DISCUSSION
Hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production and hyperferritinemia. Hemophagocytic lymphohistioctytosis can develop by genetic defects in lymphocyte cytotoxicity which is depicted as primary or familial HLH. Infections, malignancies, rheumatologic diseases or immune compromising and/or activating therapies may also trigger HLH (6).
Patients with HLH have dramatically elevated levels of numerous serum proinflammatory cytokines. This clinical condition is thought to be a cytokine storm syndrome. Besides typical laboratory findings, red blood cells, platelets, or white blood cells can be observed within the cytoplasm of the macrophages of bone marrow specimens (7).
Fever and organomegaly are the most common presenting symptoms. Cytopenia, especially anemia and thrombocytopenia, hypertriglyceridemia, hypofibrinogenemia and hyperferritinemia are typical laboratory findings. Recent reports suggest that the cytokine storm caused by SARS-CoV-2, has significant similarities with the clinical and laboratory findings of HLH. Case series have raised concerns about a hyperinflammatory process associated with COVID-19 in children, defined as MIS-C (1-5). Most children had fever lasting more than four days, and common presenting symptoms such as rashes, conjunctival injection, gastrointestinal symptoms and lethargy. Cardiac manifestations especially left ventricular failure and organomegaly may occur. Mostly high level of inflammatory markers, such as CRP, ESR, procalcitonin and ferritin occur. Many patients have lymphopenia and thrombocytopenia. Although clinical and laboratory findings of MIS-C resemble HLH, there are a few studies reporting that MIS-C is immunologically different from HLH (8, 9). Both HLH and MIS-C are conditions which patients deteriorate rapidly require rapid diagnosis and appropriate treatment (7). The treatment can be lifesaving.
Despite appropriate treatment, cytopenia, marked elevation of inflammatory markers and additionally elevated ferritin, triglyceride and D-dimer were seen in these three cases suggesting HLH occurrence. Bone marrow evaluation was performed and hemophagocytosis was observed. Hemophagocytosis has been reported for adults in association with severe COVID-19 disease however there are no reported data for children demonstrated by bone marrow aspiration (10).
Being a newly described entity, every patient may have different presentation and clinical course therefore treatment must be tailored to each patient individually. These cases highlight that MIS-C and HLH have similar findings, while deeper thrombocytopenia, very high ferritin and d-Dimer levels should suggest HLH.