OP0313 PRELIMINARY CRITERIA FOR MACROPHAGE ACTIVATION SYNDROME ASSOCIATED WITH CORONAVIRUS DISEASE-19

Background:COVID-19 runs a severe disease associated with acute respiratory distress syndrome in a subset of patients, and a hyperinflammatory response developing in the second week contributes to the worse outcome. Inflammatory features are mostly compatible with macrophage activation syndrome (MAS) observed in other viral infections despite resulting in milder changes. Early detection and treatment of MAS may be associated with a better outcome. However, available criteria for MAS associated with other causes have not been helpful.Objectives:To identify distinct features of MAS associated with COVID-19 using a large database enabling to assess of dynamic changes.Methods:PCR-confirmed hospitalized COVID-19 patients followed between March and September 2020 constituted the discovery set. Patients considered to have findings of MAS by experienced physicians and given anakinra or tocilizumab were classified as the MAS group and the remaining patients as the non-MAS group. The MAS group was then re-grouped as the cases with exact-MAS and borderline-MAS cases by the study group. Clinical and laboratory data including the Ct values of the PCR test were obtained from the database, and dynamic changes were evaluated especially for the first 14 days of the hospitalization. The second set of 162 patients followed between September-December 2020 were used as the replication group to test the preliminary criteria. In the second set, hospitalization rules were changed, and all patients required oxygen support and received dexamethasone 6mg/day or equivalent glucocorticoids. Daily changes were calculated for the laboratory items in MAS, borderline, and non-MAS groups to see the days differentiating the groups, and ROC curves and lower and upper limits (10-90%) of the selected parameters were calculated to determine the cutoff values.Results:A total of 769 PCR-confirmed hospitalized patients were analysed, and 77 of them were classified as MAS and 83 as borderline MAS patients. There was no statistically significant difference in the baseline viral loads of MAS patients compared to the non-MAS group according to the Ct values. Daily dynamic changes in the MAS group differed from the non-MAS group especially around the 6th day of hospitalization, and more than a twofold increase in ferritin and a 1.5-fold increase in D-dimer levels compared to the baseline values help to define the MAS group. Twelve items selected for the criteria are given in Table 1 below. The total score of 45 provided 79.6% sensitivity for the MAS (including borderline cases) and 81.3% specificity around days 5 and 6 in the discovery set, and a score of 60 increased the specificity to 94.9% despite a decrease in sensitivity to 40.8%. The same set provided a similar sensitivity (80.3%) in the replication, but a lower specificity (47.4-66% on days 6 to 9) due to a group of control patients with findings of MAS possibly masked by glucocorticoids.Table 1.Preliminary Criteria for Macrophage Activation Syndrome Associated with Coronavirus Disease-191.Fever (>37.0 °C)2.Ferritin concentration > 550 ng/mL3.More than 2 times increase of ferritin concentration within 7 days of disease onset4.Neutrophil count > 6000 cell/mm35.Lymphopenia < 1000 cell/mm36.Neutrophil/lymphocyte ratio > 67.D-dimer concentration > 1000 ng/ml8.More than 50% increase of D-dimer concentration within 7 days of disease onset9.CRP concetration > 50 mg/L10.LDH concentration > 300 U/L11.ALT or AST concentration > 50 U/L12.Procalcitonin concentration < 1.21 point for each positive item assessed on Days 5-7Score calculation: Total points / 12 x 100Possible MAS ≥45 and Definite MAS ≥60Conclusion:This study defined a set of preliminary criteria using the most relevant items of MAS according to the dynamic changes in the parameters in a group of COVID-19 patients. A score of 45 would be helpful to define a possible MAS group with reasonable sensitivity and specificity to start necessary treatments as early as possible.Disclosure of Interests:None declared.

