Efficacy of Tocilizumab Therapy in Different Subtypes of COVID-19 Cytokine Storm Syndrome.

BACKGROUND: Cytokine storm in COVID-19 is heterogenous. There are at least three subtypes: cytokine release syndrome (CRS), macrophage activation syndrome (MAS), and sepsis. METHODS: A retrospective study comprising 276 patients with SARS-CoV-2 pneumonia. All patients were tested for ferritin, interleukin-6, D-Dimer, fibrinogen, calcitonin, and C-reactive protein. According to the diagnostic criteria, three groups of patients with different subtypes of cytokine storm syndrome were identified: MAS, CRS or sepsis. In the MAS and CRS groups, treatment results were assessed depending on whether or not tocilizumab was used. RESULTS: MAS was diagnosed in 9.1% of the patients examined, CRS in 81.8%, and sepsis in 9.1%. Median serum ferritin in patients with MAS was significantly higher (5894 vs. 984 vs. 957 ng/mL, p < 0.001) than in those with CRS or sepsis. Hypofibrinogenemia and pancytopenia were also observed in MAS patients. In CRS patients, a higher mortality rate was observed among those who received tocilizumab, 21 vs. 10 patients (p = 0.043), RR = 2.1 (95% CI 1.0-4.3). In MAS patients, tocilizumab decreased the mortality, 13 vs. 6 patients (p = 0.013), RR = 0.50 (95% CI 0.25-0.99). CONCLUSIONS: Tocilizumab therapy in patients with COVID-19 and CRS was associated with increased mortality, while in MAS patients, it contributed to reduced mortality.

Clinical analysis of macrophage activation syndrome in adult rheumatic disease: A multicenter retrospective study.

AIM: To evaluate the clinical and laboratory characteristics, prognostic factors, and outcome of adult rheumatic disease-associated macrophage activation syndrome (MAS). METHOD: A multicenter retrospective study was performed across 4 tertiary hospitals in China between January 1, 2017 to December 31, 2019. RESULTS: There were 61 rheumatic disease patients with MAS enrolled into this retrospective clinical study. Fever and hyperferritinemia are the most frequent clinical feature and laboratory abnormality in MAS patients. Serum ferritin > 6000 ng/mL (odds ratio [OR] = 9.46, 95% CI = 2.53-47.13, P = .005) and hemophagocytosis in bone marrow smear (OR = 11.12, 95%, CI = 3.29-50.65, P = .001) were the 2 most prominent predictive factors indicating MAS occurrence. The 90-day all-cause mortality rate of all rheumatic disease patients with MAS was 22.9% (hazards ratio [HR] = 2.15, 95% CI = 0.81-6.78, P = .05). Platelets < 100 × 109 /L (HR = 3.23, 95% CI = 2.51-4.81, P = .01) and ferritin > 6000ng/mL (HR = 6.12, 95% CI = 2.93-16.27, P = .005) were independent predictors of poor outcome in rheumatic disease-associated MAS. CONCLUSION: Macrophage activation syndrome could be a fatal complication in rheumatic disease. Patients presenting with unexplained fever, serum ferritin > 6000 ng/mL, hepatosplenomegaly and cytopenia at baseline should raise the suspicion of MAS. The presence of serum ferritin > 6000 ng/mL, hepatosplenomegaly and low number of platelets was associated with poor outcome.

Macrophage activation syndrome associated with adult-onset Still's disease: a multicenter retrospective analysis.

