Background of lung transplantation for pulmonary hypertension

Prior to the advent of pulmonary arterial hypertension (PAH)-targeted therapy, PAH was a common indication for lung transplantation. The first successful lung transplant was performed as part of a heart-lung transplant for a patient with idiopathic PAH in 1982 [1]. With increasing experience in isolated lung transplantation, it became clear that right ventricular (RV) function in patients with pre-transplant pulmonary hypertension (PH) normalizes rapidly after lung transplant [2–4]. Isolated lung transplantation, particularly bilateral lung transplantation, has thus been the procedure of choice over heart-lung transplantation for PAH, allowing better organ allocation while having similar posttransplant survival [4–9].

Lung transplantation for idiopathic PAH is associated with a 3-month mortality of 22 %, which reflects the highest immediate post-lung transplant mortality of all the major indications. However, those who survive to 1 year post-lung transplant have had a median survival of 10.1 years, which reflects the second highest posttransplant survival [10].

Consideration for lung transplant for PAH

Consideration for transplantation requires careful patient selection and timing in order to optimize survival benefit in the setting of limited organ availability and limited posttransplant survival.

The most recent international guidelines recommend referral for lung transplantation for PAH for World Health Organization functional class (WHO FC) III or IV on escalating therapy, for rapidly progressive disease, and use of parenteral PAH-targeted therapy irrespective of symptoms or WHO FC [11]. Timely referral is crucial to allow for medical optimization, such as weight loss for obese patients or physical rehabilitation for debilitated patients, and to allow for appropriate timing of transplant listing. Patients with suspicion for or diagnosis of pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis should be referred for transplantation right away since they do not typically respond to PAH-targeted therapy [12].

Generally, patients with PAH are listed for lung transplantation when they are deemed to have poor prognostic markers despite PAH-targeted therapy. International guidelines suggest listing for persistent WHO FC III or IV despite at least a 3-month trial of combination PAH-targeted therapy that includes intravenous (IV) or subcutaneous (SC) prostacyclin, declining or low (<350 m) 6-min walk distance (6-MWD), cardiac index (CI) <2 L/min/m2, mean right atrial pressure (RAP) >15 mmHg, and substantial hemoptysis, pericardial effusion, or evidence of right-sided heart failure [11].

In the USA, priority on the waitlist is dictated by the lung allocation score (LAS), which provides a measure of medical urgency for transplantation based on the patient’s predicted 1-year mortality without a transplant, balanced by the expected 1-year posttransplant mortality [13]. Since its implementation, lung transplant candidates have enjoyed reduced wait times and lower waitlist mortality. Nevertheless, patients with PAH appear to have a disproportionately lower likelihood of getting transplanted and a higher likelihood of dying while waiting for a transplant compared to the other lung transplantation indications [14–16]. This has been attributed to the LAS underestimating the medical urgency of patients with PAH compared to the other indications [17]. To address this disparity, the United Network for Organ Sharing (UNOS) can grant an LAS exemption for PAH if the patient is deteriorating while on optimal therapy and has either mean RAP >15 mmHg or CI <1.8 L/min/m2. This exception grants LAS in the 90th percentile.

Natural history and prognosis of PAH

Prior to the advent of PAH-targeted therapy, the National Institutes of Health (NIH) registry showed a median survival of idiopathic PAH of 2.8 years from the time of diagnostic right heart catheterization (10). The 1-, 3-, and 5-year survival was reported to be 68, 48, and 34 %, respectively. Since the advent of PAH-targeted therapy, reported survival has significantly improved. A REVEAL Registry survival study of a mixed PAH cohort matched to the NIH cohort reported a projected median survival of 9 years and found a 1-, 3-, and 5-year survival of 93, 78, and 70 %, respectively [18]. Other studies have shown similarly improved survival since the advent of PAH-targeted therapy [19–22]. Often, patients are diagnosed with PAH with advanced disease. A French Registry study reported that >75 % had WHO FC III or IV at diagnosis [22].

