A Case of Adult-Onset Still's Disease With Hypocomplementemia.

Adult-onset Still's disease (AOSD) causes fever, rash, pharyngalgia, and arthralgia through autoinflammation. Its complement titer has not previously received attention because this usually increases during the inflammatory process. Our female patient in her 60s was admitted to the hospital with fever, rash, arthralgia, and pharyngalgia. Her white blood cell count was 19,130/µL, hemoglobin was 11.0 g/dL, platelet count was 26.0 × 104/µL, and ferritin titer was 6,175 ng/mL. Anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies were negative. The presence of infectious diseases and malignancies was excluded. She was diagnosed with hypocomplementemia at the onset of AOSD because of her low complement component 4 (C4) titer (<5.0 mg/dL). Her complement component 3 (C3) titer was 104.5 mg/dL, which was within normal limits. There was no sign of thrombotic microangiopathy (TMA) or hemophagocytosis. She was treated with high-dose corticosteroids, including pulse methylprednisolone therapy, cyclosporine, methotrexate, and intravenous immunoglobulin, but was resistant to these, and her disease repeatedly flared up. Treatment with intravenous cyclophosphamide eventually led to remission. Post-treatment, her C4 titer increased to within the normal range. Although hypocomplementemia with TMA or hemophagocytosis has been reported in AOSD patients, our patient showed no sign of either at disease onset. Hypocomplementemia of AOSD may be a sign of high disease activity and could be a predictive marker for resistance to standard therapy.

Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis.

BACKGROUND: One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. METHODS: We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. RESULTS: Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1ß, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1ß, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. CONCLUSIONS: These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.

The similar expression of both ferritin and scavenger receptors activation genes in patients with COVID19 and AOSD support their role in the pathogenesis of these diseases and identify a common mechanism at the basis of the "hyperferritinemic syndromes".

A role for COVID19 in "hyperferritinemic syndromes" has been proposed based on its clinical and serological characteristics and its similarities with AOSD. To better understand the molecular pathways responsible of these similarities, we evaluated in the PBMCs of 4 active AOSD patients, 2 COVID19 patients with ARDS, and 2 HCs the expression of genes associated with iron metabolisms, with monocyte/macrophages activation, and finally with NETs formation.

The intercorrelations between blood levels of ferritin, sCD163, and IL-18 in COVID-19 patients and their association to prognosis.

Coronavirus disease 2019 (COVID-19) is associated with immune dysregulation, severe respiratory failure, and multiple organ dysfunction caused by a cytokine storm involving high blood levels of ferritin and IL-18. Furthermore, there is a resemblance between COVID-19 and macrophage activation syndrome (MAS) characterized by high concentrations of soluble CD163 (sCD163) receptor and IL-18. High levels of ferritin, IL-18, and sCD163 receptor are associated with "hyperferritinemic syndrome", a family of diseases that appears to include COVID-19. In this retrospective cohort study, we tested the association and intercorrelations in the serum levels of ferritin, sCD163, and IL-18 and their impact on the prognosis of COVID-19. We analyzed data of 70 hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The levels of sCD163, ferritin, and IL-18 were measured and the correlation of these parameters with the respiratory deterioration and overall 30-day survival was assessed. Among the 70 patients, 60 survived 30 days from hospitalization. There were substantial differences between the subjects who were alive following 30 days compared to those who expired. The differences were referring to lymphocyte and leukocyte count, CRP, D-dimer, ferritin, sCD163, and IL-18. Results showed high levels of IL-18 (median, 444 pg/mL in the survival group compared with 916 pg/mL in the mortality group, p-value 8.54 × 10-2), a statistically significant rise in levels of ferritin (median, 484 ng/mL in the survival group compared with 1004 ng/mL in the mortality group p-value, 7.94 × 10-3), and an elevated value of in sCD163 (mean, 559 ng/mL in the survival group compared with 840 ng/mL in the mortality group, p-value 1.68 × 10-2). There was no significant correlation between the rise of ferritin and the levels sCD163 or IL-18. Taken together, sCD163, ferritin, and IL-18 were found to correlate with the severity of COVID-19 infection. Although these markers are associated with COVID-19 and might contribute to the cytokine storm, no intercorrelation was found among them. It cannot be excluded though that the results depend on the timing of sampling, assuming that they play distinct roles in different stages of the disease course. The data represented herein may provide clinical benefit in improving our understanding of the pathological course of the disease. Furthermore, measuring these biomarkers during the disease progression may help target them at the right time and refine the decision-making regarding the requirement for hospitalization.

Extreme Hyperferritinemia: Causes and Prognosis.

