Pulmonary Hypertension Associated with Bronchiolitis Obliterans after Stem Cell Transplant

Background: Bronchiolitis obliterans (BO) and pulmonary hypertension (PH) are rare and fatal complications of stem cell transplantation (SCT). BO is a non-reversible obstructive lung disease in which bronchioles are compressed and narrowed by fibrosis and/or inflammation. PH arises from increased pulmonary vascular resistance leading to increased right ventricular pressure, right heart failure, and death. PH has not been described in patients with BO after SCT.

Design/Methods: To evaluate PH in patients with BO, we retrospectively reviewed all cases of BO in 291 patients undergoing allogeneic HSCT from January 2009 to December of 2012.  Patients diagnosed with BO met standard criteria for BO diagnosis including high resolution CT evidence of air-trapping.  PH was diagnosed with echocardiography, cardiac catheterization, and autopsy.

Results: Four patients (1.4%) were diagnosed with BO. All four patients had a history of graft versus host disease, no infectious cause of respiratory symptoms, and high resolution CT evidence of BO. Two patients received PFT testing which showed decreased FEV₁.  All patients received serial echocardiography after SCT. Three of the four patients were diagnosed with PH after the diagnosis of BO (Table). All three patients had elevated estimated right ventricular pressure, with secondary signs of PH, on echocardiography. One patient underwent cardiac catheterization confirming PH, and one had findings consistent with PH on autopsy (Figure). Two patients died from respiratory failure, both received inhaled nitric oxide. The surviving patient with PH and BO required intermittent non-invasive ventilation and was treated with sildenafil for PH. The patient without PH died 192 days after SCT.

Conclusion: PH has not been described in patients with BO after SCT. The etiology of PH after BO is unclear; however, parenchymal changes in BO may lead to pulmonary vascular injury and hypertrophy.  Also, long-term hypoxemia and inflammation can lead to vasoconstriction, vascular remodeling and angiogenesis, which in turn leads to increased vessel wall proliferation. Routine screening for PH in patients with BO may assist in diagnosing PH. The treatment for PH differs from BO and there is little understanding of their interplay post-HSCT; further investigation is needed. 

Table: Patients diagnosed with BO and PH after HSCT

Diagnosis	Age at SCT (years)	Days from SCT to diagnosis of BO	Days from SCT to diagnosis of PH	Days from SCT to death
Wiskott Aldrich	0.6	233	235	Alive
AML	17.4	305	351	352
CML	10.4	158	247	1368
Aplastic Anemia	5.4	131	No diagnosis of PH	192

Figure: Pulmonary arteriole intimal and medial thickening seen in a patient with bronchiolitis obliterans