Hämophagozytische Syndrome beim Erwachsenen

Zusammenfassung

Die Hämophagozytische Lymphohistiozytose (HLH) ist ein Zytokinsturm-Syndrom, das bei Erwachsenen in der Regel durch Malignome, Infektionen oder autoinflammatorische/autoimmunologische Erkrankungen ausgelöst wird. In der Rheumatologie ist das Erkrankungsbild besser als Makrophagenaktivierungs-Syndrom bekannt (MAS-HLH). Die HLH entsteht auf dem Boden eines genetisch bedingten und/oder erworbenen dysfunktionalen Immunsystems. Im Unterschied zur hereditären primären HLH (pHLH) bei Kindern findet sich bei der adulten, zumeist sekundären HLH (sHLH) nur sehr selten eine monogenetische Ursache. In Einzelfällen kann sich aber eine „late onset“-genetische HLH auch erst im Erwachsenenalter manifestieren. Die Diagnose von HLH und MAS wird verzögert durch die unspezifische Symptomatik (Fieber, Zytopenie, Ferritinanstieg, Splenomegalie, Multiorganversagen), die sich mit der Grunderkrankung oder einem SIRS überlagern kann. Die namengebende Hämophagozytose lässt sich nur bei einem Teil der Patienten nachweisen. sHLH und MAS-HLH weisen unbehandelt eine hohe Mortalität auf. Diagnosekriterien für pHLH und MAS sowie das standardisierte HLH-2004-Therapieprotokoll wurden in der Pädiatrie kontinuierlich in klinischen Studien entwickelt. In angepasster Form werden Kriterien und Substanzen des pädiatrischen HLH-Protokolls auch bei Erwachsenen angewendet. Zunehmend kommen neue Therapien zum Einsatz, welche die Hyperzytokinämie und deren Auswirkungen bei HLH und MAS bremsen (z. B. Ruxolitinib oder Anakinra). Der folgende Artikel soll eine Übersicht zu Epidemiologie, Diagnostik und Therapie von HLH und MAS bei Erwachsenen geben.

Abstract

Adult haemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome that is usually triggered by malignancies, infection or autoinflammatory/autoimmunological diseases. In rheumatology, HLH is better known as macrophage activation syndrome (MAS-HLH). HLH is the result of a genetically determined and/or acquired dysfunctional immune system. In contrast to hereditary primary HLH (pHLH) in children, HLH in adults is termed acquired or secondary HLH (sHLH). Monogenic disease in adult HLH is rare except for individual cases of a “late-onset” manifestation of genetic disease. The diagnosis of HLH and MAS is often delayed due to unspecific symptoms (fever, cytopenia, highly elevated ferritin, splenomegaly, multiorgan failure), which can overlap with the underlying disease or SIRS. The name-giving haemophagocytosis is only detected in a subfraction of patients. sHLH and MAS are associated with significantly increased mortality if left untreated. Diagnostic criteria for pHLH and sJIA-MAS as well as the standardised HLH-2004 therapy protocol have been continuously developed in paediatric clinical studies. In an adapted form, these criteria and individual elements of the paediatric protocol are also used for adults. Novel molecular therapies are increasingly being used to slow down hypercytokinaemia and its detrimental effects in HLH and MAS (e. g. ruxolitinib, anakinra, tocilizumab). This review article aims to provide an overview of the epidemiology, diagnostics and therapy of HLH and MAS in adults.

Schlüsselwörter

Adulte HLH - Hämophagozytische Lymphohistiozytose - Makrophagenaktivierungssyndrom

