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 .
 hemophagocytic lymphohistiocytosis is a clinic pathologic entity characterized by increased proliferation and activation of benign macrophages with hemophagocytosis throughout the reticuloendothelial system . 
 it is a potentially lethal disorder due to an uncontrolled immune response to a triggering agent . 
 hps may be primary , or secondary to malignancy , infections , auto - immune diseases , and pharmacotherapy . 
 hps is a rare , but life - threatening complication . 
 herein , we described a female patient with hps with secondary sepsis . 
 our objective was to raise the importance of early diagnosis of hfs by presenting a representative case . 
Introduction
Case Report
Discussion
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