Background/Purpose: Increased ferritin is considered biomarker highly suggestive of primary and secondary HLH and it is one of the HLH-2004 diagnostic and MAS guidelines (1,2), nevertheless it could also be elevated in other inflammatory conditions. Interferon-gamma (IFNγ) and IFNγ-induced chemokines, particularly CXCL9, have been demonstrated to be markedly elevated in patients with primary and secondary HLH.

Methods: We describe eight patients with hyperferritinemia who fully or partially met the HLH-2004 diagnostic guideline, but in which the subsequent clinical course and further investigations led to different diagnosis that required different therapies and to investigate the CXCL9 levels in identify diseases that may mimic HLH. To be noted that soluble CD25 was not measured in these patients. Serum CXCL9 levels were analyzed by DuoSet ELISA KIT DY392 (R&D Systems, Minneapolis, Minn). Normal values of CXCL9 are lower than 700 pg/ml.

Results: We identified 8 patients with laboratory features suggestive of HLH, included high ferritin levels (>500 ng/ml). Three of these patients met five of the HLH-2004 criteria, two of them met four criteria and the others two met three criteria. One patient presented only high serum ferritin level and cytopenia. CXCL9 levels were <300 pg/ml in seven of them and approximately 600 pg/ml in one patient. The clinical disease course and the other investigations ruled out the diagnosis of HLH and every patient received a different diagnosis. None of them received treatment for HLH (Table 1).

Table 1. Patients’ features

Conclusion: Since HLH is a life-threatening condition, early recognition and promptly therapy are essential to modify the disease course. One of the most typical feature of primary and secondary HLH is high ferritin level. Due to the severity of the disease, sometimes patients need to be treated before all criteria are fulfilled. The eight patients reported had features highly suggestive of HLH and met the HLH-2004 criteria, or part of them. However they all received a different final diagnosis. Despite all presented with high ferritin levels, CXL9 was low in all. CXCL9 is a chemokine specifically induced by IFNγ, and has been demonstrated to be markedly elevated in patients with primary and secondary HLH due to the activation of the IFNγ pathway. In these cases CXCL9 was able to differentiate diseases with high ferritin that mimics HLH. High CXCL9 levels appear to be a potential specific biomarker for HLH diagnosis. Early dosage of CXCL9 levels in patients with hyperferritinemia and with clinical suspicion of HLH may be helpful for a timely differential diagnosis.

Reference

1. Henter JI et al. Pediatr Blood Cancer 2007 Feb; 48(2):124-31.
2. Ravelli A et al.Ann Rheum Dis. 2016 Mar;75(3):481-9.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hemophagocytic-lymphohistiocytosis-hlh-mimickers-cxcl9-as-a-potential-biomarker-distinguishing-hlh-from-other-hyperferritinemic-syndromes/