the term hemophagocytosis describes the pathologic finding of activated macrophages , engulfing erythrocytes , leukocytes , platelets , and their precursor cells . hlh is an unusual syndrome characterized by fever , splenomegaly , jaundice , and the pathologic finding of hemophagocytosis ( phagocytosis by macrophages of erythrocytes , leukocytes , platelets , and their precursors ) in bone marrow and other tissues . we report an adult patient who presented with systemic inflammatory response syndrome and features consistent with severe sepsis and septic shock , who subsequently received a diagnosis of secondary hlh . we reviewed the relationship between hlh and septic shock from the perspective of an intensivist . a 50 years female presented to intensive care unit ( icu ) with fever , rash , and loss of appetite . she was admitted in an outside hospital with 24 h of epigastric abdominal pain radiating to her flanks . there was no history of night sweats , weight loss , new medications , or toxin exposure . on admission , she presented with a temperature of 38.5c , a heart rate of 120/min , and an erythematous scaling rash covering over 50% of her body surface area , with increased scaling over her scalp . her abdomen was soft and nontender , with splenomegaly palpable 3 cm below the costal margin . there was no peripheral lymphadenopathy , and the rest of her physical exam was unremarkable . her initial blood work consisted of an elevated ferritin and lactic acid dehydrogenase ( ldh ) level , pancytopenia , acute kidney injury , hepatitis , and hypofibrinogenemia . broad - spectrum empirical antibiotics were administered for the presumed diagnosis of sepsis , but without apparent benefit . over a period of 24 days , she developed pressor - dependent hypotension , acute respiratory distress syndrome ( ards ) , acute kidney injury , bicytopenia ( anemia and thrombocytopenia ) , deranged liver functions ( transaminitis ) , and coagulopathy ; and increased inflammatory markers c - reactive protein and patent cooperation treaty . the clinical course in this patient met the criteria for severe sepsis and septic shock except in that it was unclear whether associated infections were causative . persistent fever , severe pancytopenia , hyperferritinemia , hypertriglyceridemia , increased ldh , and splenomegaly eventually prompted bone marrow aspiration ( bma ) leading to the diagnosis of hlh . no family history of hlh was found , and a primary familial form was considered unlikely . according to the computed tomography ( ct ) scan and bone marrow biopsy results , no hematological malignancy was thought to be responsible for a secondary form . despite an extensive multi - site sampling and serological studies , laboratory tests for viral infection including epstein - barr virus , cytomegalovirus , herpes simplex virus , viral hepatitis b and c , hiv were unremarkable . prolonged fever , splenomegaly , bicytopenia , hypofibrinogenemia , hyperferritinemia , and hypertriglyceridemia confirmed the diagnosis of hfs . the delay in diagnosis due to its rare incidence leads the patient to secondary sepsis in spite of aggressive and symptomatic treatment . hlh is a rare disease characterized by uncontrolled proliferation of mature histiocytes , hemophagocytosis , and up - regulation of inflammatory cytokines . the more typical findings are fever , peripheral cytopenia affecting two lineages at least , hepatosplenomegaly , hypertriglyceridemia and/or hypofibrinogenemia , and hemophagocytosis . recently , the histiocyte society updated its guidelines and proposed to add three diagnostic criteria : hyperferritinemia decreased or absent natural killer ( nk ) cell activity , and high soluble interleukin-2 receptor serum levels . they were present in our patient , who developed high persistent fever , severe pancytopenia , splenomegaly on abdominal ct scan , and very high plasma levels of ferritin , triglycerides , and ldh . the hlh-2004 diagnostic criteria considered the gold standard are largely based on studies of children with familial hlh . many of the criteria have poor operating characteristics when considered in the differential diagnosis of septic shock in adults . fever , anemia , thrombocytopenia , hypofibrinogenemia , and hypertriglyceridemia are common features of both syndromes . several studies show that hyperferritinemia consistent with hlh ( > 500 g / l ) occurs in the majority of adults with septic shock . the sensitivity of diagnostic criteria such as hypertriglyceridemia , hypofibrinogenemia , and splenomegaly may be no better than about 50% . the sensitivity of nk cell activity and soluble cd-25 levels approaches 100% , but these tests are not widely available . a strict requirement to fulfill five hlh-2004 diagnostic criteria in the adult patient in an icu could delay potentially lifesaving therapy . other available hlh-2004 criteria should be used in conjunction , with consideration of the limitations in their operating characteristics and logistics in the icu . in our opinion , hlh treatment should be considered in patients with the clinical syndrome of unremitting severe sepsis and/or septic shock with bicytopenia or pancytopenia , elevated ferritin levels , prompting for a bma , which will show histiocytic hemophagocytosis . therapy should be started in all cases with high suspicion after diagnostic tests have been initiated , but regardless of whether the results of all examinations have been obtained . among patients who are acutely ill or deteriorating , we suggest hlh - specific therapy based on the hlh-94 protocol or enrollment in a clinical trial rather than treatment based on the hlh-2004 protocol . hlh-94-based therapy includes etoposide and dexamethasone given at tapering doses over 8 weeks , with intrathecal methotrexate and hydrocortisone for those with central nervous system involvement . additional supportive measures include transfusion of blood products as indicated , induction of amenorrhea , and use of prophylactic antibiotics . the response to initial therapy is a major factor in determining the need for additional therapy including hematopoietic cell transplant . a short course of intravenous ( iv ) methylprednisolone ( 12 mg / kg / d ) is often sufficient in treating hs associated with secondary infections . this treatment is given in concert with adequate anti infectious agents , and it must be administered for the shortest time necessary for correction of the most life - threatening symptoms associated with hs because of the added immunosuppression in the context of severe infection . new antiviral drugs such as cidofovir or ribavirin and rituximab ( anti - cd20 antibody ) may be useful . consideration should be given to the use of iv immunoglobulin in infection - associated hs , to minimize the risk of immunosuppression . importantly , however , the initiation of hlh - specific therapy for severely ill patients should not be delayed while awaiting resolution of a system infection . clinicians are encouraged to enter patients in clinical trials such as the hybrid immunotherapy for hlh trial in the united states ( hit - hlh ; nct01104025 ) or the euro - hit - hlh trial in europe ( eudract201100205214 ) . further study of hlh , may provide important insights into the optimal treatment of sepsis , perhaps leading to the identification of a subset of patients with sepsis in which tissue damage secondary to a hyper inflammatory state might be ameliorated by immunosuppressive therapy .