Sarcoidosis-associated pulmonary hypertension: Diagnostic evaluation in adults

INTRODUCTION — Sarcoidosis is a multisystemic disease of unknown etiology that is characterized pathologically by nonnecrotizing granulomatous inflammation. Sarcoidosis-associated pulmonary hypertension (SAPH) is increasingly recognized as a complication of sarcoidosis. The diagnosis of SAPH is often delayed and is associated with a poor prognosis. Thus, early recognition and management is important so that patients can be treated promptly.

This topic will review the epidemiology, pathogenesis, and diagnostic evaluation of SAPH. The treatment of SAPH and diagnosis and management of other complications of sarcoidosis are discussed separately.

●(See "Sarcoidosis-associated pulmonary hypertension: Treatment and prognosis in adults".)

●(See "Clinical manifestations and diagnosis of sarcoidosis" and "Management and prognosis of cardiac sarcoidosis" and "Cutaneous manifestations of sarcoidosis".)

●(See "Treatment of pulmonary sarcoidosis: Initial approach".)

●(See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)

●(See "Overview of extrapulmonary manifestations of sarcoidosis".)

●(See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)

●(See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

●(See "Clinical manifestations and diagnosis of sarcoidosis" and "Management and prognosis of cardiac sarcoidosis" and "Cutaneous manifestations of sarcoidosis".)

●(See "Sarcoid myopathy".)

●(See "Kidney disease in sarcoidosis".)

●(See "Neurologic sarcoidosis".)

●(See "Clinical manifestations and diagnosis of sarcoidosis" and "Management and prognosis of cardiac sarcoidosis" and "Cutaneous manifestations of sarcoidosis".)

●(See "Sarcoidosis of bone".)

●(See "Cutaneous sarcoidosis: Management".)

Several societies have provided guidance on the evaluation and management of SAPH including the American Thoracic Society [1] and the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) [2]. Our recommendations are mostly in keeping with this guidance.

DEFINITION AND CLASSIFICATION — Pulmonary hypertension (PH) is defined as mean pulmonary artery pressure (mPAP) >20 mmHg at rest, measured by right heart catheterization. Although poorly defined, PH is considered severe if mPAP is ≥35 mmHg or if mPAP is >20 mmHg with a right atrial pressure >14 mmHg, pulmonary vascular resistance (PVR) >5 Wood units (WU), and/or cardiac index <2 L/min/m² [3]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Diagnosis'.)

Patients with PH are classified into five groups based upon etiology and mechanism (table 1) [4]. SAPH is typically classified as group 5 (PH due to unclear or multifactorial mechanisms) since the cause is multifactorial. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Group 5: PH due to multifactorial mechanisms'.)

Patients with sarcoidosis may have contributions from one or more classes including the following:

●Group 1 (pulmonary arterial hypertension; rare)

●Group 2 (PH due to left-sided heart disease)

●Group 3 (PH due to chronic lung diseases or hypoxemia)

●Group 4 (PH due to chronic thromboembolic disease or pulmonary artery obstruction)

●Group 5 (PH due to several mechanisms including contributions for comorbidities, such as sleep apnea or portal hypertension)

The contribution from each class may vary such that a patient may have one class as the dominant form of PH while another patient may have mixed components from more than one class.

PH may also be subcategorized hemodynamically as the following (table 2) [4]:

●Precapillary PH – mPAP >20 mmHg with pulmonary artery wedge pressure (PAWP) ≤15 mmHg and PVR ≥3 WU.

●Postcapillary PH – mPAP >20 mmHg with PAWP >15 mmHg and PVR <3 WU.

●Combined pre- and postcapillary PH (Cpc-PH) – mPAP >20 mmHg with PAWP >15 mmHg and PVR ≥3 WU.

EPIDEMIOLOGY — Among patients with sarcoidosis, the average incidence of SAPH is approximately 5 percent but ranges from 2 to 21 percent [5-17]. The distribution of SAPH is worldwide, and there appears to be no racial, ethnic, age, or sex predilection [18,19].

Several factors influence SAPH rates including different definitions (eg, mean pulmonary artery pressure [mPAP] ≥25 mmHg, mPAP >20 mmHg), the method used to assess PH (eg, transthoracic echocardiogram [TTE] versus right heart catheterization [RHC]), and different study populations (eg, general population versus pretransplant patients).

