Extreme hyperferritinaemia, soluble interleukin‐2 receptor, and haemophagocytic lymphohistiocytosis

We read with interest the recent British Society of Haematology Guidelines on investigation and management of raised serum ferritin (Cullis et al, 2018), which admirably summarizes a diverse body of literature and provides practical, evidence-based advice for clinicians. The recommendation that marked hyperferritinaemia >10 000 μg/l should prompt consideration of both common (e.g. liver and renal disease, infection, malignancy) and rare [e.g. adult-onset Still disease (AOSD), haemophagocytic lymphohistiocytosis (HLH)] conditions is welcome, and we would like to submit some further comments on this topic. Due to high mortality rates in adults with HLH, often in excess of 50% (Hayden et al, 2016), the most critical question in those with extreme hyperferritinaemia is whether or not they have HLH. The main source of serum ferritin is secretion by macrophages via non-classical lysosomal pathways (Cohen et al, 2010); thus it is not surprising that ferritin is markedly elevated in haemophagocytic syndromes. In children, serum ferritin >10 000 μg/l is considered highly suspicious for HLH, based on a study with 10 paediatric HLH cases demonstrating 90% sensitivity and 96% specificity for this threshold (Allen et al, 2008). Similarly, in adults, extreme hyperferritinaemia has been said to be “nearly pathognomonic” for iron overload, AOSD, histiocyte disorders and HLH. However, at least four recently reported large studies (n > 50) in adults examining serum ferritin thresholds >3000 μg/l (Wormsbecker et al, 2015), 4000 μg/l (Thorne et al, 2018), 10 000 μg/l (Otrock et al, 2017) and 50 000 μg/l (Schram et al, 2015) have demonstrated conclusively that hyperferritinaemia is non-specific for HLH (Table 1). All of these studies reported that iron overload (typically transfusion-related), liver disease/hepatocellular injury, infection, haematological malignancy and renal failure were consistently more common causes of extreme hyperferritinaemia than haemophagocytic syndromes. 25% transfusion 19% liver disease 18% multifactorial 35% iron overload 24% malignancy 21% infection 26% haematological malignancy 16% liver failure 14% HLH 14% infection 65% renal failure 54% hepatocellular injury 46% infection 17% (19) HLH 3% (3) MAS Consequently, there is a need for simple, widely available biomarkers of immune activation and hypercytokinaemia to differentiate HLH from other causes of extreme hyperferritinaemia. The soluble interleukin-2 receptor (sIL2R) is an easily measured cytokine biomarker with equal sensitivity and greater specificity than ferritin. sIL2R is, in fact, the only cytokine included in the Histiocyte Society's 2004 diagnostic criteria for HLH, a condition often described as “cytokine storm” (Lin et al, 2017). In a recent study of adult HLH, we reported specificity of 93% for sIL-2R >10 000 u/ml and an area under the receiver-operator characteristic curve of 0·90 [95% confidence interval (CI) 0·83–0·97] compared to 0·78 for ferritin (95% CI 0·67–0·88) (Hayden et al, 2017). Clinically, we find sIL2R very helpful in differentiating HLH from mimickers such as sepsis, liver disease, haemolysis and transfusion. Furthermore, much like ferritin, sIL2R is a dynamic marker of disease activity and can facilitate monitoring of response to treatment. The sIL2R assay is a simple and inexpensive marker of T-cell activation and we encourage other centres to consider its implementation. L.C., A.H. and A.M. collected the data and wrote the paper.

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