Hyperinflammation in critically ill
Author: Bahr Greenwood, Tatiana von
Date: 2021-12-03
Location: Eva & Georg Klein-salen, Solnavägen 9, Biomedicum, Karolinska Institutet, Solna
Time: 09.00
Department: Inst för kvinnors och barns hälsa / Dept of Women's and Children's Health
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Thesis (1.923Mb)
Abstract
Background: A wide spectrum of inflammatory responses, with overlapping characteristics, is encountered in critically ill patients in intensive care. At one extreme, critically ill patients may develop the potentially fatal condition secondary hemophagocytic lymphohistiocytosis (sHLH), characterized by excessive inflammation (hyperinflammation), driven by a ‘cytokine storm’, and multiple organ failure. Infections, malignancies and autoimmune diseases are the most common conditions associated with the development of sHLH. Prompt diagnosis and early appropriate intervention is crucial to improve survival in sHLH. Corticosteroids are a cornerstone of HLH therapy. The addition of the cytotoxic drug etoposide has been instrumental in the successful treatment of primary HLH, and may reduce morbidity and mortality also in selected cases of sHLH. While it is established that defective lymphocyte cytotoxicity causes primary HLH , the cause of sHLH remains incompletely understood.
Aims: The overall aim of the thesis was to broaden our knowledge of hyperinflammation and HLH in critically ill, with a focus on intensive care, to better identify the critically ill patients with hyperinflammation that could benefit from anti-inflammatory therapy, in order to reduce morbidity and improve survival. We also aimed to investigate the role of cytotoxic lymphocytes, and possible genetic correlations, in the pathogenesis of hyperinflammation and sHLH in critically ill.
Methods: The studies included several critically ill patient cohorts in intensive care, some with extracorporeal membrane oxygenation (ECMO) support, with various underlying conditions.
Results: Secondary HLH was encountered in critically ill patients in intensive care with a high proportion of malignancies and immunosuppression, in influenza AH1N1 infected patients, in severe dengue, and in systemic autoimmune conditions. The mortality in sHLH in critically ill is high. HLH patients were generally younger, with fewer comorbidities and predominantly male. Hyperferritinemia, which correlated with elevated soluble IL-2R and CRP, and thrombocytopenia were identified in critically ill in ICU, and were more prominent in inflammatory responses such as sepsis. However, the highest median levels of ferritin, and soluble IL-2R, were observed in HLH patients, who also demonstrated other common manifestations of sHLH such as cytopenias, elevated liver function tests and triglycerides, hemophagocytosis in the bone marrow and splenomegaly. In global diseases, such as severe dengue and pandemic influenza AH1N1, we found that a proportion of patients do develop hyperinflammation, albeit not always recognized which therefore limits appropriate treatment. A subset of critically ill patients not meeting HLH criteria (i.e. with <5 of 8 diagnostic HLH-2004 criteria and a median HScore of 138), but with high SOFA score (median 16.5) and fatal outcome, had similar levels of ferritin to HLH patients and highly elevated liver tests, but HLH patients had a significantly higher ferritin/ALT ratio, a possible novel diagnostic aid for the diagnosis of HLH. A faster rate of increase of ferritin was associated with a higher risk of death. In critically ill in ICU and severe dengue, elevated AST and SOFA score were independent risk factors of mortality. Reduced absolute numbers of NK cells and CTLs, and reduced lymphocyte cytotoxicity, were observed in critically ill, more prominent in sHLH patients with hyperferritinemia, probably contributing to the development of sHLH. Rare variants in HLH-causing genes were identified in a few patients. With regard to specific treatment, a number of children with severe MAS-HLH despite conventional therapy responded promptly to the addition of moderately dosed etoposide.
Conclusions: Secondary HLH can be identified in various conditions in critically ill patients, who should be monitored for signs of hyperinflammation and progressive organ failure for prompt HLH evaluation using currently available diagnostic tools, including ferritin and soluble IL-2R, and additional helpful parameters. Early diagnosis and appropriate HLH-directed therapy, including etoposide in selected cases, is likely beneficial to reduce morbidity and improve survival in sHLH.
Aims: The overall aim of the thesis was to broaden our knowledge of hyperinflammation and HLH in critically ill, with a focus on intensive care, to better identify the critically ill patients with hyperinflammation that could benefit from anti-inflammatory therapy, in order to reduce morbidity and improve survival. We also aimed to investigate the role of cytotoxic lymphocytes, and possible genetic correlations, in the pathogenesis of hyperinflammation and sHLH in critically ill.
Methods: The studies included several critically ill patient cohorts in intensive care, some with extracorporeal membrane oxygenation (ECMO) support, with various underlying conditions.