Most studies have used TTE to identify PH, which have likely overestimated the incidence of SAPH. By contrast, most studies that used RHC employed a threshold mPAP ≥25 mmHg for the diagnosis of PH rather than the revised threshold of >20 mmHg, which has likely underestimated the incidence of SAPH [5,9,12,14,15,20,21]. The best data comes from a cumulative analysis of two separate European cohorts totaling 510 patients with sarcoidosis [14,15], which estimated that the prevalence of TTE-defined PH was 10 percent and RHC-defined PH (mPAP ≥25 mmHg) was 2.9 percent [12].

Rates are higher among those with severe pulmonary disease. For example, among sarcoidosis patients with signs and symptoms of PH, the prevalence of SAPH approaches 50 percent [6,22], and among those awaiting lung transplantation, the prevalence increases to 74 percent [13,23,24].

It is unclear if there is a predominant PH phenotype in patients with sarcoidosis. Although data vary from study to study, collectively, they suggest that most patients phenotypically behave as class 3 PH [5,12,25]. In the largest series to date of patients with SAPH, 70 percent had evidence of class 3 PH, 17.5 percent had evidence of class 4 PH (mostly due to compression of pulmonary vasculature), 7.5 percent had evidence of class 2 PH, and <1 percent had evidence of group 1 pulmonary arterial hypertension [25].

PATHOGENESIS — In pulmonary sarcoidosis, a variety of mechanisms can lead to SAPH. Because several mechanisms contribute to SAPH, it is most often classified as group 5 PH, but patients with SAPH may have dominant features of any one of the classes of PH or have combined features of one or more class (table 1). (See 'Definition and classification' above and 'Postdiagnostic testing and phenotyping' below.)

Cardiac dysfunction — Sarcoidosis-related left ventricular (LV) systolic or diastolic dysfunction has been implicated in the pathogenesis of SAPH (ie, group 2 PH) [26-28], which can be exacerbated by coexistent comorbidities (eg, obesity [29] and systemic arterial hypertension [30]).

The exact contribution of cardiac dysfunction to SAPH is unclear. One study of 130 patients with suspected SAPH, estimated that among those who had PH, almost one-third had PH with LV dysfunction [31]. Another study reported postcapillary PH in only 7.5 percent of patients with right heart catheterization-confirmed PH [25].

Manifestations and diagnostic evaluation of suspected cardiac sarcoidosis are discussed separately. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

Pulmonary parenchymal disease — Progressive fibrotic lung disease due to sarcoidosis has been implicated in the pathogenesis of SAPH (ie, group 3 PH phenotype). Hypoxic vasoconstriction and obliteration of the pulmonary vascular bed are suggested mechanisms in this population. In support of this mechanism, PH is common in those with severe lung disease requiring lung transplant (eg, >65 percent) [18,19,32]. However, PH does not always correlate well with the degree of pulmonary fibrosis [6,7,33,34], suggesting other mechanisms are also involved.

Pulmonary vascular disease — The spectrum of vascular mechanisms leading to SAPH is broad and includes sarcoidosis-related vasculopathy, direct vascular involvement by sarcoid granulomas, compression of the pulmonary vasculature by lymphadenopathy or mediastinal fibrosis, and venous thromboembolic (VTE) disease.

●Vasculopathy – While some patients with SAPH have a precapillary pulmonary arterial hypertension (PAH) phenotype, whether the same proliferative vasculopathy that is present in patients with PAH occurs in SAPH is unknown. The pathogenesis of PAH is discussed separately. (See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)".)

●Direct vascular involvement – Granulomatous angiitis has been reported by several groups. As an example, several pathologic studies that have examined lung tissue obtained at autopsy, transbronchial biopsy, or from explanted lung have shown that the pulmonary vasculature is frequently involved by granulomatous inflammation, irrespective of sarcoidosis stage on the chest radiograph [33,35-38].

