Introduction: Macrophage activation syndrome (MAS) is a rare but life-threatening systemic inflammatory complication, usually arising from superimposed viral infections or flares of underlying rheumatological conditions. It is characterized by an uncontrolled immune response, involving the expansion of T-Cells, Macrophages, and the hypersecretion of pro- inflammatory cytokines. The pathophysiology of this disease is not fully understood, and the diagnostic criteria have been debated. In 2016, an international panel of experts released new guidelines for the classification criteria of MAS, with greater sensitivity, specificity, and laboratory guidelines. Our case provides support for these new guidelines, and is possibly the first published after their release. Furthermore, treatment using glucocorticoids and alternative immunosuppressants is also reviewed. Case Report: A 33-year-old Hispanic male without significant history presented with an unremitting fever for five days, associated with myalgias, fatigue, night sweats, and a rash. Upon admission, he was tachycardic, hypotensive and febrile at 103°F (39.4°C). Physical examination revealed
MAS is still underrecognized and usually results in delayed in diagnosis, which leads to high morbidity and mortality. This literature review was conducted in the context of the clinical manifestations and the laboratory abnormalities in MAS, which might provide some clues for an early diagnosis. The best ways for an early recognition and a satisfactory diagnosis were based on the relative changes in the overall parameters from the baseline, together with a thorough and continuous physical examination for these kinds of patients. At present, diagnostic criteria have been proposed for HLH, MAS-associated systemic juvenile idiopathic arthritis, and an MAS-associated systemic lupus erythematosus. Therefore, selecting the proper diagnostic criteria for use is essential because not all of the criteria are suitable for every autoimmune disease. Keywords: hemophagocytic lymphohistiocytosis, systemic juvenile idiopathic arthritis, systemic lupus erythematosus, Kawasaki disease, autoimmune diseases, early diagnosis
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MAS in sJIA is an intriguing but potentially life- threatening condition with reported mortality rates of 22–30 % [1, 6]. Therefore, prompt diagnosis and initi- ation of treatment is of vital importance. Critically reviewing published literature on MAS in sJIA confirms the notion that both diagnosis and treatment still rely more on experience than on evidence based medicine. There are no prospectively validated diagnostic criteria for MAS in sJIA. Since clinical and laboratory character- istics of MAS in sJIA resemble those of primary HLH, diagnostic criteria designed for primary HLH(HLH- 2004)  have been used in diagnosing acquired forms like MAS , however with limitations. For diagnosis of MAS, at least 5 of 8 criteria, comprising more ad- vanced tests that are not routinely performed, need to be present. Also, cut-off values of the HLH protocol fall in the cytopenia range and since sJIA is characterized by high levels of leukocytes and platelets, a relative decrease in these parameters may be more suitable for recogni- tion of early MAS.
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Although all these criteria are considered suitable for detecting MAS in sJIA, it has been argued that the rela- tive change in laboratory values over time may be more relevant for making an early diagnosis than the decrease below, or increase above, a certain threshold, as stipu- lated by the criteria. 1 16–19 Note that patients with active sJIA often have elevated platelet counts as well as increased levels of ferritin or ﬁ brinogen as part of the underlying in ﬂ ammatory process. 20 21 Thus, the occur- rence of a relative decline (in the case of platelet count or ﬁ brinogen) or elevation (in the case of ferritin) in these laboratory biomarkers, rather than the achieve- ment of an absolute threshold required by the criteria, may be suf ﬁ cient to herald the occurrence of MAS in the setting of sJIA. 12 18
Coffernils et al. suggested that markedly elevated serum ferritin levels should raise the suspicion of HLH and war- rant a bone marrow study . However, demonstration of hemophagocytosis in bone marrow is only one of the criteria in the diagnosis of HLH and bone marrow histology is not always necessary in diagnosing HLH in AOSD patients, considering patients’ inconvenience and benefit . More- over, hemophagocytosis might not be present in the initial stages of the acquired forms of HLH due to autoimmune or inflammatory diseases. Thus, the detection of macrophage hemophagocytosis on bone marrow biopsy specimens is not required for the diagnosis of MAS . Also, in order not to delay the diagnosis, the new classification criteria include only laboratory (high ferritin, triglycerides and aspartate transaminase, and low platelet count and fibrinogen level) and no clinical variables, with the exception of fever . Although designed for use in clinical research, criteria can be applied in individual patients.
