The clinical presentation of MAS is generally acute and occasionally, dramatic, requiring the admission of the patient to the ICU. The onset of the syndrome is usually heralded by the sudden occurrence of non-remitting high fever, profound drop in all three blood cell lines (leukopenia, anemia, and thrombocytopenia), liver enlargement, splenomegaly and generalized lymphadenopathy, and increase in serum liver enzymes. There is often an abnormal coagulation profile, with prolongation of prothrombin and partial thromboplastin times, hypofibrinogenemia, detectable fibrin degradation products, and increase in D-dimers. As a result, patients may have purpura, easy bruising, and mucosal bleeding. High concentrations of triglycerides and lactic dehydrogenase and low sodium levels are observed frequently. The acute phase of MAS is usually marked by a sharp rise of ferritin, often above 5000–10,000 ng/ml. Measurement of serum ferritin level may assist in the diagnosis of MAS and is a useful indicator of disease activity, therapy response, and prognosis [61]. Central nervous system dysfunction is seen in around one-third of cases and may cause lethargy, irritability, disorientation, headache, seizures, or coma. Renal, pulmonary, and cardiac involvement may develop in the sickest patients, who progress to develop multi-organ failure.

In children with sJIA, the clinical picture of MAS may mimic sepsis or a flare of the underlying disease. However, the pattern of non-remitting fever is different from the remitting high-spiking fever typical of sJIA flare. Moreover, patients may show a paradoxical improvement in the underlying inflammatory disease at the onset of MAS, with disappearance of signs and symptoms of arthritis and a fall in the ESR. The latter phenomenon is mainly related to the hypofibrinogenemia secondary to fibrinogen consumption and liver dysfunction and helps explain the utility of the ferritin-ESR ratio. A characteristic feature of the syndrome may be seen on bone marrow examination, which reveals numerous morphologically benign macrophages exhibiting hemophagocytic activity (Fig. 22.3). Such cells may infiltrate the lymph nodes and spleen as well as many other organs in the body and may be responsible for several clinical manifestations of the syndrome. However, in patients with MAS, the bone marrow aspirate does not always show hemophagocytosis (present in approximately 60 % of patients), and, in a mouse model of fulminant MAS, hemophagocytosis was only revealed when blocking IL-10, a finding that suggested that IL-10 responsiveness can change the spectrum of disease severity, including the presence of hemophagocytosis [45]. Therefore, failure to reveal hemophagocytosis does not exclude the diagnosis of MAS. It is still unclear whether MAS is a discrete clinical event or whether it represents the most severe end of the spectrum of disease activity in sJIA. Since some sJIA patients develop MAS repeatedly and others never develop MAS, there may be a genetic predisposition (perhaps cytolytic defects) for up to half of the sJIA patients to be at risk for MAS [56]. Table 22.1 shows the main clinical and laboratory features of MAS complicating sJIA. The comparison of the features of active sJIA and MAS is presented in Table 22.2.

Although most instances of MAS lack an identifiable precipitating factor, the syndrome has been associated with a number of triggers, including a flare of the underlying disease; toxicity of aspirin or other nonsteroidal anti-inflammatory drugs; viral, bacterial, or fungal infections; a second injection of gold salts; or a side effect of second-line or biologic medications [61].

MAS episodes are reported most frequently during a flare of active underlying sJIA, and, in about 20 % of patients, the syndrome occurs at the time of sJIA onset [22]. However, it is well known that MAS may be incited by an infection, particularly by members of the herpesvirus family. Epstein-Barr virus is the most common causative viral agent, but virtually any infectious agent can precipitate the development of MAS.

In several reports, the trigger of MAS has been related to modifications in drug therapy. A young girl with sJIA was described who developed MAS 24 h after the first methotrexate administration [62]. The shortness of the time interval between MTX dosing and onset of MAS and the characteristics of clinical symptoms (particularly the intense and generalized itching) argued for a hypersensitivity or idiosyncratic reaction, a mechanism similar to that hypothesized in the pathogenesis of MAS secondary to gold salt injections. Considering the large number of medications associated with MAS, it is reasonable to suppose a lack of direct causality in many cases. Additional therapies are often required in patients with severe underlying rheumatic disease, which means that the susceptibility to MAS may be increased by the exacerbation of disease activity, rather than by medication toxicity. In the recent years, instances of MAS in sJIA patients during treatment with biologic medications have been described. However, the role of these drugs in the induction of MAS is controversial, as published experience for the use of IL-1 blocking therapy for the treatment of refractory sJIA-associated MAS has been favorable. In fact, increasing the dose of IL-1 blockade typically helps to control MAS in children with sJIA [63].

Severe episodes of MAS have been observed among patients who had undergone autologous bone marrow transplantation for sJIA refractory to conventional therapies [64, 65]. Although in most of these cases an infectious trigger for MAS was identified, it was hypothesized that the complication was due to stringent T cell depletion, with resultant inadequate control of macrophage activation. After an adaptation of the protocol, consisting in less profound T cell depletion, better control of systemic disease before transplantation, and slow tapering of corticosteroids after the procedure, no further cases of MAS have been reported.

