Biol Blood Marrow Transplant 19 (2013) 1546e1556

American Society for BloodASBMTand Marrow Transplantation

Review

Pulmonary Hypertension after Hematopoietic Stem CellTransplantation

Christopher E. Dandoy 1,*, Russel Hirsch 2, Ranjit Chima 3, Stella M. Davies 1,Sonata Jodele 1

1Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio2Division of Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio3Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

Article history:

Received 3 July 2013Accepted 16 July 2013

Key Words:Pulmonary hypertensionPulmonary arterialhypertensionPulmonary veno-occlusivediseaseThrombotic microangiopathy

Financial disclosure: See Acknowl* Correspondence and reprint

Division of Bone Marrow TransplChildren’s Hospital Medical Centecinnati, OH 45229.

E-mail address: christopher.dan

1083-8791/$ e see front matter �http://dx.doi.org/10.1016/j.bbmt.20

a b s t r a c tPulmonary hypertension (PH) is a potentially fatal complication of hematopoietic stem cell transplantation(HSCT). Given its nonspecific clinical presentation, it is likely that this clinical entity is underdiagnosed afterHSCT. Data describing the incidence, risk factors, and etiology of PH in HSCT recipients are minimal. Physi-cians caring for HSCT recipients should be aware of this severe post-transplant complication because timelydiagnosis and treatment may allow improved clinical outcomes. We summarize the pathophysiology, clinicalpresentation, diagnosis, and management of PH in HSCT recipients.

� 2013 American Society for Blood and Marrow Transplantation.

INTRODUCTIONPulmonary hypertension (PH) is an uncommon and po-

tentially fatal condition associated with increased pulmo-nary vascular resistance and elevated right ventricularpressure. Elevated pulmonary arterial pressures can lead topermanent changes in the pulmonary vasculature, rightventricular failure, and death. The incidence of PH inhematopoietic stem cell transplantation (HSCT) recipients isunknown. The initial symptoms of PH are nonspecific, anddiagnosis can be challenging in this complex population. Themost commonly reported types of PH in HSCT recipientsare pulmonary arterial hypertension (PAH) and pulmonaryveno-occlusive disease (PVOD), depending on the location ofvascular injury. There are no uniform clinical managementstrategies given the paucity of data describing PH in HSCTrecipients. In this review, we summarize the pathophysi-ology, clinical presentation, available diagnostic tools, andclinical interventions for HSCT recipients with PH.

PH AND HSCTThe first account of PH as a complication of HSCT was

published in 1984 by Troussard et al. [1], who reportedautopsy findings consistent with PH in a 12-year-old boywho underwent HSCT for acute lymphoblastic leukemia.Including the report from Troussard et al., PH in HSCTrecipients has been described in 40 patients and reported in16 single patient case reports and 7 case series of 2 to8 patients [1-23]. This paucity of data provides little insightinto the etiology, incidence, and risk factors for PH after HSCT

edgments on page 1554.requests: Christopher E. Dandoy, MD,ant and Immune Deficiency, Cincinnatir, 3333 Burnet Avenue, MLC 7015, Cin-

doy@cchmc.org (C.E. Dandoy).

2013 American Society for Blood and Marrow13.07.017

but offers opportunity for further investigation and devel-opment of screening strategies and treatment approaches.

In reported cases, 55% of patients had underlying diag-nosis of malignancy, 15% immunodeficiencies, and 30% ge-netic disorders or marrow failure syndromes. PH is describedas occurring after myeloablative regimens (73%) as well asreduced-intensity regimens. PH has been reported in bothchildren and adults, with a median age at transplant of12.6 years (range, 1 month to 51 years), although mostreports describe children [1-23]. This may indicate reportingbias, because PH is very infrequent in children, perhapsmaking authors more likely to report the finding.

All patients who developed PH presented with new-onset respiratory symptoms such as tachypnea, hypoxia,and respiratory distress, and these symptoms occurreda median of 70 days after transplant (range, 0 to 365). In the40 patients reported in the literature, overall mortality was55% (22 of 40), with 86% (19/22) of deaths attributed to PHand 14% (3 of 22) to relapse of the primary malignancy[1-23]. Patients had variable pulmonary vasculatureinvolvement. Most patients (28 of 40, 70%) were diagnosedwith PAH involving the pulmonary arterioles only, withdocumented pulmonary arteriolar injury on the tissuespecimens and/or increased arterial vascular resistancemeasured by cardiac catheterization [3,7,10,11,13,14,17,18,21-23].Nine patients (23%) were reported to have PVOD, withpulmonary venule involvement and vascular congestiononly [1,2,4,5,8,12,16,19,20]. Two patients (5%) were diag-nosed as having mixed arteriolar-venous pathology, and,finally, 1 patient had no documentation of the vascularcomponent involved [2,6].

Underlying endothelial injury can clearly occur both on thepre- and postpulmonary capillary vasculature. However,further investigation is required to understand themechanismof endothelial damage. Patients received a variety of therapiesfor PH, including steroids, anticoagulants, prostacyclines,

Transplantation.

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inhalednitric oxide (iNO), defibrotide, andphosphodiesterase-5 inhibitors (sildenafil), limiting any conclusions about theeffectiveness of clinical interventions [1-23]. Data indicate thatboth pediatric and adult patients undergoing HSCT are at riskofdevelopingPH, andPHshouldbeconsidered inpatientswhodevelop cardiorespiratory symptoms after transplantation.

