orphan. E. Cerrone reports no conflicts of interest related to this manuscript. E-M. Jutant reports speaker fees from Boehringer, Chiesi, GSK and MSD and support to attend meetings from MSD. G. Kovacs reports institutional grants from J&J, Boehringer and MSD; speaker fees from MSD, Boehringer, AOP Orphan, Chiesi, Ferrer, J&J; and advisory board participation for MSD, Boehringer, Ferrer, AOP Orphan, Liquidia, United Therapeutics, J&J, Gossamer and United Therapeutics. L.J. Meijboom reports no conflicts of interest related to this manuscript. K.M. Olsson reports institutional grants from Acceleron, MSD and Janssen; consulting fees from Acceleron, Actelion, Janssen, Ferrer, Merck and AOP Health; speaker fees from Acceleron, Actelion, AOP Health, Janssen, OMT, MSD and Ferrer; and support to attend meetings from Acceleron, MSD and Janssen. D-H. Park reports speaker fees and support to attend meetings from MSD. A. Seferian reports no conflicts of interest related to this manuscript. O. Sitbon reports institutional grants from AOP Orphan, Ferrer, Gossamer, Janssen and MSD; consulting fees from AOP Orphan, Ferrer, Gossamer Bio, Janssen, Liquidia, MSD, Pulmovant, Respira Therapeutics and United Therapeutics; and speaker fees from Aerovate, AOP Orphan, Janssen, Ferrer and MSD, participation in steering committees and data safety monitoring boards for Altavant, Gossamer Bio, AOP Orphan and Respira Therapeutics. J-L. Vachiery reports consulting fees from Merck, BPI France, Gossamer Bio, Liquidia, Pulmovant, Tectonic Therapeutics, Inhibikase Therapeutics and Insmed, speaker fees from Janssen, Boehringer and Novartis, support for meeting attendance from MSD and patents with GK and J&J. A. Vonk Noordegraaf reports institutional grants from MSD and speaker fees from MSD, Actelion and Ferrer, and is a current Associate editor for the European Respiratory Review . D. Montani reports institutional grants from Gossamer and MSD and speaker fees from Bayer, Boehringer, Chiesi, Gossamer, GSK, Jazz Pharmaceuticals, Ferrer and MSD. E.J. Nossent reports institutional grants from Boehringer, BV, Abbvie and PEXAS; speaker fees from Ferrer and Boehringer; and advisory board participation for MSD and Gossamer Bio.

Support statement: No funding declared.

Supplementary material

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Associated Data

Supplementary Materials

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary figure 1

ERR-0337-2025.SUPPLEMENT