The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome – a systematic review

Krei, Julia Marie; Møller, Holger Jon; Larsen, Julie Brogaard

doi:10.1111/cei.13543

Cited by 47 publications

(29 citation statements)

References 43 publications

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“…To the best of our knowledge, no comparative study of AOSD, HLH, and MAS has been ever performed in adults, whereas there are numerous studies comparing sJIA, HLH, and MAS in pediatric populations. Krei et al recently conducted a systematic review of 14 studies regarding the potential role of IL-18 in the diagnosis of HLH or MAS mainly in children (17). In that review, the serum IL-18 levels of the patients with active sJIA were approx.…”

Section: Discussionmentioning

confidence: 99%

“…Macrophage activation syndrome (MAS), an acquired form of HLH that occurs in autoimmune diseases, is a common and serious complication of AOSD, and it is especially difficult to distinguish AOSD-related MAS from HLH or MAS with other underlying diseases (16). It was recently revealed that serum IL-18 levels are increased in primary (genetic) and secondary HLH, especially in pediatric patients, and several reports have compared the serum IL-18 levels between pediatric HLH cases and patients with systemic juvenile idiopathic arthritis (sJIA), a homolog of AOSD in children (17). There have been few similar comparative studies between AOSD and adult HLH.…”

Section: Introductionmentioning

confidence: 99%

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Usefulness of Interleukin-18 as a Diagnostic Biomarker to Differentiate Adult-Onset Still’s Disease With/Without Macrophage Activation Syndrome From Other Secondary Hemophagocytic Lymphohistiocytosis in Adults

et al. 2021

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BackgroundInterleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the ‘cytokine storm’ such as adult-onset Still’s disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). The differences in IL-18 between AOSD and HLH, especially in adults, is uncertain. Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH. In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group).Patients and MethodsWe enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS. The clinical features and laboratory data were compared between the AOSD and adult HLH groups. In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups. A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18. We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group.ResultsSerum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data. Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and ‘arthralgia or arthritis’ are independent factors useful in the differential diagnosis of AOSD from adult HLH. In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83–1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data.ConclusionsIL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Usefulness of Interleukin-18 as a Diagnostic Biomarker to Differentiate Adult-Onset Still’s Disease With/Without Macrophage Activation Syndrome From Other Secondary Hemophagocytic Lymphohistiocytosis in Adults

et al. 2021

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“…Our retrospective findings need to be confirmed by further studies, as the number of HLH diagnoses could have been underestimated (potentially incomplete medical coding) or overestimated (low specificity of HLH-2004 and HScore criteria). Besides, the advent of the cytokine era supporting HLH diagnosis (27)(28)(29) was not available in most patients of our cohort due to both retrospective design, time of inclusion and parameters unscreened routinely. In addition, retrospective etiological diagnosis can be difficult, as various concomitant etiologies can lead to HLH.…”

Section: Discussionmentioning

confidence: 99%

High Mortality of HLH in ICU Regardless Etiology or Treatment

et al. 2021

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Background: Adult hemophagocytic lymphohistiocytosis (HLH) is highly lethal in the ICU. The diagnostic and therapeutic emergency that HLH represents is compounded by its unknown pathophysiological mechanisms. Here, we report on a large cohort of adult HLH in the ICU (ICU-HLH). We analyzed prognostic factors associated with mortality to define the diagnostic and therapeutic challenges in this specific population.Methods: This retrospective study included adult patients diagnosed with HLH in four ICUs in Marseille, France between 2010 and 2020. Patients who fulfilled the HLH-2004 criteria (≥ 4/8) and/or had an HScore ≥ 169 were diagnosed with HLH. HLH was categorized into four groups according to etiology: sepsis-associated HLH, intracellular infection-associated HLH, malignancy-associated HLH, and idiopathic HLH.Results: Two hundred and sixty patients were included: 121 sepsis-associated HLH (47%), 84 intracellular infection-associated HLH (32%), 28 malignancy-associated HLH (11%), and 27 idiopathic HLH (10%). The ICU mortality rate reached 57% (n = 147/260) without a statistical difference between etiological groups. Independent factors associated with mortality in multivariate analysis included age (OR (5 years) = 1.31 [1.16–1.48], p < 0.0001), SOFA score at ICU admission (OR = 1.37 [1.21–1.56], p < 0.0001), degradation of the SOFA score between ICU arrival and HLH diagnosis (Delta SOFA) (OR = 1.47 [1.28–1.70], p < 0.0001), the presence of bone-marrow hemophagocytosis (OR = 5.27 [1.11–24.97], p = 0.04), highly severe anemia (OR = 1.44 [1.09–1.91], p = 0.01), and hypofibrinogenemia (OR = 1.21 [1.04–1.41], p = 0.02).Conclusions: In this large retrospective cohort study of critically ill patients, ICU-HLH in adults was associated with a 57% mortality rate, regardless of HLH etiology or specific treatment. Factors independently associated with prognosis included age, presence of hemophagocytosis in bone-marrow aspirates, organ failure at admission, and worsening organ failure during the ICU stay. Whether a rapid diagnosis and the efficacy of specific therapy improve outcome is yet to be prospectively investigated.

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“…Currently, anakinra (IL1Ra), rilonacept (IL1 inhibitor) and canakinumab (anti-IL1β) have been successfully studied in clinical research with comparable long-term efficacy where half of treated patients achieved remission [ 61 , 64 – 67 ]. IL18 may be another target for treatment of sJIA resistant to IL1 and IL6 inhibition, as far as higher levels of IL18 have been associated with high ferritin levels reported in MAS [ 68 , 69 ].…”

Section: Treatmentmentioning

confidence: 99%

Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches

et al. 2021

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Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. Depending on the number of joints affected, presence of extra-articular manifestations, systemic symptoms, serology and genetic factors, JIA is divided into oligoarticular, polyarticular, systemic, psoriatic, enthesitis-related and undifferentiated arthritis. This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. Greater understanding of JIA as a collective of complex inflammatory diseases is discussed within the context of therapeutic interventions, including traditional non-biologic and up-to-date biologic disease-modifying anti-rheumatic drugs. Whilst the advent of advanced therapeutics has improved clinical outcomes, a considerable number of patients remain unresponsive to treatment, emphasising the need for further understanding of disease progression and remission to support stratification of patients to treatment pathways.

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The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome – a systematic review

Cited by 47 publications

References 43 publications

Usefulness of Interleukin-18 as a Diagnostic Biomarker to Differentiate Adult-Onset Still’s Disease With/Without Macrophage Activation Syndrome From Other Secondary Hemophagocytic Lymphohistiocytosis in Adults

Usefulness of Interleukin-18 as a Diagnostic Biomarker to Differentiate Adult-Onset Still’s Disease With/Without Macrophage Activation Syndrome From Other Secondary Hemophagocytic Lymphohistiocytosis in Adults

High Mortality of HLH in ICU Regardless Etiology or Treatment

Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches

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