Key words

adult HLH - macrophage activation syndrome - haemophagocytic lymphohistiocytosis

Publication History

Article published online:
16 November 2020

• Literatur

• 1 Bykowa O. Zur Frage der Systemretikulose. Virchows Arch Pathol Anat Physiol Klin Med 1929; 273: 255-265
• 2 Scott RB, Robb-Smith AHT. Histiocytic Medullary Reticulosis. The Lancet 1939; 2: 194-198
• 3 Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child 1952; 27: 519-525
• 4 Risdall RJ, McKenna RW, Nesbit ME. et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979; 44: 993-1002
• 5 Stéphan JL, Zeller J, Hubert P. et al. Macrophage activation syndrome and rheumatic disease in childhood: a report of four new cases. Clin Exp Rheumatol 1993; 11: 451-456
• 6 Schulert GS, Canna SW. Convergent pathways of the hyperferritinemic syndromes. Int Immunol 2018; 30: 195-203
• 7 Emile J-F, Abla O, Fraitag S. et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 2016; 127: 2672-2681
• 8 Karakike E, Giamarellos-Bourboulis EJ. Macrophage Activation-Like Syndrome: A Distinct Entity Leading to Early Death in Sepsis. Front Immunol 2019; 10: 55
• 9 Colafrancesco S, Alessandri C, Conti F. et al. COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome?. Autoimmun Rev 2020; 19: 102573
• 10 Ramos-Casals M, Brito-Zerón P, López-Guillermo A. et al. Adult haemophagocytic syndrome. The Lancet 2014; 383: 1503-1516
• 11 Mao H, Tu W, Qin G. et al. Influenza virus directly infects human natural killer cells and induces cell apoptosis. J Virol 2009; 83: 9215-9222
• 12 Chuang H-C, Lay J-D, Hsieh W-C. et al. Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome. Blood 2005; 106: 3090-3096
• 13 Sumegi J, Barnes MG, Nestheide SV. et al. Gene expression profiling of peripheral blood mononuclear cells from children with active hemophagocytic lymphohistiocytosis. Blood 2011; 117: e151-e160
• 14 Miettunen PM, Narendran A, Jayanthan A. et al. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatol Oxf Engl 2011; 50: 417-419
• 15 Cifaldi L, Prencipe G, Caiello I. et al. Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol Hoboken NJ 2015; 67: 3037-3046
• 16 Strippoli R, Carvello F, Scianaro R. et al. Amplification of the response to Toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage activation syndrome. Arthritis Rheum 2012; 64: 1680-1688
• 17 Miao Y, Zhu H-Y, Qiao C. et al. Pathogenic Gene Mutations or Variants Identified by Targeted Gene Sequencing in Adults With Hemophagocytic Lymphohistiocytosis. Front Immunol 2019; 10: 395
• 18 Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts. Curr Opin Pediatr 2012; 24: 9-15
• 19 Ishii E, Ohga S, Imashuku S. et al. Nationwide Survey of Hemophagocytic Lymphohistiocytosis in Japan. Int J Hematol 2007; 86: 58-65
• 20 Birndt S, Schenk T, Heinevetter B. et al. Hemophagocytic lymphohistiocytosis in adults: collaborative analysis of 137 cases of a nationwide German registry. J Cancer Res Clin Oncol 2020; 146: 1065-1077
• 21 Kim J-M, Kwok S-K, Ju JH. et al. Reactive Hemophagocytic Syndrome in Adult Korean Patients with Systemic Lupus Erythematosus: A Case-Control Study and Literature Review. J Rheumatol 2012; 39: 86-93
• 22 Ahn SS, Yoo B-W, Jung SM. et al. In-hospital mortality in febrile lupus patients based on 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome. Semin Arthritis Rheum 2017; 47: 216-221
• 23 Tada Y, Inokuchi S, Maruyama A. et al. Are the 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome applicable to patients with adult-onset Still’s disease?. Rheumatol Int 2019; 39: 97-104
• 24 Ahn SS, Yoo B-W, Jung SM. et al. Application of the 2016 EULAR/ACR/PRINTO Classification Criteria for Macrophage Activation Syndrome in Patients with Adult-onset Still Disease. J Rheumatol 2017; 44: 996-1003
• 25 Carter SJ, Tattersall RS, Ramanan AV. Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatol Oxf Engl 2019; 58: 5-17
• 26 Gavand P-E, Serio I, Arnaud L. et al. Clinical spectrum and therapeutic management of systemic lupus erythematosus-associated macrophage activation syndrome: A study of 103 episodes in 89 adult patients. Autoimmun Rev 2017; 16: 743-749
• 27 Liu A-C, Yang Y, Li M-T. et al. Macrophage activation syndrome in systemic lupus erythematosus: a multicenter, case-control study in China. Clin Rheumatol 2018; 37: 93-100
