Multiorgan failure due to hemophagocytic syndrome: A case report
© Mayordomo-Colunga et al; licensee BioMed Central Ltd. 2008
Received: 28 August 2008
Accepted: 03 October 2008
Published: 03 October 2008
Hemophagocytic syndrome (HFS) is a potentially lethal disorder due to an uncontrolled immune response to a triggering agent. Our objective is to raise the importance of HFS early diagnosis by presenting a representative case.
A sixteen-year-old girl with Still disease diagnosis developed a progressive multiorgan failure including acute respiratory distress (ARDS), anemia and thrombopenia, elevated liver enzymes, renal failure, coagulopathy with hypofibrinogenemia, and acute phase reactants elevation despite broad-spectrum antibiotics. A bone marrow puncture-biopsy was performed, and hemophagocytosis was found. Prolonged fever, splenomegaly, bicytopenia, hypofibrinogenemia, hyperferritinemia and hypertriglyceridemia confirmed HFS diagnosis. She received intensive care support therapy including mechanical ventilation and specific therapy according to HLH 2004 protocol, with a very good response.
Our case shows complexity of HFS diagnosis, due to septic shock-like manifestations. Early diagnosis is essential to start appropriate treatment achieving a better outcome.
Hemophagocytic syndrome (HFS) is a rare disorder characterized by prolonged fever, cytopenias, hepatosplenomegaly, hypertriglyceridemia, disseminated intravascular coagulation (DIC)-like coagulopathy and bone marrow, spleen, liver or lymphatic nodes histiocytosis [1–3]. A sudden presentation, like a septic shock is possible making its early recognition a challenging diagnosis . It is well known that HFS could be a severe complication in some infections (mainly virals) or in some underlying diseases, such as chronic juvenile arthritis (CJA) [3, 5, 6]. Moreover, it is one of the differential diagnosis in fever of unknown origin .
Blood analysis on admission
12.200/mm3 (with a marked left shift)
Direct bilirrubin directa
C reactive protein
A high positive end-expiratory pressure (PEEP) was set due to hypoxemia (up to 14 cmH2O), with a PO2/FiO2 of 141. Thorax radiography showed bilateral diffuse infiltrates, and slight cardiomegaly. Inotropic support was needed (dopamine at 15 μg/kg/minute) and a perfusion with furosemide (0.5 mg/kg/hour) was started. Laboratory analysis showed abnormal values for haemoglobin (7.7 g/dL), platelets (29,000/mm3) and coagulation times including hypofibrinogenemia (85 mg/dL). She received red blood cell concentrates, platelets and fresh frozen plasma. The same antibiotherapy was maintained and acute liver failure support treatment was started.
She is currently being followed as an outpatient. She had two reactivations of her rheumatoid disorder, with a good response to corticoids.
HFS is an activation of mononuclear phagocyte system cells, with hemophagocytosis in bone marrow and the rest of reticuloendothelial system. This syndrome can be either primary/familial (familial hemophagocytic lymphohistiocytosis – FHL) or reactive/secondary. FHL has a recessive autosomal inheritance and it develops in children younger than 2 years, even though in rare cases it can feature later on . It is rapidly lethal and it is sometimes related to some immunological diseases (X-linked lympho-proliferative, Chediak Higashi and Griscelli syndromes).
Secondary HFS has a better outcome than primary HFS. It is triggered mainly by viral infections (especially Ebstein-Barr virus) , and also by bacterial, parasitic and fungal infections. It can also develop during malignancies and rheumatoid disorders (kwown in this case as macrophagic activation syndrome), as in our patient .
The activation of mononuclear system cells occurs due to a hypersecretion of proinflammatory cytokines (IFNγ, TNFα, IL6, IL10, M-CSF), as a consequence of a triggering agent, which is often a viral infection . The underlying problem is a T and Natural Killers cells dysfunction, which leads to an uncontrolled immunological response  due to inability to eliminate the triggering agent. All viral, bacterial, parasitic and fungal cultures performed in our case were negative.
Impaired perforine function due to gene mutations seems to play an important role in HFS pathogenesis, as reported in literature . They are implicated in cytotoxicity by forming a death-inducing pore in target cell .
HFS diagnosis is made basing on clinical and histological criteria. Five out of 8 criteria must be fulfilled. Absence of hemophagocytosis does not exclude the diagnosis . Multiorgan failure is the most severe presentation of HFS. In pediatrics, multiorgan failure is usually caused by sepsis. In the present case, the initial diagnosis was septic shock. Therefore, HFS has to be included between the causes of multiorgan failure in pediatrics to permit an early diagnosis and treatment. Central nervous system (CNS) is often involved, which has been linked with a poor prognosis . Even though our patient developed a very severe form of HFS, there seemed to be no CNS involvement, and this agrees with the good outcome.
Treatment is nowadays applied according to HLH 2004 protocol, which is designed for primary HFS and also used in severe secondary HFS cases. Aggressive immunochemotherapy is given (dexamethasone, cyclosporine A, etoposide and in patients with CNS symptoms or abnormal CSF, also intrathecal methotrexate and corticoids) . After initial treatment, bone marrow transplantation is indicated in primary disease and in severe and persistent secondary HFS .
Without treatment, this is a lethal disorder. Mortality is high depending in reactive HFS on underlying disorder. In Henter's study, in which 113 patients under 15 years of age were included, survival rate at 3.1 years was 51% in primary cases, while it was 55% in reactive ones. All patients had received treatment according to HLH 1994 protocol .
Our patient had a very good outcome, without any sequelae. Early recognition of this syndrome to apply specific therapy as well as multiorganic failure treatment in PICU, are management key factors. HFS is probably underdiagnosed, as multiorgan failure is usually explained by other more common causes like septic shock. 
Written informed consent was obtained from the patient and his parents for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
acute phase reactants
chronic juvenile arthritisl CNS: central nervous system
disseminated intravascular coagulation
familial hemophagocytic lymphohistiocytosis
macrophage colony-stimulating factor
positive end-expiratory pressure
pediatric intensive care unit
partial pressure of arterial oxygen/fraction of inspired oxygen ratio
tumor necrosis factor.
The authors gratefully acknowledge the assistance of the medical and nursing staff of our Pediatric Intensive Care Unit.
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