Thinking Beyond HLH: Clinical Features of Patients with Concurrent Presentation of Hemophagocytic Lymphohistiocytosis and Thrombotic Microangiopathy

Abstract

<h3>Introduction</h3> Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation largely driven by high levels of interferon gamma. The clinical HLH presentation can have considerable overlap with other inflammatory conditions. We present a cohort of patients with therapy refractory HLH referred to our center who were found to have simultaneous presentation of complement mediated thrombotic microangiopathy (TMA). Figure 1 contains the diagnostic criteria for both HLH and TMA. <h3>Objectives</h3> • Recognize presenting symptoms of HLH • Recognize presenting symptoms of TMA • Recognize that HLH and TMA can present concurrently <h3>Methods</h3> Patients of any age with frontline therapy refractory hemophagocytic lymphohistiocytosis (HLH) who were treated at our institution from January 2012 through December 2018 were identified by retrospective chart review after Institutional Review Board (IRB) approval. All patients were prospectively screened for TMA as part of clinical care as previously described. Patient demographics, disease characteristics, HLH and TMA targeted therapy, complications, intervention and laboratory assessment were captured from the electronic medical record. <h3>Results</h3> Sixteen of 23 patients with HLH met high risk TMA criteria (Figure 2). Renal failure requiring renal replacement therapy, severe hypertension, serositis and gastrointestinal bleeding were documented only in patients with HLH who had concomitant complement mediated TMA. Patients with HLH and without TMA required ventilatory support mainly due to CNS symptoms, such as status epilepticus, while those with HLH and TMA had respiratory failure predominantly associated with pulmonary hypertension, a known presentation of pulmonary TMA (Figure 2). Ten patients received eculizumab for complement mediated TMA management while being treated for HLH. All patients who received the complement blocker eculizumab, in addition to the interferon gamma blocker emapalumab, had complete resolution of their TMA and survived (Figure 2). <h3>Conclusion</h3> Our observations suggest co-activation of both interferon and complement pathways as a potential culprit in the evolution of thrombotic microangiopathy in patients with inflammatory disorders like HLH and may offer novel therapeutic approaches for these critically ill patients. TMA should be considered in children with HLH and multi-organ failure, as early institution of a brief course of complement blocking therapy in addition to HLH targeted therapy may improve clinical outcomes in these patients (Figure 3).