Late Onset Pulmonary Arterial Hypertension after Successful HSCT for Familial HLH

Familial hemophagocytic lymphohistiocytosis (FHLH) has often been associated with high transplant-related mortality, typically from a variety of causes in the first 100 days post-HSCT.  We report a case of occult pulmonary hypertension that developed 3 years after HSCT for FHLH.  The patient was born at 28 weeks with a NICU course consisting of mild respiratory distress syndrome and unilateral grade II intraventricular hemorrhage.  At 2.5 months of age, he developed fevers, splenomegaly, progressive pancytopenia, hypofibrinogenemia, hyperferritinemia, and bone marrow hemophagocytosis.  He underwent initial treatment per HLH-2004 with good response.  Genetic analysis revealed homozygous perforin 1 mutations.  He proceeded with a 5/6 cord blood transplant with Bu/Cy/VP-16/ATG conditioning and GVHD prophylaxis with cyclosporine and steroids.  He achieved successful engraftment with stable 100% donor chimerism.

Post-HSCT course was complicated by engraftment syndrome, steroid-responsive grade II skin and gut aGVHD, severe VOD treated with defibrotide, and prolonged intubation.  He developed persistent renal failure, presumably due to chronic calcineurin toxicity.  He underwent cadaveric renal transplant 10 months after HSCT.  Clinical care over the next two years was all outpatient, but complicated by BK nephropathy.

Two months prior to his death, he presented with tachypnea and oxygen desaturation.  CXR showed mild peribronchial opacities.  Respiratory viral panel and echocardiogram were normal.  His symptoms resolved quickly with albuterol.  He was re-admitted a week later with similar symptoms.  Repeat CXR and echocardiogram were unchanged.  Due to persistent symptoms, he underwent bronchoscopy that was positive for P. jirovecii and was treated with high-dose Bactrim.  One month after completing treatment, he presented to an outside ER with acute onset of dyspnea.  He rapidly decompensated into PEA and was unable to be resuscitated.  Autopsy showed intimal and medial thickening of his pulmonary arteries with marked luminal narrowing, consistent with pulmonary arterial hypertension (PAH). 

There is one prior case report of two pediatric FHLH patients who died in the first year post-HSCT with PAH discovered on autopsy.  Despite successful HSCT, there appears to be a pathologic link between FHLH and PAH, both early and late post-HSCT.  PAH should be considered in any FHLH patient with respiratory symptoms and improved screening techniques are critically needed.