Involvement is most often perivenular (61 to 65 percent) but may also be arterial (11 percent) or venoarterial (24 to 31 percent) (image 1). Granulomatous angiitis can lead to perivascular fibrosis and an occlusive vasculopathy. When this occurs in the small veins, it may lead to a rare mechanism of SAPH similar clinically to pulmonary veno-occlusive disease (PVOD) [39-41]. The pathogenesis of PVOD is discussed separately. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Pathogenesis and risk factors'.)

●Extrinsic pulmonary artery compression – SAPH has been reported to occur in the setting of extrinsic compression of the pulmonary arteries [42,43] and pulmonary veins by enlarged and/or calcified mediastinal lymph nodes or by mediastinal fibrosis [44,45]. Left atrial compression by lymphadenopathy is another potential mechanism that may be evident on computed tomographic (CT) imaging [46,47]. It should be noted that PH due to extrinsic compression is not considered true group 4 PH.

●Venous thromboembolic (VTE) disease – Several population-based studies identified a two- to threefold increased risk of acute VTE in patients with sarcoidosis, which may contribute to the development or worsening of PH in this population [48-50]. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

In addition, chronic thromboembolic PH has also been reported in patients with sarcoidosis [51]. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

Contributing comorbidities — Sarcoidosis is associated with comorbidities that may contribute to the pathogenesis of SAPH, including the following:

●Obstructive sleep apnea (OSA) – There is a high prevalence of OSA reported in patients with sarcoidosis (>50 percent) [52-56]. Patients with OSA may have nocturnal intermittent hypoxemia, which can induce pulmonary vasoconstriction and worsen PH. Glucocorticoids, as a treatment for sarcoidosis, may also increase the risk of OSA [56]; whether this potential mechanism is counterbalanced by improvement in underlying lung disease is unclear. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults", section on 'Sleep disordered breathing'.)

●Portopulmonary hypertension (POPH) – Although portal hypertension is rare in this population, POPH has been reported in the setting of sarcoid-related hepatic involvement [57,58]. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis", section on 'Hepatic'.)

IDENTIFICATION OF AT-RISK PATIENTS

Algorithmic overview — In patents with an established diagnosis of sarcoidosis, we have a low threshold to suspect PH. However, recognizing PH is challenging as the signs and symptoms of PH overlap with those of pulmonary parenchymal and cardiac sarcoidosis. This frequently leads to a delay in the diagnosis, sometimes as long as 15 years [18]. Our overall approach is as follows (algorithm 1):

●In patients with sarcoidosis, we pay close attention to select signs and symptoms of PH, pulmonary function tests (PFTs), and imaging features, much of which is often performed during diagnostic evaluation and follow-up. (See 'Symptoms and signs' below and 'Pulmonary function testing' below and 'Imaging' below.)

●Once clinically suspected, we generally repeat chest CT and PFTs if they have not recently been performed (eg, previous 12 months). We additionally perform indices of oxygenation (eg, peripheral oxygen saturation (SpO₂), six-minute walk test [6MWT]) and assess for right ventricular (RV) strain by obtaining brain natriuretic peptide (BNP) levels and electrocardiography (ECG). (See 'Oxygenation and six-minute walk test' below and 'Laboratory testing' below and 'Electrocardiography' below.)

●Using this information, we select patients for diagnostic testing, typically transthoracic echocardiography (TTE). (See 'Diagnostic evaluation' below and 'Transthoracic echocardiography (TTE)' below.)

●TTE findings together with clinical findings determine who undergoes right heart catheterization. (See 'Selecting patients for right heart catheterization' below.)

Symptoms and signs — SAPH is most commonly seen as a late complication in long-established pulmonary sarcoidosis [32,59,60], although detection early in the course has been described [61].

The most common initial symptom of SAPH is progressive exertional dyspnea [6]. We maintain a high suspicion for SAPH in patients with sarcoidosis who have any one or more of the following [18,22,62,63]:

●Dyspnea that is either unexplained or disproportionately severe in comparison to imaging, spirometry, and lung volume assessment.

●Dyspnea that is persistent or severe despite anti-inflammatory therapy.

●Dyspnea that is new in onset or associated with worsening functional class (table 3).

●Exertional chest pain, syncope, or other manifestations of right-sided heart failure (eg, fatigue, lower extremity edema, anorexia, and increased abdominal girth due to ascites, loud pulmonic component of second heart sound).

