Pulmonary hypertension associated with bronchiolitis obliterans after hematopoietic stem cell transplantation

Pulmonary hypertension (PH) is a rare and potentially fatal complication of hematopoietic stem cell transplantation (HSCT). PH arises from increased pulmonary vascular resistance leading to increased right ventricular pressure (RVP), right heart failure and death.¹ PH is often difficult to diagnose as symptoms can be nonspecific, including shortness of breath, fatigue, weakness and hypoxemia, and may also result in death if left untreated.²

Bronchiolitis obliterans (BO) is a significant cause of morbidity and mortality in post-lung transplant and HSCT patients.³ BO is a non-reversible obstructive lung disease, in which bronchioles are compressed and narrowed by fibrosis and/or inflammation. This compression leads to persistent hypoxia. BO occurs in 3–10% of HSCT patients, is associated with chronic GvHD, and has an overall poor prognosis.^4,5

Development of PH has been associated with BO in lung transplant patients; however, it has not been described in the HSCT population.⁶ Long-term hypoxemia can lead to vascular remodeling and angiogenesis, which in turn leads to vessel wall proliferation and increased vascular resistance.⁷ Little is understood regarding the interplay between PH and BO post HSCT. Although BO may be causative of PH, the treatment strategies for each are vastly different. We present three HSCT patients who developed BO and were subsequently found to have PH.

We conducted a retrospective review of all patients treated at Cincinnati Children’s Hospital Medical Center from January 2009 to December 2012. All patients with a clinical diagnosis of BO were identified, clinical records reviewed and data was extracted.

The National Institute of Health’s (NIH) consensus definition for BO after HSCT was used to diagnose BO.³ In patients unable to obtain pulmonary function testing secondary to age, BO was diagnosed using all of the following criteria established by Ratjen et al.⁸: airway obstruction hypoxemia without normalization after beta-2 agonist treatment, absence of pulmonary infiltrates, absence of infectious organisms from bronchoalveolar lavage, and evidence of air trapping on high-resolution computed tomography.

The diagnosis of PH was made using standard criteria and included echocardiography, cardiac catheterization and/or autopsy.^1,9,10 Echocardiography screening included assessment of left heart function, estimation of RVP and measurement of intraventricular septal flattening.¹¹ Echocardiography has a high sensitivity for predicting PH; however, the specificity is low until the estimated RVP approaches 50% of the systemic pressure.^9,10 Therefore, patients with a RVP ≥ 50% systemic pressure were diagnosed with PH after review by a PH specialist.²

We evaluated all allogeneic HSCT patients treated at Cincinnati Children’s Hospital Medical Center from 2009–2012 (n = 291). Four patients (1.4%) were diagnosed with BO during the study period. The median patient age was 7.9 years (range, 0.6–17.4), and two patients diagnosed with BO were male. BO was diagnosed at a median of 196 days (range 131–305 days) after HSCT. Three of the patients (75%) were diagnosed with PH after the diagnosis of BO at a median of 91 days (range 46–833 days). The three patients diagnosed with PH and BO were administered myeloablative conditioning regimens, while the one patient without PH was administered a reduced intensity conditioning regimen. All four patients had a history of chronic GvHD at the time of BO diagnosis (Table 1).

Table 1.

Demographics of patients diagnosed with bronchiolitis obliterans

Patient number	Primary diagnosis	Age at HSCT (years)	Conditioning (Prep)	Graft source	Day 100 acute GvHD grade	Organ/ site of chronic GVHD	Days from HSCT to diagnosis of BO	Days from HSCT to diagnosis of PH	Mechanism of PH diagnosis	Treatment for PH	Cause of death	Days from HSCT to death
1	WAS	0.6	MAC (Bu/Cy/ATG)	BM	2	Skin	233	1066	Echocardiography, cardiac catheterization	Yes (Sildenafil)	N/A	Alive
2	AML	17.4	MAC (Bu/Cy/ATG)	PBSC	3	GI	305	351	Echocardiography	Yes (iNO)	GvHD, BO	352
3	CML	10.4	MAC (Bu/Cy/ATG)	BM	1	Skin, eyes, nails	158	247	Echocardiography, autopsy	No	BO, PH	1368
4	BMF	5.4	RIC (Cam/Flu/Mel)	BM	3	Skin, GI, liver	131	No PH	N/A	N/A	GvHD, BO	192

Abbreviations: BM=bone marrow; BMF=bone marrow failure; BO =bronchiolitis obliterans; Bu=busulfan; Cam =campath; Cy= cyclophosphamide; Flu= fludarabine; HSCT= hematopoietic stem cell transplant; iNO = inhaled nitric oxide; Mel =melphalan; MAC=myeloablative conditioning; PBSC= peripheral blood stem cell; RIC= reduced intensity conditioning; WAS=Wiskott Aldrich Syndrome.

All four patients diagnosed with BO had high-resolution CT demonstrating air trapping, clinical signs of airway obstruction hypoxemia, absence of pulmonary infiltrates on chest X-ray and absence of infectious organisms from bronchoalveolar lavage. The older patients (patients 2 and 3) underwent pulmonary function testings showing decreased forced expiratory volume in one second (FEV₁) and a decreased ratio of FEV1 to vital capacity (FEV1/FVC < 7).