Seven case series describing PH after HSCT are summa-rized in Table 1. The exact incidence of PH in HSCT populationremains unknown due to a lack of prospective studies;however, the prevalence of PH was reported in a few retro-spective reports. Schechter et al. [23] performed a retro-spective analysis of all pediatric patients who underwentserial autologous transplantation for central nervous systemtumors between 2001 and 2010. They found PH in 3 of 20patients (15%), with 2 dying from progressive respiratorydisease. Steward et al. [11] described PH occurring in 8 of 29pediatric patients (28%) with malignant infantile osteopet-rosis over a 6-year period of time, suggesting a possibleparticular susceptibility in children with that diagnosis. Fiveof the 8 children (62%) with osteopetrosis died from respi-ratory disease. In a recent pediatric series, Jodele et al. [22]reported a prevalence of PH of 2.4% (5 of 209), with 80%PH-associated mortality. In this report, all patients whodeveloped PH were also diagnosed with transplant-associated thrombotic microangiopathy (TA-TMA), suggest-ing that endothelial damage due to TA-TMA may play a rolein the pathogenesis of PH.

Pulmonary complications after HSCT are common andcaused by various etiologies, so PH can be overlooked [24].PH should be considered in patients who develop respiratorysymptoms after HSCT. Prospective studies are needed todetermine the incidence of PH as well as associated riskfactors and to allow for targeted screening of high-risk cases.Further research to determine the underlying cause andmechanism of endothelial injury in PH will help identifyfuture therapies and prevention strategies.

HEMODYNAMICS OF PHThe main function of the right ventricle is to deliver

venous blood to the pulmonary vasculature for oxygenexchange. The right ventricle is sensitive to increased after-load, mainly determined by pulmonary vascular resistance.Excessive and prolonged increase of afterload due to PHimpairs right ventricular filling and contractility [25]. Overtime, continued pressure overload cannot be sustained bythe right ventricle, which leads to decreased elasticity andimpaired contractility. Patients may experience repeatedacute right-sided heart decompensation and eventuallyglobal cardiac dysfunction and death [26].

A mean pulmonary artery pressure of 8 to 20 mm Hg isconsidered normal, and PH is defined as a mean pulmonaryartery pressure >25 mm Hg at rest [27]. Elevation ofpulmonary artery pressure can be caused by primary PAH,left-sided heart disease, lung disease, and thromboembolicdisease [28]. Table 2 reviews the various hemodynamicdefinitions of PH that can assist in the diagnosis and under-lying etiology.

CLASSIFICATIONIn 2008, the 4th World Symposium of Pulmonary

Hypertension created consensus general guidelines anda classification of PH, dividing PH into 5 large subtypes[29,30]: PAH, PH from left-sided heart disease, PH due tolung disease, chronic thromboembolic PH, and PH withunclear multifactorial mechanisms (Table 3). The reported

cases of PH after HSCT have been classified as PAH, PVOD,and PVOD with pulmonary arterial involvement. In general,PH after HSCT that is not a consequence of heart disease fallsinto the first category of this classification. The underlyingdiagnoses for which transplant is performed, for example,myeloproliferative disorders, as well as potential complica-tions from HSCT, such as heart disease and thromboembo-lism, can give rise to PH of various classifications. In general,PH occurring in older persons as a consequence of theseknown etiologies is not reported in the HSCT literature,weighting the literature toward younger persons with directvascular injury specific to HSCT, which is the major focus ofthis review.

Pulmonary Arterial HypertensionPAH is defined by a progressive increase of pulmonary

arterial vascular resistance leading to right ventricular failureand premature death. Histopathologically, PAH is character-ized by vascular proliferation and remodeling of all 3 levels ofthe vessel wall, with proliferative and obstructive changesincluding endothelial, smooth muscle cells, and fibroblasts[31]. Pulmonary vasoconstriction is a significant earlycomponent in PAH. Early in the disease, PAH might beasymptomatic or may present with very nonspecific symp-toms such as exertional dyspnea and fatigue, making earlydiagnosis in HSCT patients very challenging. If untreated,PAH results in a progressive increase in mean pulmonaryartery pressure and pulmonary vascular resistance, leadingto right ventricular failure and death [32].

PAH evolves after a trigger, causing pulmonary arterioleintimal damage later and resulting in hypertrophy throughsmooth muscle proliferation and fibroblast infiltration. Thetrigger may also result from an increase in intravascular wallstress and presumed intimal damage [33].

PAH has been reported in nearly all forms of inherited andacquired hemolytic anemias as well as in patients with TA-TMA [4,15,22,34]. In sickle cell and paroxysmal nocturnalhemoglobinuria, the NO pathway is shown to be involved inPH, as decreased synthesis or consumption of NOmay lead toincreased vasoconstriction [32,35]. PH has also been shownto develop in patients with HSCT-associated-TMA. TA-TMAoccurs when endothelial injury, in the context of HSCT,causes microangiopathic hemolytic anemia and plateletconsumption, resulting in thrombosis and fibrin depositionin the microcirculation and end-organ injury [36,37]. Thekidney is most commonly affected, but untreated TA-TMAmay evolve into multivisceral disease that also affects thelungs, with associated PAH.