OBJECTIVES: To explore the clinical features, treatments, and prognostic factors of adult-onset Still's disease (AOSD)-associated macrophage activation syndrome (MAS), we conducted a multicenter retrospective clinical study of AOSD-associated MAS patients. METHODS: AOSD patients were collected from six tertiary hospitals in China. Medical charts were reviewed and clinical information was recorded and analyzed. RESULTS: There were 447 AOSD patients enrolled into this retrospective clinical study. Among them, 55 were diagnosed with MAS. Liver dysfunction was the most reliable predictive factor for the screening of MAS in AOSD patients (OR = 75.744, 95%CI = 23.015-249.284, p < 0.0001). In multivariate analysis, clinical features including platelets < 100 × 109/L (OR = 9.546, p = 0.005), aspartate transaminase (AST) > 120 U/L (OR = 25.853, p < 0.0001), triglycerides > 3 mmol/L (OR = 12.9833, p = 0.011)), ferritin > 1500 ng/mL (OR = 5.513, p = 0.050), as well as hemophagocytosis in bone puncture (OR = 18.132, p = 0.001) were highly associated with the occurrence of MAS. The mortality rate of total AOSD patients was 4.47%, MAS was the main cause of death in AOSD patients (OR = 11.705, 95%CI = 4.783-28.647, p < 0.0001). PLT ≤ 100 × 109/L (p = 0.0001), fibrinogen < 1.5 g/L (p = 0.0286), splenomegaly (p = 0.0002), and liver dysfunction (p = 0.0008) highly suggested poor prognosis. CONCLUSION: MAS occurrence is the major cause of death in AOSD patients. Notable liver dysfunction, as well as splenomegaly, low number of platelets or neutrophils, high levels of serum ferritin, and reduced level of fibrinogen are risk factors for poor outcome. Key Points • This is a multicenter retrospective study of AOSD-associated MAS with large number of cases.

Prognosis, complications and treatment response in systemic juvenile idiopathic arthritis patients: A single-center experience.

AIM: Systemic juvenile idiopathic arthritis (sJIA) is a distinctive subtype of JIA characterized by systemic features and poor outcome. We aimed to investigate demographic and clinical features, long-term treatment response and disease complications in a large sJIA cohort. METHODS: Patients diagnosed with sJIA followed up at a pediatric rheumatology outpatient department from January 2003 to December 2017 were included. Demographic and clinical features, long-term treatment response and disease complications were retrospectively collected. RESULTS: A total of 168 sJIA patients (51.8% female, 48.2% male) were included: 31.5% with monocyclic, 13.7% polycyclic and 54.8% with persistent clinical course. Corticosteroids were initially used in all patients. Methotrexate was used in 75% and cyclosporine A was used in 17.3% patients. Biological drugs were used in 42.8% patients; etanercept in 29.7%, anakinra in 16%, canakinumab in 16%, tocilizumab in 10% patients. Remission off medication was achieved in 82 (48.8%). Macrophage activation syndrome (MAS) was present in 11.9%, growth retardation in 11.3% patients. Eight percent (4/50) of patients had low bone mineral density. Three patients (1.78%) died due to MAS secondary multiorgan insufficiency and infection. CONCLUSION: The disease is characterized with diverse clinical presentation and possibly severe complications. MAS complicated with multiorgan insufficiency is the major mortality factor. Corticosteroids represent the mainstay of the initial treatment. In patients resistant to classic treatment, biological drugs should be timely introduced.

Macrophage Activation-Like Syndrome: A Distinct Entity Leading to Early Death in Sepsis.

Hemophagocytic lymphohistocytosis (HLH) is characterized by fulminant cytokine storm leading to multiple organ dysfunction and high mortality. HLH is classified into familial (fHLH) and into secondary (sHLH). fHLH is rare and it is due to mutations of genes encoding for perforin or excretory granules of natural killer (NK) cells of CD8-lymphocytes. sHLH is also known as macrophage activation syndrome (MAS). Macrophage activation syndrome (MAS) in adults is poorly studied. Main features are fever, hepatosplenomegaly, hepatobiliary dysfunction (HBD), coagulopathy, cytopenia of two to three cell lineages, increased triglycerides and hemophagocytosis in the bone marrow. sHLH/MAS complicates hematologic malignancies, autoimmune disorders and infections mainly of viral origin. Pathogenesis is poorly understood and it is associated with increased activation of macrophages and NK cells. An autocrine loop of interleukin (IL)-1ß over-secretion leads to cytokine storm of IL-6, IL-18, ferritin, and interferon-gamma; soluble CD163 is highly increased from macrophages. The true incidence of sHLH/MAS among patients with sepsis has only been studied in the cohort of the Hellenic Sepsis Study Group. Patients meeting the Sepsis-3 criteria and who had positive HSscore or co-presence of HBD and disseminated intravascular coagulation (DIC) were classified as patients with macrophage activation-like syndrome (MALS). The frequency of MALS ranged between 3 and 4% and it was an independent entity associated with early mortality after 10 days. Ferritin was proposed as a diagnostic and surrogate biomarker. Concentrations >4,420 ng/ml were associated with diagnosis of MALS with 97.1% specificity and 98% negative predictive value. Increased ferritin was also associated with increased IL-6, IL-18, IFNγ, and sCD163 and by decreased IL-10/TNFα ratio. A drop of ferritin by 15% the first 48 h was a surrogate finding of favorable outcome. There are 10 on-going trials in adults with sHLH; two for the development of biomarkers and eight for management. Only one of them is focusing in sepsis. The acronym of the trial is PROVIDE (ClinicalTrials.gov NCT03332225) and it is a double-blind randomized clinical trial aiming to deliver to patients with septic shock treatment targeting their precise immune state. Patients diagnosed with MALS are receiving randomized treatment with placebo or the IL-1ß blocker anakinra.

Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation.

Post-hoc subgroup analysis of the negative trial of interleukin-1ß receptor antagonist (IL1RA) for septic shock suggested that patients with features of macrophage activation syndrome (MAS) experienced a 50% relative risk reduction for mortality with treatment. Here we seek a genetic basis for this differential response. From 1341 patients enrolled in the ProCESS trial of early goal directed therapy for septic shock, we selected 6 patients with MAS features and the highest ferritin, for whole exome sequencing (mean 24,030.7 ηg/ml, ±SEM 7,411.1). In total 11 rare (minor allele frequency <5%) pathogenic or likely pathogenic variants causal for the monogenic disorders of Familial Hemophagocytic Lymphohistiocytosis, atypical Hemolytic Uremic Syndrome, Familial Mediterranean Fever, and Cryopyrin-associated Periodic Fever were identified. In these conditions, seven of the identified variants are currently targeted with IL1RA and four with anti-C5 antibody. Gene-targeted precision medicine may benefit this subgroup of patients with septic shock and pathogenic immune variation.

Macrophage Activation Syndrome in Patients Affected by Adult-onset Still Disease: Analysis of Survival Rates and Predictive Factors in the Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale Cohort.

OBJECTIVE: Macrophage activation syndrome (MAS) is a reactive form of hemophagocytic lymphohistiocytosis, which can complicate adult-onset Still disease (AOSD). We investigated AOSD clinical features at the time of diagnosis, to assess predictors of MAS occurrence. Further, we analyzed the outcomes of patients with AOSD who experience MAS. METHODS: Patients with AOSD admitted to any Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale center were retrospectively analyzed for features typical of AOSD, MAS occurrence, and their survival rate. RESULTS: Of 119 patients with AOSD, 17 experienced MAS (12 at admission and 5 during followup). Twelve patients with MAS at first admission differed from the remaining 107 in prevalence of lymphadenopathy and liver involvement at the time of diagnosis. In addition, serum ferritin levels and systemic score values were significantly higher in the patients presenting with MAS. At the time of diagnosis, the 5 patients who developed MAS differed from the remaining 102 in the prevalence of abdominal pain, and they showed increased systemic score values. In the multivariate analysis, lymphadenopathy (OR 7.22, 95% CI 1.49-34.97, p = 0.014) and abdominal pain (OR 4.36, 95% CI 1.24-15.39, p = 0.022) were predictive of MAS occurrence. Finally, MAS occurrence significantly reduced the survival rate of patients with AOSD (p < 0.0001). CONCLUSION: MAS occurrence significantly reduced the survival rate in patients with AOSD. Patients with MAS at baseline presented an increased prevalence of lymphadenopathy and liver involvement, as well as high serum ferritin levels and systemic score values. The presence of lymphadenopathy and abdominal pain was associated with MAS occurrence.

Hypofibrinogenemia Is Associated With Poor Outcome and Secondary Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome in Pediatric Severe Sepsis.