MAS can be difficult to distinguish from several conditions. However, an early diagnosis is essential to select the appropriate therapeutic interventions in a timely manner. Some of the MAS features, such as lymphadenopathy, splenomegaly, and hyperferritinemia, are common manifestations of active sJIA and may not differentiate MAS from a conventional sJIA flare. Because many features are shared between MAS and cSLE (e.g., cytopenia, splenomegaly, fever), MAS is also probably an underdiagnosed complication of cSLE [6]. When a patient with cSLE presents with unexplained fever and cytopenia, MAS should be considered and investigations, including measurement of ferritin level, should be carried out.

Because MAS bears close clinical similarities with FHLH or acquired virus-associated HLH (VA-HLH), its differentiation from these conditions may be challenging, particularly when MAS develops at onset of sJIA in the absence of arthritis. Onset at a very young age, positive family history, and more profound cytopenias are clues to differentiate FHLH from MAS. Notably, a recent comparative analysis showed that neutrophil count and CRP were significantly higher in patients with MAS than in patients with FHLH/VA-HLH. Furthermore, a soluble CD25 level <79,000 U/l indicated MAS, rather than FHLH/VA-HLH [66].

Other clinical entities associated with hepatic dysfunction, coagulopathy, cytopenias, or encephalopathy must also be considered in the differential diagnosis of MAS. In some sJIA patients, the combination of hepatic dysfunction with encephalopathy may be due to Reye syndrome: a viral prodrome, unexplained vomiting, behavioral changes and increasing of serum aminotransferase, ammonia level, and prothrombin time, coupled with minimal change in serum bilirubin, are all important features of this illness [67]. The hemorrhagic symptoms seen in MAS may resemble those seen in thrombotic thrombocytopenic purpura (TTP), but the microangiopathic anemia with the finding of fragmented red blood cells in the peripheral blood smears, which is characteristic of TTP, is not typically seen in MAS. However, it should be taken into account that TTP may occasionally complicate the most severe instances of MAS. It is also important to note that MAS is not a diagnosis of exclusion but rather an end common pathway/complication of many hyper-inflammatory states.

Intracellular bacterial infections and zoonotic diseases frequently presenting with hepatosplenomegaly and leukopenia, such as Brucella, Rickettsia spp, and visceral leishmaniasis, bear a close resemblance to MAS [68]. The clinical and laboratory picture of visceral leishmaniasis may be indistinguishable from that of MAS patients. Leishmania donovani and Leishmania infantum infections by themselves can cause secondary forms of HLH. A bone marrow aspirate, with a microscopic direct examination of Leishmania spp in the hematopoietic cells and in vitro culture of bone marrow aspirates, helps to make the correct diagnosis. Throughout the world, it is also important to consider epidemics caused by hemorrhagic fever viruses (e.g., dengue, Crimean-Congo, and possibly Ebola) as causes of potentially treatable MAS [69].

The difficulties in making the diagnosis, the recent therapeutic progress, and the advances in understanding MAS pathophysiology highlight the need for diagnostic tools and well-established diagnostic guidelines. Diagnostic criteria would also be useful for research purposes and use in literature reports.

The recognition that MAS shares many similarities with HLH has led some clinicians to advocate the use of the HLH diagnostic guidelines (Table 22.3) to diagnose this syndrome in children with sJIA [70]. However, HLH criteria are not necessarily suitable for use in identifying MAS in sJIA. Due to the prominent inflammatory nature of sJIA, the occurrence of a relative drop in white blood cell count, platelets, or fibrinogen rather than the absolute decrease required by the HLH criteria may be more useful to make an early diagnosis. Furthermore, the threshold level for hyperferritinemia required for the diagnosis of HLH (500 ng/ml) may not discriminate MAS from a flare of sJIA. It is well known that many patients with active sJIA, in the absence of MAS, have ferritin levels above than threshold [71]. In the acute phase of MAS, ferritin levels may peak to greater than 5000 ng/ml. Other HLH criteria that are not readily applicable to MAS are the demonstration of low or absent natural killer cell activity or soluble IL-2 receptor α chain above normal limits for age. These tests are not routinely performed in most pediatric rheumatology centers.

In 2005, preliminary diagnostic guidelines for MAS complicating sJIA were published [72] (Table 22.4). These guidelines have the merit of being data-driven and not merely based on expert consensus. However, the study that led to their development had several limitations, including the lack of several laboratory measurements in a number of patients and insufficient data for some of the laboratory parameters evaluated. In addition, the criteria have yet to be validated.

A recent study compared the performance of HLH-2004 diagnostic guidelines and preliminary MAS diagnostic guidelines in differentiating sJIA-associated MAS from two confusable conditions, represented by active sJIA without MAS and febrile systemic infections, in a large patient sample collected in a multinational survey [73]. The authors found that the preliminary MAS guidelines achieve the best trade-off between sensitivity and specificity in differentiating MAS from sJIA flare and febrile systemic infections. The poorer performance of the HLH-2004 guidelines was mainly explained by the low frequency of the items cytopenia and hypofibrinogenemia in patients with MAS, mainly due to their too stringent thresholds. It is well known that patients with sJIA often have increased white blood cell and platelet counts as well as increased serum levels of fibrinogen as part of the underlying inflammatory process. Thus, the occurrence of a relative decline in these laboratory parameters, rather than the absolute decrease required by the HLH-2004 guidelines, can be more useful to make an early diagnosis of MAS.