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- Bahr Greenwood, Tatiana von
(författare)
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Hyperinflammation in critically ill
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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- Greenwood, Tatiana von Bahr, et al.
(författare)
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Clinical and laboratory signs of haemophagocytic lymphohistiocytosis associated with pandemic influenza A (H1N1) infection in patients needing extracorporeal membrane oxygenation A retrospective observational study
- 2021
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Ingår i: European Journal of Anaesthesiology. - : Lippincott Williams & Wilkins. - 0265-0215 .- 1365-2346. ; 38:7, s. 692-701
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Severe pandemic influenza has been associated with the hyperinflammatory condition secondary haemophagocytic lymphohistiocytosis (HLH).OBJECTIVES: To determine the frequency, degree, character and possible cause of influenza-associated HLH in critically ill patients with severe acute respiratory distress syndrome due to influenza A (H1N1) infection requiring extracorporeal membrane oxygenation (ECMO) support at our hospital.DESIGN: A retrospective observational study.PATIENTS AND SETTING: Medical data were retrieved retrospectively from 11 consenting patients of thirteen adults infected with pandemic influenza A (H1N1) 2009 requiring ECMO between July 2009 and January 2010 at the ECMO Centre of Karolinska University Hospital, Stockholm, Sweden. All patients were evaluated for HLH using HLH-2004 criteria and HScore.RESULTS: Eleven patients (median age 31 years) were included in the study and all survived. All patients showed signs of multiple organ dysfunction and pronounced inflammation, more severe in the four patients with HLH who had significantly higher peak serum concentrations of ferritin (P = 0.024), alkaline phosphatase (P = 0.012) and gamma-glutamyl transferase (P = 0.024), lower concentration of albumin (P = 0.0086) and more frequently hepatomegaly (P = 0.048). Abnormal lymphocyte cytotoxicity (lytic units <10) and a low proportion of natural killer (NK) cells were observed in three of four patients with HLH. Notably, we found a significant inverse correlation between serum ferritin concentration and NK cell and cytotoxic T lymphocyte percentages (r(s) = -0.74, P = 0.0013 and r(s) = -0.79, P = 0.0025, respectively). One HLH patient received HLH-directed cytotoxic therapy, another intravenous immunoglobulin and the other two no specific HLH-directed therapy.CONCLUSION: Critically ill patients, including healthy young adults, with pandemic influenza may develop HLH and should be monitored for signs of hyperinflammation and increasing organ dysfunction, and evaluated promptly for HLH because HLH-directed therapy may then be beneficial. The association of low NK percentages with hyperferritinaemia may suggest a role for reduced NK cell numbers, possibly also cytotoxic T lymphocytes, and subsequently reduced lymphocyte cytotoxicity, in the pathogenesis of hyperinflammation and secondary HLH.
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| 6. |
- von Bahr Greenwood, Tatiana, et al.
(författare)
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Elevated ferritin and soluble CD25 in critically ill are associated with parameters of (hyper)inflammation and lymphocyte cytotoxicity
- 2019
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Ingår i: Minerva Anestesiologica. - : Edizioni Minerva Medica. - 0375-9393 .- 1827-1596. ; 85:12, s. 1289-1298
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Critically ill may develop a potentially fatal hyperinflammation, secondary (acquired) hemophagocytic lymphohistiocytosis (sHLH), the cause of which is unclear. We evaluated serum ferritin and soluble CD25 (sCD25) in critically ill, and their association with other parameters of inflammation and critical illness. Moreover, aiming to better understand the pathogenesis of sHLH, we also evaluated lymphocyte cytotoxicity parameters and correlations with the inflammatory markers ferritin and sCD25.METHODS: In a prospective observational study, 32 patients with ferritin ≥500 μg/L (24 with sepsis) were studied on admission to an intensive care unit (ICU) with regard to ferritin and corresponding clinical and laboratory features including sCD25, and detailed lymphocyte cytotoxicity and genetic analyses whenever possible.RESULTS: Critically ill patients had elevated, positively correlated levels of serum ferritin and sCD25 (rs=0.465, p=0.008); both associated with other risk factors of poorer outcome in critically ill, such as thrombocytopenia (rs=-0.534, p=0.002 and rs=-0.421, p=0.018, respectively), and sCD25 with hypoalbuminemia (rs=-0.678, p<0.001) and life support treatments (rs=0.479, p=0.006). Interestingly, ferritin levels were inversely associated with NK- cell cytotoxicity (rs=-0.462, p=0.047) and degranulation (rs=-0.504, p=0.030). Moreover, of four patients with abnormally low cytotoxicity, three (75%) had <5% circulating NK-cells.CONCLUSIONS: Our study suggests that hyperferritinemia and sCD25 correlate with other laboratory parameters indicative of severe hyperinflammation and organ dysfunction in critically ill ICU-patients, indicating their value in identifying hyperinflammatory critically ill patients for early intervention. Furthermore, it suggests that hyperferritinemia and hyperinflammation may partly be associated with a low percentage circulating NK-cells, and hence, the associated low lymphocyte cytotoxicity.
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