OBJECTIVES: Some children with sepsis exhibit a sustained hyperinflammatory response that can trigger secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Although hypofibrinogenemia is a shared feature of sepsis and hemophagocytic lymphohistiocytosis, there are no data about fibrinogen as a biomarker to identify children with sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap. We hypothesized that hypofibrinogenemia is associated with poor outcomes and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome and has utility as a screening biomarker for this sepsis phenotype. DESIGN: A retrospective cohort study of patients less than or equal to 21 years treated for severe sepsis from January 2012 to December 2014. SETTING: Emergency department and PICU at a single academic children's hospital. PATIENTS: Consecutive patients with greater than or equal to one episode of hypofibrinogenemia (serum fibrinogen < 150 mg/dL) within 7 days of sepsis were compared with a random sample of patients without hypofibrinogenemia using an a priori sample size target of 190. Thirty-eight patients with hypofibrinogenemia were compared with 154 without hypofibrinogenemia. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was "complicated course" (composite of 28-d mortality or ≥ two organ failures at 7 d). Secondary outcomes were 28-day mortality and fulfillment of diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. We used Wilcoxon rank-sum, Fisher exact test, and multivariable logistic regression to compare patients with versus without hypofibrinogenemia. Patients with hypofibrinogenemia were more likely to have a complicated course (73.7% vs 29.2%; p < 0.001), 28-day mortality (26.3% vs 7.1%, p = 0.002), and meet diagnostic criteria for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (21.1% vs 1.3%; p < 0.001). After controlling for confounders, hypofibrinogenemia remained associated with complicated course (adjusted odds ratio, 8.8; 95% CI, 3.5-22.4), mortality (adjusted odds ratio, 6.0; 95% CI, 2.0-18.1), and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (adjusted odds ratio, 27.6; 95% CI, 4.4-173). CONCLUSIONS: Hypofibrinogenemia was independently associated with poor outcome and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome in pediatric sepsis. Measurement of fibrinogen may provide a pragmatic biomarker to identify children with possible sepsis/secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap for whom further diagnostic testing and consideration of adjunctive immunomodulatory therapies should be considered.

Features, Treatment, and Outcomes of Macrophage Activation Syndrome in Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: To describe the features and treatment of macrophage activation syndrome (MAS) in a single-center cohort of patients with childhood-onset systemic lupus erythematosus (SLE), and to compare childhood-onset SLE manifestations and outcomes between those with and those without MAS. METHODS: We included all patients with childhood-onset SLE followed up at The Hospital for Sick Children from 2002 to 2012, and identified those also diagnosed as having MAS. Demographic, clinical, and laboratory features of MAS and SLE, medication use, hospital and pediatric intensive care unit (PICU) admissions, as well as damage indices and mortality data were extracted from the Lupus database. Student's t-tests and Fisher's exact tests were used to compare continuous and categorical variables, respectively. We calculated incidence rate ratios of hospital and PICU admissions comparing patients with and those without MAS, using Poisson models. Kaplan-Meier survival analysis was used to examine the time to disease damage accrual. RESULTS: Of the 403 patients with childhood-onset SLE, 38 (9%) had MAS. The majority (68%) had concomitant MAS and SLE diagnoses. Fever was the most common MAS clinical feature. The frequency of renal and central nervous system disease, hospital admissions, the average daily dose of steroids, and time to disease damage were similar between those with and those without MAS. We observed a higher mortality rate among those with MAS (5%) than those without MAS (0.2%) (P = 0.02). CONCLUSION: MAS was most likely to develop concomitantly with childhood-onset SLE diagnosis. The majority of the MAS patients were successfully treated with corticosteroids with no MAS relapses. Although the numbers were small, there was a higher risk of death associated with MAS compared to SLE without MAS.

Macrophage activation syndrome in Still's disease: analysis of clinical characteristics and survival in paediatric and adult patients.

Macrophage activation syndrome (MAS) is a reactive form of hemophagocytic lymphohistiocytosis, complicating Still's disease, both in paediatric and adult patients. In this work, we aimed to investigate clinical picture and outcome of Still's disease patients developing MAS. We performed a retrospective analysis of patients, both paediatrics and adults, affected by Still's disease attending our department. During the follow-up, each patient was investigated for MAS occurrence and possible predictors, clinical and laboratory factors, were analysed. We evaluated 50 patients affected by Still's disease, 21 paediatric and 29 adult patients. Ten patients experienced MAS (five adult and five paediatric patients) and its development significantly reduced the survival rate when compared with patients without this complication (p < 0.0001). The analysis of possible predictors showed that high-value systemic score (p = 0.03) and high levels of serum ferritin (p = 0.002) were independently associated with an increased likelihood of MAS. MAS occurrence significantly reduced survival rate in both paediatric and adult patients affected by Still's disease. The high levels of serum ferritin and an elevated systemic score, at the time of diagnosis, were significantly associated with MAS.