Pulmonary Veno-Occlusive DiseasePVOD is an uncommon entity, with an incidence of .1 to

.2 cases per million and was first termed in 1966 as anobstructive disease of the pulmonary veins [38]. PVOD affectsthe pulmonary venules, with some reports mentioningarteriolar involvement. In the general consensus guidelines,PVOD is listed as a distinct category under PAH [29]. Theclinical presentation of PAH and PVOD are the same, andgenetic abnormalities in the bone morphogenetic proteinreceptor type II (BMPR2) defect has been found in both typesof PH [39]. Simonneau et al. [40] proposed that both PVODand PAH may be a different aspect of the same disease andnoted that it is not possible to differentiate PVOD fromPAHbyclinical symptoms alone nor by cardiac catheterization. Ulti-mately, the diagnosis of PVOD or PAH can only be made bylung biopsy to determine the exact vascular compartment

Table 1Reported Case Series (2 or more cases) of Patients Who Developed PH after HSCT

Reference Age atTransplantation

Sex Diagnosis ConditioningRegimen

HSCTType

PHClassification

Diagnosis of PH Symptoms Diagnosis Modality Treatment Outcome

Hackmanet al. [2]

4 yr F ALL MA MRD � 2 PVOD, arterialinvolvement

Day þ46 ofsecond SCT

Dyspnea Biopsy Methylprednisolone Died from relapseddisease

4 yr M ALL MA MRD PVOD Day þ60 Dyspnea ECHO, Cath Methylprednisolone Alive at day þ230Steward

et al. [11]3.5 mo M MIO MA MRD PAH Day þ8 Tachypnea, hypoxia ECHO Defibrotide Died of PH1 mo M MIO MA MMRD PAH Day þ20 Tachypnea, hypoxia ECHO iNO, epoprostenol, nicardipine Died of PH2 mo F MIO MA MRD PAH Day þ48 Tachypnea, hypoxia ECHO iNO, defibrotide, epoprostenol Alive at 25 mo1.5 mo F MIO MA MMRD PAH Day þ49 Tachypnea, hypoxia Cath iNO, surfactant, epoprostenol Died of PH3 mo F MIO MA MUD PAH Day þ53 Tachypnea, hypoxia ECHO iNO, epoprostenol Alive at 31 mo1 mo F MIO MA MMRD PAH Day þ65 Tachypnea, hypoxia ECHO iNO Died of PH8 mo M MIO MA MMRD PAH Day þ60 Tachypnea, hypoxia ECHO, Cath Defibrotide, epoprostenol Alive 3 mo later8 mo M MIO MA MMRD PAH Day þ96 Tachypnea, hypoxia ECHO, autopsy iNO, defibrotide,

methylprednisoloneDied of PH

Limsuwanet al. [14]

15 yr M ALL MA MRD PAH 8 mo Dyspnea, hypoxia, syncope CT, ECHO, Cath, biopsy Iloprost, sildenafil, beraprost Alive at 12 mo16 yr F CML MA MUD PAH 4 mo Dyspnea, edema CT scan, CXR, ECHO, Cath Beraprost, sildenafil Alive at 6 mo

Limsuwanet al. [18]

19 yr M ALL MA NR PAH 8 mo Syncope, desaturations ECHO, Cath, biopsy Iloprost, sildenafil, beraprost Alive at 48 mo20 yr F CML MA MUD PAH 4 mo Dyspnea, edema CT, ECHO, Cath Sildenafil, beraprost Alive at 30 mo7 mo F HLH RIC MMUD PAH 9 mo Respiratory distress,

respiratory failureCT, autopsy None Died, PH found on

autopsyZeilhofer

et al. [21]4 mo F HLH RIC MMUD PAH 4 mo Respiratory distress, hypoxia ECHO, autopsy iNO Died of PH1.8 yr M XLP RIC MMUD PAH Day þ169 Respiratory distress,

respiratory failureECHO, autopsy iNO Died of PH

Jodeleet al. [22]

5.8 yr F FA MA MUD PAH Day þ79 Hypoxia, respiratory failure ECHO, Cath iNO, atrial septostomy Died of PH6 mo M HLH RIC MMUD PAH Day þ208 Hypoxia, respiratory failure ECHO, autopsy iNO Died of PH1.8 yr M XLP RIC MRD PAH Day þ71 Hypoxia, respiratory failure Autopsy iNO Died of PH10.4 yr F CML MA MUD PAH Day þ250 Hypoxia, respiratory failure ECHO, biopsy Sildenafil Alive3 mo M ATRT MA SAT PAH Day þ7 of

second SCTTachypnea, hypoxia ECHO, biopsy None Died of disease

progressionSchechter

et al. [23]4 mo F ATRT MA SAT PAH Day þ5 of 3rd SCT Respiratory failure ECHO, biopsy iNO, steroids Died of PH32 mo M Medulo MA SAT PAH Day 0 of 3rd SCT Hypoxia, respiratory distress ECHO, biopsy iNO Died of PH

ALL indicates acute lymphoblastic leukemia; ATRT, atypical teratoid rhabdoid tumor; Cath, cardiac catheterization; CML, chronic myeloid leukemia; CXR, chest x-ray; ECHO, echocardiography; HLH, hemophagocytic lym-phohistiocytosis; MA, myeloablative regimen; Medulo, medulloblastoma; MIO, malignant infantile osteopetrosis; MMRD, mismatched related donor; MRD, matched related donor; MMUD, mismatched unrelated donor; MUD,matched unrelated donor; NR, not reported; RIC, reduced-intensity conditioning; SAT, sequential autologous transplant; XLP, X-linked lymphoproliferative disorder.