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Cytokine Profiles of Macrophage Activation Syndrome Associated with Rheumatic Diseases

The Journal of Rheumatology ◽

10.3899/jrheum.090662 ◽

2010 ◽

Vol 37 (5) ◽

pp. 967-973 ◽

Cited By ~ 56

Author(s):

JUNKO MARUYAMA ◽

SHIGEKO INOKUMA

Keyword(s):

Rheumatic Diseases ◽

Lupus Erythematosus ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Laboratory Data ◽

Serum Levels ◽

Interferon Γ ◽

Cytokine Profiles ◽

Factor Α ◽

Activation Syndrome

Objective.To elucidate the cytokine profiles of macrophage activation syndrome (MAS) in relation to underlying rheumatic diseases and prognosis.Methods.The clinical features and laboratory data of 18 patients with MAS and rheumatic diseases were retrospectively analyzed. Serum levels of macrophage colony-stimulating factor (M-CSF), interleukin 18 (IL-18), tumor necrosis factor-α, interleukin 6, interferon-γ, ferritin, and ß2-microglobulin (ß2m) were measured. These data were compared between underlying diseases and between those who died and those who recovered.Results.Of the 18 patients with MAS, 9 had underlying systemic lupus erythematosus (SLE), 7 had adult-onset Still’s disease (AOSD), 1 had rheumatoid arthritis (RA), and 1 had antiphospholipid syndrome. Three patients with SLE and 1 patient with RA died. The serum M-CSF and IL-18 levels were substantially elevated in all the patients. In the patients with SLE, the M-CSF level was higher than the IL-18 level (median: 4879 vs 1341 pg/ml, p = 0.0054), and it was the reverse in the patients with AOSD (5883 vs 228,350 pg/ml, p = 0.0017). The serum M-CSF and ß2m levels were significantly higher in the patients who died than in those who recovered (M-CSF: 18,245 vs 3404 pg/ml, p = 0.019; ß2m: 18.8 vs 5.4 mg/dl, p = 0.0058).Conclusion.The cytokine profiles associated with MAS differed between patients with SLE and patients with AOSD. The patients with SLE showed a prominent increase in serum M-CSF levels, as did the patients with AOSD in serum IL-18 level. Patients who died had higher serum M-CSF and ß2m levels, and this suggests that aggressive treatment for patients with MAS and these profiles should be promptly started.

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Retrospective Evaluation of Patients with Systemic Juvenile Idiopathic Arthritis: A Single-centre Experience

Aktuelle Rheumatologie ◽

10.1055/a-1450-1436 ◽

2021 ◽

Author(s):

Esra Bağlan ◽

Semanur Özdel ◽

Tülin Güngör ◽

Evra Çelikkaya ◽

Deniz Karakaya ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Systemic Juvenile Idiopathic Arthritis ◽

Clinical Signs ◽

Clinical Information ◽

Clinical Findings ◽

Single Centre ◽

Significant Difference ◽

Activation Syndrome

Abstract Objective Systemic juvenile idiopathic arthritis is one of the subtypes of juvenile idiopathic arthritis. This type of disease accounts for approximately 10–20% of all cases of juvenile idiopathic arthritis. It typically affects both sexes equally and is usually present in children under 5 years. This study aimed to evaluate the demographic and clinical features of patients who were followed up for the diagnosis of sJIA in a single centre, the treatments they received, the responses to the treatment and the course of the disease. Methods All patients with systemic juvenile idiopathic arthritis who were evaluated at Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Department of Paediatric Rheumatology, between January 2017 and January 2020 were included in this study. Descriptive features, clinical information, medications, treatment responses and long-term prognosis of patients were evaluated retrospectively. Results The study included 40 patients. 60% (n=24) of the patients were female and 40% (n=16) were male. The diagnosis age of the patients was 7.77±4.82 years and the patients were followed up for an average of 48±41 months. All of the patients had fever at the time of diagnosis. The 3 most common clinical signs after fever were arthralgia, hepatomegaly and lymphadenopathy (65, 55 and 50%, respectively). Ten patients (32.5%) had macrophage activation syndrome at admission. No significant difference was detected between the groups with and without macrophage activation syndrome concerning age, gender and clinical findings. Leukocyte, haemoglobin, platelet and erythrocyte sedimentation rates were significantly lower in the macrophage activation syndrome group compared with the other group, and ferritin was significantly higher. The C-reactive protein value was higher in the group without macrophage activation syndrome, but the difference was not statistically significant. While all patients received corticosteroid therapy as the initial therapy, 87.5% of these patients were administered pulse methylprednisolone therapy. In the follow-up, 21 patients (52.5%) needed biological treatment. Twenty-seven patients (67.5%) had a monocyclic course, 3 patients (7.5%) had a polycyclic course and 10 patients (25%) had a persistent polyarticular course. Conclusion Early diagnosis and treatment of systemic juvenile idiopathic arthritis are important because of the risk of developing macrophage activation syndrome – the most lethal complication. In our evaluation, it was seen that laboratory parameters could provide more guidance than clinical findings. Although steroids are the cornerstone of therapy, biological agents are effective in patients who are not responsive to steroid therapy.