More than three decades ago, the prevalence of death in juvenile rheumatoid arthritis (JRA) was examined and fatal cases occurred most frequently in patients with sys- temic JRA [7,8]. Mortality associated with soJIA is typi- cally caused by Macrophage Activation Syndrome or infectious complications related to immune suppressive therapy. The association of myocarditis with soJIA and adult-onset Still’s disease has been described, but its prevalence in this disease is unclear since myocarditis may be subclinical and escape recognition by electrocar- diography and echocardiography [3,9-16]. Furthermore, the definitive diagnosis of myocarditis requires micro- scopic evaluation of myocardial tissue. In soJIA, pericar- ditis typically accompanies myocarditis, but isolated myocarditis (as seen in this patient) has also been described .
/l) respectively. She was referred for further investigation; her bone marrow biopsy showed occasional haemophagocytosis; flow cytometry perforin ex- pression was present, there was normal granule release (CD107a) on activation of CD8 and NK cells and her CD56 + ve cells were normal (82.4%) compared to the control (71.5%). A basic auto-immune screen was negative (anti-neutrophil cytoplasmic antibodies (ANCA), rheuma- toid factor, anti-nuclear antibodies (ANA), anti-double- stranded DNA (anti-dsDNA), and anti-cyclic citrullinated peptide (anti-CCP)). A presumed diagnosis of secondary HLH was made as she fulfilled HLH criteria without any genetic cause with normal granule release. She was treated with dexamethasone (8 weeks), etoposide (12 weeks), cyclosporine A (weaned from 7 months) as per HLH 2004 protocol. She made a good recovery, her biochem- ical markers normalised (ferritin 42 μg/l, CRP <5 mg/l, ALT 26 IU/ml, platelets 260 x 10 9 /l, Hb 120 g/l) and she remained well for 20 months.
In most cases, molecular testing will confirm the diagno- sis. Targeted gene analysis versus whole genome approaches will depend on the specific clinical scenario. Occasionally, a combination of clinical features will suffice to make the di- agnosis, even without genetic confirmation. However, iden- tifying the exact genetic alteration can be useful to establish a genotype-phenotype correlation. In other words, certain genetic mutations are known to predict the occurrence or se- verity of specific cancer types within a given syndrome. Such genotype-phenotype correlations are known for many, but not all, CPSs. For example in VHL, truncating and missense mutations confer a higher risk of renal cell carcinoma (RCC), whereas deletions in the gene are associated with a decreased risk of RCCs. Prenatal diagnosis can also be performed in situations in which the genetic alteration is known.
ABSTRACT. Kawasaki disease (KD) patients are known to be at increased risk for coronary artery lesions. We present evidence of another possible complication associated with KD: macrophage activation syndrome (MAS). In this case, a patient with KD and prolonged fever developed MAS. This case is of particular interest because of the late age of onset and recurrent nature of KD as well as the complication of MAS. We also present a review of the literature that supports the inclusion of MAS as an infrequent complication of KD. Pediatrics 2003;112:e495–e497. URL: http://www.pediatrics.org/cgi/ content/full/112/6/e495; Kawasaki disease, macrophage activation syndrome, hemophagocytosis, intravenous im- munoglobulin.
Lung homogenates were prepared from WT and CARD9-deﬁcient mice on days 7 and 14 postinoculation with C. neoformans strain H99 or LW10 and analyzed for Th1-associated (IL-2, IFN- ␥ , IL-12p40, and IL-12p70), Th2-associated (IL-4, IL-5, IL-13, and IL-10), Th17-associated (IL-17), and proinﬂammatory (IL-1 ␣ , IL-1 ␤ , tumor necrosis factor alpha [TNF- ␣ ], and IL-6) cytokines and chemokines (granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], monocyte chemotactic peptide 1 [MCP-1]/CC chemokine ligand 2 [CCL2], macrophage inﬂamma- tory protein 1 ␣ [MIP-1 ␣ ]/CCL3, MIP-1 ␤ , CCL4, RANTES [regulated on activation, normal T cell expressed and secreted]/CCL5, Eotaxin/CCL11, keratinocyte-derived chemokine [KC]/CXC chemokine ligand 1 [CXCL1]) levels (Table 1). Among these cytokines, we observed signiﬁcant increases in IL-17, CCL3, CCL4, and CXCL1 production on day 14 postinoculation in WT mice infected with C. neoformans strain H99 compared to CARD9-deﬁcient mice infected with H99 (boldface values). We noted an overall increase in proinﬂammatory, Th1-type and Th2-type cytokine and chemokine levels in mice infected with C. neoformans strain H99 when comparing day 7 to day 14 values. We also observed signiﬁcantly increased production of IL-17 on days 7 and 14 postinoculation, and we observed increased IL-12p70 levels on day 14 postinoculation in WT mice infected with LW10 compared to pulmonary cytokine levels observed in CARD9- deﬁcient mice inoculated with LW10. On the other hand, murine CARD9 deﬁciency signiﬁcantly increased levels of IL-6, multiple Th2-associated cytokines (IL-4, IL-5, and IL-13) and several chemokines (G-CSF, CCL2, CCL3, and CCL11) in pulmonary homog- enates prepared from CARD9-deﬁcient mice on day 14 postinoculation compared to WT mice inoculated with LW10, consistent with a “dysregulated” immune response. Studies indicated that a predominant Th2-type cytokine milieu is associated with nonprotective anticryptococcal immune responses, disease progression, and increased susceptibility to pulmonary cryptococcosis (15–18). Together our data identiﬁed that CARD9 deﬁciency results in diminished Th17 and increased Th2-type cytokine produc- tion and nonprotective immune responses against pulmonary C. neoformans infection. Additionally, the chemokine production appears to not be compromised in CARD9- deﬁcient mice and enhanced, presumably as a compensatory response to the increased pulmonary fungal burden.