Important poor prognostic markers for PAH found in multivariate analysis of the REVEAL registry include WHO FC III or IV, low 6-MWD, high serum brain natriuretic peptide (BNP), high RAP, elevated pulmonary vascular resistance (PVR), low CI, evidence of pericardial effusion on echocardiogram, renal insufficiency, resting systolic blood pressure <110 mmHg, heart rate >92, low diffusing capacity for carbon monoxide, male sex and age >60 years, and having associated connective tissue disease or diagnosis of portopulmonary hypertension [23]. These prognostic factors were validated as a survival prediction tool, the REVEAL risk score for PAH, in a subsequent study [24]. Other reported markers of poor prognosis include low tricuspid annular plane systolic excursion (TAPSE) on echocardiogram, low pulmonary artery saturation, and low peak O2 uptake (<10.4 mL O2/kg/min) or peak systolic arterial pressure <120 mmHg on cardiopulmonary exercise testing (CPET) [25]. In addition to the one-time baseline measurements described above, follow-up assessment after initiation of PAH-targeted therapy has also been shown to inform prognosis [21]. In a single-center prospective observational study of patients with idiopathic PAH, reduced transplant-free survival was associated with 3- to 12-month follow-up assessments showing WHO FC III or IV, CI <2.5 L/min/m2, and serum NT-proBNP >1800 ng/L [21]. These prognostic markers are the basis for goal-directed treatment of PAH [25–27]. As these prognostic indicators suggest, most patients with PAH die from progressive right-sided heart failure and related complications [28, 29].

Medical management of PAH on the waiting list

Medical management has become the cornerstone of treatment for PAH and the primary tool for bridging to lung transplantation. Prior to consideration for lung transplantation for PAH, PAH-targeted therapies need to be tried and escalated. Patients listed for lung transplantation for PAH should be on maximally tolerated PAH-targeted therapy, including IV or SC prostacyclin therapy. Close outpatient follow-up with careful volume management and serial monitoring of prognostic variables with careful assessment for evidence of deterioration is crucial.

Current FDA-approved therapies for PAH target the established pathobiological pathways contributing to pulmonary vascular vasoconstriction and remodeling: impaired prostacyclin and nitric oxide signaling and excessive endothelin signaling (Table 1) [30]. To date, epoprostenol is the only PAH-targeted medication to have ever shown survival benefit in a randomized controlled trial. Subsequent drugs have been approved based on 6-MWD benefit with or without benefit in hemodynamics, symptoms, and/or time to clinical worsening. While evidence supporting sequential add-on therapy is more robust, evidence supporting the use of up-front combination therapy is lacking and is currently being studied.

Table 1 FDA approved PAH-targeted medications
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Initiation PAH-targeted therapy depends on the severity of disease dictated by prognostic markers, chiefly WHO FC, as well as markers indicating high-risk disease (Table 2) [25–27, 31]. Patients with WHO FC IV or otherwise high-risk disease warrant more aggressive PAH-targeted therapy. Guidelines recommend escalation of therapy by increasing the dosing of current therapy or adding a drug from a different class if patients are not able to achieve prognosis-associated goals on follow-up assessments (Table 2) [27, 31].

Table 2 Goals of therapy and determination of low- and high-risk PAH, per existing guidelines
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Patients with initial WHO FC IV or deteriorating to WHO FC IV while on therapy should be offered IV or SC prostacyclin therapy (Table 1). Because of the survival benefit shown in its seminal randomized controlled trial, epoprostenol is somewhat favored over IV or SC treprostinil for treatment of WHO FC IV or otherwise high-risk patients [32]. At doses two to three times that of epoprostenol, however, treprostinil is thought to be similarly effective [25]. While dosing for either drug is titrated to side effects to desired effect, most patients benefit from doses between 20–40 ng/kg/min with epoprostenol and 20–80 ng/kg/min with treprostinil. Treprostinil has the added advantage of SC infusion and a longer half-life, facilitating outpatient use. Inhaled prostacyclins (iloprost and treprostinil) and oral treprostinil are considered less efficacious and thus should be transitioned to IV or SC prostacyclin for WHO FC IV or otherwise high-risk PAH. Once a sufficient stable dose of IV or SC prostacyclin is achieved and the patient continues to be WHO FC IV or otherwise high risk, further sequential addition of an endothelin receptor antagonist (ERA) and either phosphodiesterase-5 (PDE-5) inhibitor or soluble guanylate cyclase stimulator (sGCS) can be considered. For patients who forgo IV or SC prostacyclin as an option (due to personal preference or inability to maintain its complex delivery system), an inhaled prostacyclin, ERA, and either PDE-5 inhibitor or sGCS can be offered as second-line therapy, likely requiring sequential combination between classes to maximize therapeutic effect.