These symptoms, while suspicious for PH, are nonspecific and can overlap with cardiac or pulmonary parenchymal sarcoidosis [64]. Symptoms such as weight gain with fluid retention can also occur in patients receiving glucocorticoid therapy for sarcoidosis.

Symptoms which occur in sarcoidosis that are not suggestive of PH include cough and wheezing.

Pulmonary function testing — If SAPH is suspected, we obtain a full set of PFTs, if not recently performed. PFTs include spirometry, lung volumes, and diffusing capacity for carbon monoxide (DLCO).

The suspicion for PH should be raised when any of the following is present [6,8,10,18,65]:

●The DLCO is disproportionately lower than that expected for the degree of lung function as measured by the forced vital capacity (FVC). Although an FVC/DLCO ratio >1.6 has been proposed as a predictive factor for systemic sclerosis-related PH, the same ratio has not been adequately studied as a predictor for SAPH. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening", section on 'Abnormal pulmonary function (low diffusion)'.)

●The DLCO is <50 percent predicted in the absence of pulmonary fibrosis on imaging.

●The DLCO is <30 percent with evidence of pulmonary fibrosis (ie, stage 4 sarcoidosis on chest radiography).

●A decrease in DLCO by 15 percent without change in lung volumes.

While useful, PFTs have poor predictive capacity and there is no absolute value of FVC or DLCO that can accurately predict SAPH. In addition, near-normal lung function does not exclude the diagnosis. In a study of 127 patients with sarcoidosis who had "near-normal" lung function (FVC >70 percent, forced expiratory volume in one second >70 percent, and DLCO >60 percent), the prevalence of SAPH detected by TTE (RV systolic pressure >40 mmHg) was as high as 28.3 percent [66].

Imaging

Chest radiograph — The presence of stage 4 sarcoidosis (eg, extensive bronchovascular disease, pulmonary fibrosis) is a risk factor for development of SAPH and usually warrants evaluation with TTE (image 2). However, patients without evidence of pulmonary sarcoidosis may still have PH (image 3). (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Chest radiograph'.)

Chest computed tomography — When SAPH is suspected, we perform chest CT, if not recently performed [59,60,67,68]:

●Chest CT can confirm extensive parenchymal sarcoidosis, which is a risk factor for SAPH.

●Chest CT can identify other contributors to SAPH, such as mediastinal adenopathy (calcified or noncalcified) and mediastinal fibrosis that may compress and restrict blood flow in pulmonary vessels.

●Chest CT allows assessment of other features suggestive of SAPH including the following:

•Enlarged pulmonary artery diameter (corrected to the patient's body surface area)

•Enlarged main pulmonary artery diameter to ascending aorta diameter ratio (PA:AA diameter ≥1)

•Enlarged RV

Other imaging — RV or pulmonary artery enlargement incidentally noted on other imaging (eg, cardiac magnetic resonance imaging, abdominal CT) raises suspicion for SAPH and should prompt evaluation with TTE.

Oxygenation and six-minute walk test — When SAPH is suspected, we perform a formal 6MWT. Both reduced six-minute walk distance (eg, <350 m) and ambulatory oxygen desaturation (eg, <90 percent) are associated with a diagnosis of SAPH [8,18,19,60,69]. There is a strong inverse correlation between 6MWT and presence of SAPH [60], with the relationship being stronger with walk distances <350 m. One series reported that patients who desaturate below 90 percent during the 6MWT were approximately 12 times more likely to have SAPH [8]. (See "Overview of pulmonary function testing in adults", section on 'Six-minute walk test'.)

Hypoxemia at rest, measured by SpO₂ or by arterial blood gas, is another key predictor of SAPH [6,8,13,18,19,60,70]. For example, in 363 patients with sarcoidosis who were listed for lung transplantation, poor oxygenation was the only independent risk factor for the presence of SAPH [13].

However, in sarcoidosis, poor oxygenation parameters and reduced six-minute walk distances are not diagnostic of PH and can be affected by a variety of factors independent of PH, including musculoskeletal disease, cardiac dysfunction, parenchymal lung disease, depression, and fatigue [7].

