Clinical Features Of Macrophage Activation Syndrome Research Articles

Macrophage activation syndrome in children with Kikuchi-Fujimoto disease

BackgroundKikuchi-Fujimoto disease (KFD) is typically a benign, self-limiting inflammatory disease. However, some patients may have a prolonged or recurrent disease course, or present with life-threatening complications such as macrophage activation syndrome (MAS). In this study, we aimed to describe the incidence and clinical features of MAS in KFD and to access potential laboratory markers for the diagnosis of KFD-associated MAS.MethodsPatients with KFD were retrospectively enrolled from January 2015 to November 2021 at Shenzhen Children’s Hospital. Clinical data were collected from inpatient or outpatient medical records. Data collected included clinical manifestations, laboratory and imaging findings, treatment, and clinical outcomes. Data were analyzed using GraphPad Prism 8.0 statistical software (GraphPad Software Inc., La Jolla, CA, USA). A receiver operating characteristic (ROC) curve analysis was further performed to access the potential predictors for the KFD-MAS diagnosis.ResultsOf 58 patients with a histological diagnosis of KFD, 15 (25.9%) patients had MAS. Compared to patients without MAS, patients with KFD-MAS presented with a higher proportion of skin rash (26.7%, p = 0.01), glucocorticoid treatment (80%, p = 0.003), and disease recurrence (33.3%, p = 0.04). KFD-MAS patients had lower absolute peripheral white blood cell (WBC, p = 0.02), platelet (p = 0.002), serum albumin levels (p = 0.01), and lymphocyte count (p < 0.0001), and higher lactate dehydrogenase (LDH) levels (p < 0.0001). ROC curve analysis showed that the cutoff values of absolute lymphocyte count, an absolute platelet count, serum albumin level, and serum LDH level for KFD-MAS diagnosis were < 1235/μL, < 171 × 106/μL, < 35.6 g/L, and > 679 IU/mL, respectively.ConclusionsThe presence of KFD-MAS in children may be more common than previously expected, especially in those with skin rash. KFD-MAS may be associated with a higher recurrence rate. An extremely elevated serum LDH level and moderate to severe lymphopenia may be useful diagnostic markers for MAS in KFD.Trial registrationNot applicable; this was a retrospective study.

Comparison of serum cytokine profiles in macrophage activation syndrome complicating different background rheumatic diseases in children.

To compare the cytokines involved in the development of macrophage activation syndrome (MAS) in different background rheumatic diseases and to identify serum biomarkers for MAS diagnosis. Serum neopterin, IL-6, IL-18 and soluble TNF receptor (sTNFR) type I (sTNFR-I) and type II (sTNFR-II) levels were determined using ELISA in 12 patients with SLE, including five with MAS; 12 patients with JDM, including four with MAS; 75 patients with Kawasaki disease (KD), including six with MAS; and 179 patients with systemic JIA (s-JIA), including 43 with MAS. These results were compared with the clinical features of MAS. Serum neopterin, IL-18 and sTNFR-II levels were significantly higher during the MAS phase than during the active phase in patients with all diseases. Furthermore, serum sTNFR-I levels were significantly higher during the MAS phase than during the active phase in patients with SLE, KD and s-JIA. Receiver operating characteristic (ROC) curve analysis revealed that serum sTNFR-I levels for SLE, serum IL-18 levels for JDM, and serum sTNFR-II levels for KD and s-JIA had the highest areas under the ROC curve. Serum levels of these cytokines were significantly and positively correlated with serum ferritin levels. Overproduction of IFN-γ, IL-18 and TNF-α might be closely related to the development of MAS. Serum levels of sTNFR-I for SLE, IL-18 for JDM, and sTNFR-II for KD and s-JIA might be useful diagnostic markers for the transition from active phase to MAS.