Results: Secondary HLH was encountered in critically ill patients in intensive care with a high proportion of malignancies and immunosuppression, in influenza AH1N1 infected patients, in severe dengue, and in systemic autoimmune conditions. The mortality in sHLH in critically ill is high. HLH patients were generally younger, with fewer comorbidities and predominantly male. Hyperferritinemia, which correlated with elevated soluble IL-2R and CRP, and thrombocytopenia were identified in critically ill in ICU, and were more prominent in inflammatory responses such as sepsis. However, the highest median levels of ferritin, and soluble IL-2R, were observed in HLH patients, who also demonstrated other common manifestations of sHLH such as cytopenias, elevated liver function tests and triglycerides, hemophagocytosis in the bone marrow and splenomegaly. In global diseases, such as severe dengue and pandemic influenza AH1N1, we found that a proportion of patients do develop hyperinflammation, albeit not always recognized which therefore limits appropriate treatment. A subset of critically ill patients not meeting HLH criteria (i.e. with <5 of 8 diagnostic HLH-2004 criteria and a median HScore of 138), but with high SOFA score (median 16.5) and fatal outcome, had similar levels of ferritin to HLH patients and highly elevated liver tests, but HLH patients had a significantly higher ferritin/ALT ratio, a possible novel diagnostic aid for the diagnosis of HLH. A faster rate of increase of ferritin was associated with a higher risk of death. In critically ill in ICU and severe dengue, elevated AST and SOFA score were independent risk factors of mortality. Reduced absolute numbers of NK cells and CTLs, and reduced lymphocyte cytotoxicity, were observed in critically ill, more prominent in sHLH patients with hyperferritinemia, probably contributing to the development of sHLH. Rare variants in HLH-causing genes were identified in a few patients. With regard to specific treatment, a number of children with severe MAS-HLH despite conventional therapy responded promptly to the addition of moderately dosed etoposide.
Conclusions: Secondary HLH can be identified in various conditions in critically ill patients, who should be monitored for signs of hyperinflammation and progressive organ failure for prompt HLH evaluation using currently available diagnostic tools, including ferritin and soluble IL-2R, and additional helpful parameters. Early diagnosis and appropriate HLH-directed therapy, including etoposide in selected cases, is likely beneficial to reduce morbidity and improve survival in sHLH.
List of papers:
I. Elevated ferritin and soluble CD25 in critically ill patients are associated with parameters of (hyper)inflammation and lymphocyte cytotoxicity. von Bahr Greenwood T, Palmkvist-Kaijser K, Chiang SC, Tesi B, Bryceson YT, Hjelmqvist H, Henter JI. Minerva Anestesiol. 2019 Dec; 85(12): 1289-98.
Fulltext (DOI)
Pubmed
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II. Clinical and laboratory signs of haemophagocytic lymphohistiocytosis associated with pandemic influenza A (H1N1) infection in patients needing extracorporeal membrane oxygenation: A retrospective observational study. von Bahr Greenwood T, Holzgraefe B, Chiang SCC, Wang Y, Tesi B, Bryceson YT, Henter JI. Eur J Anaesthesiol. 2021 Jul 1;38(7):692-701.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Efficacy of moderately dosed etoposide in macrophage activation syndrome- hemophagocytic lymphohistiocytosis (MAS-HLH). Horne A, von Bahr Greenwood T, Chiang SCC, Meeths M, Björklund C, Ekelund M, Erensjö P, Berg S, Hagelberg S, Bryceson YT, Andersson U, Henter JI. J Rheumatol. 2021 Oct;48(10):1596-602.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Dengue infection complicated by hemophagocytic lymphohistiocytosis: Experiences from 180 patients with severe dengue. Kan FK, Tan CC, von Bahr Greenwood T, Khalid KE, Supramaniam P, Hed Myrberg I, Tan LH, Henter JI. Clin Infect Dis. 2020 June 1;70(11):2247-55.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Hyperinflammation in critically ill patients in intensive care. von Bahr Greenwood T, Chiang SCC, Wang Y, Tesi B, Pålsson S, Mellström A, Holzgraefe B, Oldner A, Rossi P, Bryceson YT, Hjelmqvist H, Henter JI. [Manuscript]
I. Elevated ferritin and soluble CD25 in critically ill patients are associated with parameters of (hyper)inflammation and lymphocyte cytotoxicity. von Bahr Greenwood T, Palmkvist-Kaijser K, Chiang SC, Tesi B, Bryceson YT, Hjelmqvist H, Henter JI. Minerva Anestesiol. 2019 Dec; 85(12): 1289-98.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Clinical and laboratory signs of haemophagocytic lymphohistiocytosis associated with pandemic influenza A (H1N1) infection in patients needing extracorporeal membrane oxygenation: A retrospective observational study. von Bahr Greenwood T, Holzgraefe B, Chiang SCC, Wang Y, Tesi B, Bryceson YT, Henter JI. Eur J Anaesthesiol. 2021 Jul 1;38(7):692-701.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Efficacy of moderately dosed etoposide in macrophage activation syndrome- hemophagocytic lymphohistiocytosis (MAS-HLH). Horne A, von Bahr Greenwood T, Chiang SCC, Meeths M, Björklund C, Ekelund M, Erensjö P, Berg S, Hagelberg S, Bryceson YT, Andersson U, Henter JI. J Rheumatol. 2021 Oct;48(10):1596-602.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Dengue infection complicated by hemophagocytic lymphohistiocytosis: Experiences from 180 patients with severe dengue. Kan FK, Tan CC, von Bahr Greenwood T, Khalid KE, Supramaniam P, Hed Myrberg I, Tan LH, Henter JI. Clin Infect Dis. 2020 June 1;70(11):2247-55.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Hyperinflammation in critically ill patients in intensive care. von Bahr Greenwood T, Chiang SCC, Wang Y, Tesi B, Pålsson S, Mellström A, Holzgraefe B, Oldner A, Rossi P, Bryceson YT, Hjelmqvist H, Henter JI. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Henter, Jan-Inge
Co-supervisor: Hjelmqvist, Hans
Issue date: 2021-11-11
Rights:
Publication year: 2021
ISBN: 978-91-8016-343-9
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