We do not perform advanced cardiopulmonary exercise testing unless the etiology of dyspnea is unclear after evaluation. (See "Cardiopulmonary exercise testing in the evaluation of unexplained dyspnea".)

Laboratory testing — There are no serologic tests that definitively identify SAPH. We typically measure BNP or N-terminal pro-BNP (NT-proBNP). While elevated BNP or NT-proBNP may reflect RV strain from SAPH, they are nonspecific and may alternatively indicate the presence of cardiac sarcoidosis [7,60,71].

Electrocardiography — Patients with sarcoidosis typically undergo annual ECG monitoring for detection of potential cardiac involvement. While ECG abnormalities such as p-pulmonale, right axis deviation, RV hypertrophy or strain, and right bundle branch block can be observed in patients with cardiac sarcoidosis, they are more likely indicators of significant SAPH. Patients with these ECG features should undergo evaluation for PH with TTE. Conversely, it is important to note a normal ECG does not exclude the diagnosis of SAPH. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Electrocardiography'.)

DIFFERENTIAL DIAGNOSIS — For patients with symptoms in whom PH is suspected, the differential diagnosis includes a wide spectrum of cardiopulmonary and other disorders, most of which are distinguished by routine investigations performed for PH. Further details regarding this differential are provided separately. (See "Approach to the patient with dyspnea" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial differential diagnosis'.)

Cardiac and pulmonary parenchymal involvement with sarcoidosis are the major conditions that require differentiating. Chest CT, transthoracic echocardiography, and right heart catheterization are often key steps that provide clues to differentiate these conditions. (See 'Diagnostic evaluation' below and "Clinical manifestations and diagnosis of cardiac sarcoidosis" and "Clinical manifestations and diagnosis of sarcoidosis".)

DIAGNOSTIC EVALUATION

Forming an individualized diagnostic strategy — For patients at risk for SAPH, we use a multidisciplinary team (MDT) of sarcoidosis and PH experts to facilitate an appropriate diagnostic strategy for each patient (algorithm 1). The MDT is particularly crucial for deciding who should get transthoracic echocardiography (TTE) and subsequent right heart catheterization (RHC). This approach is outlined in more detail below, but can be briefly summarized:

●For patients with both clinical symptoms and objective findings on physical examination, chest imaging, pulmonary function tests (PFTs), electrocardiography, or six-minute walk test (6MWT) suggesting risk for SAPH (see 'Identification of at-risk patients' above), we typically pursue further evaluation with TTE. We do not routinely perform TTE in asymptomatic patients or patients without risk factors PH (table 4) [1,2]. (See 'Transthoracic echocardiography (TTE)' below and 'Identification of at-risk patients' above.)

●We then use TTE assessment in conjunction with clinical findings and the expected need for and type of therapeutic intervention to select patients for RHC. (See 'Selecting patients for right heart catheterization' below.)

Transthoracic echocardiography (TTE) — There is no ideal approach or agreed upon criteria to select patients for TTE. For patients in whom clinical features and/or objective testing raise the suspicion for SAPH, we perform TTE rather than routinely performing TTE in every patient with sarcoidosis [1,2].

In our practice, we perform TTE in symptomatic patients who have one or more objective findings listed on the table (table 4 and algorithm 1) (see 'Identification of at-risk patients' above).

While this selective approach to TTE assessment is like that used in patients with suspected PH from nonsarcoidosis etiologies, only limited data support it in patients with sarcoidosis. It has been estimated that if TTE is performed in patients with clinically suspected SAPH, 29 percent will be abnormal, among which PH would be confirmed by RHC in approximately three-quarters and excluded in the remainder [1]. One prospective study in 479 "unscreened" patients with sarcoidosis found an intermediate and high PH probability on TTE (table 5) in 6 and 2.7 percent of patients, respectively, and confirmed PH in 3.5 percent [72].

The value of TTE may be more limited in a significant subset (up to 50 percent) of patients with sarcoidosis due to inability to detect or adequately measure tricuspid regurgitant velocity (TRV) [22,72].

We discuss the results of TTE and our clinical findings with the MDT to determine subsequent testing, typically RHC. Indications for RHC are discussed below. (See 'Selecting patients for right heart catheterization' below.)