It is important to note that, despite current guidelines, IV or SC prostacyclin appears to be underutilized even by centers expert at managing PAH. A study of the REVEAL Registry reported that at the time of death, only 43 % of patients with PAH were on IV or SC prostacyclin therapy [33]. Among patients assessed as WHO FC IV 6 months prior to PAH-associated death, only 59 % were on IV or SC prostacyclin therapy. While many barriers for its use exist, IV or SC prostacyclin is considered the most potent PAH-targeted therapy available. It should thus be offered to patients with severe disease, especially if lung transplantation is being entertained.

ERAs and either PDE-5 inhibitors or the sGCS riociguat are appropriate as initial therapy for patients with WHO FC II–III [31]. Their ease of use, lower cost, and better side effect profile make them favorable options compared to prostacyclin therapy for WHO FC III patients without high-risk features. Patients who remain WHO FC III or not at goal despite ERA and/or either PDE-5 inhibitor or sGCS therapy should be considered for add-on prostacyclin therapy.

Adjunctive therapies for medical management of PAH include diuretics for careful fluid management, use of supplemental oxygen to avoid hypoxemia, and evaluation and treatment of sleep disordered breathing. In order to remain acceptable for transplantation, patients need to maintain physical conditioning, have adequate nutrition, and avoid excesses in body mass index. Often, physical rehabilitation and nutrition consultations are needed. Digoxin may augment of cardiac output in PAH, though evidence is limited to one short-term study [34]. It can also potentially be helpful for rate control in atrial tachyarrhythmias [25, 26]. Evidence supporting the use of anticoagulation is limited to uncontrolled studies in idiopathic PAH. It is recommended as an adjunct for idiopathic, familial, and anorexigen-associated PAH [25, 26]. The role for anticoagulation is less clear for PAH associated with connective tissue disease and congenital heart disease since these forms of PAH confer higher risk for bleeding.

An important aspect of medical management of PAH is close follow-up to assess for response to therapy, clinical deterioration, volume status, and side effects of treatment. With follow-up, patients need to be assessed for presence of high-risk markers and whether goals of therapy are being met (Table 2), and therapy needs to be adjusted accordingly [25–27, 31]. Assessments should include serial 6-min walk tests, labs to assess BNP, renal function and liver function, and serial echocardiograms to assess right heart function and evidence of pericardial effusion. Right heart catheterization can also be used to assess response to therapy and to evaluate clinical deterioration and consideration for lung transplantation. Once listed for lung transplantation, serial follow-up and assessments can allow for updates in LAS and consideration for LAS exemption and help maintain transplantation acceptability. For patients who are at risk for a prolonged wait time, various strategies to bridge to lung transplantation can be considered.

Atrial septostomy

Atrial septostomy can be used to bridge to lung transplantation, especially for patients who are likely to have a longer wait time. By creating an inter-atrial right-to-left shunt, this procedure unloads the right heart, improving hemodynamics and cardiac output at the cost of reduced arterial oxygen saturation (SaO2) from the shunting [35]. Despite this trade-off, there is a net improvement in oxygen delivery with associated improvement in WHO FC. In a series of 34 patients, 94 % of whom were WHO FC III or IV, atrial septostomy was associated with a median survival of 60 months as well as improved WHO FC, CI, and 6-MWD [36]. It has also been used to facilitate upper body cannulation for veno-venous extracorporeal membrane oxygenation (ECMO) with the reinfusion flow directed through the atrial septostomy into the left atrium [37]. Despite these potential benefits, atrial septostomy is considered a high-risk procedure with a significant learning curve, and it is done uncommonly. It is associated with a 1-month mortality of up to 15 %, though this may reflect the large number of patients undergoing this procedure as a rescue therapy in the setting of decompensated right-sided heart failure [35]. Careful selection of patients is thus warranted. Contraindications include mean RAP >20 mmHg, resting room air SaO2 <90 %, and high left-sided filling pressures.

Management of decompensated right-sided heart failure in PAH

Patients with PAH awaiting lung transplantation are at high risk for potentially devastating deterioration from decompensated right-sided heart failure. Reported in-hospital mortality for decompensated right-sided heart failure from PAH has ranged from 14 to 32 % [38, 39]. Such patients are often critically ill requiring intensive care unit management, at risk for multiorgan dysfunction related to obstructive or mixed shock. Two series reported in-hospital mortality of 41 and 46 % when catecholamine support is needed for decompensated right-sided heart failure from PAH [38, 40].