Three Hypothetical Inflammation Pathobiology Phenotypes and Pediatric Sepsis-Induced Multiple Organ Failure Outcome.

OBJECTIVES: We hypothesize that three inflammation pathobiology phenotypes are associated with increased inflammation, proclivity to develop features of macrophage activation syndrome, and multiple organ failure-related death in pediatric severe sepsis. DESIGN: Prospective cohort study comparing children with severe sepsis and any of three phenotypes: 1) immunoparalysis-associated multiple organ failure (whole blood ex vivo tumor necrosis factor response to endotoxin < 200 pg/mL), 2) thrombocytopenia-associated multiple organ failure (new onset thrombocytopenia with acute kidney injury and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 activity < 57%), and/or 3) sequential multiple organ failure with hepatobiliary dysfunction (respiratory distress followed by liver dysfunction with soluble Fas ligand > 200 pg/mL), to those without any of these phenotypes. SETTING: Tertiary children's hospital PICU. PATIENTS: One hundred consecutive severe sepsis admissions. INTERVENTIONS: Clinical data were recorded daily, and blood was collected twice weekly. MEASUREMENTS AND MAIN RESULTS: Multiple organ failure developed in 75 cases and eight died. Multiple organ failure cases with any of the three inflammation phenotypes (n = 37) had higher inflammation (C-reactive protein, p = 0.009 and ferritin, p < 0.001) than multiple organ failure cases without any of these phenotypes (n = 38) or cases with only single organ failure (n = 25). Development of features of macrophage activation syndrome and death were more common among multiple organ failure cases with any of the phenotypes (macrophage activation syndrome: 10/37, 27%; death: 8/37, 22%) compared to multiple organ failure cases without any phenotype (macrophage activation syndrome: 1/38, 3%; p = 0.003 and death: 0/38, 0%; p = 0.002). CONCLUSIONS: Our approach to phenotype categorization remains hypothetical, and the phenotypes identified need to be confirmed in multicenter studies of pediatric multiple organ dysfunction syndrome.

Application of the 2016 EULAR/ACR/PRINTO Classification Criteria for Macrophage Activation Syndrome in Patients with Adult-onset Still Disease.

OBJECTIVE: To evaluate the clinical significance of the 2016 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR)/Pediatric Rheumatology International Trials Organization (PRINTO) classification criteria for macrophage activation syndrome (MAS) in patients with adult-onset Still disease (AOSD). METHODS: We performed a retrospective analysis of patients with AOSD with fever who were admitted to Severance Hospital between 2005 and 2016. The patients with AOSD were evaluated for MAS using the 2016 classification criteria for MAS. Clinical features, laboratory findings, and overall survival were analyzed. Logistic regression analysis was used to evaluate the factors associated with in-hospital mortality. RESULTS: Among 64 patients with AOSD, 36 (56.3%) were classified as having MAS. The overall survival rate was significantly lower in patients with MAS than in those without (67% vs 100%, p < 0.001). Multivariate analysis showed that a low erythrocyte sedimentation rate, a low albumin level, an increase in ferritin of over 2 folds, and the development of MAS on admission were significantly associated with mortality in patients with AOSD. CONCLUSION: The 2016 EULAR/ACR/PRINTO classification criteria for MAS are potentially useful for the identification of patients with AOSD at high risk for a poor outcome. Febrile patients with AOSD should be monitored with the 2016 classification criteria for MAS in the early diagnosis and proper treatment of MAS.

In-hospital mortality in febrile lupus patients based on 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome.

