We searched Medline and Embase for articles published from Jan 1, 1974, to Sept 29, 2011, with the term “hemophagocytic syndrome”. We selected articles that included adult cases (age >17 years) in which the cause of haemophagocytic syndrome was clearly detailed. Duplicate publications, paediatric cases, experimental studies, and articles with incomplete or irrelevant information were excluded. We selected articles that described clinical series in adults (including at least ten patients) to
SeminarAdult haemophagocytic syndrome
Introduction
Haemophagocytic syndrome is an immune-mediated life-threatening disease, which was first described in 1939 by paediatricians Scott and Robb-Smith,1 and is caused by impaired natural killer and cytotoxic T-cell function. Clinically, the syndrome is characterised by fever, hepatosplenomegaly, and cytopenia and the finding of activated macrophages in haemopoietic organs. It has been given several different names, including macrophage activation syndrome, which was used for patients with rheumatological diseases such as juvenile idiopathic arthritis.2 In 1991, the Histiocyte Society proposed the name haemophagocytic lymphohistiocytosis.3
Haemophagocytic lymphohistiocytosis can occur at any age, but most clinical guidelines, prospective studies, and treatment trials have focused on paediatric patients. Little scientific analysis of adult haemophagocytic lymphohistiocytosis has been done, although an observational study4 in almost 300 Japanese hospitals identified that 40% of haemophagocytic lymphohistiocytosis cases occur in adults. This Seminar updates our current knowledge of haemophagocytic lymphohistiocytosis and focuses mainly on clinical aspects that might help specialists treating adults with haemophagocytic lymphohistiocytosis.
Section snippets
Epidemiology
Haemophagocytic lymphohistiocytosis is a rare disease, with an estimated yearly incidence of one per 800 000 people and one to ten per 1 million children in Italy, Sweden, and the USA.5, 6, 7, 8 Geographical variability is a key epidemiological characteristic of haemophagocytic lymphohistiocytosis. Figure 1 summarises the country of origin and causes of 2197 reported (panel 1) cases of adult haemophagocytic lymphohistiocytosis—identified in our search strategy—of which almost 50% are in Japan.
Causes
Haemophagocytic lymphohistiocytosis has traditionally been classified according to the cause of disease and is divided into primary (genetic) and secondary (reactive), which are subclassified as viral, autoimmune, or neoplasia related;40 although nearly a third of reported cases in adults have more than one underlying cause. In children, underlying genetic defects play a predominant part in the development of haemophagocytic lymphohistiocytosis. In adults, the two main groups of causative
Pathophysiology
A defect in granule mediated cytotoxicity, which is important in killing cells,50 is the underlying common mechanism in both genetic and reactive forms of haemophagocytic lymphohistiocytosis. The perforin and Fas systems play a part in the maintenance of homoeostasis of dendritic cells and restrict T-cell activation by antigen presentation.51 Enhanced antigen presentation and repeated interferon γ-dependent stimulation of Toll-like receptors are postulated as causal mechanisms of the
Clinical presentation
The first symptoms of haemophagocytic lymphohistiocytosis are non-specific with a generally acute or subacute (1–4 weeks) clinical presentation.13, 19, 21 The cardinal features are continuous high fever (>38·5°C) and enlarged lymphohaemopoietic organs (adenopathies and hepatosplenomegaly) on examination. A quarter of adult patients might also have non-specific cutaneous involvement, including erythematous rashes, oedema, petechiae, or purpura; special attention should be paid to subcutaneous,
Diagnosis
Haemophagocytic lymphohistiocytosis should be suspected in patients presenting with unattributable, continuous high fever, and evidence of multiple organ involvement. Some laboratory findings might support the clinical suspicion together with histopathological evidence of haemophagocytosis (panel 2). Therefore, diagnosis of haemophagocytic lymphohistiocytosis relies on the coexistence of various clinical, laboratory, and histopathological findings, although none are pathognomonic alone. The
Differential diagnosis
The first diagnostic challenge is to differentiate whether the clinical picture is due to haemophagocytic lymphohistiocytosis or a severe presentation of infection, autoimmune disease, or neoplastic disease associated with haemophagocytic lymphohistiocytosis. In previously healthy people, a clinical picture resembling haemophagocytic lymphohistiocytosis might be seen in presentations of viral primary infections or the onset of neoplastic or autoimmune disease. In patients with underlying
Supportive treatments
The theoretical basis for treatment of haemophagocytic lymphohistiocytosis requires a triple simultaneous approach. First, support measures are essential because of frequent life-threatening presentation. Second, the elimination of triggers (mainly infection) is crucial to remove the stimuli that initiate abnormal immune system activation. Third, suppression of the inflammatory response and cell proliferation (neoplasia), or both, by immunosuppressive and cytotoxic drugs, respectively, is
Specific treatments
No randomised, controlled clinical trials have investigated potential treatments for haemophagocytic lymphohistiocytosis. All treatment studies in adults have been uncontrolled and retrospective and included less than 20 patients (table 2).34, 91, 92, 93, 94, 95, 96, 97 Likewise, most studies have investigated drugs at different doses and in various combinations. Therefore, treatment decisions continue to be based on clinical experience and expert opinion.
Active infections in a patient with
Follow-up and patient outcome
Close clinical and biological follow-up is essential during the first weeks of treatment because absence of response at 2–3 weeks is often a sign of refractory haemophagocytic lymphohistiocytosis. C-reactive protein concentration and erythrocyte sedimentation rate might be useful to monitor disease activity and assess intercurrent bacterial infection or therapeutic response. Some studies30, 110 have suggested an association between the therapeutic response and a rapid reduction in laboratory
Future perspectives
The very broad pathogenic scenario of haemophagocytic lymphohistiocytosis, in which genetic defects, predisposing diseases, and triggers of different causes are mixed together with the high mortality rate, makes the disease one of the most complicated disorders. Although most efforts have focused on investigation of the disease in children, this tendency has changed in recent years and various studies are trying to shed light on adult haemophagocytic lymphohistiocytosis.
Risma and Jordan121 have
Conclusion
Haemophagocytic lymphohistiocytosis is an increasingly recognised disorder in adults. It has a life-threatening clinical presentation that affects a wide range of organ systems. Haemophagocytic lymphohistiocytosis manifests in patients with a range of underlying diseases but, unlike in children where the study of haemophagocytic lymphohistiocytosis is led by paediatricians, in adults many medical specialties are involved. We show that there is little evidence for adult haemophagocytic
Search strategy and selection criteria
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