Disruption of vascular endothelial homeostasis in systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: The dynamic roles of angiopoietin-1 and -2

To assess the role of angiopoietin (Ang)-1 and Ang-2 and to investigate the clinical significance of serum levels of them in systemic juvenile idiopathic arthritis (s-JIA)-associated macrophage activation syndrome (MAS), we determined these levels in 51 patients with s-JIA, 11 patients with polyarticular JIA (poly-JIA), 12 patients with virus associated hemophagocytic syndrome (VAHS), 12 patients with Kawasaki disease (KD), and 15 age-matched healthy controls (HC). The results were compared with clinical features of MAS. During the MAS phase, serum Ang-1 levels were significantly decreased compared with those during the active and inactive phases. Serum Ang-2/1 ratio were significantly elevated during the MAS phase, compared with those during the active and inactive phases. There was a rapid increase in the Ang-2/1 ratio at the onset of MAS. Serum Ang-1 and the Ang-2/1 ratio significantly correlated with measures of disease activity, including AST and LDH. Ang-2/1 dysregulation was also observed in patients with VAHS, whereas not observed in most cases of KD. The homeostasis of vascular endothelial function by Ang-1 and Ang-2 is disrupted in MAS. Serum Ang-1 levels and the Ang-2/1 ratio might represent promising indicators of disease activity for MAS.

Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab.

In pivotal trials, canakinumab has been shown to be effective in the treatment of systemic juvenile idiopathic arthritis (JIA), but reported adverse events have included macrophage activation syndrome (MAS). This study was undertaken to assess the impact of canakinumab on MAS incidence. An independent MAS Adjudication Committee (MASAC), consisting of 3 of the authors, was convened, and a search of databases from clinical studies of canakinumab treatment in systemic JIA was performed using MASAC-specified adverse event terms to identify potential MAS events. These were then adjudicated as "probable MAS," "possible MAS," or "MAS unlikely," using criteria developed by the MASAC. MAS rates were expressed as numbers of cases per 100 patient-years. Of 72 potential MAS cases identified, 21 events (19 with canakinumab treatment; 2 with placebo treatment) in 19 patients were adjudicated as being probable MAS and 10 events in 9 patients as being possible MAS. Systemic JIA was well controlled in the majority of canakinumab-treated patients at the time of MAS. The time period between initiation of canakinumab treatment and onset of MAS ranged from 3 to 1,358 days (median 292 days). When the rates of probable MAS events were compared between canakinumab-treated patients (2.8 per 100 patient-years) and placebo-treated patients (7.7 per 100 patient-years), the difference was not significant (-4.9 [95% confidence interval -15.6, 5.9]). There were 3 deaths due to MAS-related complications (2 in patients receiving canakinumab; 1 in a patient receiving placebo); full recovery was reported in all other patients. Infections were the most common trigger of MAS, and the clinical features of MAS were not modified by canakinumab. Canakinumab does not have a significant effect on MAS risk or its clinical features in patients with systemic JIA. Infections are the most common trigger, and MAS occurs even in patients whose systemic JIA is well controlled with this treatment.

Clinical features of macrophage activation syndrome in the adult northern Chinese population

Macrophage activation syndrome (MAS) is a relatively rare but potentially fatal complication of childhood rheumatic illnesses. We sought to provide insight for the timely recognition and diagnosis of MAS and efficacious disease management in adults with rheumatic diseases. Clinical files for eight adult MAS patients treated at the Second Affiliated Hospital of Harbin Medical University were analyzed for clinical manifestations, laboratory investigations, therapeutic measurements and clinical outcomes. The study included male and female patients with ages ranging from 16 to 59 years old. All patients were diagnosed with underlying rheumatic diseases with five patients having adult-onset Still's disease (AOSD), two patients having systemic lupus erythematosus (SLE) and one patient having Sjögren's syndrome (SS). The interval from fever onset to MAS diagnosis varied from seven days to 40 days. The most common clinical presentations were prolonged high fever, respiratory symptoms and jaundice. No patients had symptoms involving the central nervous system (CNS). Laboratory findings showed peripheral cytopenias, elevated liver enzymes, elevated triglycerides, hypofibrinogenemia and bone marrow hemophagocytosis. Potential effective treatments for MAS include glucocorticoid plus immunoglobulin therapy, but delays in diagnosis and treatment may lead to a fatal disease course. MAS in adults may not be as rare as was once thought, although the clinical features of MAS in adults often differ from those seen in children. The MAS mortality in adults is far higher than that for children. A diagnosis of MAS should be considered when a patient with rheumatic disease presents with prolonged high fever, peripheral cytopenia and liver failure. Collection of bone marrow aspirates is critical for accurate diagnosis and MAS therapy should begin as early as possible.