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Table 2Hemodynamic Definitions of PH

Definition Characteristics Clinical Groups of PH

Precapillary PH Mean pulmonary arterypressure >25 mm Hgand decreased capillarywedge pressure

� PAH� PH to lung disease� Chronic

thromboembolic PH� PH with unclear and

or multifactorialmechanisms

Postcapillary PH Mean pulmonary arterypressure >25 mm Hgand increased capillarywedge pressure

� Left-sided heartdisease PH

PH is defined as a mean pulmonary artery pressure >25 mm Hg. PHsecondary to left-sided heart disease will have increased capillary wedgepressures in comparison with all other clinical groups of PH. Adapted fromBossone et al. [28].

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injured. Clinically, differentiation of the 2 entities (PAH andPVOD) is likely not key, because treatment is similar. One-year mortality reported in the literature in patients withPVOD is as high as 70% [41].

PH from Left-Sided Heart DiseasePH caused by left-sided heart disease may occur in some

patients, especially those with left-sided heart dysfunctionbefore transplantation [42]. Congestive heart failure maydevelop from any or a combination of cardiotoxic medica-tions, mitral or aortic stenosis, coronary artery disease, orinfectious myocarditis [29]. This type of PH occurs because ofan increase in left atrial pressure with pulmonary venouscongestion, which creates a passive increase in pulmonaryarterial pressure. It is important that patients with suspectedPH have a comprehensive cardiac assessment.

PH Due to Hypoxia and Interstitial Lung DiseasePatients undergoing HSCT are at risk of developing

interstitial pneumonitis, bronchiolitis obliterans, bronchio-litis obliterans with organizing pneumonia, diffuse alveolardamage, and lymphocytic interstitial pneumonia, amongothers [43]. Development of PH has been associated withbronchiolitis obliterans in lung transplant patients [44].

Table 3Updated Clinical Classification of PH

Classification

1. PAH� Idiopathic PAH� Heritable� Drug and toxin induced� Associated with chronic hemolytic anemia� PVOD2. PH due to left-sided heart disease� Systolic dysfunction� Diastolic dysfunction� Valvular disease3. PH due to lung diseases and/or hypoxia� Chronic obstructive pulmonary disease� Interstitial lung disease� Pulmonary diseases with mixed restrictive and obstructive pattern� Sleep-disordered breathing� Alveolar hypoventilation disorders4. Chronic thromboembolic PH5. PH with unclear multifactorial mechanisms� Hematological disorders: myeloproliferative disorders, splenectomy� Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis,

vasculitis� Metabolic disorders: glycogen storage disease, Gaucher disease

Consensus general classifications taken from the 4th World Symposium of Pulmon

Long-term hypoxemia can lead to vascular remodeling andangiogenesis, which in turn leads to increased vessel wallproliferation and increased vascular resistance [45].

PH Due to Miscellaneous CausesType 5 PH encompasses disorders with multifactorial

mechanisms, each of which alone are rare but significant,because these patients may present for HSCT and may havePH before the transplantation starts. Patients with myelo-proliferative disorders and those who have undergonesplenectomy have a higher incidence of PH, althougha mechanism for this has not been reported [46,47]. Patientswith systemic disorders such as Langerhans cell histiocytosisand sarcoidosis are at high risk of developing PH secondaryto chronic inflammation and destruction of the vascular bed[48,49]. Patients with underlyingmetabolic disorders such asGaucher disease are at risk of developing PH secondary toglycolipid-laden macrophages infiltrating pulmonary capil-laries and causing intimal fibrosis [50].

Steward et al. [11] described PH in 29% of pediatricpatients (8 of 28) who underwent HSCT for malignantinfantile osteopetrosis. Their report identified 6 patients(75%) who required assisted ventilation and 5 patients (62%)who died from respiratory complications. The underlyingetiology of PH in patients with osteopetrosis is not known,but PH should be strongly considered in the differentialdiagnosis of respiratory distress in children with osteopet-rosis after HSCT.

PATHOLOGICAL FINDINGS IN PH AFTER HSCTPH after HSCT has been described as affecting both

pulmonary arterioles and venules [6,13,22,51,52]. Histo-pathological changes found in PAH affect all vascular layers ofarterioles, including proliferation of the smooth muscle cells,intimal proliferation, medial hypertrophy, fibrotic changes,adventitial thickening, and perivascular inflammatory infil-trates (Figure 1A) [29,53,54]. Plexogenic lesions can form inpatients with chronic PAH (Figure 1B). In patients with TA-TMA and PAH, the vascular lesions may show endothelialinjury and vascular wall hypertrophy of different age and

Etiology

� Due to remodeling of pulmonary arteries and arterioles� Increased pulmonary vascular resistance

� Increased pulmonary artery pressure due to left-sided heart disease� No increase in pulmonary vascular resistance

� PH due to chronic lung disease

� PH due to thromboemboli� Unclear etiology

ary Hypertension with brief description of etiology [29,30].

