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.