Top

Published in:

Open Access 01-12-2022 | Nosocomial Infection | Research

Etoposide treatment in secondary hemophagocytic syndrome: impact on healthcare-associated infections and survival

Authors: Thibault Dupont, Michael Darmon, Eric Mariotte, Virginie Lemiale, Jehane Fadlallah, Adrien Mirouse, Lara Zafrani, Elie Azoulay, Sandrine Valade

Published in: Annals of Intensive Care | Issue 1/2022

Abstract

Background

Etoposide remains the cornerstone of symptomatic management of critically ill patients with secondary hemophagocytic syndrome (sHS). Risk of healthcare-associated infections (HAIs) in this setting with etoposide has never been assessed. We sought to evaluate the association between etoposide administration, HAIs occurrence and survival in critically ill adult patients with sHS. In this retrospective single-center study conducted in a university hospital ICU between January 2007 and March 2020, all consecutive patients with sHS were included. HAIs were defined as any microbiologically documented infection throughout ICU stay. Competing risk survival analysis was performed to determine factors associated with HAIs. Propensity score-based overlap weighting was performed to adjust for factors associated with etoposide use.

Results

168 patients with a median age of 49 [38, 59] were included. Forty-three (25.6%) patients presented with at least 1 microbiologically documented HAI throughout ICU stay. After adjustment, cumulative incidence of HAI was higher in patients receiving etoposide (p = 0.007), while survival was unaffected by etoposide status (p = 0.824). By multivariable analysis, etoposide treatment was associated with a higher incidence of HAIs (sHR 3.75 [1.05, 6.67]), whereas no association with survival (sHR 0.53 [0.20, 1.98]) was found. Other factors associated with increased mortality after adjustment included age, immunodepression, male sex, SOFA score > 13, and occurrence of HAI.

Conclusions

In patients with sHS, etoposide treatment is independently associated with increased occurrence of HAIs, whereas no association with survival was found. Intensivists should be aware of increased infectious risk, to promptly detect and treat infections in this specific setting. Studies to assess benefits from prophylactic anti-infectious agents in this setting are warranted and the lack of benefit of etoposide on survival needs to be interpreted cautiously.

Available only for authorised users

Knaak C, Schuster FS, Nyvlt P, et al. Treatment and mortality of hemophagocytic lymphohistiocytosis in adult critically ill patients: a systematic review with pooled analysis. Crit Care Med. 2020;48(11):e1137–46. https://doi.org/10.1097/CCM.0000000000004581.CrossRefPubMed

Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol. 2019;10:119. https://doi.org/10.3389/fimmu.2019.00119.CrossRefPubMedPubMedCentral

Aulagnon F, Lapidus N, Canet E, et al. Acute kidney injury in adults with hemophagocytic lymphohistiocytosis. Am J Kidney Dis. 2015;65(6):851–9. https://doi.org/10.1053/j.ajkd.2014.10.012.CrossRefPubMed

Klein C, Kleinschmidt-DeMasters BK, Liang X, Stence N, Tuder RM, Moore BE. A review of neuropathological features of familial and adult hemophagocytic lymphohistiocytosis. J Neuropathol Exp Neurol. 2019;78(3):197–208. https://doi.org/10.1093/jnen/nlz001.CrossRefPubMed

Valade S, Azoulay E, Galicier L, et al. Coagulation disorders and bleedings in critically ill patients with hemophagocytic lymphohistiocytosis. Medicine (Baltimore). 2015;94(40): e1692. https://doi.org/10.1097/MD.0000000000001692.CrossRef

Seguin A, Galicier L, Boutboul D, Lemiale V, Azoulay E. Pulmonary involvement in patients with hemophagocytic lymphohistiocytosis. Chest. 2016;149(5):1294–301. https://doi.org/10.1016/j.chest.2015.11.004.CrossRefPubMed

Kim MM, Yum MS, Choi HW, et al. Central nervous system (CNS) involvement is a critical prognostic factor for hemophagocytic lymphohistiocytosis. Korean J Hematol. 2012;47(4):273. https://doi.org/10.5045/kjh.2012.47.4.273.CrossRefPubMedPubMedCentral

Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31. https://doi.org/10.1002/pbc.21039.CrossRefPubMed

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. 2020. https://doi.org/10.1002/art.38690.CrossRef

10.

Machowicz R, Janka G, Wiktor-Jedrzejczak W. Similar but not the same: differential diagnosis of HLH and sepsis. Crit Rev Oncol Hematol. 2017;114:1–12. https://doi.org/10.1016/j.critrevonc.2017.03.023.CrossRefPubMed

11.

Tudesq JJ, Valade S, Galicier L, et al. Diagnostic strategy for trigger identification in severe reactive hemophagocytic lymphohistiocytosis: a diagnostic accuracy study. Hematol Oncol. 2020. https://doi.org/10.1002/hon.2819.CrossRefPubMed

12.

Arca M, Fardet L, Galicier L, et al. 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. 2015;168(1):63–8. https://doi.org/10.1111/bjh.13102.CrossRefPubMed

13.

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(25):2728–38. https://doi.org/10.1182/blood-2017-06-788349.CrossRefPubMedPubMedCentral

14.

