Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment?

Abstract

IntroductionHyperferritinemia is associated with increased mortality in pediatric sepsis, multiple organ dysfunction syndrome (MODS), and critical illness. The International Histiocyte Society has recommended that children with hyperferritinemia and secondary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) should be treated with the same immunosuppressant/cytotoxic therapies used to treat primary HLH. We hypothesized that patients with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS can be successfully treated with a less immunosuppressant approach than is recommended for primary HLH.MethodsWe conducted a multi-center cohort study of children in Turkish Pediatric Intensive Care units with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS treated with less immunosuppression (plasma exchange and intravenous immunoglobulin or methyl prednisolone) or with the primary HLH protocol (plasma exchange and dexamethasone or cyclosporine A and/or etoposide). The primary outcome assessed was hospital survival.ResultsTwenty-three children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS were enrolled (median ferritin = 6341 μg/dL, median number of organ failures = 5). Univariate and multivariate analyses demonstrated that use of plasma exchange and methyl prednisolone or intravenous immunoglobulin (n = 17, survival 100%) was associated with improved survival compared to plasma exchange and dexamethasone and/or cyclosporine and/or etoposide (n = 6, survival 50%) (P = 0.002).ConclusionsChildren with hyperferritinemia and secondary HLH/sepsis/MODS/MAS can be successfully treated with plasma exchange, intravenous immunoglobulin, and methylprednisone. Randomized trials are required to evaluate if the HLH-94 protocol is helpful or harmful compared to this less immune suppressive and cytotoxic approach in this specific population.

Prognostic Factors and Long-Term Outcome in 52 Turkish Children With Hemophagocytic Lymphohistiocytosis*

“…The identification of prognostic risk factors for early death in HLH is a challenging task (36)(37)(38)(39)(40). A previous comprehensive study in 232 children with HLH has suggested that hyperbilirubinemia, thrombocytopenia, hyperferritinemia (> 2,000), and persistent fever at diagnosis and at 2 weeks of HLH treatment are important risk factors predicting early death (36).…”

Hemophagocytic Lymphohistiocytosis Single Center Experience

“…Ferritin düzeyinin 500 mg/dl üzerinde olması tanı kriteri olarak kabul görürken, aynı zamanda tanıda 2000 mg/dl üzerin-deki değerlerin kötü prognozu işaret ettiği gösteril-miştir (4,9,15) . Tüm olgularımızda yüksek ateşle birlikte saptadığımız en sık bulgu değişik oranlarda bulunan ferritin yüksekliği oldu.…”

Pathogenesis of Systemic Inflammatory Diseases in Childhood: ?Lessons From Clinical Trials of Anti-Cytokine Monoclonal Antibodies for Kawasaki Disease, Systemic Onset Juvenile Idiopathic Arthritis, and Cryopyrin-Associated Periodic Fever Syndrome?

“…Blood values are reported to specifically show an elevation of inflammatory factors such as CRP and SAA, leukocytosis usually >15,000/μL with 70 to 90% mature neutrophils with no left shift, elevated levels of IL-6 and IL-18, an increased level of hemoxygenase (HO)-1 [48] and an elevation of the ferritin level [49]. Its clinical diagnosis, however, is made by exclusion of infectious disease, other rheumatic disease or malignancy including leukemia.…”

“…However, the pathophysiological mechanisms in macrophage activation syndrome have gradually become apparent, and clinical manifestations and the fluctuating laboratory parameters can be explained by the presence of excessive amounts of inflammatory cytokines [9]. Thus, macrophage activation syndrome can be managed at this time by the following approaches: alleviation of activated macrophages and dendritic cells by corticosteroids in addition to anticoagulant therapy; inhibition of the mitochondrial permeability transition by cyclosporine to deal with tissue/cellular injury caused by inflammatory cytokines; and plasma exchange to reduce excessive inflammatory cytokines [49]. These treatments are life-saving for most patients in our hospital.…”