Selecting patients for right heart catheterization — RHC is the gold standard for the diagnosis of PH, but it is costly, resource-limited, and an invasive procedure. We use RHC in diagnostic evaluation of SAPH to establish a definitive diagnosis of PH (when needed), assess for evidence of left-heart disease, and longitudinally evaluate the potential hemodynamic benefits of a therapeutic intervention. (See "Sarcoidosis-associated pulmonary hypertension: Treatment and prognosis in adults".)

Patient selection for RHC depends upon TTE findings, clinical suspicion for SAPH, and the impact of testing on the decision to implement potential future therapies. When selecting patients with suspected SAPH for RHC, we use a similar strategy to those without sarcoidosis in whom PH is suspected [4]. However, our threshold to perform RHC is typically lower in this population. In our experience, RHC is often needed in suspected SAPH since it can distinguish precapillary from postcapillary disease (ie, group 1, 3, and 4 from group 2 PH phenotype) (table 2 and table 1), determine whether PH is multifactorial in nature, and therefore accurately inform therapeutic decisions.

●TTE findings – TTE plays a key role in deciding who is selected for RHC. We use a strategy that was outlined by the European Society of Cardiology/European Respiratory Society (ECS/ERS) for assessing the likelihood of the presence of PH on echocardiography [4]. This standardized approach stratifies PH probability into low, intermediate, or high based on the maximal TRV and measurements of secondary echocardiographic signs for PH in the right ventricle, right atria/inferior vena cava, and pulmonary artery diameter (table 5). General principles of patient selection for RHC on TTE findings are the following:

•In those with a low probability of having PH on TTE, we do not generally perform RHC (although there may be exceptions). For most patients with a high probability of PH on TTE, we perform RHC unless RHC would not change management; RHC is performed to make a definitive diagnosis, clarify the PH subtype (when needed), and/or obtain a baseline assessment prior to a therapeutic trial. We assess patients with intermediate probability or inconclusive TTE on a case-by-case basis. Further details regarding this assessment are provided elsewhere:

-(See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)

-(See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Low probability of pulmonary hypertension on echocardiography'.)

-(See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Intermediate or high probability of pulmonary hypertension on echocardiography (assess left heart)'.)

•For those with evidence of left ventricular systolic dysfunction on TTE, investigations targeted at possible cardiac involvement with sarcoidosis is reasonable before making a decision about performing a RHC.

●Clinical features of PH – Specific clinical management questions may also influence the decision to proceed with RHC independent of TTE-based assessment of PH likelihood (eg, evaluation for lung transplantation, severe otherwise unexplained dyspnea, uncertain cardiac sarcoidosis contribution to disease). RHC may also be appropriate in patients with a strong clinical suspicion for SAPH based on symptoms, hypoxemia, or PFTs despite a low probability on TTE. This approach is similar to that used for patients with suspected PH without sarcoidosis. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization' and 'Identification of at-risk patients' above.)

DIAGNOSIS — A definitive diagnosis of SAPH is made based on right heart catheterization (RHC) demonstrating an elevated mean pulmonary artery pressure >20 mmHg while supine and at rest.

However, in some patients, we consider a diagnosis of "likely SAPH" in the absence of RHC data using clinical and noninvasive testing. For example, SAPH is likely in patients with minimal symptoms who have an intermediate or high probability of PH on echocardiography that is not explained by significant left heart disease and/or by chronic lung disease due to sarcoidosis. However, treatment decisions that involve PH-specific therapy should never be made in patients without a definitive diagnosis by RHC. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Definitions' and "Sarcoidosis-associated pulmonary hypertension: Treatment and prognosis in adults".)

POSTDIAGNOSTIC TESTING AND PHENOTYPING — As with other patients diagnosed with PH, the postdiagnostic evaluation focuses on identifying the predominant pathophysiology/phenotype and other contributing comorbidities. This assessment is best performed as a collaborative effort between experts in sarcoidosis and PH. Once the relative contribution of various etiologies and the dominant phenotype have been determined, a therapeutic plan can be put into place. (See "Sarcoidosis-associated pulmonary hypertension: Treatment and prognosis in adults", section on 'PH phenotype-targeted therapy'.)