Imashuku S, Kuriyama K, Teramura T, et al. Requirement for etoposide in the treatment of epstein-barr virus-associated hemophagocytic lymphohistiocytosis. J Clin Oncol. 2001;19(10):2665–73. https://doi.org/10.1200/JCO.2001.19.10.2665.CrossRefPubMed

15.

European Centre for Disease Prevention and Control. Healthcare-associated infections acquired in intensive care units. London: Nature Publishing Group; 2017.

16.

Vincent JL. international study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323. https://doi.org/10.1001/jama.2009.1754.CrossRefPubMed

17.

Apodaca E, Rodríguez-Rodríguez S, Tuna-Aguilar EJ, Demichelis-Gómez R. Prognostic factors and outcomes in adults with secondary hemophagocytic lymphohistiocytosis: a single-center experience. Clin Lymphoma Myeloma Leuk. 2018;18(10):e373–80. https://doi.org/10.1016/j.clml.2018.06.014.CrossRefPubMed

18.

Jones AE, Trzeciak S, Kline JA. The sequential organ failure assessment score for predicting outcome in patients with severe sepsis and evidence of hypoperfusion at the time of emergency department presentation. Crit Care Med. 2009;37(5):1649–54. https://doi.org/10.1097/CCM.0b013e31819def97.CrossRefPubMedPubMedCentral

19.

Austin PC, Fine JP. Practical recommendations for reporting Fine-Gray model analyses for competing risk data. Stat Med. 2017;36(27):4391–400. https://doi.org/10.1002/sim.7501.CrossRefPubMedPubMedCentral

20.

Gray RJ. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16(3):1141–54.CrossRef

21.

A proportional hazards model for the subdistribution of a competing risk. Journal of the American Statistical Association. 94. 446. 2021 https://doi.org/10.1080/01621459.1999.10474144

22.

Thomas LE, Li F, Pencina MJ. Overlap weighting: a propensity score method that mimics attributes of a randomized clinical trial. JAMA. 2020;323(23):2417. https://doi.org/10.1001/jama.2020.7819.CrossRefPubMed

23.

Li F, Thomas LE. Addressing extreme propensity scores via the overlap weights. Am J Epidemiol. 2018. https://doi.org/10.1093/aje/kwy201.CrossRefPubMedPubMedCentral

24.

Velasco E, Thuler LC, Martins CA, Dias LM, Gonçalves VM. Nosocomial infections in an oncology intensive care unit. Am J Infect Control. 1997;25(6):458–62. https://doi.org/10.1016/s0196-6553(97)90067-5.CrossRefPubMed

25.

Stoclin A, Rotolo F, Hicheri Y, et al. Ventilator-associated pneumonia and bloodstream infections in intensive care unit cancer patients: a retrospective 12-year study on 3388 prospectively monitored patients. Support Care Cancer Cancer. 2020;28(1):193–200. https://doi.org/10.1007/s00520-019-04800-6.CrossRef

26.

Rajagopala S, Singh N, Agarwal R, Gupta D, Das R. Severe hemophagocytic lymphohistiocytosis in adults-experience from an intensive care unit from North India. Indian J Crit Care Med. 2012;16(4):198–203. https://doi.org/10.4103/0972-5229.106501.CrossRefPubMedPubMedCentral

27.

Nahum E, Ben-Ari J, Stain J, Schonfeld T. Hemophagocytic lymphohistiocytic syndrome: unrecognized cause of multiple organ failure. Pediatr Crit Care Med. 2000;1(1):51–4. https://doi.org/10.1097/00130478-200007000-00010.CrossRefPubMed

28.

La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465–77. https://doi.org/10.1182/blood.2018894618.CrossRefPubMed

Title: Etoposide treatment in secondary hemophagocytic syndrome: impact on healthcare-associated infections and survival
Authors: Thibault Dupont
Michael Darmon
Eric Mariotte
Virginie Lemiale
Jehane Fadlallah
Adrien Mirouse
Lara Zafrani
Elie Azoulay
Sandrine Valade
Publication date: 01-12-2022
Publisher: Springer International Publishing
Keywords: Nosocomial Infection
Hemophagocytic Lymphohistiocytosis
Hemophagocytic Lymphohistiocytosis
Published in: Annals of Intensive Care / Issue 1/2022
Electronic ISSN: 2110-5820
DOI: https://doi.org/10.1186/s13613-022-01075-9

At a glance: The STEP trials

Springer Medicine

Etoposide treatment in secondary hemophagocytic syndrome: impact on healthcare-associated infections and survival

Abstract

Background

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2022

Definition and evolution of right ventricular dysfunction in critically ill COVID-19 patients. Author’s reply

Infected pancreatic necrosis complicating severe acute pancreatitis in critically ill patients: predicting catheter drainage failure and need for necrosectomy

Health-related quality of life of COVID-19 two and 12 months after intensive care unit admission

Monitoring of circulating monocyte HLA-DR expression in a large cohort of intensive care patients: relation with secondary infections

Continuous prolonged prone positioning in COVID-19-related ARDS: a multicenter cohort study from Chile

Reply to: intensive care unit-to-unit capacity transfers are associated with increased mortality—no hasty conclusions in the event of a crisis