Skip to Main Content

We have a new app!

Take the Access library with you wherever you go—easy access to books, videos, images, podcasts, personalized features, and more.

Download the Access App here: iOS and Android



  • Hemophagocytic lymphohistiocytosis (HLH) is a disease syndrome associated with high morbidity and mortality.

  • HLH can be divided into primary HLH versus secondary HLH caused by infections, rheumatologic disorders, or malignancies.

  • Due to the complexity of HLH, diagnosis requires the presence of specific clinical and laboratory criteria.

  • Treatment of primary HLH incorporates dexamethasone and etoposide, while the treatment of secondary HLH includes therapies directed at underlying causes.

  • Novel therapeutics are being developed that target key components of inflammatory pathways.


Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening condition that is characterized by overactivation of the immune system, leading to systemic inflammation, cytokine storm, and multiorgan failure.1 This hyperinflammatory state manifests with signs and symptoms including fever, cytopenias, rash, disseminated intravascular coagulation, acute liver failure, and encephalopathy.2 The first reported case of HLH was described by James W. Farquhar and Albert E. Claireaux in 1952. Originally coined “familial hemophagocytic reticulosis,” it was thought to be a rare familial disorder that was characterized by proliferation of histiocytes in solid organs and phagocytosis of blood cells.3 Today, HLH is broadly divided into primary and secondary HLH. Primary disease, most commonly seen in children (median age of onset = 1.8 years), is driven by inborn errors of immunity that ultimately impair the cytotoxic function of natural killer (NK) and CD8+ T cells.1,2 Encompassed within the diagnostic overlap of primary HLH are other inherited immunodeficiency syndromes such as familial HLH (F-HLH), Chediak-Higashi syndrome, Griscelli syndrome, and type II Hermansky-Pudlak syndrome.4

Autosomal recessive mutations associated with F-HLH include pathogenic variants in genes encoding the following proteins: Perforin (PRF1), Munc13-4 (UNC13D), MUNC18-2 (STXBP2), and Syntaxin11 (STX11).5 Although primarily viewed as a condition afflicting pediatric populations, germline variants associated with primary HLH have been discovered in adults presenting with their first episode of HLH.6 Secondary HLH is most commonly observed in nonpediatric patient populations and is driven by a triggering event that leads to immune dysregulation and a sustained hyperinflammatory state. Common predisposing conditions include infection, especially by Epstein-Barr virus (EBV), malignancy, and autoimmune diseases such as juvenile idiopathic arthritis or systemic lupus erythematosus.7 When HLH occurs in the setting of known rheumatologic disease, it is typically referred to as macrophage activation syndrome (MAS).8 In some cases of HLH, an associated disease state is never identified.9 Differentiating between the various forms of HLH is paramount, because in the setting of primary HLH, definitive treatment incorporates toxic therapies including chemotherapy and hematopoietic stem cell transplantation. Because of relatively nonspecific symptoms that mimic more common conditions, intensivists are often the first clinicians to diagnose patients with HLH after clinical deterioration warrants admission to the intensive care unit. As discussed below, a high degree of clinical suspicion for HLH is warranted due to clinical features that resemble other etiologies of ...

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.