OBJECTIVE: To evaluate the clinical significance of the 2016 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR)/Pediatric Rheumatology International Trials Organization (PRINTO) classification criteria for macrophage activation syndrome (MAS) in patients with febrile systemic lupus erythematosus (SLE). METHODS: We performed a retrospective analysis of SLE patients with fever, who were admitted to Severance Hospital between December 2005 and May 2016. Patients were evaluated for MAS using the 2016 classification criteria for MAS. Clinical features and laboratory findings were compared and overall survival rate was analyzed. Forward and backward stepwise logistic regression analysis was used to evaluate the factors associated with in-hospital mortality. RESULTS: Among 157 patients with SLE, 54 (34.3%) were considered to have MAS on admission (n = 42) and during admission (n = 12). For patients who already have MAS on admission, their baseline laboratory findings demonstrated lower CRP, platelets, total protein, albumin, complement C3, fibrinogen and higher AST, ALT, total bilirubin, ferritin, and triglyceride. The overall survival rate was significantly lower in patients with MAS than without MAS (64.8% vs. 97.0%, p < 0.001). Multivariate analysis showed that the presence of MAS was significantly associated with in-hospital mortality in febrile SLE patients (OR = 64.5; 95% CI: 7.6-544.4; p < 0.001). CONCLUSIONS: The 2016 classification criteria for MAS is useful to identify febrile SLE patients at high risk for in-hospital mortality. Monitoring febrile SLE patients with the new 2016 classification criteria might aid in the early detection of MAS.

Prognostic factors of macrophage activation syndrome, at the time of diagnosis, in adult patients affected by autoimmune disease: Analysis of 41 cases collected in 2 rheumatologic centers.

Macrophage activation syndrome (MAS) is a rare, life-threatening disease in which early diagnosis and aggressive therapeutic strategy may improve the outcome. Due to its rarity, epidemiologic data are still lacking. Hyperferritinemia is frequently associated with MAS and might modulate the cytokine storm, which is involved in the development of multiple organ failure. In this paper, we investigated clinical data, treatments, and outcome of a homogeneous cohort of 41 adult MAS patients, complicating autoimmune rheumatic diseases. MAS-related death occurred in 17 patients (42.5%) during the follow-up, and older age and increased serum ferritin levels, at the time of diagnosis, were significantly associated with mortality. In conclusion, adult MAS is associated with high mortality rate. Some clinical features at diagnosis may be predictive of MAS-associated death.

High-Volume Hemofiltration in Critically Ill Patients With Secondary Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome: A Prospective Study in the PICU.

OBJECTIVES: Hemophagocytic lymphohistiocytosis, which includes primary (familial) and secondary hemophagocytic lymphohistiocytosis, is a fatal disease in children. Macrophage activation syndrome was defined in patients who met secondary hemophagocytic lymphohistiocytosis criteria with an underlying autoimmune disease. High-volume hemofiltration has shown beneficial effects in severe sepsis and multiple organ dysfunction syndrome. Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome shares many pathophysiologic similarities with sepsis. The present study assessed the effects of high-volume hemofiltration in children with secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. DESIGN: A single-center nonrandomized concurrent control trial. SETTING: The PICU of Shanghai Children's Hospital, Shanghai Jiao Tong University. PATIENTS: Thirty-three critically ill secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome patients treated between January 2010 and December 2014. INTERVENTIONS: Thirty-three patients were divided into two groups: high-volume hemofiltration + hemophagocytic lymphohistiocytosis-2004 group (17 cases) or hemophagocytic lymphohistiocytosis-2004 group (16 cases). High-volume hemofiltration was defined as an ultrafiltrate flow rate of 50-70 mL/kg/hr. Clinical and biological variables were assessed before initiation and after 48 and 72 hours of high-volume hemofiltration therapy. MEASUREMENTS AND MAIN RESULTS: The total mortality rate was 42.4% (14/33), but mortality at 28 days was not significantly different between the two groups (high-volume hemofiltration + hemophagocytic lymphohistiocytosis-2004 group: five deaths, 29.4%; hemophagocytic lymphohistiocytosis-2004 group: nine deaths, 56.3%; chi-square, 2.431; p = 0.119). Children received high-volume hemofiltration for 60.2 ± 42.0 hours. After 48 and 72 hours respectively, a significant decrease in serum ferritin (p < 0.001), aspartate aminotransferase (p = 0.037 and p < 0.001), total bilirubin (p = 0.041 and p = 0.037), and serum creatinine (p = 0.006 and p = 0.004) levels were observed. Furthermore, the natural killer-cell activity up-regulated (p = 0.047) after 72 hours. Furthermore, significantly decreased levels of serum tumor necrosis factor-α (from 91.5 ± 44.7 ng/L at 48 hr to 36.7 ± 24.9 ng/L at 72 hr; p = 0.007)) and interleukin-6 (from 46.9 ± 21.1 ng/L at 48 hr to 27.7 ± 14.5 ng/L at 72 hr; p < 0.0001) were observed. After 7 days, patients receiving high-volume hemofiltration had significantly lower bilirubin, creatinine, ferritin, procalcitonin, lactate dehydrogenase level, tumor necrosis factor-α, and interleukin-6 levels, and needed less mechanical ventilation compared with hemophagocytic lymphohistiocytosis-2004 group patients. No serious adverse events were observed. CONCLUSIONS: High-volume hemofiltration may improve organ function by decreasing cytokine levels (tumor necrosis factor-α and interleukin-6). High-volume hemofiltration may be an effective adjunctive treatment in secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

