Hemophagocytic lymphohistiocytosis: review of etiologies and management

George, Melissa R

The genetic causes of HLH can be divided into two groups: 1) FHL and 2) immune deficiencies such as CHS, GS, and XLPS. FHL was first described in 1952 by Farquhar and Claireaux, 2 with HLH as the only manifestation. 3 They described the tragic case of two siblings who developed a rapidly fatal illness, with fever, diarrhea, and vomiting, at 9 weeks of age and termed the illness familial hemophagocytic reticulosis. The children had hepatosplenomegaly without lymphadenopathy. They also had pancytopenia. Both infants died, and at autopsy, histiocyte proliferation with active hemophagocytosis was readily apparent in the lymph nodes, spleen, liver, and kidney. A third child from the same family was unaffected, but the fourth was affected, as reported by Farquhar in 1958. 3 Numerous other cases under various other names have been reported in the medical literature, including familial erythrophagocytic lymphohistiocytosis, familial lymphohistiocytosis, and generalized lymphohistiocytic infiltration to name a few. [190] [191] [192] [193] [194] [195] [196] A high percentage (up to 24%) of FHL cases are associated with parental consanguinity. 8 As for immune deficiency syndromes associated with HLH, CHS, and GS, both have abnormalities of cellular granules. CHS typically features albinism and recurrent pyogenic infections due to deficient white blood cells with decreased chemotaxis and containing giant lysosomal inclusion bodies. GS also features albinism/hypopigmentation and neutrophil dysfunction. XLPS is associated with a marked vulnerability to EBV infection and subsequent viral-associated HLH and an immune system predisposed to lymphomas and dysgammaglobulinemia. 18 Up to 60% of patients may develop EBV-HLH in this rare condition. Other conditions associated with a predisposition to HLH and reported in the literature include common variable immunodeficiency, 197, 198 renal transplant patients, 144, 199 Hermansky-Pudlak syndrome, 200, 201 to name a few.