Infection and sepsis appears to commonly precipitate decompensated right-sided heart failure in PAH. In two series, about 25 % of cases were attributed to infection, which was in turn associated with high ICU mortality [39, 40]. It is thought that right-sided heart failure in PAH leads to reduced perfusion pressure in the gastrointestinal tract, predisposing PAH patients to intestinal bacterial translocation resulting in infection and sepsis [41, 42]. Thus, high clinical suspicion for and timely treatment of infection and sepsis are important in the management of decompensated right-sided heart failure in PAH.

Arrhythmias present another important cause of decompensated right-sided heart failure in PAH. A 6-year retrospective study of 231 patients with PAH showed an annual incidence of supraventricular tachyarrhythmias of 2.8 % per patient with a 6-year cumulative incidence of 11.7 % [43]. The arrhythmias mostly consisted of atrial flutter and atrial fibrillation (84 % of supraventricular tachycardias) and were associated with clinical deterioration and decompensated right-sided heart failure. Sustained atrial fibrillation was associated with over 80 % 1-year mortality, compared to 6 % if sinus rhythm was restored. As such, when patients with right-sided heart failure due to PAH develop a supraventricular tachycardia, cardioversion and maintenance of sinus rhythm are recommended [25, 26]. The use of a beta-blocker or calcium channel blocker may exacerbate right-sided heart failure and thus should be avoided in the decompensated patient. Digoxin may help with rate control. Notably, ventricular tachycardia and ventricular fibrillation are rare dysrhythmias in PAH and associated right-sided heart failure, contributing to 8 % of initial rhythms for cardiac arrest in PAH in one series [44].

Other physiologic stressors, such as pregnancy, trauma, surgery, and general anesthesia can contribute to decompensation. Surgeries, general anesthesia, and even moderate sedation need to be considered carefully and avoided if possible. If needed, they should be done at experienced PAH centers.

When decompensated, patients are typically fluid overloaded. They usually require negative fluid balance with diuretic therapy or renal replacement therapy with hemofiltration. Fluid unloading may improve RV function and overall hemodynamics. Excessive fluid removal however may contribute to hypotension and shock, especially if there is concomitant sepsis.

Optimization of pulmonary vasodilator therapy is needed for decompensated right-sided heart failure due to PAH. Aggressive initiation and uptitration of IV or SC prostacyclin is indicated, as previously discussed. Patients with decompensated PAH while on an inhaled prostacyclin should be considered for transition to IV or SC prostacyclin. Initiation and aggressive uptitration of IV or SC prostacyclin therapy may be limited by hypotension in decompensated patients. Catecholamine support has been used to hemodynamically support prostacyclin uptitration, though supporting evidence is limited [45]. Initiation of an ERA or either a PDE-5 inhibitor or the sGCS riociguat in the setting of decompensated right-sided heart failure has not been studied, but it may be considered as add-on therapy for patients on a stable regimen of parenteral prostacyclin therapy. Initiation of PDE-5 inhibitors or the sGCS riociguat during decompensated right-sided heart failure may exacerbate hypotension and should be done with caution. Rescue therapy with inhaled nitric oxide or inhaled iloprost should be considered.