All three patients diagnosed with PH and BO had elevated estimated RVP > 50% systemic pressure, with secondary signs of PH, on echocardiography. Other causes of PH such as left ventricular depression, pulmonary emboli, hemolytic anemia, thrombotic microangiopathy, and pulmonary veno-occlusive disease were not found in the three patients with PH.²

Patient 1 developed intermittent hypoxia and respiratory failure and required multiple hospital admissions, including five pediatric intensive care unit (PICU) stays, in the 3 years following the diagnosis of BO. These PICU admissions were secondary to hypoxia and respiratory distress, and were attributed to worsening BO. Nearly 3 years after the diagnosis of BO, echocardiography revealed significantly elevated right ventricular pressure diagnostic for PH. Cardiac catheterization confirmed the diagnosis of PH, and the patient was started on sildenafil by the pediatric PH team. Upon review of previously completed echocardiography, subtle findings suggestive of PH were present from the time of BO diagnosis. After the initiation of sildenafil, Patient 1 required significantly less respiratory support and has only required one admission to the PICU in over 2 years. Additionally, after 2 years of treatment and improved PH, Patient 1 was weaned off sildenafil and continued on azithromycin, montelukast and intermittent oxygen for BO.

Patient 2 was admitted to the PICU 18 days after BO diagnosis for respiratory failure with hypercapnia and was started on high-dose methylprednisolone, extracorporeal photopheresis and inhaled nitric oxide without improvement of symptoms. Echocardiography performed 40 days after the diagnosis of BO was diagnostic for PH. Patient 2 died shortly after the diagnosis of PH.

Patient 3 developed hypoxia and respiratory failure and required multiple hospital admissions, including three prolonged PICU stays, after the diagnosis of BO. Patient 3 was admitted to the PICU 3 years after BO diagnosis with hypoxia and respiratory failure and was started on inhaled nitric oxide without improvement of symptoms. Patient 3 died nearly 4 years after HSCT. Retrospective review of the echocardiograms revealed septal flattening and elevated RVP consistent with PH. Autopsy findings were consistent with PH and classic obliterative bronchiolitis (Figure 1).

Figure 1.

Pathology findings on autopsy of a 14-year-old female with pulmonary hypertension and bronchiolitis obliterans. (a) Lung pathology consistent with pulmonary hypertension; intimal fibrous thickening and medial muscular hypertrophy (arrows) with significant narrowing of the vessel lumen (stars) in a middle-sized artery in the peripheral portion of the lung. (b) Pathology consistent with bronchiolitis obliterans; plugs of loose fibrous tissue filling bronchiolar lumens, alveolar ducts and spaces (arrows).

Patient 4 developed progressive respiratory failure and was transferred to the PICU for distress the day BO was diagnosed. Patient 4 died shortly after the diagnosis of BO, approximately 6 months after HSCT.

Eleven out of the 291 patients (3.7%) were diagnosed with PH during the study period. In the other eight patients, PH was attributed to transplant-associated thrombotic microangiopathy.^12,13

To our knowledge, PH has not been described in patients with BO after HSCT. Three out of the four patients in this cohort diagnosed with BO were eventually found to have PH, which suggests that this may be an under-recognized complication. Among the three patients with both BO and PH, no alternative etiologies for PH were observed, including left ventricular dysfunction, thrombosis, hemolytic anemia and thrombotic microangiopathy. One patient who did survive in this cohort received PH-specific therapy (sildenafil), which may have contributed to a decreased incidence of acute respiratory decompensations, and may have improved pulmonary vascular circulation.

This study was limited by a small sample size and no routine screening for PH and BO. The true incidence of PH in patients with BO after HSCT remains unknown. BO in the post-lung transplant population shares a similar pathophysiology with BO post-HSCT. A retrospective analysis of 386 lung transplant recipients with BO relisted for transplantation demonstrated a prevalence of PH of 32.5% based on right heart catheterization.⁶ It also remains unclear how the severity of BO might affect the incidence of PH. However, given the high rates of mortality from both PH and BO, our institution has now begun screening all patients diagnosed with BO with echocardiography.

In 2008, the 4th World Symposium of Pulmonary Hypertension created consensus general guidelines and a classification of PH.¹⁴ World Health Organization (WHO) Group III includes a heterogeneous collection of lung diseases and/or hypoxia, which lead to PH. Patients undergoing HSCT are at risk of developing interstitial pneumonitis, BO with organizing pneumonia, diffuse alveolar damage and lymphocytic interstitial pneumonia.¹⁵ Disorders of lung parenchyma, such as BO, share a similar mechanism to WHO Group III and may be classified in a similar manner.

Patients diagnosed with PH need specific treatment and are ideally managed under cardiology supervision. The initial focus of therapy is to optimize cardiac function, especially if PH has caused right ventricular compromise. We recommend routine echocardiographic screening of all patients with BO, paying particular attention to right ventricular systolic function and estimated pressures. Patients suspected of having PH should be referred for further evaluation to a cardiologist.²

PH is an increasingly recognized entity affecting patients after HSCT, though the lack of prospective studies limits insight into the etiology, incidence and risk factors for PH. We previously suggested that PH should be considered in any HSCT patient with hypoxemia, respiratory failure or ongoing vasculopathy such as transplant-associated microangiopathy, intravascular hemolysis hers Limited or thrombosis.² Data from this case series would suggest that patients with BO should also be screened regularly. Since hypoxemia presents in both BO and PH, hypoxemia in a patients with BO is typically attributed to worsening BO, however, as shown in Patient 1’s clinical course, PH may contribute to hypoxemia and should be considered. Conversely, patients with BO lack respiratory symptoms during the milder, earlier stages of disease resulting in poor recognition.⁵ Further studies are warranted to determine the overall incidence of PH in patients with BO, and the impact that treatment of PH in this setting has on overall outcome.