Among the five primary PH classifications (table 1), which are based upon etiology and mechanism, SAPH may either have a single dominant phenotype or have combined contributions from more than one etiology:

●Sarcoid-related cardiac dysfunction (leading to dominant group 2 PH phenotype)

●Sarcoid-related pulmonary parenchymal disease (leading to dominant group 3 PH phenotype)

●Sarcoid-related pulmonary vascular involvement (thromboembolism, leading to group 4 dominant PH phenotype or direct obstruction of the pulmonary artery)

●Combined mechanisms (leading to group 5 PH)

SAPH is mostly classified as group 5 PH since the pathogenesis is often multifactorial (see 'Pathogenesis' above). Among the SAPH phenotypes, group 3 PH is the most common while group 1 pulmonary arterial hypertension phenotype is rare in sarcoidosis. The distribution of subclass phenotypes in SAPH is described above. (See 'Epidemiology' above and 'Definition and classification' above.)

To fully evaluate contributions from individual etiologies and assess contributing roles of any other comorbidities, adjunct testing may be needed. For example, on a case-by-case basis, we evaluate the need for the following:

●CT pulmonary angiography (CTPA) – In patients with right heart catheterization-confirmed SAPH, we typically obtain CTPA, if not already performed. The enhancement of the pulmonary vasculature with contrast in CTPA, which is not obtained with chest CT, can identify arterial and veno-atrial compression, segmental arterial and venous occlusion, or chronic pulmonary emboli (ie, group 4 PH phenotype). (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Computed pulmonary arteriography'.)

●Ventilation-perfusion (V/Q) scan – In most patients, we also obtain a V/Q scan, if not already performed. This is the preferred imaging modality to exclude chronic thromboembolic PH (CTEPH; ie, group 4 PH due to CTEPH), but it can also help identify significant regional flow disturbance from mediastinal lymphadenopathy in SAPH [45]. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Ventilation perfusion lung scanning'.)

●Fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) – We also evaluate most patients with SAPH using fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET). FDG-PET together with CT chest and V/Q scanning may further inform the clinician about any contribution from cardiac inflammation or extrinsic compression of the pulmonary vasculature (ie, contribution of group 4 PH phenotype). For example, if compressive lymphadenopathy is FDG-PET-active, PH may be responsive to anti-inflammatory therapy. (See "Sarcoidosis-associated pulmonary hypertension: Treatment and prognosis in adults", section on 'PH with vascular obstruction or thromboembolism'.)

In the evaluation of SAPH, it has been proposed that FDG-PET identifies persistent (potentially reversible) granulomatous inflammation in areas otherwise believed to represent scarred areas in chest radiograph stage 4 pulmonary sarcoidosis [73,74]. Absence of FDG uptake suggests nonviable fibrosis and can be used as justification to not expose a patient to anti-inflammatory therapy. (See "Sarcoidosis-associated pulmonary hypertension: Treatment and prognosis in adults", section on 'Anti-inflammatory therapy' and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Less commonly needed imaging'.)

●Cardiac magnetic resonance imaging (MRI) – If cardiac sarcoidosis needs to be excluded (eg, group 2 PH phenotype), we perform cardiac MRI. Cardiac MRI is the technique of choice in the evaluation of patients with suspected cardiac sarcoid. Cardiac MRI can help discern the contribution of cardiac disease to SAPH (eg, those with symptoms or signs suggestive of group 2 PH). Some clinicians also additionally perform FDG-PET for this reason. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

●Polysomnography – We perform polysomnography in patients with increased probability of having obstructive sleep apnea (OSA; obesity, poor nonrestorative sleep, positive screening questionnaires). For those in whom OSA testing is not indicated, we perform continuous overnight oximetry to look for nocturnal desaturation that may occur in association with underlying pulmonary disease. Indications for sleep testing are provided separately. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

●Other tests – Other postdiagnostic tests that may need to be considered during the classification phase of evaluation are discussed separately (eg, human immune deficiency testing, liver function tests). (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

EARLY DETECTION OF SAPH — We do not routinely perform transthoracic echocardiography (TTE) on asymptomatic patients with sarcoidosis or patients in whom there is no suspicion for PH. Rather, we have a low threshold to perform TTE in patients who are considered at risk for developing PH as a complication of their disease. These risk factors are discussed above (table 4). (See 'Identification of at-risk patients' above.)

