Tocilizumab added to conventional therapy reverses both the cytokine profile and CD8+Granzyme+ T‐cells/NK cells expansion in refractory hemophagocytic lymphohistiocytosis

To the Editor, Hemophagocytic lymphohistiocytosis (HLH) is a lifethreatening syndrome characterized by severe systemic inflammation and uncontrolled activation of natural killer (NK) and cytotoxic CD8+ T-cells, which both contribute to organ damage. In patients with HLH, overproduction of Th1 [interferon gamma (IFN-γ), interleukin 2 (IL-2), IL-6, IL-12 and tumour necrosis factor alpha (TNF-α)] cytokines contrasts with low levels of Th2 cytokines (IL-4) [1]. Overproduction of IL-10 is observed during the acute phase of the disease, as expected during IFN-γ overproduction [2]. Diagnostic criteria of HLH were developed in the HLH-2004 protocol and include an increased soluble CD25 (sCD25) [3]. The association of high levels of IFN-γ and IL-10 with normal or moderately elevated levels of IL-6 differentiates HLH from infection [4]. Besides primary/familial HLH mainly observed in childhood, most secondary forms occur in the setting of infection, malignancy or rheumatologic disorders. Corticosteroids, cyclosporine, etoposide or TNF-α can reverse HLH in most patients with underlying systemic disease or cancer [5]. To date, no firm consensus treatment emerged, and the treatment of refractory HLH remains challenging. In 2013, a 59-year-old patient was referred to our intensive care unit (ICU) for acute renal and respiratory failure and features of HLH including hemophagocytosis in bone-marrow aspirate, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, anaemia and low platelet count, a slightly enlarged spleen, and a dramatic increase of sCD25. Two months before his admission, he developed autoimmune manifestations characterized by arthritis, myositis, lung interstitial disease, acral cutaneous sclerosis and dry syndrome. Immunological tests showed low complement C3, C4, CH50 components, type III cryoglobulin, polyclonal hypergammaglobulinemia, positive Coombs’ test, high levels of anti-SSA, anti-SSB, anti-PMScl, anti-double strand DNA and anti-citrullinated peptides antibodies. He had been receiving corticosteroids for 2months (0.5–1mg/kg/day) without any improvement of the autoimmunity-related organ disorders. At admission in the ICU, diagnosis of HLH was retained. Abnormal liver tests, acute renal failure requiring dialysis and a moderate encephalopathy were observed.