Prognostic Factors of Death in 151 Adults With Hemophagocytic Syndrome: Etiopathogenically Driven Analysis

Objective: To characterize the etiologies and clinical features at diagnosis of patients with hemophagocytic lymphohistiocytosis (HLH) and correlate these baseline features with survival using an etiopathogenically guided multivariable model.

Patients And Methods: The Spanish Group of Autoimmune Diseases HLH Study Group, formed in 2013, is aimed at collecting adult patients with HLH diagnosed in internal medicine departments between January 3, 2013, and October 28, 2017.

Results: The cohort consisted of 151 patients (91 men; mean age, 51.4 years). After a mean follow-up of 17 months (range, 1-142 months), 80 patients died. Time-to-event analyses for death identified a worse survival curve for patients with neoplasia (<.001), mixed microbiological infections (=.02), and more than 1 infection (=.01) and glucocorticoid monotherapy (=.02). According to univariate analyses, platelets of less than 100,000/mm (hazard ratio [HR], 3.39; 95% CI, 1.37-8.40), leukopenia (HR, 1.81; 95% CI, 1.01-3.23), severe hyponatremia (HR, 1.61; 95% CI, 1.02-2.54), disseminated intravascular coagulation (HR, 1.87; 95% CI, 1.05-3.34), bacterial infection (HR, 1.99; 95% CI, 1.09-3.63), mixed microbiological infections (HR, 3.42; 95% CI, 1.38-8.46), and 2 or more infectious triggers (HR, 2.95; 95% CI, 1.43-6.08) were significantly associated with death. In contrast, peripheral adenopathies (HR, 0.63; 95% CI, 0.40-0.98) and the immunosuppressive drug/intravenous immunoglobulin/biological therapies (HR, 0.44; 95% CI, 0.20-0.96) were protective against all-cause mortality. Multivariable Cox proportional hazards regression analysis identified 2 or more infectious triggers (HR, 3.14; 95% CI, 1.28-7.68) as the only variable independently associated with death.

Conclusion: The mortality rate of adult patients diagnosed with HLH exceeds 50%. Infection with more than 1 microbiological agent was the only independent variable associated with mortality irrespective of the underlying disease, epidemiological profile, clinical presentation, and therapeutic management.

Citing Articles

Hemophagocytic Lymphohistiocytosis (HLH) Following Immune Checkpoint Therapy (ICT).

Gajagowni S, Wang E, Wang J, Campbell M, Siddiqui B Case Rep Oncol Med. 2025; 2025():5582848.

PMID: 39816730 PMC: 11729509. DOI: 10.1155/crom/5582848.

Etoposide Therapy of Cytokine Storm Syndromes.

Henter J, von Bahr Greenwood T Adv Exp Med Biol. 2024; 1448:525-551.

PMID: 39117837 DOI: 10.1007/978-3-031-59815-9_35.

Patients with Hemophagocytic Lymphohistiocytosis Who Need Intensive Care Can Be Successfully Rescued by Timely Using Etoposide-Based HLH Regimens.

Lv K, Cheng X, Zhou Y, Yu M, Wang S, Shen H Int J Gen Med. 2024; 17:431-446.

PMID: 38333019 PMC: 10850986. DOI: 10.2147/IJGM.S443774.

Asian Variant Intravascular Lymphoma: A Look at the Laboratory Data of Lactase Dehydrogenase and Soluble Interleukin-2 Receptor.

Kakehi E, Kotani K Cureus. 2023; 15(12):e50243.

PMID: 38077686 PMC: 10710366. DOI: 10.7759/cureus.50243.

A clinical analysis of hemophagocytic syndrome secondary to autoimmune diseases.

Liu Y, Li Q, Su Y, Che G, Liu Y, Qiao P Arch Rheumatol. 2023; 38(3):406-418.

PMID: 38046247 PMC: 10689015. DOI: 10.46497/ArchRheumatol.2023.9728.

References

Bae C, Jung J, Kim H, Suh C . Reactive hemophagocytic syndrome in adult-onset Still disease: clinical features, predictive factors, and prognosis in 21 patients. Medicine (Baltimore). 2015; 94(4):e451. PMC: 4602979. DOI: 10.1097/MD.0000000000000451. View

Valade S, Azoulay E, Galicier L, Boutboul D, Zafrani L, Stepanian A . Coagulation Disorders and Bleedings in Critically Ill Patients With Hemophagocytic Lymphohistiocytosis. Medicine (Baltimore). 2015; 94(40):e1692. PMC: 4616770. DOI: 10.1097/MD.0000000000001692. View

