We describe for the first time a case of macrophage activation syndrome in a child with hyperimmunoglobulinemia D with periodic fever syndrome who required intensive care support. Up-regulated monokine production, high serum levels of triglycerides and ferritin, clotting abnormalities with hypofibrinogenemia, and rapidly evolving pancytopenia should alert the clinician to the possible diagnosis of macrophage activation syndrome, even in autoinflammatory diseases characterized basically by the periodic recurrence of unprovoked inflammatory attacks. Bone marrow aspiration showing well-differentiated macrophages phagocytosing hematopoietic elements remains the main tool for a final diagnosis, and cyclosporine is the best strategy for treatment.

BackgroundHemophagocytic syndrome (HPS) is clinically defined as a combination of fever, liver dysfunction, coagulation abnormalities, pancytopenia, progressive macrophage proliferation throughout the reticuloendothelial system, and cytokine over-production, and may be primary or secondary to infectious, auto-immune, and tumoral diseases. The most consistent association is with viral infections but, as it is still debated whether any micro-organisms are involved in its pathogenesis, we critically appraised the literature concerning HPS and its relationship with infections.DiscussionInfection-dependent HPS has been widely observed, but there are no data concerning its incidence in children. A better understanding of the pathophysiology of HPS may clarify the interactions between the immune system and the variously implicated potential infectious agents. Epstein-Barr virus (EBV) infection has been prominently associated with HPS, with clonal proliferation and the hyperactivation of EBV-infected T cells. However, a number of other viral, bacterial, fungal, and parasitic infections have been reported in association with HPS. In the case of low-risk HPS, corticosteroids and/or intravenous immunoglobulin or cyclosporine A may be sufficient to control the biological process, but etoposide is recommended as a means of reversing infection-dependent lymphohistiocytic dysregulation in high-risk cases.SummaryHPS is a potential complication of various infections. A polymerase chain reaction search for infectious agents including EBV, cytomegalovirus and Leishmania is recommended in clinical settings characterised by non-remitting fever, organomegaly, cytopenia and hyperferritinemia.

Hyperimmunoglobulinemia D/periodic fever syndrome is caused by recessively inherited mutations in the mevalonate kinase gene and is characterized by persistently high polyclonal serum IgD titre and recurrent febrile attacks. No conventional therapy exists for preventing the typical recurrent inflammatory picture of patients. A host of studies have evidenced that elevated levels of various cytokines, such as interleukin-1 (IL-1), mark febrile attacks in this disease and that IL-1 might represent a suitable therapeutic target. We describe the case of a 7-year-old female-child with an established diagnosis of hyperimmunoglobulinemia D/periodic fever syndrome in whom anakinra, IL-1 receptor antagonist, was daily administered at the dosage of 1 mg/kg/day by subcutaneous injection for 18 months after numerous disappointing attempts with non-steroidal anti-inflammatory drugs, steroids, colchicine and etanercept through the years. The clinical response under anakinra treatment was recorded through a standardized diary, whilst inflammation parameters were serially measured in comparison with the half-year before starting anakinra. Frequency and severity of fever attacks were totally reduced by anakinra and this is the first child demonstrating that symptoms of hyperimmunoglobulinemia D/periodic fever syndrome might be at least extenuated by anakinra, though not abolished.

This paper emphasizes and discusses the medical approach with anakinra in CINCA syndrome presenting with hydrocephalus in which a consistent control of the neurological picture can be obtained.