• 28 Kishida D, Sakaguchi N, Ueno K-I. et al. Macrophage activation syndrome in adult dermatomyositis: a case-based review. Rheumatol Int 2020; 40: 1151-1162
• 29 Sandler RD, Tattersall RS, Schoemans H. et al. Diagnosis and Management of Secondary HLH/MAS Following HSCT and CAR-T Cell Therapy in Adults; A Review of the Literature and a Survey of Practice Within EBMT Centres on Behalf of the Autoimmune Diseases Working Party (ADWP) and Transplant Complications Working Party (TCWP). Front Immunol 2020; 11: 524
• 30 La Rosée P, Horne A, Hines M. et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood 2019; 133: 2465-2477
• 31 Henter J-I, Horne A, Aricó M. et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48: 124-131
• 32 Gars E, Purington N, Scott G. et al. Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis. Haematologica 2018; 103: 1635-1641
• 33 Schram AM, Campigotto F, Mullally A. et al. Marked hyperferritinemia does not predict for HLH in the adult population. Blood 2015; 125: 1548-1552
• 34 Hayden A, Lin M, Park S. et al. Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv 2017; 1: 2529-2534
• 35 Tabata C, Tabata R. Possible prediction of underlying lymphoma by high sIL-2R/ferritin ratio in hemophagocytic syndrome. Ann Hematol 2012; 91: 63-71
• 36 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: 2613-2620
• 37 Ravelli A, Minoia F, Davì S. et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis 2016; 75: 481-489
• 38 Schulert GS, Minoia F, Bohnsack J. et al. Effect of Biologic Therapy on Clinical and Laboratory Features of Macrophage Activation Syndrome Associated With Systemic Juvenile Idiopathic Arthritis. Arthritis Care Res 2018; 70: 409-419
• 39 Ravelli A, Minoia F, Davì S. et al. Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. RMD Open 2016; 2: e000161
• 40 Minoia F, Bovis F, Davì S. et al. Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Ann Rheum Dis 2019; 78: 1357-1362
• 41 Ravelli A, Davì S, Minoia F. et al. Macrophage Activation Syndrome. Hematol Oncol Clin North Am 2015; 29: 927-941
• 42 Shimizu M, Nakagishi Y, Inoue N. et al. Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Clin Immunol 2015; 160: 277-281
• 43 Inoue N, Shimizu M, Tsunoda S. et al. Cytokine profile in adult-onset Still’s disease: Comparison with systemic juvenile idiopathic arthritis. Clin Immunol 2016; 169: 8-13
• 44 Ichida H, Kawaguchi Y, Sugiura T. et al. Clinical Manifestations of Adult-Onset Still’s Disease Presenting With Erosive Arthritis: Association With Low Levels of Ferritin and Interleukin-18. Arthritis Care Res 2014; 66: 642-646
• 45 Nagafuji K, Nonami A, Kumano T. et al. Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis. Haematologica 2007; 92: 978-981
• 46 Bergsten E, Horne A, Aricó M. et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood 2017; 130: 2728-2738
• 47 Imashuku S, Kuriyama K, Sakai R. et al. Treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in young adults: A report from the HLH studyl center. Med Pediatr Oncol 2003; 41: 103-109
• 48 Henter J-I, Chow C-B, Leung C-W. et al. Cytotoxic therapy for severe avian influenza A (H5N1) infection. The Lancet 2006; 367: 870-873
• 49 Wang Y, Huang W, Hu L. et al. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis. Blood 2015; 126: 2186-2192
• 50 Greil C, Roether F, La Rosée P. et al. Rescue of Cytokine Storm Due to HLH by Hemoadsorption in a CTLA4-Deficient Patient. J Clin Immunol 2017; 37: 273-276
• 51 Nusshag C, Morath C, Zeier M. et al. Hemophagocytic lymphohistiocytosis in an adult kidney transplant recipient successfully treated by plasmapheresis: A case report and review of the literature. Medicine (Baltimore) 2017; 96: e9283
• 52 Kahn PJ, Cron RQ. Higher-dose Anakinra Is Effective in a Case of Medically Refractory Macrophage Activation Syndrome. J Rheumatol 2013; 40: 743-744
• 53 Cavalli G, Luca GD, Campochiaro C. et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol 2020; 2: e325-e331
• 54 Goldsmith SR, Saif Ur Rehman S, Shirai CL. et al. Resolution of secondary hemophagocytic lymphohistiocytosis after treatment with the JAK1/2 inhibitor ruxolitinib. Blood Adv 2019; 3: 4131-4135
• 55 La Rosée P. Alleviating the storm: ruxolitinib in HLH. Blood 2016; 127: 1626-1627