Hemophagocytic lymphocystiocytosis and the related disorder macrophage activation syndrome

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of hyperinflammation. Fever, organomegaly and hyperferritinemia are characteristic. It is an emerging disorder yet widely underdiagnosed and considered a "must not miss” condition due to high mortality.

It is the topic of a New England Journal review, Hemophagocytic Lymphohistiocytosis, published earlier this year.

HLH is subdivided into primary and secondary forms. Primary HLH comprises a group of heritable disorders of immune system regulation. It is mainly a pediatric entity and is therefore not the focus of this discussion. Secondary HLH refers to HLH triggered by another known disease. Infections, autoimmune (rheumatic) disease (especially adult Stills and SLE) as well as neoplasia are the main trigger categories. There are usually underlying susceptibility factors present. Macrophage activation syndrome (MAS) is the subset of HLH triggered by rheumatic disease. While theoretically any infectious agent could be a trigger, certain patterns deserve mention. Active Epstein-Barr infection is most commonly noted among infections. Influenza has been reported as an associated infection. According to the review, COVID is believed to be a rare trigger.  Potential confusion lies in the fact that cytokine storm was a characteristic of severe COVD infection in 2020 and 2021. Of note, in light of a recent case on our wards, ehrlichiosis is a known trigger with, mentioned in the review, reports of as many as 16% of cases of ehrlichiosis being complicated by HLH.

When should it be suspected? Consider it and check ferritin and triglyceride levels in critical illness of uncertain etiology. Think of it particularly in sepsis like critical illness that does not have a clear source or is not responding to treatment as expected. The Hscore (available on MD Calc) his good “test” characteristics. 

What is the treatment approach?

In secondary HLH, in addition to treatment of the underlying disease, immunosuppressive therapy is used and generally centers around high-dose glucocorticoids and etoposide. By this point in the evaluation and treatment sequence expert consultation is necessary.