Figure 1. Lung pathology of pulmonary hypertension. (A) Lung pathology of pulmonary arterial hypertension. Severe muscle proliferation (a) and intimal prolif-eration (b), with almost complete obliteration of the vessel lumen (c) in a patient with severe PH. The internal (d) and external elastic lamina (e) are still present. (B)Plexogenic pulmonary arteriopathy. Complicated plexogenic lesions in a completely obliterated vessel in a patient with severe PH. Multiple tortuous vessels are seenin the previous vessel lumen (arrows). (C and D) PVOD; patchy thickening of alveolar septa and intimal fibrosis narrowing the pulmonary veins (arrows). (Reprintedfrom Miura et al. [55] with permission from Elsevier). A, B, and C are H & Eestained images at 40�. D is an elastica-van Giesonestained image at 40�.

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severity, often causing vascular microthrombi and interstitialhemorrhages.

Histologically, PVOD is characterized by extensive occlu-sion of the pulmonary venuleswith fibrous tissue that evolvesinto sclerotic occlusion without thrombosis (Figure 1C).Anti-a-actin staining may show involvement of the smoothmuscle cells as well as myofibroblasts within the venules[39,54,55].

DIAGNOSIS OF PHMedical and Family History

Early identification and diagnosis of PH is critical so thattimely treatment may be initiated before right-sided heartfailure and irreversible cardiac compromise. In HSCTpatients, family history might be unrevealing because mostrisk factors are associated with HSCT therapy or complicationin these patients. Questions should be directed to identifyrelatives with PH or early cardiac disease and detailedthrombophilia history to identify events of deep veinthrombosis or pulmonary emboli.

Differential Diagnosis of Respiratory Symptoms afterTransplantation

The most common pulmonary complications after trans-plantation include infectious pneumonia, acute respiratorydistress syndrome, pulmonary edema, diffuse alveolarhemorrhage, heart failure, interstitial pneumonitis, idiopathicpneumonia syndrome, bronchiolitis obliterans, and orga-nizing pneumonia [24,56]. PH is rarely included in the differ-ential diagnosis of respiratory distress post-transplantationand can be easily overlooked. The most common respiratorysymptoms reported in patients with PH in the literature areacute hypoxemia (72%), dyspnea (33%), and acute respiratoryfailure (37%) with no clear underlying cause [3-25]. It is notuncommon that hypoxemia and acute respiratory failure

occur after additional stressors such as anesthesia or a septicevent, likely inducing acute collapse of already injuredpulmonary vessels [3]. It is important to consider PHamong other common diagnoses after HSCT in patients withunexplained hypoxemia or respiratory distress, especially inthose requiring intensive care, so appropriate diagnosticstudies can be initiated [57].

Clinical Symptoms of PHThe initial symptoms of PH, including shortness of breath,

fatigue, dizziness, weakness, and hypoxemia, can be vagueand difficult to differentiate in the post-transplantationpatient. Edema and ascites may develop in later stagesfrom increased venous congestion [29,58]. Patients withadvanced disease develop progressive tachypnea andhypoxemia preceding respiratory failure. Unrecognized anduntreated PH in HSCT patients is nearly always lethal.

Findings on Physical ExaminationInitial findings on physical examination in patients with

PH may be subtle. However, with more advanced PH, phys-ical signs become more obvious. Peripheral signs of elevatedcentral venous pressure such as jugular venous distensionare well recognized in adult clinical practice but may beoverlooked in children. Peripheral, flank, or periorbitaledema may be present [32]. Hepatomegaly or ascites arefurther indications of elevated central venous pressure butmay be difficult to differentiate from other causes in patientsafter HSCT. A parasternal lift and palpable second heartsound component in the second left intercostal space aresurface manifestations of an exaggerated second heartsound. These are borne out on auscultation when an exag-gerated pulmonic component of the second heart soundmaybe heard. A holosystolic murmur may be audible in thetricuspid area if tricuspid regurgitation is present, and an

Table 4Echocardiographic Guidelines for the Diagnosis of PH

Echocardiographic Evaluation Likelihood of PH

TRV <2.8 m/s and SPAP <36 mm Hg withno secondary characteristics of PH

Unlikely

TRV of 2.9-3.4 m/s and SPAP of 37-50 mm Hgor secondary characteristics of PH

Possible

TRV >3.4 m/s and SPAP >50 mm Hg with orwithout secondary signs of PH

Likely

Echocardiograph evaluation of the tricuspid regurgitant velocity (TRV) isneeded to calculate the systolic pulmonary artery pressure (SPAP). Thesevalues help determine the likelihood of a diagnosis of PH. Guidelinesadopted from the European Society of Cardiology Guidelines [29,30].

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early diastolic decrescendo murmur in the pulmonic area,representative of pulmonary insufficiency, is also occasion-ally heard. In the face of deteriorating ventricular function,third and fourth sound gallops may also become evident[58]. These findings are representative of both failing systolicfunction and deteriorating ventricular compliance, whenmore active atrial contraction becomes necessary to fill theright ventricle and maintain adequate output.

Chest RadiographyUp to 90% of patients with advanced PH have abnormal

findings on chest x-ray. These findings can include promi-nence of the pulmonary artery, enlarged hilar vessels, anddecreased peripheral vessels. In the early stages of PH,radiological studies may not show any lung abnormalitiesand vascular changes might be difficult to appreciate [22]. PHshould be considered in the differential diagnosis of anyHSCT patient with “unexplained” hypoxemia or respiratorydistress without obvious radiological lung abnormalities ordocumented infections [58].