Inotropic and vasopressor therapies are often needed in decompensated right-sided heart failure due to PAH. Unfortunately, the guiding evidence for which agents to use is limited. Dobutamine infusion has been associated with improved RV function and may augment pulmonary vasodilation and thus improve right ventricular-pulmonary arterial (RV-PA) coupling [46]. However, its chronotropic effects may worsen hemodynamics and induce supraventricular tachycardia, and at higher doses, beta-2 effects may further drop blood pressure. IV milrinone, a PDE-3 inhibitor, has similar inotropic and pulmonary vasodilatory effects as dobutamine but with less chronotropic effects. It thus serves as a reasonable alternative to dobutamine [47]. Nevertheless, milrinone also has systemic vasodilatory effects and can worsen hypotension when given intravenously. Successful use of inhaled milrinone as rescue therapy has been reported in a limited number of cases of decompensated PAH [48]. This formulation is thought to allow for inotropic and pulmonary vasodilatory effects without significant systemic vasodilation. Norepinephrine has some inotropic and chronotropic effects but acts more potently as a peripheral vasoconstrictor. While it has been found in preclinical studies to increase mean pulmonary artery pressure (PAP) and PVR at higher doses, it may be useful in decompensated PAH to improve cardiac output, improve coronary perfusion pressure, and manage concomitant distributive shock [49, 50]. Dopamine also has inotropic and chronotropic effects but with less peripheral vasoconstrictive effects compared to norepinephrine. It may reduce or have neutral effects on PVR [51, 52]. It is also associated with higher rates of tachycardia and tachyarrhythmias compared to norepinephrine, which may limit its use [53]. The use of epinephrine in PAH is not well reported, but it has potent inotropic and chronotropic effects and increases systemic vascular resistance at higher doses. Animal studies suggest a neutral if not favorable effect on PVR, possibly better than that of dopamine [54–56]. It however is also associated with higher rates of tachyarrhythmias, myocardial ischemia, and mesenteric ischemia, limiting its use. Vasopressin has been found to improve pulmonary vascular resistance while constricting systemic vessels with typical doses. As such, it is considered a preferred vasopressor in PAH [57–60]. In contrast, phenylephrine tends to increase mean PAP, PVR, and reduce cardiac output and probably should be avoided in decompensated PAH [61].

Avoiding hypoxemia and hypercapnea is important to prevent further pulmonary vasoconstriction [57]. Unfortunately, severe PAH predisposes to hypoxemia by reducing the mixed venous oxygen content due to reduced cardiac output and by increasing any chance for right-to-left shunt through a patent foramen ovale or other right to left shunt. Further, the increased dead space ventilation seen in PAH can increase the propensity for hypercapnea, which can in turn exacerbate PVR. These respiratory derangements may lead to a need for mechanical ventilator support. The use of mechanical ventilation, however, can further increase PVR and contribute to decompensated right-sided heart failure. It is associated with high in-hospital mortality [38]. As such positive pressure ventilation should be avoided as much as possible. Additionally, the potential need for sedation and/or analgesia with intubation and ventilatory support places the patient at risk for further decompensation and death. Nevertheless, if intubation and mechanical ventilation are needed, we recommend minimal use of sedation and analgesia and preferred use of etomidate or ketamine as an induction agent if needed with concomitant catecholamine support to reduce the risk of further decompensation. Lower positive end-expiratory pressure and tidal volumes are preferred to minimize effects on PVR. An important consideration is that complications of mechanical ventilator use, such as ventilator associated pneumonia, sepsis, and multiorgan failure, may preclude transplant listing. Additionally, bridging to lung transplant with mechanical ventilation is associated with worse posttransplant outcomes. As a result, prolonged need for endotracheal intubation and mechanical ventilation is considered a contraindication for lung transplantation.

Critically ill decompensated PAH patients should be assessed for continued acceptability for active listing. Often, patients with multiorgan dysfunction or suspected infection are considered poor transplant candidates and warrant inactivation from the waitlist. In select cases, however, bridging to lung transplantation via extracorporeal life support may be considered.

Extracorporeal life support

For select patients who are otherwise moribund in decompensated right-sided heart failure, ECLS offers both circulatory and oxygenation support while awaiting lung transplantation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is the modality of choice for patients with PAH and right-sided heart failure [62, 63]. VA-ECMO involves a large bore cannula draining the central venous circulation. Blood is then pumped through an oxygenator and returned to the arterial circulation. This modality can provide complete circulatory support and allows for decompression of the RV, normalization of RV function, and reversal of the sequelae of right-sided heart failure. Its application in awake patients can obviate the need for mechanical ventilator support and thus avoid complications related to prolonged mechanical ventilation that may otherwise preclude active transplant listing [64]. Unfortunately, the traditional VA-ECMO involves femoral cannulation, which limits lower extremity movement due to the risk of cannula dislodgment. This then precludes ambulation and adequate physical conditioning while awaiting transplantation. The resulting physical debilitation itself may result in inactivation from the waitlist. In order to facilitate adequate physical conditioning required for continued active transplant listing, upper body cannulation ECMO strategies have been used for PAH. These include internal jugular venous to subclavian arterial cannulation, pulmonary arterial to left atrial cannulation (requiring a median sternotomy), and right internal jugular dual-lumen veno-venous cannula with the output jet directed through a preexisting intra-atrial defect or a septostomy [37, 64–67].

