Abstract
Within the group of patients with sepsis, a subset will rapidly deteriorate and die early. These patients meet many of the features of the macrophage activation syndrome, characterized by fever, cytopenias of two or more lineages, hypertriglyceridemia or hypofibrinogenemia, hepatobiliary dysfunction, coagulopathy, encephalopathy, and bone marrow phagocytosis. Using the hemophagocytic lymphohistiocytosis (HLH)-2004 classification criteria or the HScore classification system, it is estimated that almost 3.5–5% of critically ill patients with sepsis suffer from macrophage activation syndrome. The hallmark of macrophage activation syndrome pathogenesis is a cytokine storm elicited by tissue macrophages, natural killer cells, and CD8 lymphocytes, with excess production of interleukin (IL)-1β and of interferon-gamma playing a major role. Since bone marrow aspirates cannot routinely be performed, diagnosis relies on biomarkers. Serum ferritin >4420 ng/ml provides 97.9% specificity and 97.1% negative predictive value for diagnosis and is associated with almost 67% mortality after 10 days. Retrospective analysis of a former trial in severe sepsis revealed that anakinra treatment that blocks IL-1β offered 30% reduction in 28-day mortality in patients with features of macrophage activation syndrome. The ongoing PROVIDE study (Clinicaltrials.gov Identifier: NCT0333225) that aims to prospectively assess the impact of anakinra in sepsis patients with macrophage activation syndrome is anticipated to enrich our knowledge on the prevalence of this condition among patients with septic shock and the therapeutic potential of anakinra.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Karakike E, Giamarellos-Bourboulis EJ. Macrophage activation-like syndrome: a distinct entity leading to early death in sepsis. Front Immunol. 2019;10:55.
Gars E, Purlington N, Chisholm K, et al. Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis. Haematologica. 2018;103:1635–41.
Henter JI, Horne AC, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;16:124–31.
Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66:2613–20.
Demirkol D, Yildizdas D, Bayrakci B, et al. Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment? Crit Care. 2012;16:R52.
John TM, Jacob CN, Ittycheria CC, et al. Macrophage activation syndrome following Acinetobacter baumannii sepsis. Int J Infect Dis. 2012;16:e223–4.
Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44:275–81.
Kappoor S, Morgan CK, Siddique MA, Gunrupalli KK. Intensive care unit complication and outcomes of adult patients with hemophagocytic lymphohistiocytosis: a retrospective study of 16 cases. World J Crit Care Med. 2018;7:73–83.
Lachmann G, Spies C, Schenk T, Brunkhorst F, Balzer F, La Rosée P. Hemophagocytic lymphohistocytosis: potentially underdiagnosed in intensive care units. Shock. 2018;50:149–55.
Meena NK, Sinokrot O, Duggal A, et al. The performance of diagnostic criteria for hemophagocytic lymphohistiocytosis in critically ill patients. J Intensive Care Med. 2019; March 12 https://doi.org/10.1177/0885066619837139, [Epub ahead of print].
Gualdoni GA, Hofmann GA, Wohlfarth P, et al. Prevalence and outcome of secondary hemophagocytic lymphohistocytosis among SIRS patients: results from a prospective cohort study. J Clin Med. 2019;8:541.
Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A, et al. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. BMC Med. 2017;15:172.
Crayne CB, Albeituini S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol. 2019;10:119.
Burn TN, Weaver L, Rood JE, et al. Genetic deficiency of IFNγ reveals IFNγ-independent manifestations of murine hemophagocytic lymphohistiocytosis. Arthritis Rheumatol. 2019; August 9, https://doi.org/10.1002/art.41076, [Epub ahead of print].
Ruscitti P, Cipriani P, DiBenedetto P, et al. H-ferritin and proinflammatory cytokines are increased in bone marrow of patients affected by macrophage activation syndrome. Clin Exp Immunol. 2017;191:220–8.
Karakike E, Adami ME, Lada M, et al. Late peaks of HMGB1 and sepsis outcome: evidence for synergy with chronic inflammatory disorders. Shock. 2019;52:334–9.
Cui Y, Xiong X, Ren Y, Wang F, Wnag C, Zhang Y. CD163 as a valuable diagnostic and prognostic biomarker of sepsis-associated hemophagocytic lymphohistiocytosis in critically ill children. Pediatr Blood Cancer. 2019;66:e27909.
La Rosée P, Horne AC, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133:2465–77.
Opal SM, Fisher CJ Jr, Dhainaut JF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med. 1997;25:1115–24.
Sönmez HE, Demir S, Bilginer Y, Özen S. Anakinra treatment in macrophage activation syndrome: a single center experience and systemic review of the literature. Clin Rheumatol. 2018;37:3329–35.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2020 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Giamarellos-Bourboulis, E.J., Netea, M.G. (2020). Macrophage Activation Syndrome in Sepsis: Does It Exist and How to Recognize It?. In: Vincent, JL. (eds) Annual Update in Intensive Care and Emergency Medicine 2020. Annual Update in Intensive Care and Emergency Medicine. Springer, Cham. https://doi.org/10.1007/978-3-030-37323-8_21
Download citation
DOI: https://doi.org/10.1007/978-3-030-37323-8_21
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-37322-1
Online ISBN: 978-3-030-37323-8
eBook Packages: MedicineMedicine (R0)