ElectrocardiographyElectrocardiograms of patients with PH may show

evidence of right atrial enlargement or right ventricularhypertrophy with peaked P waves, right axis deviation,excessive electrical forces in the anterior leads, and rightbundle branch block pattern. Electrocardiography is sensitiveas a tool for diagnosing right ventricular hypertrophy but isnot sufficiently specific as a screening tool to rule out PH [59].

High-Resolution Chest Computed Tomography andMagnetic Resonance Imaging

Computed tomography (CT) is a useful modality in iden-tifying patients with PH, and high-resolution CT scannersallow for improved resolution, shorter scanning times, andshorter breath holds. Dilation of the pulmonary artery is animportant finding in patients with PH and, when detected onCT scan, has a 77.4% sensitivity and 89.6% specificity ofdetecting PH [60]. High-resolution CT is helpful in identifyingpatients with pulmonary PVOD and can show interstitiallung edema, diffuse ground-glass opacities with a cen-trilobular distribution, adenopathy, and septal lines [61]. CTscans can give insight to underlying etiologies of PH such aspulmonary emboli.

Cardiac magnetic resonance imaging (MRI) is the goldstandard for functional and structural assessment of right-sided cardiopulmonary circulation [60]. Cardiac MRI canprovide an excellent anatomical and functional evaluationwithout radiation exposure, and it enables the radiologist toevaluate for right atrial dilation, right ventricle hypertrophy,and septal flattening [62]. Finally, MRI can provide informa-tion on right ventricular global dysfunction [26]. CT and MRImay not be options for critically ill HSCT patients and are notsuitable for longitudinal monitoring and will likely onlyidentify symptoms of advanced disease.

EchocardiographyTransthoracic echocardiography is an excellent noninva-

sive screening tool for PH [29,63]. Dedicated echocardiog-raphy specifically targeting signs of PH should be requestedand should be interpreted by a cardiologist or PH specialist. Itis important to note that in most institutions, routine echo-cardiography requested to evaluate cardiac function will notinclude a comprehensive right-sided heart evaluation andwill not be sufficient to rule out PH. For this reason, specific

echocardiographic protocols have been developed for thispurpose. An example of such an echocardiographic protocolfor evaluation of PH is shown in Appendix 1.

Using echocardiography, right ventricular pressure can beestimated with interrogation of the Doppler regurgitant jetvelocity across the tricuspid valve if tricuspid regurgitation ispresent. In the absence of tricuspid regurgitation, dedicatedechocardiography to specifically evaluate PH may revealsubtle findings otherwise overlooked. These less direct signsof PH may include evidence of right-sided heart chamberdilation, right ventricular hypertrophy, systolic septal flat-tening, or dilated pulmonary arteries. These signs may notalways be found in patients with mild PH, and some of thesemay be late findings [22]. Given these limitations inscreening patients with mild or early PH, the HSCT physicianshould be aware that echocardiography might need to berepeated over time.

Echocardiography is also an excellent noninvasive meansto assess the response to treatment if significant PH is foundon the initial screening study and therapy was initiated. Theintervals at which echocardiography should be repeateddepend on the severity of the diagnosed PH, extent oftreatment, and the clinical setting. Echocardiographicguidelines for diagnosis of PH are listed in Table 4.

Cardiac CatheterizationCardiac catheterization remains the gold standard in the

diagnosis of PH and should be considered in the HSCT patientsuspected of PH after proper risk and benefit assessment.During cardiac catheterization, cardiac output is directlymeasured, the impact of intracardiac shunts is evaluated,pulmonary artery pressures are measured, and pulmonaryresistance can be calculated [30]. If significant PH or eleva-tion of pulmonary resistance is present, it is recommendedthat all patients undergo acute vasodilator testing. Currently,iNO, intravenous epoprostenol, or adenosine are recom-mended, with iNO the drug of choice for acute vasodilatortesting [64,65]. The information derived from vasodilatortesting is essential for the best PH therapy selection.

In general, given the potential risks of cardiac catheteri-zation in a population with other significant comorbidities,such as those after HSCT, invasive testing is reserved forthose in whom a clear diagnosis cannot be achieved withnoninvasive means. In addition, any patient with apparenthemodynamically compromising PH (at any stage of treat-ment) should undergo cardiac catheterization, as well asthose who do not appear to be responding appropriately tofirst-line PH therapy (see Treatment of PH, below).

BIOMARKERSNovel biomarkers for PH diagnosis and monitoring after

HSCT would be valuable but are not currently available.