The significance of extreme hyperferritinemia and its association with certain diagnoses and prognoses are not well characterized. We performed a retrospective analysis of adult patients with at least one total serum ferritin (TSF) measurement ≥ 5000 µg/L over 2 years, in three university hospitals. Conditions associated with hyperferritinemia were collected, and patients were classified into 10 etiological groups. Intensive care unit (ICU) transfer and mortality rates were recorded. A total of 495 patients were identified, of which 56% had a TSF level between 5000 and 10,000 µg/L. There were multiple underlying causes in 81% of the patients. The most common causes were infections (38%), hemophagocytic lymphohistiocytosis (HLH, 18%), and acute hepatitis (14%). For TSF levels > 10,000 µg/L, there were no solid cancer or hematological malignancy without another cause of hyperferritinemia. Isolated iron-overload syndromes never exceeded TSF levels > 15,000 µg/L. Extreme hyperferritinemia (TSF levels > 25,000 µg/L) was associated with only four causes: HLH, infections, acute hepatitis and cytokine release syndromes. A total of 32% of patients were transferred to an ICU, and 28% died. Both ICU transfer rate and mortality were statistically associated with ferritin levels. An optimized threshold of 13,405 µg/L was the best predictor for the diagnosis of HLH, with a sensitivity of 76.4% and a specificity of 79.3%. Hyperferritinemia reflects a variety of conditions, but only four causes are associated with extreme hyperferritinemia, in which HLH and acute hepatitis are the most common. Extreme hyperferritinemia has a poor prognosis with increased mortality.

The beneficial role of Hepcidin peptide inhibitor in improved the symptoms of COVID-19 in diabetics: anti-inflammatory and potential therapeutic effects.

Coronavirus Disease 2019 (COVID-19) is a recent public health issue worldwide. Also, diabetes is a frequent condition with high mortality. There is a strong relationship between COVID-19 and diabetes. This article analyses the intricate relationship between COVID-19 and hepcidin. Hepcidin increases in aged non-insulin diabetic patients. Hepcidin is the last target treatment of several medications commonly used. Viral diseases, especially SARS-CoV19, can activate the hepcidin pathway leading to an elevation in the iron load. This increased iron is released into the bloodstream and results in cell death through ferroptosis, like free iron. Excess iron has pro-coagulative and toxic effects. Hepcidin overexpression and iron overload are associated with COVID-19 infection and can be considered potential targets for treatment. Several studies have shown dalteparin (anti-Hepcidin) could improve the symptoms of COVID-19 in diabetics by appropriately modulating and decreasing oxidative stress and inflammation. This finding can be leading to enhancing the existing knowledge about Therapeutic measures for reducing Covid-19 impairments in diabetics and is suggested as a possible therapeutic agent in diabetes.

Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials.

BACKGROUND: Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions. METHODS: We applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin. RESULTS: Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p < 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p < 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p < 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p < 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83-136.83], p < 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26-137.75], p < 0.0001). CONCLUSIONS: Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership ( www.pedsepsis.pitt.edu ) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.

Ferritin as prognostic marker in COVID-19: the FerVid study.

BACKGROUND: In COVID-19 patients the progressive clinical deterioration seems secondary to the activation of a cytokine storm. Ferritin is considered a direct mediator of the immune system and some evidences suggested a shared physio-pathogenic basis between COVID-19 and 'Hyperferritinemic Syndromes.' The aim of our study was to evaluate the prognostic role of ferritin in COVID-19 patients. METHODS: We retrospectively studied consecutive COVID-19 patients admitted to four Italian Internal Medicine Units. Role of potential prognostic markers was evaluated with binary logistic regression analysis and results were expressed as odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). Poor outcome was defined as death or need to transfer in the intensive care unit. RESULTS: Two hundred patients were included (mean age 68.75 ± 13.22 years). Ferritin value was highly elevated (>3000 ng/mL) in 8% of our population; 13% of patients were transferred to intensive care units and 12% of patients died. At multivariate analysis, highly elevated ferritin levels (OR 16.67 C.I. 4.89-57.57 p < 0.001) and hemoglobin < 10 g/dL (OR 8.88 C.I. 2.02-39.09 p = 0.004) were independently associated with a bad outcome.Patients with ferritin values > 3000 ng/ml appeared to have an inflammatory activation with elevated values of CRP and D-dimer and low values of lymphocyte count. CONCLUSION: Our results confirm the prognostic role of ferritin in hospitalized COVID-19 patients. Patients with high ferritin levels should be considered critically ill and treated in an adequate setting. Furthermore, COVID-19 seems to share some characteristics with hyperferritinemic syndromes with potential therapeutic implications.

