An Interesting Case of Hemophagocytic Lymphohistiocytosis Presenting with Pulmonary Hypertension

Adult hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening hyperinflammatory syndrome that presents both diagnostic and therapeutic challenges. HLH may be primary and related to an underlying genetic abnormality or secondary to infection, malignancy, or rheumatologic condition. We describe a case of HLH in a latently EBV-/CMV-/HBV-immune 52-year old male presenting with severe pulmonary hypertension. He was intolerant of the HLH 2004 protocol but responded to salvage therapy with anti-CD52 monoclonal therapy (alemtuzumab).

The patient was previously healthy with a diagnosis of axonal-pattern CIDP five years prior. He had a one year history of mild progressive exertional dyspnea and experienced a flu-like illness treated as presumed H1N1 infection five months prior. He presented to hospital with progressive respiratory distress, fevers and weight loss, culminating in respiratory failure requiring mechanical ventilation for 4 days. Investigations revealed severe pulmonary hypertension (RVSP 112 mmHg), nephrotic range proteinuria, transaminitis, hyperferritenemia (ferritin 4240 ug/L) and hepatosplenomegaly. Initial hematologic investigations revealed an isolated thrombocytopenia (IVIG and steroid non-responsive), soon followed by hemolytic anemia with an oxidative blood film. Initial bone marrow biopsy showed normal hematopoiesis, megakaryoyctic thrombocytopenia, iron deficiency, and no evidence of hemophagocytosis. Rheumatologic investigations were negative (ANA, ENA, C3, C4, p-ANCA, c-ANCA, ds-DNA, anti-GBM) and viremia investigations negative (HIV, CMV, EBV, HBV). Hematologic causes of peripherally destructive cytopenias were ruled out (DAT, PNH, methemoglobin, APLA, ADAMTS13, G6PD, PK normal). No definitive etiology of pulmonary hypertension was found and treatment was initiated with nitric oxide and sildenafil. Four weeks after initial presentation to hospital, he developed worsening pancytopenia and unexplained fevers. Repeat bone marrow examination revealed hemophagocytosis, achieving sufficient criteria for diagnosis with HLH. Repeat EBV serology was IgM positive with a viral load 7 × 10⁵/ml. HLH 2004 protocol was initiated, however within 7 days, treatment-limiting nephrotoxicity and hepatotoxicity developed, prompting discontinuation of cyclosporine and dose-reduction of etoposide. Hepatic biopsy revealed drug-induced sinusoidal necrosis with no HLH involvement. Evidence of worsening HLH (ongoing fevers, cachexia, debility, severe cytopenias requiring transfusion and filgrastim support, and increasing ferritin) prompted the use of alemtuzumab. Within 7 days of alemtuzumab initiation the ANC increased from less than 0.2 to within normal range, and within 14 days platelet count rebounded to above 50. Ferritin fell from a peak of 4756 ug/L to approximately 1500 ug/L. Treatment course was complicated by severe upper and lower gastrointestinal bleeds (necessitating massive transfusion protocol), pulmonary blastomycosis (treated with ambisome and itraconazole) and several episodes of bacteremia. Despite his precarious course in hospital, he responded to 6 weeks of treatment with alemtuzumab with continued improvement in his clinical, biochemical, and hematological manifestations of HLH. At 105 days of post-diagnosis follow-up to date, his HLH remains in remission with gradual, ongoing improvement in pulmonary hypertension. Although no clear diagnostic association has been proven, we hypothesized that either this patient's pulmonary hypertension and HLH had a common precipitant or that his pulmonary hypertension was secondary to HLH disease activity.

This is a unique case of HLH presenting concurrently with severe pulmonary hypertension, complicated by intolerance of the HLH 2004 protocol, but response to salvage anti-CD52 therapy. There is still much to be understood about the underlying pathophysiology and treatment strategies of HLH.

Off Label Use: Alemtuzumab is a monoclonal antibody which targets CD52. It is used as second-line treatment for chronic lymphocytic leukemia. It is also used off-label for other lymphocyte/NK cell disorders, such as cutaneous T-cell lymphoma and some autoimmune diseases. It has been described in off-label use for hemophagocytic lymphohistiocytosis (HLH) as a bridge to allogeneic stem cell transplant.