Table 5Biomarkers of PH

Biomarker* Relevance

Human pentraxin 3 (PTX3) Acute-phase reactant, a specific biomarker for PH reflecting pulmonary vascular degenerationN-terminal of brain natriuretic peptide (NT-ProBNP) An inactive amino-terminal fragment of brain natriuretic peptide predicts long-term outcome

in severe PH; highly specific/sensitive in PHEndothelin-1 (ET-1) Vasoconstrictor, involved in vascular remodeling; increased in PH; bosentan is an ET-1 receptor

antagonist and a potential target for therapyAngiopoietin-2 (Ang-2) Angiogenic factor essential for vascular development and maturation; correlates with disease

severity in PHBone morphogenic protein-9 (BMP-9) Circulating peptide; affects endothelial function and associated with ET-1 in PHEndoglin (Eng) Membrane glycoprotein involved in vascular remodeling; increased in patients with PH in

systemic sclerosisVascular endothelial growth factor (VEGF) Signal protein involved in vasculogenesis; potent mediator of vascular regulation in

angiogenesis; increased in PHTransforming growth factor b (active TGF-b) Multifunctional peptide secreted by cells that control epithelial cell differentiation, proliferation,

and function; found downstream of therapeutic agent losartanSoluble vascular cell adhesion molecule-1 (sVCAM-1) Endothelial adhesion molecule that correlates with PH in sickle cell disease; normally suppressed

by NO; potential treatment with ET-1 receptor antagonist bosentanAsymmetrical dimethylarginine (ADMA) NO synthase inhibitor; increased in PH in sickle cell disease and contributes to decreased

NO production

* Biomarkers used in PH for diagnostic, prognostic, or therapeutic purposes.

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Several biomarkers of PH have been studied in other clinicalsettings and are listed in Table 5.

TREATMENT OF PHPH therapy can be disease specific or supportive. Ideally,

a cardiologist or PH specialist should prescribe targeted PHtherapy after thorough patient evaluation. Figure 2 showsa suggested treatment algorithm for PH after HSCT [29,32].

Supportive TherapyThe initial focus of therapy should be aimed at optimizing

cardiac function, especially if PH has resulted in right ven-tricular compromise. Pharmacological agents useful for thispurpose are described.

DiureticsRight-sided heart failure can lead to fluid retention with

resulting hepatic congestion, pulmonary edema, ascites, and

Figure 2. Treatment algorithm for PH unresponsive to first-line therapy of hemodyterase-5; ERA, endothelin receptor antagonist. (Algorithm adopted from [29,32].)

peripheral edema. Diuretics may be indicated to preventworsening fluid retention, including hepatic congestion.Excessive rapid diuresis may lead to decreased cardiacoutput, however, so caution is required [29].

Afterload-reducing agentsAfterload-reducing agents reduce systemic vascular

resistance, improving cardiacmechanics. Although afterload-reducing agents do not work specifically on the pulmonaryvasculature, they play an important role in improving leftventricular efficiency when right ventricular hypertensionadversely affects the left ventricular morphology.

Intravenous inotropesBipyridine inotropes (eg, milrinone) selectively inhibit the

cyclic adenosine monophosphate phosphodiesterase isoen-zyme found in both cardiac and vascular smooth muscle.Inhibition leads to increased intracellular ionized calcium inheart muscle cells, increased contractility, and peripheral

namically compromising PH, reflecting clinical practice. PDE-5, phosphodies-

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vasodilation. These drugs are used as first-line agents in theface of hemodynamically compromising PH [29].

Pulmonary Vasodilator TherapyVarious drugs with differing mechanisms of action are

now available that specifically target the pulmonary vascu-lature. Although often used in combination, adverse eventprofiles and the means of administration should be takeninto account before commencing these therapies. Therapy isfrequently commenced on the basis of clinical diagnosis andechocardiographic findings. Any patient with an estimatedright ventricular pressure greater than 50% of systemicpressure should be started on treatment, even in the absenceof invasive testing (cardiac catheterization). Typical first-linetherapies are supplemental oxygen (if evidence of hypoxia)and phosphodiesterase-5 inhibitors. Nonresponse to initialtherapy or evidence of deterioration of PH with serial follow-up screening is an indication for cardiac catheterization andtherapeutic testing, before escalation to other treatmentoptions (Figure 2).

Oxygen therapyOxygen is a potent pulmonary vasodilator and is used in

most patients with PH. In patients with PH but withouthypoxemia, oxygen therapy has been shown to improvepulmonary vasodilation and perfusion [66]. In PH associatedwith hypoxemia, oxygen therapy should be administered tomaintain oxygen saturations >90%. It is vitally importantthat HSCT patients diagnosed with PH have immediateaccess to supplemental oxygen. This is particularly relevantin patients with PH in outpatient settings where symptomsmay be exacerbated by viral illness or other stressors.

Inhaled nitric oxideNO is an endogenous vasodilator produced from L-argi-

nine, oxygen, and NADPH by various NO synthase enzymes. Itis used as a signalingmolecule in vascular endothelial cells tosignal triggering smooth muscle cells relaxation. Inadequateor defective production of endogenous NO is a key mecha-nism in the development of PH. NO can be administered asa continuous inhalation (iNO) through a facemask, nasalcannula, or endotracheal tube in intubated patients. NOdiffuses rapidly throughout the pulmonary vasculature,decreasing vascular tone and relaxing pulmonary arteries.Excess iNO is rapidly converted to nitrate and methemo-globin after binding to hemoglobin and therefore causes fewsystemic side effects [67]. iNO is often used in intensive caresettings for acute management of PH due to the ease ofadministration and the favorable side-effect profile.

Calcium channel blockersOnly a small number of patients with PH (those who

respond to pulmonary vasodilator testing) benefit fromcalcium channel blocker therapy. The most commonly usedcalcium channel blockers in this setting are amlodipine,nifedipine, and diltiazem. These agents are used lessfrequently because of the availability of an increasing array ofnewer pulmonary vasodilator drugs. Calcium channelblockers are negative inotropic agents, often precluding theiruse in the face of compromised hemodynamics [68].