The use of ECMO is fraught with a high rate of complications, more commonly bleeding and infection and less commonly thromboses, hemolysis, limb ischemia, and systemic inflammatory response [62, 63]. It requires the use of anticoagulation, though newer systems require lower activated prothrombin time goals. More relevant to its use to bridge to transplantation, ECMO is associated with developing new human leukocyte antigen (HLA) allo-antibodies, which can potentially preclude consideration of various donors and thus delay transplantation [68]. The etiology of this allo-sensitization is unclear, but the more frequent transfusions attributed to ECMO may be an important culprit. Regardless, patients awaiting lung transplantation on ECMO may require more frequent monitoring for HLA allo-sensitization.

Historically, the use of ECMO to bridge to lung transplantation for all indications conferred a poor 1-year survival. This survival was particularly low during the early experience of ECMO to bridge to lung transplant with 25 % 1-year survival from 2000 to 2002 [69]. But over time, posttransplant survival improved with reported 1-year survival from 2009 to 2011 of 74 %, matching the approximately 70 % 1-year survival for patients bridged to transplant with mechanical ventilation in 2009–2010 [69, 70]. This dramatic improvement in outcomes is in part attributable to improved ECMO technology with development of the centrifugal pump, heparin-coated circuits, and lower-resistance polymethylpentene oxy-genators [70]. Improved patient selection for and timing of initiation of ECMO likely also contributed to posttransplant outcomes. While prolonged ECMO use prior to transplant has been reported, duration on ECMO while awaiting lung transplantation is associated with worse posttransplant outcomes [71]. Further, higher-volume lung transplant centers have better posttransplant survival for patients bridged with ECMO [70]. Using ECMO semi-electively to avoid endotracheal intubation and mechanical ventilation in the otherwise awake patient may further improve outcomes, particularly for patients with PAH for whom mechanical ventilation is associated with exceedingly high mortality. In one small retrospective study, this strategy of bridging with ECMO to avoid endotracheal intubation and mechanical ventilation has been associated with a 6-month posttransplant survival of 80 % compared to 50 % for the historical control of patients bridged with mechanical ventilator support [64]. While not yet studied, using upper body cannulation techniques to allow for ambulation and aggressive physical conditioning may further improve posttransplant outcomes.

In addition to ECMO, a pumpless ECLS system, designated as the NovaLung lung assist device, has been used to successfully bridge patients with decompensated PAH to lung transplantation [72, 73]. This system uses low-impedance oxy-genators bypassing the diseased pulmonary vasculature to decompress the right heart. It depends on the right heart to drive blood flow through the device. For its application in decompensated PAH, a cannula drains the main PA and another returns oxygenated blood to the left atrium, unloading the right heart. The limited use of this still-experimental device required initial stabilization with femoral VA-ECMO support prior to transition to NovaLung with catheter insertion performed via median sternotomy. While still being studied, such low-impedance lung assist devices may provide an important tool to bridge otherwise moribund PAH patients to lung transplantation.

Despite the improved posttransplant outcomes for patients bridged with ECLS, its use continues to be controversial. Pre-transplant ECLS is certainly resource intensive with associated significant pre- and posttransplant morbidity and mortality. Given worse posttransplant outcomes, ECLS bridging puts into question the appropriateness of allocating organs to these patients compared to those not needing such intensive pre-transplant support who usually have better posttransplant outcomes. Nevertheless, the contemporary experience and further advancements in ECLS appear to result in acceptable outcomes. It needs to be emphasized however that these outcomes are seen in centers experienced in ECLS and lung transplantation. As such, the use of ECLS as a bridge to lung transplantation for PAH should be considered carefully for select patients at experienced lung transplant centers.

PH associated with lung disease

While most of our discussion has been focused on PAH, PH frequently complicates the spectrum of parenchymal lung diseases for which lung transplantation may be considered [74]. Among patients listed for lung transplantation, PH has been reported to affect 46 % of patients with idiopathic pulmonary fibrosis, 74 % of patients with sarcoidosis, 92 % of pulmonary Langerhans cell histiocytosis, 50 % of patients with chronic obstructive pulmonary disease (COPD). Patients with comorbid PH and parenchymal lung disease consistently face substantially worse functional impairment and higher mortality compared to otherwise similar patients without PH [74–82].

