Plasma Exchange, Methylprednisolone, IV Immune Globulin, and Now Anakinra Support Continued PICU Equipoise in Management of Hyperferritinemia-Associated Sepsis/Multiple Organ Dysfunction Syndrome/Macrophage Activation Syndrome/Secondary Hemophagocytic Lymphohistiocytosis Syndrome*
Year: 2014
Type: article
Abstract: Of the 75,000 children treated in the United States each year for severe septic shock (1), there is small subset that, in fact, has a pathologic activation of the immune system that can require a different set of diagnostic and therapeutic modalities. This hyperimmune state, characterized by a cytokine storm and systemic inflammatory response syndrome, can be divided into two broad categories: 1) primary degree familial hemophagocytic lymphohistiocytosis (FHLH) caused by an autosomal recessive mutation(s) in genes required for natural killer (NK) and CD8+ T cells to exocytose cytotoxic granules and kill viruses and cancer cells, as well as induce programmed cell death in activated immune cells, thereby limiting the host immune response and ability to turn off macrophage and lymphocyte activation and proliferation, and 2) hyperferritinemia-associated sepsis/multiple organ dysfunction syndrome (MODS)/macrophage activation syndrome (MAS)/secondary degree hemophagocytic lymphohistiocytosis (HLH) caused by pathologic immune activation in patients without a perforin-related genetic defect in NK or cytotoxic T lymphocyte (CTL) function. In 1994, to address the dismal 4% survival rate attributed to FHLH if left untreated (2), the Histiocyte Society launched a prospective multicenter study (HLH-94) using combined treatment with etoposide, cyclosporine A, and dexamethasone ± intrathecal methotrexate ± bone marrow transplantation that resulted in 55% 3-year survival (3). Unfortunately, as reported by Castillo and Carcillo (4), the clinical and laboratory criteria used for HLH-94, subsequently HLH-2004, have low specificity for FHLH. Genetic studies, although clinically available, require upwards of 3 weeks for results and are therefore used primarily to judge risk of recurrence and identify at-risk family members. NK-cell degranulation assays have shown promising results in a study by Bryceson et al (5); however, they are not widely available for clinical use. In pediatric sepsis, decreased NK activity is the norm, but it is related to acutely reduced numbers of NK cells leading to decreased NK activity per peripheral blood mononuclear cell (6) rather than decreased NK-cell granulation per cell which leads to decreased NK activity in FHLH. As a result of these limitations, and to ensure adequate treatment of children with FHLH, patients with hyperferritinemia-associated sepsis/MAS/MODS/secondary degree-HLH may be unnecessarily treated with highly immunosuppressive regimens. The current standard of care for sepsis/MODS/MAS is intensive care support for failing organ systems, appropriate antibiotics use, and limited immunosuppression (7–9). In septic patients, who often have normal individual NK-cell function but a reduced number of NK cells (6), the use of chemotherapeutic agents may prevent recovery of NK cell and CTL numbers leading to immunoparalysis and opportunistic secondary infections. Demirkol et al (7) published a cohort study comparing the HLH-94 protocol to a less immunosuppressive regimen for children with hyperferritinemia, hemophagocytosis, and sepsis/MODS/MAS/secondary degree-HLH. Their univariate and multivariate analysis demonstrated improved survival in children treated with plasma exchange and methylprednisolone (not dexamethasone) and/or IV immune globulin (IVIG) compared with children who received highly immunosuppressive regimens based on HLH-94 (survival 100% vs 50%; p = 0.002). The results suggest that patients with hyperferritinemia-associated sepsis/MAS/MODS/secondary degree-HLH can have improved outcomes with control of inflammation that does not cause significant immune suppression or prevention of NK-cell/CTL recovery. Anakinra (Kineret; Amgen, Thousand Oaks, CA), a recombinant interleukin (IL)-1 receptor antagonist, has been shown to control inflammation in multiple disease processes, including hemophagocytic syndromes (8–11), and would not be expected to cause significant cytopenias or risk of secondary infection. In this issue of Pediatric Critical Care Medicine, Rajasekaran et al (12) present a single-center case series of eight critically ill patients with hyperferritinemia-associated sepsis/MAS/MODS/secondary degree-HLH treated with anakinra. The diagnosis was based on HLH-2004 criteria which requires at least five of eight clinical features: fever, splenomegaly, cytopenia more than or equal to 2 cell lines, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis, hyperferritinemia more than or equal to 500 ng/mL, low NK-cell activity, and elevated soluble CD25. Ultimately, the diagnosis and decision to use anakinra was made in consultation with subspecialty services and after infectious etiologies had been excluded. Anakinra