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SOLUBLE ST2 AND CD163 AS POTENTIALBIOMARKERS TO DIFFERENTIATE PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS FROM MACROPHAGE ACTIVATION SYNDROME

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2019.008 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Zhuo Gao ◽

Yini Wang ◽

Jingshi Wang ◽

Jia Zhang ◽

Zhao Wang

Keyword(s):

Healthy Subjects ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Serum Levels ◽

Haemophagocytic Lymphohistiocytosis ◽

Soluble St2 ◽

Tnf Α ◽

Significant Difference ◽

Ifn Γ ◽

Activation Syndrome

Abstract Background and Objective: The differentiation of primary haemophagocytic lymphohistiocytosis (pHLH) and macrophage activation syndrome (MAS) poses a challenge to hematologists. The aim of this study was (1) to compare the levels of soluble ST2 (sST2), sCD163, IL-10, IFN-γ, TNF-α and IL-18 in patients with pHLH and MAS and (2) to investigate whether they can help differentiate the two diseases. Methods: A total of 54 participants were recruited in this study, including 12 pHLH patients, 22 MAS patients and 20 healthy subjects. We measured the levels of sST2 and sCD163 in serum by ELISA. The serum levels of IL-10, IFN-γ, TNF-α and IL-18 were detected using a Luminex 200 instrument. Results: The serum levels of sST2 and sCD163 in MAS patients were markedly higher than that in pHLH patients (363.13 ± 307.24 ng/ml vs 80.75 ± 87.04 ng/ml, P = 0.004; 3532.72 ± 2479.68 ng/ml vs 1731.96 ± 1262.07 ng/ml, P = 0.046). There was no significant difference in the expression of IFN-γ (306.89 ± 281.60 pg/ml vs 562.43 ± 399.86 pg/ml), IL-10 (20.40 ± 30.49 pg/ml vs 8.3 ± 13.14 pg/ml), IL-18 (463.33 ± 597.04 pg/ml vs 1247.82 ± 1318.58 pg/ml) and TNF-α (61.48 ± 84.69 pg/ml vs 106.10 ±77.21 pg/ml) between pHLH and MAS. Conclusion: Patients with pHLH and MAS show some differences in cytokine profiles. The elevated levels of IFN-γ, IL-10, IL-18 and TNF-α can contribute to the diagnosis of HLH, but may not discriminate pHLH from MAS. Levels of sST2 and sCD163 may serve as markers to distinguish pHLH from MAS.

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Patients with Very Early-onset Systemic Juvenile Idiopathic Arthritis Exhibit More Inflammatory Features and a Worse Outcome

The Journal of Rheumatology ◽

10.3899/jrheum.120386 ◽

2013 ◽

Vol 40 (3) ◽

pp. 329-334 ◽

Cited By ~ 23

Author(s):

RICARDO A.G. RUSSO ◽

MARÍA M. KATSICAS

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Growth Retardation ◽

Early Onset ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Joint Destruction ◽