Secondary macrophage activation syndrome due to autoimmune, hematologic, infectious and oncologic diseases. Thirteen case series and review of the literature.

OBJECTIVE: Describe the demographic characteristics and disorders of patients with diagnosis of Macrophage Activation Syndrome (MAS) in the December 2008 - January 2014 period. METHODS: Medical records were reviewed from diagnosis of MAS and after discharge until January 2014. Patients were divided into 4 groups according to the primary disease: Autoimmune (AI), Hemato - oncologic (HO), Infectious (Inf) and Oncologic (Onc). The variables were analyzed among the 4 groups and between AI and HO. RESULTS: Thirteen patients [7 men, with a median of 54 years (32-63)] were studied. The etiologies were: 5 AI, 5 HO, 2 Inf. and 1 Onc. disease. Hemophagocitc cells were found in the ascitic fluid of one patient. A patient with MAS secondary to IgG4-related disease was found. CONCLUSIONS: Mortality, prognosis and disease progression may be influenced by the delay in diagnosis, treatment initiation and etiology of MAS. HO ill patients had a worse prognosis.

Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients.

OBJECTIVE: To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA). METHODS: In this multinational, multicenter study, pediatric rheumatologists and hemato-oncologists entered patient data collected retrospectively into a web-based database. RESULTS: A total of 362 patients, 22% of whom had MAS at the onset of systemic JIA, were included in the study by 95 investigators from 33 countries. The most frequent clinical manifestations were fever (96%), hepatomegaly (70%), and splenomegaly (58%). Central nervous system dysfunction and hemorrhages were recorded in 35% and 20% of the patients, respectively. Platelet count and liver transaminase, ferritin, lactate dehydrogenase, triglyceride, and d-dimer levels were the sole laboratory biomarkers showing a percentage change of >50% between the pre-MAS visit and MAS onset. Evidence of macrophage hemophagocytosis was found in 60% of the patients who underwent bone marrow aspiration. MAS occurred most frequently in the setting of active underlying disease, in the absence of a specific trigger. Nearly all patients were given corticosteroids, and 61% received cyclosporine. Biologic medications and etoposide were given to 15% and 12% of the patients, respectively. Approximately one-third of the patients required admission to the intensive care unit (ICU), and the mortality rate was 8%. CONCLUSION: This study provides information on the clinical spectrum and current management of systemic JIA-associated MAS through the analysis of a very large patient sample. MAS remains a serious condition, as a sizeable proportion of patients required admission to the ICU or died.

Macrophage activation syndrome in children with systemic lupus erythematosus and children with juvenile idiopathic arthritis.

OBJECTIVE: To describe patient demographics, interventions, and outcomes in hospitalized children with macrophage activation syndrome (MAS) complicating systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA). METHODS: We performed a retrospective cohort study using data recorded in the Pediatric Health Information System (PHIS) database from October 1, 2006 to September 30, 2010. Participants had International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for MAS and either SLE or JIA. The primary outcome was hospital mortality (for the index admission). Secondary outcomes included intensive care unit (ICU) admission, critical care interventions, and medication use. RESULTS: A total of 121 children at 28 children's hospitals met the inclusion criteria, including 19 children with SLE and 102 children with JIA. The index admission mortality rate was 7% (8 of 121 patients). ICU admission (33%), mechanical ventilation (26%), and inotrope/vasopressor therapy (26%) were common. Compared to children with JIA, those with SLE had a similar mortality rate (6% versus 11%, respectively; exact P = 0.6). More patients with SLE than those with JIA received ICU care (63% versus 27%; P = 0.002), received mechanical ventilation (53% versus 21%; P = 0.003), and had cardiovascular dysfunction (47% versus 23% received inotrope/vasopressor therapy; P = 0.02). Children with SLE and those with JIA received cyclosporine at similar rates, but more children with SLE received cyclophosphamide and mycophenolate mofetil, and more children with JIA received interleukin-1 antagonists. CONCLUSION: Organ system dysfunction is common in children with rheumatic diseases complicated by MAS, and more organ system support is required in children with underlying SLE than in children with JIA. Current treatment of pediatric MAS varies based on the underlying rheumatic disease.