Nair V, Das S, Sharma A, Sharma S, Sharma P, Ray S . A clinicopathological analysis of 26 patients with infection-associated haemophagocytic lymphohistiocytosis and the importance of bone marrow phagocytosis for the early initiation of immunomodulatory treatment. Postgrad Med J. 2012; 89(1050):185-92. DOI: 10.1136/postgradmedj-2012-130955. View

Kogawa K, Sato H, Asano T, Ohga S, Kudo K, Morimoto A . Prognostic factors of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children: report of the Japan Histiocytosis Study Group. Pediatr Blood Cancer. 2014; 61(7):1257-62. DOI: 10.1002/pbc.24980. View

Jin Y, Xie Z, Yang S, Lu G, Shen K . Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: a retrospective study of 78 pediatric cases in mainland of China. Chin Med J (Engl). 2010; 123(11):1426-30. View

Arca M, Fardet L, Galicier L, Riviere S, Marzac C, Aumont C . Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering disease and early treatment with etoposide. Br J Haematol. 2014; 168(1):63-8. DOI: 10.1111/bjh.13102. View

Riviere S, Galicier L, Coppo P, Marzac C, Aumont C, Lambotte O . Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am J Med. 2014; 127(11):1118-1125. DOI: 10.1016/j.amjmed.2014.04.034. View

Lambotte O, Khellaf M, Harmouche H, Bader-Meunier B, Manceron V, Goujard C . Characteristics and long-term outcome of 15 episodes of systemic lupus erythematosus-associated hemophagocytic syndrome. Medicine (Baltimore). 2006; 85(3):169-182. DOI: 10.1097/01.md.0000224708.62510.d1. View

Henter J, Horne A, Arico M, Egeler R, Filipovich A, Imashuku S . HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2006; 48(2):124-31. DOI: 10.1002/pbc.21039. View

10.

Lerolle N, Laanani M, Riviere S, Galicier L, Coppo P, Meynard J . Diversity and combinations of infectious agents in 38 adults with an infection-triggered reactive haemophagocytic syndrome: a multicenter study. Clin Microbiol Infect. 2015; 22(3):268.e1-8. DOI: 10.1016/j.cmi.2015.11.018. View

11.

Schram A, Comstock P, Campo M, Gorovets D, Mullally A, Bodio K . Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. Br J Haematol. 2015; 172(3):412-9. DOI: 10.1111/bjh.13837. View

12.

Otrock Z, Eby C . Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol. 2014; 90(3):220-4. DOI: 10.1002/ajh.23911. View

13.

Qiang Q, Zhengde X, Shuang Y, Kunling S . Prevalence of coinfection in children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2011; 34(2):e45-8. DOI: 10.1097/MPH.0b013e31822d4ea7. View

14.

Jin Z, Wang Y, Wang J, Wu L, Pei R, Lai W . Multivariate analysis of prognosis for patients with natural killer/T cell lymphoma-associated hemophagocytic lymphohistiocytosis. Hematology. 2017; 23(4):228-234. DOI: 10.1080/10245332.2017.1385191. View

15.

Zhou M, Li L, Zhang Q, Ma S, Sun J, Zhu L . Clinical features and outcomes in secondary adult hemophagocytic lymphohistiocytosis. QJM. 2017; 111(1):23-31. DOI: 10.1093/qjmed/hcx183. View

16.

Barba T, Maucort-Boulch D, Iwaz J, Bohe J, Ninet J, Hot A . Hemophagocytic Lymphohistiocytosis in Intensive Care Unit: A 71-Case Strobe-Compliant Retrospective Study. Medicine (Baltimore). 2015; 94(51):e2318. PMC: 4697985. DOI: 10.1097/MD.0000000000002318. View

17.

Chen H, Kuo H, Wang L, Yu H, Shen J, Kwang K . Childhood macrophage activation syndrome differs from infection-associated hemophagocytosis syndrome in etiology and outcome in Taiwan. J Microbiol Immunol Infect. 2007; 40(3):265-71. View

18.

Bergsten E, Horne A, Arico M, Astigarraga I, Egeler R, Filipovich A . Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017; 130(25):2728-2738. PMC: 5785801. DOI: 10.1182/blood-2017-06-788349. View

19.

Fardet L, Lambotte O, Meynard J, Kamouh W, Galicier L, Marzac C . Reactive haemophagocytic syndrome in 58 HIV-1-infected patients: clinical features, underlying diseases and prognosis. AIDS. 2010; 24(9):1299-306. DOI: 10.1097/QAD.0b013e328339e55b. View

20.

Kumakura S, Murakawa Y . Clinical characteristics and treatment outcomes of autoimmune-associated hemophagocytic syndrome in adults. Arthritis Rheumatol. 2014; 66(8):2297-307. PMC: 4271677. DOI: 10.1002/art.38672. View