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the variability of this assessment and makes it more likely that this lower sensitivity reflects real differ- ences in the facial features among people with PWS. Higher likelihood of difficulty in recognizing facial features among practitioners who rarely see affected individuals with PWS further decreases the value of characteristic facial features as a diagnostic criterion. In general, the sensitivities of the minor criteria were lower than those of the major criteria (Table 2). One would expect the sensitivities of the criteria de- creased fetal activity and neonatal hypotonia to be similar as they are etiologically related. Variability in the mothers’ perception of decreased fetal activity may explain the relatively lower sensitivity of this criterion.
RPMI 1640 containing sodium bicarbonate was injected into the peritoneal cavity. The abdominal skin on the peritoneum areas was given massage several times. Then the injected liquid was drawn using a Pasteur pipette and collected in a sterile container. In this case, a little change of color occurred in the liquid. From 15 ml of medium injected into the peritoneum of mice, almost 15 ml of liquid containing macrophages was recovered. This cell suspension was centrifuged (2000 rpm, 3 minutes at lab temperature). Supernatant was decanted and then 20 ml culture medium (cell culture containing 10 percent calf serum and antibiotics) was added to the cell pack. This procedure was repeated twice. Using trypan blue dye, the vital cell counting was carried out. The 100 µl of macrophage suspension with 100 µl trypan blue solution was mixed. Then a drop of it was placed on the slide, covered with glass cover slip and live cells were counted using 40 X magnification. Finally 10 4 cells per ml were
testicular lipomatosis and thyroid nodules, in order to increase the diagnostic rates for this disorder [1, 2]. There is currently insufficient data to include meningiomas in the diagnostic criteria of CS due to its prevalence in the general population . Meningiomas however have been described in a number of previous case reports  and the multiplicity of these lesions is of note in this patient. A thin walled lung cyst and pancreatic lipomas were additional findings in this patient’s imaging studies. These have been noted in previous case reports [6, 7] and possibly represent hamartomatous lesions. Further study is therefore warranted to ascertain the relevance of these findings to CS.
In university students, FA was associated with evening hyperphagia and craving to eat in the evening. Depres- sion and poor sleep quality were associated with morn- ing anorexia, depressed mood later in the day, and sleep problems. Furthermore, in students, psychopathology was less associated with the core features of NES and the distress/impairment criterion. For each criterion, students had fewer associations with psychopathology; there were no associations in students that were not present in the older community sample. Thus, students may exhibit a milder, incomplete form of NES consistent with onset appearing in late adolescence and early adult- hood . It is also likely that some of the differences be- tween the students and community samples were due to the lower frequency of BMI values ≥25 in the student sample. It has been suggested that NES may contribute to increased weight over time  which may be why BMI is only related to the proposed NES diagnostic cri- teria in the community adult sample.