The incidence of macrophage activation syndrome in children with rheumatic disorders.

AIM: Macrophage activation syndrome (MAS) is a rare complication of childhood with rheumatic disease. This syndrome has been reported as a complication of many rheumatic diseases, most commonly in systemic onset of juvenile idiopathic arthritis (SoJIA). The aim of this study was evaluation the rate, symptoms and outcome of MAS in a pediatric rheumatology department in Tehran during 10 years. METHODS: Retrospective review of cases of MAS from the charts of 120 patients with juvenile idiopathic arthritis and systemic lupus erythematosus (SLE). Collected data base of 5 children with MAS from 1998 to 2007, in Children Hospital Medical Center, In Tehran University were collected. RESULTS: Totally 120 patients evaluated in this study including 108 JIA and 12 SLE. Five patients (four girls), and (one boy) were considered to have evidence of MAS. The incidence of MAS in our study was 4.2%. This rate for all JIA patients was 3.7% and for SoJIA, SLE and juvenile idiopaticarthritis (JIA) and polyarticular RF negative JIA was 8.2%, 16.7% and 2.8%, respectively. Mean age of MAS onset was 4.9 years, and duration of rheumatologic disease prior to MAS, 22 months. Four cases (80%) had abnormal liver function during the disease course, and coagulopathy. Bone marrow examination supported the diagnosis with definite haemophagocytosis in four cases (80%). The mortality rate was 40%. CONCLUSION: Although MAS is a rare complication of rheumatologic disorders, because it is potentially fatal it must be thought in each childhood rheumatic disorders with suddenly changes in general condition and decrease peripheral cells.

Experience with hemophagocytic lymphohistiocytosis/macrophage activation syndrome at a single institution.

BACKGROUND: Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) is a serious and potentially life threatening histiocytic disorder in children and adults. The most commonly used protocol-based therapy includes corticosteroids, cyclosporine-A, and etoposide. However, patients are often started on corticosteroid alone with or without the addition of intravenous gamma-globulin. The role of the various therapies in HLH/MAS remains undefined. OBJECTIVE: To identify patient-related factors that led to the use of full protocol therapy (HLH 1994/2004) and to determine treatment-related factors that were associated with adverse outcome including relapse and death. DESIGN/METHODS: Patients who were diagnosed with HLH/MAS between January 1998 and December 2005 were included in this study. RESULTS: Thirty-eight patients had a median age of 9.1 years at diagnosis. Underlying diagnoses were: viral/other 42%; rheumatologic 37%; and malignancy 21%. Initial treatment included corticosteroids 29%; intravenous immunoglobulin (IVIG) 18%; steroids+IVIG 8%; cyclosporine 5%; etoposide 5%; HLH protocol 32%. Etoposide was eventually used in 21% (3/14) of rheumatology and 75% (18/25) viral/other patients. In all, 5/14 (36%) rheumatology and 12/16 (75%) viral/other patients required intensive care unit admission, and 1/14 (7.1%) rheumatology, and 6/16 (38%) viral/other patients died. Three children received a bone marrow transplant. Eleven of 38 (29%) patients died, despite 8 having received etoposide therapy. Three deaths were secondary to underlying malignancy and one from transplant-related complication for malignancy. CONCLUSIONS: Patients with HLH are at high risk for death early in their disease course. However, corticosteroids and/or IVIG may be sufficient as first-line therapy for patients with underlying rheumatologic disease who present with HLH/MAS. Further prospective studies are required to more precisely define early risk factors for poor outcomes in this often fatal disease.