Disease Onset ◽

Damage Index ◽

Systemic Juvenile Idiopathic Arthritis ◽

Activation Syndrome

Objective.Systemic juvenile idiopathic arthritis (SJIA) frequently leads to disability and damage. Predictive factors for a poor outcome include persistent systemic features and younger age at onset. We describe and analyze disease features in patients with early-onset (EO) SJIA (disease onset before age 18 mo) and compare them to patients with later-onset (LO) disease.Methods.Clinical features at onset, activity measures (occurrence of macrophage activation syndrome, remission), and outcome measures for disability [Childhood Health Assessment Questionnaire (CHAQ) ≥ 0.5] and damage [radiographic joint destruction, Juvenile Arthritis Damage Index (JADI) score, growth retardation] observed during followup were analyzed retrospectively in patients with SJIA followed for ≥ 3 years since disease onset.Results.In total 132 patients were included. SJIA started at age ≤ 18 months in 19 (14%) patients and at a later age in 113 (86%) children. At onset, serositis (p < 0.01) and hepatomegaly (p < 0.05) were more frequent in EO patients, who also exhibited lower hemoglobin levels (p < 0.03) and higher platelet counts (p < 0.03) than patients with LO. Macrophage activation syndrome occurred in 20 patients (11 EO and 9 LO; p < 0.0001). Remission was achieved by 49 patients (37%; 4 EO and 45 LO). At last visit, destructive hip disease (p < 0.04), growth retardation (p < 0.01), radiographic damage (p < 0.02), and disability (p < 0.04) were more frequent in patients with EO disease, who had higher JADI scores (p < 0.003).Conclusion.Patients with EO exhibited a more aggressive and destructive disease course than patients with LO SJIA.

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Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis under Treatment with Tocilizumab

The Journal of Rheumatology ◽

10.3899/jrheum.140288 ◽

2015 ◽

Vol 42 (4) ◽

pp. 712-722 ◽

Cited By ~ 51

Author(s):

Shumpei Yokota ◽

Yasuhiko Itoh ◽

Tomohiro Morio ◽

Naokata Sumitomo ◽

Kaori Daimaru ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Clinical Laboratory ◽

Laboratory Data ◽

Systemic Juvenile Idiopathic Arthritis ◽

Clinical Manifestations ◽

Safety Evaluation ◽

Laboratory Findings ◽

Activation Syndrome

Objective.To identify macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA) undergoing tocilizumab (TCZ) treatment, and to confirm laboratory marker changes and responses to treatment in patients with MAS receiving TCZ.Methods.In Japan, 394 patients with sJIA were registered in an all-patient registry surveillance of TCZ as of January 15, 2012. TCZ (8 mg/kg) was administered every 2 weeks to patients with sJIA. MAS, hemophagocytic lymphohistiocytosis, or Epstein-Barr virus–associated hemophagocytic syndrome (EB-VAHS) was reported in 23 of these patients (25 events). The Safety Evaluation Committee of Tocilizumab for JIA reviewed these cases and clinically evaluated the data and laboratory findings using their own therapeutic experience. Events were categorized into 4 groups: definitive MAS, probable MAS, EB-VAHS, and non-MAS.Results.The committee’s review revealed 3 events of definitive MAS in 3 patients, 12 events of probable MAS in 11 patients, 2 events of EB-VAHS in 2 patients, and 8 events of non-MAS in 8 patients. There were 2 patients who developed 2 events: 2 events in 1 patient were classified into definitive MAS and probable MAS, and 2 events in another patient were classified into probable MAS. In patients with definitive or probable MAS, common clinical manifestations and laboratory findings of MAS were observed. Changes in laboratory data observed in patients with EB-VAHS were similar to those observed in patients with MAS.Conclusion.These results suggest that the clinical/laboratory features in the course of MAS appear to be similar among patients regardless of whether TCZ is administered. Similarities in the pathophysiological background of MAS and EB-VAHS were also suggested.

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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

Frontiers in Immunology ◽

10.3389/fimmu.2021.750114 ◽

2021 ◽

Vol 12 ◽

Author(s):

Toshihiko Shiga ◽

Yuji Nozaki ◽

Daisuke Tomita ◽

Kazuya Kishimoto ◽

Yasuaki Hirooka ◽

...

Keyword(s):

Logistic Regression ◽

Differential Diagnosis ◽

Roc Curve ◽

Hemophagocytic Lymphohistiocytosis ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Laboratory Data ◽

Adult Onset Still’S Disease ◽

Adult Onset Still's Disease ◽

Activation Syndrome

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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