Soluble CD25 in serum: a potential marker for subclinical macrophage activation syndrome in patients with active systemic onset juvenile idiopathic arthritis

Laboratory and immunological abnormalities seen in overt macrophage activation syndrome (MAS) may be observed in patients with untreated new onset systemic onset juvenile idiopathic arthritis (SoJIA). We investigated the prevalence of clinical and traditional laboratory markers of MAS as well as soluble CD163 and soluble interleukin (IL)-2Rα (CD25) in active SoJIA patients. Thirty-three consecutive patients with active SoJIA (International League of Associations for Rheumatology criteria), 11 patients with active polyarticular JIA (polyJIA) (disease control) and two patients with MAS with SoJIA were included in the study. Clinical data, complete blood count, coagulation profile, biochemical tests were performed. Soluble CD25 and soluble CD163 levels were estimated by enzyme-linked immunosorbent assay. Of the 33 active SoJIA patients, 22 were male, the mean age at onset of disease was 6.77 ± 4.48 years and the duration of disease was 4.39 ± 4.6 years. Of the 11 polyJIA patients seven were boys. None of the SoJIA patient had clinical features of MAS. Fibrinogen < 2.5 g/L was present in 14/33 patients with SoJIA but in only 1/11 in polyJIA. Both patients with MAS had thrombocytopenia, leucopenia and reduced fibrinogen levels. sCD25 > 7500 pg/mL seen in MAS was present in eight patients with active SoJIA. Among these eight patients, four had multiple laboratory abnormalities suggestive of MAS. Indeed, one of the patients had past history of MAS. Elevated sCD63 (> 1800 ng/mL) was seen in four patients with SoJIA. Laboratory abnormalities associated with MAS are not uncommon in active SoJIA. Soluble CD25 > 7500 pg/mL may be a marker to detect children with subclinical MAS.

Macrophage Activation Syndrome in the Acute Phase of Kawasaki Disease

Rare cases of macrophage activation syndrome (MAS) occurring during the acute phase of Kawasaki disease (KD) have been reported. We sought to characterize, review treatment, and outcomes of KD patients with clinical features of MAS. Medical histories of patients treated for KD and MAS between January 2001 and March 2008 were reviewed. Of 638 KD patients seen, 12 (1.9%) had additional clinical findings usually associated with MAS; 7 of them were males older than 5 years (6.1%; odds ratio: 6.8, P=0.002). Clinically, 9 patients had at least 4 of 5 KD clinical signs, and all patients had prolonged fever beyond initial intravenous immunoglobulin treatment. Hepatosplenomegaly, cytopenia in two or more cell lines, hypertriglyceridemia and/or hypofibrinogenemia, and increased D-dimers were seen in 11 patients. Hyperferritinemia and elevated hepatic enzymes were seen in all patients. Four patients had biopsy-proven evidence of hemophagocytosis. All but 2 patients met at least 5 of 8 criteria necessary for MAS diagnosis. Treatment beyond the standard KD protocol (aspirin + intravenous immunoglobulin) was necessary in all but 1 patient. All patients eventually recovered with no long-term sequelae. A high index of suspicion for clinical features associated with MAS is warranted for KD patients to provide appropriate and timely treatment.

Macrophage activation syndrome.

Macrophage activation syndrome (MAS) is a serious complication of childhood systemic inflammatory disorders that is thought to be caused by excessive activation and proliferation of T lymphocytes and macrophages. Recent findings in hemophagocytic lymphohistiocytosis, a disease that is clinically similar to MAS, highlight the possible pathogenetic role of a defective function of perforin, a protein involved in the cytolytic processes and control of lymphocyte proliferation. Although the clinical features of MAS have been well documented, early diagnosis can be difficult. Measurement of the serum ferritin level may assist in the diagnosis and may be a useful indicator of disease activity, therapy response, and prognosis. The recognition that MAS belongs to the secondary or reactive hemophagocytic syndromes has led to the proposal to rename it according to the contemporary classification of histiocytic disorders. Cyclosporin A has been found effective in patients with corticosteroid-resistant MAS. A recent report has suggested that etanercept may be a useful adjunctive therapeutic agent.