Relação entre os níveis de ferritina e o prognóstico da COVID-19 / Relationship between ferritin levels and the prognosis of COVID-19

O elevado nível de ferritina sérica tem sido associado à COVID-19 grave devido à sua estimulação por citocinas relacionadas com o processo inflamatório. Embora este aumento seja esperado, esta revisão propõe analisar o quão elevado o nível de ferritina pode estar relacionado com esta severidade. Nesta linha de pensamento, a hiperferritinemia na COVID-19 poderia ser um importante fator de previsão e outra forma de compreender as complicações da COVID-19 - coagulopatia, síndrome do desconforto respiratório agudo (SDRA). Além disso, esta correlação tem sido vista como uma possível quinta síndrome entre as outras "síndromes hiperferritinêmicas", todas caracterizadas por ferritina sérica elevada; esta é uma comparação e análise pertinente em termos de tratamentos. [au]

The high level of serum ferritin has been associated with severe COVID-19 due to its stimulation by cytokines related to the inflammatory process. Although this increase is expected, this review proposes to analyze how high ferritin can be related to this severeness. According to this premise, the hyperferritinemia on COVID-19 could be an important factor of prediction and another way to understand the complications of COVID-19 -coagulopathy, acute respiratory distress syndrome (ARDS). Furthermore, this correlation has been seen as a possible fifth syndrome among the other "hyperferritinemic syndromes", which are all characterized by high serum ferritin; this is an pertinent comparison and analyzation in terms of treatments. [au]

Case Report: Rapid Recognition and Immune Modulation of Secondary HLH Due to Disseminated HSV Infection.

We describe the case of a newborn who presented with multiple organ dysfunction syndrome (MODS) and hyperferritinemia, who eventually met criteria for hemophagocytic lymphohistiocytosis (HLH) due to disseminated herpes simplex virus 1 (HSV-1). While the cytokine storm abated after administration of multiple immune modulatory therapies including dexamethasone, etoposide, intravenous immune globulin, anakinra, as well as the interferon gamma antagonist emapalumab, multiple organ dysfunction syndrome progressed. Care was withdrawn after 5 days. Subsequent genetic testing did not reveal any mutations associated with familial HLH. This case highlights that even with appropriate antiviral treatment and immune suppression, disseminated HSV is often fatal. Further study is warranted to determine whether early immune modulatory therapy including interferon gamma blockade can interrupt the HLH inflammatory cascade and prevent progression of MODS.

Optimal serum ferritin level range: iron status measure and inflammatory biomarker.

This report provides perspectives concerning dual roles of serum ferritin as a measure of both iron status and inflammation. We suggest benefits of a lower range of serum ferritin as has occurred for total serum cholesterol and fasting blood glucose levels. Observations during a prospective randomized study using phlebotomy in patients with peripheral arterial disease offered unique insights into dual roles of serum ferritin both as an iron status marker and acute phase reactant. Robust positive associations between serum ferritin, interleukin 6 [IL-6], tissue necrosis factor-alpha, and high sensitivity C-reactive protein were discovered. Elevated serum ferritin and IL-6 levels associated with increased mortality and with reduced mortality at ferritin levels <100 ng mL-1. Epidemiologic studies demonstrate similar outcomes. Extremely elevated ferritin and IL-6 levels also occur in individuals with high mortality due to SARS-CoV-2 infection. Disordered iron metabolism reflected by a high range of serum ferritin level signals disease severity and outcomes. Based upon experimental and epidemiologic data, we suggest testing the hypotheses that optimal ferritin levels for cardiovascular mortality reduction range from 20 to 100 ng mL-1 with % transferrin levels from 20 to 50%, to ensure adequate iron status and that ferritin levels above 194 ng mL-1 associate with all-cause mortality in population cohorts.

Successful treatment of refractory hyperferritinemic syndromes with canakinumab: a report of two cases.

BACKGROUND: Hyperferritinemic syndromes are systemic inflammatory disorders characterized by a dysfunctional immune response, which leads to excessive activation of the monocyte-macrophage system with hypercytokinemia and may pursue a rapidly fatal course. CASE PRESENTATION: We describe two patients of 11 and 9 years of age with hyperferritinemic syndromes, one with impending macrophage activation syndrome (MAS) and one with overt MAS, who were refractory or intolerant to conventional therapies, but improved dramatically with canakinumab. CONCLUSIONS: Our report indicates that canakinumab may be efficacious in the management of hyperferritinemic syndromes, including MAS.

COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy.

SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still's disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.