Phosphodiesterase-5 inhibitorsPhosphodiesterase-5 inhibitors increase the effects of NO

by inhibiting breakdown. Increased NO results in vasodila-tion and decreased smooth muscle proliferation. Sildenafil,

tadalafil, and other phosphodiesterase inhibitors have beenshown to improve symptoms and length of distance during6-minute walk tests as well as hemodynamic parameters[69]. These drugs are generally administered orally, withsome available as intravenous formulations. The side-effectprofile of these drugs is generally benign (headaches, hypo-tension, and priapism), but the US Food and Drug Adminis-tration has recently limited the use of sildenafil in patientswith heritable or idiopathic PHdue to an increase inmortalitywhen used at higher doses in those specific populations.

Endothelin receptor antagonistsEndothelin is a potent vasoconstrictor implicated in the

pathogenesis of PAH. Endothelin has been found to causepulmonary arteriole smooth muscle vasoconstriction andproliferation, fibroblast proliferation, and endothelium pro-liferation. Nonselective endothelin receptor antagonists (eg,bosentan and ambrisentan) have become a part of the stan-dard of care in patientswith chronic PAH [70]. These drugs areadministeredorally andhave a side-effect profile that includeshepatotoxicity, idiosyncratic anemia, and peripheral edema.Monthly liver enzyme and complete blood counts are man-datory for any patients treated with these drugs.

ProstanoidsPatients with PAH have reduced prostacyclin synthase,

resulting in decreased production of prostacyclin I2, a potentvasodilator. Prostanoids, such as epoprostenol and trepros-tinil, are potent vasodilators, acting directly on pulmonaryand systemic vascular beds to cause vasodilation [71]. Theyhave been shown to improve functional class and exercisetolerance as well as survival in PAH [72,73]. These drugs dohave significant side effects, including nausea and vomitingwith initial commencement in a dose-dependent manner,diarrhea, jaw pain, and headache. Many different modes ofadministration have been developed, although the mostcommon means of delivery when used chronically is bycontinuous intravenous infusion through tunneled centrallines. Treprostinil is stable at room temperature (comparedwith epoprostenol, which requires continuous cooling) andhas a substantially longer half-life. Treprostinil can beadministered subcutaneously, and an inhaled form is nowavailable in the United States. Orally administered prosta-noids are not yet available in the United States.

Other Therapies for PHOral anticoagulation

Patients with PH secondary to thromboembolic diseaseand thosewith extensive late disease from any etiology are atrisk of developing worsening disease from intrapulmonarymicrothrombi [65]. Oral anticoagulation with a target Inter-national Normalized Ratio of 2.0 is generally recommended[29]. The risk-to-benefit ratio of anticoagulation in patientswith PH after HSCT should be carefully weighed because ofthe high risk of bleeding complications.

Atrial septostomyInvasive therapeutic measures might be required in HSCT

patients with acute right-sided heart failure attributed to PH.Under these circumstances, right ventricular output is dimin-ished, resulting in decreased left atrial return, impaired leftventricular preload, and a low cardiac output state. An atrialseptostomy allows right to left shunting at the atrial level andprovides adequate left atrialfilling. Cardiac output is enhancedat the expense of lower systemic arterial saturations. The

Figure 3. Proposed algorithm for evaluation of possible PH after HSCT. (Algorithm adopted from Jodele et al. [22].)

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improved cardiac output compensates for the decrease inhemoglobin oxygenation due to the shunt, and tissue oxygendelivery is typically enhanced [29].

CONCLUSIONSThe lack of prospective studies evaluating PH after HSCT

limits insight into the etiology, incidence, and risk factors forPH. PH should be considered in any HSCT patient withhypoxemia, respiratory failure, or symptoms of TMA, intra-vascular hemolysis, or thrombosis, especially those who arecritically ill (Figure 3). Recognition of PH in this populationrequires a high degree of awareness followed by targetedevaluation and clinical intervention, guided by an experi-enced cardiologist. Noninvasive diagnostic methods such asechocardiography are readily available and should be usedfor PH evaluation, recognizing that early signs of PHmight bemissed, requiring diagnostic follow-up if respiratory orcardiac symptoms persist. HSCT physicians should seekprompt consultation with an experienced cardiologist whenPH is suspected. It is also important to properly communicatethe PH diagnosis to the anesthesia team in any HSCT patientscheduled for procedures requiring sedatives because PHmay be exacerbated by such interventions, placing patientsat risk for acute respiratory decompensation.

Our incomplete understanding of the etiology of PH inHSCT patients limits targeted noninvasive diagnostic andtherapeutic options, especially in children undergoingtransplantation. Children and young persons with PH post-HSCT likely have a different mechanism of disease fromolder persons with typical PH associated with long-standingheart disease or multiple emboli. Reports of an associationwith TA-TMA support the hypothesis that PH post-HSCT isdue to endothelial injury as a consequence of complementactivation [37]. Careful prospective studies, including state-of-the-art diagnostics and biomarker studies, will helpelucidate mechanisms of disease and optimal therapy.

ACKNOWLEDGMENTSFinancial disclosure: There are no funding sources to

report.Conflict of interest statement: There are no conflicts of

interest to report.

SUPPLEMENTARY DATASupplementary data related to this article can be found

online at http://dx.doi.org/10.1016/j.bbmt.2013.07.017.

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