was started at median hospital day 5 (range, 3–13 d) and continued until there was improvement in patient symptoms and inflammatory markers (range, 5–31 d). Several children additionally received IV immunoglobulin and/or corticosteroids. The primary findings from this series are a mortality rate of 12% (1/8), a 67.1% decline in C-reactive protein (p = 0.03), and a 63.8% decline in ferritin (p = 0.3) after starting anakinra. Importantly, neutrophil and lymphocyte counts were not observed to change significantly and no infections were attributed to anakinra treatment. The report by Rajasekaran et al (12) is a retrospective case series and therefore primarily descriptive. Similar to other reports on HLH, there is difficulty and controversy in making a definitive diagnosis for these eight patients given the overlapping phenotypic presentations. However, their use of anakinra is supported by additional case reports and small case series of successful treatment for patients with hyperferritinemia-associated sepsis/MAS/MODS/secondary degree-HLH with and without the HLH-2004 protocol. Reports of anti-inflammatory management include the following: 1) Demirkol et al (7) treatment with plasma exchange, IVIG, and corticosteroids; 2) Teachey et al (13) report successful treatment of secondary degree-HLH associated with blinatumomab with IL-6 receptor-directed therapy; 3) interferon (IFN)-α was successful in two patients with reactive HLH (14) (possibly by inducing hepatic production of IL-1ra); and 4) several additional reports on the use of anakinra (8–11). In addition, a post hoc analysis by Shakoory et al (15) of the randomized placebo-controlled trial of anakinra in adults with severe sepsis finds anakinra infusion at 1–2 mg/kg/hr for 72 hours reduced mortality two-fold in adults with severe sepsis and MAS/hemophagocytic syndrome defined by hepatobiliary dysfunction and disseminated intravascular coagulation. Concurrently, our understanding of the pathophysiologic mechanisms and treatment of primary and secondary HLH/MAS are being advanced through basic and translational research. Animal models have been developed for FHLH using genetic knockouts, and more recently, a model of secondary HLH/MAS was reported using repeated immune stimulation in genetically normal animals (16). In this murine model, reported by Behrens et al (16), Toll-like receptor 9 (TLR9) of the innate immune system is stimulated with CpG oligodeoxynucleotides leading to cytopenias, splenomegaly, hyperferritinemia, and hepatitis. Similarly, in a murine model of peritonitis and liver injury, CpG injection is shown to induce cytokine production by macrophages and hepatic mononuclear cells with increased mortality (17). This hyperferritinemia-associated sepsis/MAS/MODS/secondary degree-HLH phenotype associated with TLR9 stimulation is exacerbated in knockout mice deficient in native hepatic IL-1ra production and ameliorated by IFN-α-induced production of IL-1ra or with direct administration of recombinant IL-1ra (anakinra) in vivo (18). In addition, a role for ferritin as a proinflammatory cytokine was demonstrated in hepatic stellate cells in vitro via nuclear factor-κB activation and increased expression of IL-1β, inducible nitric oxide synthase, and other proinflammatory mediators (19). Rosário et al (20) have proposed including four clinical syndromes commonly associated with hyperferritinemia—MAS, Still disease, septic shock, and catastrophic antiphospholipid syndrome—under a common syndrome termed “hyperferritinemia syndrome.” Developing phenotypes of pathologic immune activation, in addition to the phenotypes of patient symptoms, will continue to be important for the study and treatment of these patients moving forward. At present, without randomized studies in children, it is still reasonable to consider any approach from supportive management to anti-inflammatory management to use of HLH-94 protocol to manage children with hyperferritinemia-associated sepsis/MAS/MODS/secondary degree-HLH. For what it is worth, in our clinical practice, we use a “risk factors” approach as described by Demirkol et al (7). For patients meeting at least five of eight HLH-2004 criteria, we consider the following factors as high risk for FHLH: 2 years old or younger, consanguinity, death of a family member due to unspecified febrile illness, or primary CNS disease classified as high risk for primary HLH. For those who do not have these risk factors, we consider plasma exchange, solumedrol, IVIG, and anakinra which have all performed well in case series in this population or tocilizumab, daclizumab, and IFN-α which have also been successful in case reports for this group. Equipoise in the treatment of hyperferritinemia-associated sepsis/MAS/MODS/secondary degree-HLH is prudent until randomized clinical trials to guide therapy are evident.
Source: Pediatric Critical Care Medicine
Institutions: Pennsylvania State University, University of Pittsburgh
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2068658592