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: Sarcoidosis" and "Society guideline links: Pulmonary hypertension in adults".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and pathogenesis – Sarcoidosis-associated pulmonary hypertension (SAPH) is a clinically important complication of sarcoidosis that is associated with increased morbidity and mortality. (See 'Introduction' above.)

•SAPH affects approximately 5 percent of patients with sarcoidosis and tends to be a late complication. (See 'Epidemiology' above.)

•Several mechanisms contribute to the development of SAPH, including cardiac sarcoidosis, diffuse lung parenchymal disease, and involvement of the pulmonary vasculature (eg, vasculopathy, thromboembolism, vascular obstruction/compression, granulomatous angiitis). (See 'Pathogenesis' above.)

●At-risk patients – Once sarcoidosis is diagnosed, we evaluate patients for the risk of developing pulmonary hypertension (PH).

•Evaluation – We use clinical evaluation, pulmonary function tests, imaging features, oxygenation indices, and parameters of right ventricular strain/failure (eg, brain natriuretic peptide, electrocardiography) to identify those with sarcoidosis who are at risk of developing SAPH. (See 'Identification of at-risk patients' above.)

•Risk factors – Factors derived from that evaluation that are associated with an increased risk of SAPH are listed in the table (table 4).

●Diagnostic testing – Once SAPH is suspected, it is prudent that the patient be evaluated by sarcoidosis and PH experts who can jointly devise an appropriate diagnostic strategy for each individual patient.

•Transthoracic echocardiography (TTE) – For patients in whom clinical features and initial testing support SAPH, we perform TTE (table 4). We do not perform TTE in asymptomatic patients or patients without supportive features of SAPH. (See 'Diagnostic evaluation' above and 'Transthoracic echocardiography (TTE)' above and 'Early detection of SAPH' above.)

TTE determines the probability of PH (low, intermediate, or high probability) and is interpreted in a similar fashion to that in patients with suspected non-sarcoidosis-related PH (table 5). This evaluation is discussed separately:

-(See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)

-(See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Low probability of pulmonary hypertension on echocardiography'.)

-(See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Intermediate or high probability of pulmonary hypertension on echocardiography (assess left heart)'.)

•Right heart catheterization (RHC) – The decision to proceed with RHC is similar in principle to that in patients without sarcoidosis in whom PH is suspected. These details are provided separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization'.)

However, in general, our threshold to perform RHC is lower in this population since it can distinguish precapillary (group 1, 3, and 4 PH phenotypes) from postcapillary disease (group 2 PH phenotype) (table 2 and table 1) and determine whether PH is multifactorial in nature. TTE, clinical suspicion for SAPH, and the impact of testing on the decision to implement potential future therapies determine the need for RHC. (See 'Selecting patients for right heart catheterization' above.)

In brief our approach is the following:

-In patients with a low probability of having PH on TTE, we do not generally perform RHC.

-In patients with a high probability of PH on TTE, we perform RHC unless the results would not change management.

-In patients with an intermediate probability of PH or inconclusive TTE, we assess the need for RHC on a case-by-case basis.

-In addition, select features on clinical evaluation may also prompt RHC (eg, evaluation for lung transplantation, unexplained dyspnea, assessment of the potential contribution of cardiac and pulmonary parenchymal sarcoidosis to PH).

●Diagnosis and postdiagnostic phenotyping

•Diagnosis – A definitive diagnosis of SAPH is made on RHC findings that demonstrate an elevated mean pulmonary artery pressure >20 mmHg supine and at rest. (See 'Diagnosis' above and 'Definition and classification' above.)

•Phenotyping – Identifying a dominant etiology/phenotype is important for assigning a therapeutic plan. SAPH is generally classified as group 5 PH (table 1) since the pathogenesis is often multifactorial. However, patients with sarcoidosis may also have a predominant PH class phenotype. For this assessment, we use existing data and obtain additional adjunctive testing, if needed. Additional detail is provided separately. (See 'Postdiagnostic testing and phenotyping' above and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)