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 Ravelli, A., De Benedetti, F., Viola, S. and Martini, A. (1996) Macrophage Activation Syn- drome in Systemic Juvenile Rheumatoid Arthritis Successfully Treated with Cyclosporine. The Journal of Pediatrics , 128, 275-278. http://dx.doi.org/10.1016/S0022-3476(96)70408-0  Balamuth, N.J., Nichols, K.E., Paessler, M. and Teachey, D.T. (2007) Use of Rituximab in
the syndrome was not dependent on B or T cells, implying that TLR9 activation of innate immune cells is sufficient to initiate the disease. We also show that NK cells were dispensable for disease. However, deleting both T/B cells and NK cells simultaneously resulted in disease attenuation, suggesting that the disease is at least partially dependent on the presence of both populations together. We further show that DCs were capable of IFN-γ tran- scription after CpG treatment and that deletion of conventional DCs (cDCs) resulted in a partial reduction of circulating IFN-γ in response to CpG administration. We also identified IL-10 as a negative regulator of the MAS-like pathology. Mice made hypore- sponsive to IL-10 developed a more severe phenotype, including the presence of large amounts of hemophagocytosis, a pathologic finding not seen when IL-10 signaling is intact. Based on these findings, we propose what we believe to be a new model for the MAS-like cytokine storm syndromes, in which overstimulation of innate immunity by TLRs rather than adaptive immunity is suf- ficient for disease development and in which the spectrum of dis- ease severity is in part controlled by responsiveness to IL-10. Results
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Neither MTS, the oral findings, mesoaxial polydactyly, nor hypothalamic hamartoma are pathognomonic as each can occur in other entities as well. However, the present study shows that the combination of MTS with one (or more) of the three other signs is pathognomonic for the diagnosis of OFD VI. Therefore we suggest that these form the diagnostic criteria for OFD VI (Table 4). We realize that no patient with MTS and hypothalamic hamartoma but without oral or limb defects has been described to date, but in theory can occur and then our criteria would be sufficient for the diagnosis of OFD VI. We are aware that the suggested diagnostic criteria do not match the inclusion criteria for this study. We derived the inclusion criteria from the literature while the diagnostic criteria are based on the literature and the present study. Indeed both patient 4 and the siblings patients 12 and 13 do not fulfill the diagnostic criteria suggested here (although the siblings fulfill the criteria together).
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Abstract: Systemic juvenile idiopathic arthritis (SJIA) is a disease marked with arthritis and several features of systemic inflammation including fevers, rashes, hepatosplenomegaly, lymphadenopathy, and serositis. The presentation can be variable and arthritis can be a later feature. Macrophage activation syndrome can be a life-threatening complication of this illness and requires early recognition and prompt therapy. Advancements in understanding the biology of SJIA have led to the development of cytokine-targeted therapies, mainly interleukin-1 (IL-1) and IL-6 inhibitors that have significantly improved outcomes. In this review, we provide an update on the advances in the understanding of SJIA biology and also the therapeutic options. Keywords: systemic juvenile idiopathic arthritis, IL-1 inhibitors, IL-6 inhibitors, anakinra, tocilizumab, canakinumab, macrophage activation syndrome
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suggest that genetics may also play a major role in contributing to hyperinflammation and particularly to macrophages hyper-responses. Indeed, data in the animals clearly support this hypothesis. The most stud- ied model of genetically driven HLH are perforin knock-out mice which, upon LCMV infection, develop full blown HLH and die . When UNC13d deficient mice are crossed with mice deficient for MYD88, which is a central element in TLR intracellular signalling, the animals are protected from disease development, demonstrating that, at least in animals, TLR signalling and macrophage responses are crucial . Indirect evidence in humans has been provided by a study suggesting that a polymorphism in IRF5, a transducer of intracellular TLR, is associated with the risk of MAS in patients with sJIA . In addition and much more importantly, direct evidence in humans is provided by the recent observation that gain of function mutations of NLRC4, an inflammasome sensor, cause a disease characterized by recurrent or dramatic HLH. This observation demonstrates in humans that genetically induced abnormalities in autoinflammation cause HLH. The disease, still described in very few patients appear to be characterized by early onset of fever, skin rash, severe gastro-intestinal involvement, splenomegaly and recurrent, severe MAS/HLH [38, 39]. Immunological studies revealed that the most striking abnormality is represented by surprisingly high levels of IL-18 pointing to the fact that the NLRC4 protein is particularly important in regulating IL-18 production and further supporting the role of IL-18 as a predisposing factor to HLH/MAS .
Case presentation: A 26-year-old Mauritanian and Berber woman was followed for primary Sjögren ’ s syndrome. After a voluntary cessation of her usual background treatment, she was admitted to our department for an outbreak of her illness. A clinical examination revealed anemic syndrome, peripheral polyarthritis, coughing rales at both pulmonary bases, and fever at 39.5 °C. On biologic examination, there was bicytopenia with anemia at 5.70 g/ dl, lymphopenia at 796/mm 3 , a biological inflammatory syndrome with a sedimentation rate at 137 mm in the first hour, C-reactive protein at 97 mg/l, hyperferritinemia at 1778 mg/l (9 normal value), and hypergammaglobulinemia at 20.7 g/l of polyclonal appearance. The triglycerides were 1.95 g/l (1.4 normal value) and the lactate