Fulminant encephalopathy in a child with hyperferritinemic sepsis: a case report.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is epidemic in intensive care units and recognized as a fatal complication of sepsis. SAE is characterized by diffuse brain dysfunction and the correct diagnosis of SAE requires ruling out direct central nervous system (CNS) infection or other types of encephalopathy, such as hepatic encephalopathy, pulmonary encephalopathy, and other encephalopathy. CASE PRESENTATION: We reported a rare case of a 5-year-old girl who presented with abdominal pain, vomiting, recurrent seizures, and coma. Brain magnetic resonance imaging (MRI) showed diffuse white matter abnormalities in the brain on day 1. Cerebrospinal fluid (CSF) tests revealed that protein levels and glucose levels were normal without pleocytosis. CSF PCRs for pathogens were all negative. The electroencephalography examination demonstrated diffuse, generalized and slow background activity. The patient showed the symptom of hyperferritinemic sepsis with multiple organ dysfunction syndrome (MODS). SAE was also diagnosed by ruling out other encephalitis or encephalopathy. The patient made marked improvements of clinical symptoms and the lesions on brain imaging disappeared completely within two months after appropriate treatment including antibiotic treatments, methylprednisolone, intravenous immunoglobulin, membrane-based therapeutic plasma exchange (TPE), and continuous renal replacement therapy (CRRT). CONCLUSIONS: SAE can be a fatal complication of sepsis which asks for immediate diagnosis and treatment. Few reports have focus on MRI imaging findings on the early onset of hyperferritinemic sepsis with MODS since these children were too ill to undergo an MRI scan. However, SAE might appear before other systemic features of sepsis are obvious, and MRI could show abnormal lesion in the brain during the early course. Therefore, MRI should be performed early to diagnose this fatal complication which would play important roles in improving the clinical outcomes by early initiation with appropriate treatments.

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.

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.

Advances in immunopathogenesis of macrophage activation syndrome during rheumatic inflammatory diseases: toward new therapeutic targets?

INTRODUCTION: Macrophage activation syndrome (MAS) is a severe, hyperinflammatory life-threatening syndrome, generally complicating different rheumatic diseases. Despite the severity of the disease, little is known about the pathogenic mechanisms and, thus, possible targeted therapies in the management of these patients. Areas covered: In this review, we aimed to update the current pathogenic knowledge of MAS, during rheumatic diseases, focusing mainly on immunologic abnormalities and on new possible therapeutic strategies. Expert commentary: The difficult pathogenic scenario of MAS, in which genetic defects, predisposing diseases, and triggers are mixed together with the high mortality rate, make it difficult to manage these patients. Although most efforts have been focused on investigating the disease in children, in recent years, several studies are trying to elucidate the possible pathogenic mechanism in adult MAS patients. In this context, genetic and immunological studies might lead to advances in the knowledge of pathogenic mechanisms and possible new therapeutic targets. In the future, the results of ongoing clinical trials are awaited in order to improve the management and, thus, the survival of these patients.

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.

Extreme hyperferritinemia in the setting of acute myeloid leukaemia: a case report of hemophagocytic lymphohistiocytosis.

INTRODUCTION: Major hyperferritinemia is a rare feature in clinical laboratories associated with a wide variety of disorders, including hemophagocytic lymphohistiocytosis (HLH). The diagnosis of HLH is based on clinical and biological criteria, such as those proposed by the Histiocyte Society. However, several of these criteria are not relevant in the specific setting of hematologic malignancies. MATERIALS AND METHODS: A 69-year-old male was treated for an acute myeloid leukaemia. On day 15 after the start of chemotherapy, he developed severe sepsis with high fever, low blood pressure and hepatosplenomegaly. RESULTS: Blood tests were marked by extreme hyperferritinemia (191,000 µg/L, reference range: 26-388 µg/L) with increased C-reactive protein (87.0 mg/L) and procalcitonin (1.94 µg/L) and aspartate aminotransferase (499 U/L 37 °C) in the setting of chemotherapy-induced aplasia. This unusual extreme ferritinemia led to suspect HLH triggered by an invasive infection. Under intensive treatment, the clinical status improved and ferritin levels significantly decreased. CONCLUSIONS: The diagnosis of HLH is usually based on clinical and biological criteria, mainly fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis and hyperferritinemia. In this patient, the diagnosis of HLH was challenging because several criteria, such as hypertriglyceridemia, hemophagocytosis and hypofibrinogenemia, were absent. In addition, some criteria of HLH are not relevant in the setting of hematologic malignancy, in which fever, splenomegaly, cytopenias and elevated lactate dehydrogenase are commonly observed independently of HLH. This unusual case of extremely high ferritinemia emphasizes the important weight of the ferritin level for the diagnosis of HLH in adult patients in the setting of hematologic malignancies.

Hyperferritinemic syndrome: Still's disease and catastrophic antiphospholipid syndrome triggered by fulminant Chikungunya infection: a case report of two patients.

There are four medical conditions characterized by high levels of ferritin, the macrophage activation syndrome (MAS), adult onset Still' s disease (AOSD), catastrophic antiphospholipid syndrome (CAPS), and septic shock, that share similar clinical and laboratory features, suggesting a common pathogenic mechanism. This common syndrome entity is termed "the hyperferritinemic syndrome." Here, we describe two different cases of hyperferritinemic syndrome triggered by Chikungunya fever virus infection: a 21-year-old female with SLE and a 32-year-old male patient who developed AOSD after the coinfection of dengue and Chikungunya viruses.