Laboratory Studies
The recognition that macrophage activation syndrome (MAS) is clinically similar to HLH has led many clinicians to use the diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH) in the diagnosis of macrophage activation syndrome. [35] However, the use of HLH criteria in patients with macrophage activation syndrome is associated with several problems; the chief problem is the requirement for tissue confirmation. A 2014 retrospective analysis concluded that HLH-2004 guidelines are likely not appropriate for identification of MAS in children with systemic juvenile idiopathic arthritis (SJIA), and that preliminary MAS guidelines showed the strongest ability to identify MAS in SJIA. [36]
The pathognomonic feature of the syndrome is bone marrow examination that reveals numerous well-differentiated macrophages actively phagocytosing hematopoietic cells. Such cells may be found in various other organs as well and may account for many of the systemic manifestations. However, in patients with HLH and macrophage activation syndrome, the bone marrow aspirate sample does not always reveal hemophagocytosis. [37] Furthermore, hemophagocytosis is not always demonstrable at onset. In HLH, hemophagocytosis may be detected more frequently in liver, lymph node, or splenic biopsy samples than in bone marrow samples. However, performing a biopsy of these organs is contraindicated in children with macrophage activation syndrome in the presence of intravascular coagulopathy. Moreover, the failure to document hemophagocytosis does not exclude the diagnosis of HLH. A 2014 study concluded that hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome andhemophagocytic lymphohistiocytosis. [38] These problems emphasize the need to identify criteria that obviate the need for tissue diagnosis.
To identify criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis (SJIA), the diagnostic sensitivity and specificity of the clinical and laboratory features of the syndrome were recently scrutinized. [30, 39, 40] Based on these results, preliminary diagnostic guidelines for macrophage activation syndrome complicating SJIA were established.
The diagnosis of macrophage activation syndrome requires the presence of any 2 or more the following laboratory criteria or 2 or more of the following clinical criteria:
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Laboratory criteria
Decreased platelet count (< 262 x 109/L)
Elevated aspartate aminotransferase levels (>59 U/L)
Decreased WBC count (< 4 x 109/L)
Hypofibrinogenemia (≤2.5 g/L)
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Clinical criteria
CNS dysfunction (eg, irritability, disorientation, lethargy, headache, seizures, coma)
Hemorrhages (eg, purpura, easy bruising, mucosal bleeding)
Hepatomegaly (≥3 cm below the costal margin)
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Histopathologic criterion: Evidence of macrophage hemophagocytosis is found in the bone marrow aspirate sample. The demonstration of hemophagocytosis in bone marrow samples may be required in doubtful cases.
The above criteria are of value only in patients with active SJIA. The thresholds of laboratory criteria are provided only as an example. The clinical criteria are probably more useful as classification criteria rather than as diagnostic criteria because they often occur late in the course of macrophage activation syndrome and, therefore, may be of limited value in the early diagnosis of the syndrome.
Other abnormal clinical features in macrophage activation syndrome associated with SJIA not listed above include nonremitting high fever, splenomegaly, generalized lymphadenopathy, and paradoxical improvement of signs and symptoms of arthritis.
Other abnormal laboratory findings in macrophage activation syndrome associated with SJIA not listed above include anemia, a lowered erythrocyte sedimentation rate, elevated alanine aminotransferase levels, increased bilirubin levels, presence of fibrin degradation products, elevated lactate dehydrogenase levels, hypertriglyceridemia, low sodium levels, decreased albumin, and hyperferritinemia.
Because universally agreed on diagnostic criteria for macrophage activation syndrome complicating SJIA are not available, a multinational collaborative effort aimed to generate new criteria for diagnosing macrophage activation syndrome as a complication of SJIA is currently underway. The first step of the project has led to the identification of, by means of a Delphi survey, the clinical, laboratory and histopathologic features of macrophage activation syndrome that were felt to be most important by a large sample of international pediatric rheumatologists with experience with macrophage activation syndrome in children with SJIA. [41]
The diagnostic performance of potential criteria will be scrutinized further in the second phase of the study, through the analysis (ongoing) of real patient data. The final set of criteria is meant to be established in a consensus conference of experts using a combination of statistical and consensus formation techniques. The ultimate goal of the project is to develop a core set of criteria that is both highly sensitive and specific. These criteria will assist physicians in macrophage activation syndrome diagnosis in children with SJIA and enable quick institution of appropriate therapy.
As previously reported, diagnosis of macrophage activation syndrome may be particularly challenging in patients with systemic lupus erythematosus (SLE) because it may mimic the clinical and laboratory features of the underlying disease. Recently, preliminary diagnostic guidelines for macrophage activation syndrome complicating juvenile SLE were developed. [42]
The main laboratory findings of macrophage activation syndrome include the following:
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Cytopenias
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Abnormal serum hepatic enzyme levels
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Coagulopathy
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Decreased erythrocyte sedimentation rate
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Hypertriglyceridemia
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Hyponatremia
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Hypoalbuminemia
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Hyperferritinemia
The initial laboratory evaluation should include the following:
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CBC count with platelets and reticulocyte count
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Acute phase reactants (ie, erythrocyte sedimentation rate and C-reactive protein [CRP] levels)
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Markers of liver and kidney function
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Ferritin levels: Hyperferritinemia is an important laboratory hallmark of macrophage activation syndrome that has received increasing attention; elevated ferritin levels (often >10,000 ng/mL) have been reported in the acute phase of macrophage activation syndrome. Furthermore, a good correlation between ferritin levels and response to therapy has been observed; a decrease in ferritin levels is associated with a favorable course of macrophage activation syndrome. Recent studies have shown that low levels of glycosylated ferritin, in the presence of high level of total serum ferritin, may be another helpful marker for diagnosis. [43, 44] A retrospective analysis by Ruscitti et al that included 50 Still’s disease patients (21 pediatric and 29 adult) reported that at diagnosis, high levels of serum ferritin and an elevated systemic score were associated with MAS. [45]
Other Tests
Gene expression profiling and determination of sIL-2R alpha and sCD163 concentration in peripheral blood have been suggested as useful tools for identifying early macrophage activation syndrome in patients with SJIA. [46, 47] However, the routine use of these diagnostic techniques outside of a research context is still unavailable in most laboratories worldwide.
Histologic Findings
The pathognomonic feature of the syndrome is bone marrow examination that reveals numerous well-differentiated macrophages actively phagocytosing hematopoietic cells. Such cells may be found in various other organs, as well, and may account for many of the systemic manifestations. However, in patients with macrophage activation syndrome, the bone marrow aspirate does not always show hemophagocytosis. Moreover, failure to reveal hemophagocytosis does not exclude the diagnosis of macrophage activation syndrome.