With the advent of PAH-targeted therapy, it is easy to imagine that PH may be a treatable dimension of their disease and improve their transplantation window. Nevertheless, while several small retrospective studies suggest hemodynamic and functional benefit, it is unclear whether PAH-targeted therapy changes outcomes. Further, PAH-targeted therapy may result in harm in this population by possibly worsening ventilation-perfusion mismatch and pulmonary shunting by nonspecific vasodilation of a poorly ventilated lung [75]. In light of the limited data for benefit and potential for harm, the role of PAH-targeted therapy in treatment of PH in parenchymal lung disease needs to be further studied.

In the meantime, patients need to be assessed individually for potential benefit with PAH-targeted therapy. In the setting of uncertainty of PAH-targeted therapy in this population, patients should be referred to a center expert at management of PH and lung disease. As much as reasonable, patients being considered for therapy should be enrolled in a clinical study if not a randomized controlled trial. Certainly avoiding hypoxemia continues to be an important part of treatment of PH in parenchymal lung disease.

Given the potential for multiple drivers of morbidity and mortality for patients with comorbid PH and parenchymal lung disease, severe PH (mean PAP >35 mmHg) with RV dysfunction and evidence of circulatory limitation with CPET may identify patients who may best benefit from PAH-targeted therapy. According to the Fifth World Symposium on Pulmonary Hypertension recommendations, consideration for PAH-targeted therapy should be limited to those with severe PH [75]. We typically consider PAH-targeted therapy for patients with severe PH with evidence of right heart dysfunction on echocardiogram without evidence of WHO group 2 or 4 PH. Such patients represent a small minority with most lung diseases, though they are overrepresented in others. For instance, only 9 % of patients with IPF listed for lung transplantation were found to have mean PAP >40 mmHg [74]. Between 4 and 14 % of patients with COPD referred for lung transplantation were found to have mean PAP >35 mmHg [74]. In contrast, 68 % of the reported half of patients with comorbid PH and CPFE were reported to have mean PAP >35 mmHg, and nearly half of patients with pulmonary Langerhans cell histiocytosis have mean PAP >45 mmHg [83]. In patients with mild-to-moderate lung disease but severe PH, the possibility of coincident WHO group 1 PAH needs to be entertained. In such cases, the rationale for PAH-targeted therapy may be stronger. Overall, we feel that the use of a comprehensive hemodynamic and cardiopulmonary exercise evaluation in addition to accurate characterization of the parenchymal lung disease can better stratify and phenotype PH in parenchymal lung disease. This may then allow us to identify patients whose disease course is driven more by PH than their parenchymal lung disease and thus may benefit from PAH-targeted therapy.

Conclusion

For patients with PAH being considered for or awaiting lung transplantation, management of PAH to maintain transplantation acceptability is crucial. Patients should be offered optimal PAH-targeted therapy with at least IV or SC prostacyclin therapy in combination with an ERA and either a PDE-5 inhibitor or the sGCS riociguat. Adjunctive therapies should be considered, including careful fluid balance, anticoagulation for idiopathic, familial or anorexigen-associated PAH, and consideration for digoxin which may also benefit patients who have paroxysmal atrial tachyarrhythmias. Atrial septostomy may be an important adjunct for select patients at experienced centers, especially for patients who are at risk for a long waitlist time. Management of decompensated right-sided heart failure in PAH is particularly challenging, often requiring judicious fluid management, aggressive treatment of precipitating causes, such as infection or arrhythmias, and use of inotropes and vasopressors. The use of mechanical ventilator support in decompensated PAH confers exceedingly high mortality. For patients deemed appropriate, ECLS may be a better bridge to lung transplantation. Management of PH associated with lung disease continues to be controversial with limited data supporting the use of PAH-targeted therapy for this purpose. Nevertheless, there may be a more specific phenotype of patients, specifically those with severe PH with evidence of right heart dysfunction and circulatory limitation, who may benefit more from PAH-specific therapy. Such a benefit may improve the window for lung transplantation or offer palliation for those who may not be candidates. In all, the expanding understanding of PAH and its treatment has afforded improved management of patients with PAH awaiting lung transplantation. This improved PAH management has likely contributed to the overall reduced waitlist mortality despite higher disease acuity [15, 16].