Pediatric Annals

Special Issue Article 

New Onset Autoimmune Disease or Macrophage Activation Syndrome?

J. Palmer Greene, MD; Bridget M. Wild, MD

Abstract

Macrophage activation syndrome (MAS) is a potentially life-threatening condition that may complicate many pediatric rheumatologic diseases. Because of its similarity in presentation to other conditions with overlapping manifestations, such as flares of rheumatologic disease or systemic infection, and the fact that there exists no single pathognomonic clinical finding or laboratory parameter to aid in diagnosis, MAS presents a significant diagnostic challenge to the practicing pediatrician with limited access to consulting pediatric rheumatologists. Along with a review of the physiology and manifestations of the condition, we have included the most current consensus for diagnosing MAS. [Pediatr Ann. 2019;48(10):e395–e399.]

Abstract

Macrophage activation syndrome (MAS) is a potentially life-threatening condition that may complicate many pediatric rheumatologic diseases. Because of its similarity in presentation to other conditions with overlapping manifestations, such as flares of rheumatologic disease or systemic infection, and the fact that there exists no single pathognomonic clinical finding or laboratory parameter to aid in diagnosis, MAS presents a significant diagnostic challenge to the practicing pediatrician with limited access to consulting pediatric rheumatologists. Along with a review of the physiology and manifestations of the condition, we have included the most current consensus for diagnosing MAS. [Pediatr Ann. 2019;48(10):e395–e399.]

Macrophage activation syndrome (MAS) is a potentially life-threatening complication of rheumatologic diseases that can be difficult for the general practitioner to recognize. This article reviews the presentation, diagnosis, and treatment of MAS.

Illustrative Case

A 17-year-old girl with no significant past medical history presented to the emergency department (ED) with 3 days of worsening abdominal pain and fever. Physical examination revealed diffuse abdominal pain with emphasis in the right lower quadrant, which was initially concerning for appendicitis, but an abdominal computed tomography (CT) scan obtained in the ED showed a normal appendix. She was admitted to the pediatric hospitalist service at a community hospital for observation and serial abdominal examinations. Her pain was not made worse by eating, she had a normal appetite, and she had no nausea, vomiting, or diarrhea. She was sexually active with one male partner and had a gonorrhea and chlamydia test return negative. A pelvic examination elicited some cervical motion tenderness, so doxycycline and ceftriaxone were started for management of suspected pelvic inflammatory disease. Her laboratory tests at admission were notable for a complete blood count (CBC), with a white count of 5,800 per mcL, hemoglobin at 11.8 g/dL, and platelets at 83,000 per mcL; a complete metabolic panel with aspartate aminotransferase (AST) at 52 U/L, alanine aminotransferase (ALT) at 67 U/L, albumin at 2.8 g/dL and bicarbonate of 19 meq/L; a C-reactive protein (CRP) of 221.7 mg/L; a urinalysis with 1+ protein and 5 red blood cells per high power field; and fibrinogen of 377 mg/dL. Additional sexually transmitted infections testing was sent on the day of admission, and she was observed by surgery and gynecology.

On the day after admission, the patient was persistently febrile at 39.1°C and began describing sharp, substernal chest pain exacerbated by deep respirations. A repeat pelvic examination provoked no cervical motion tenderness, although her abdomen remained exquisitely tender and distended with hypoactive bowel sounds. A repeat CT scan revealed intra-abdominal and pelvic ascites, bilateral pleural effusions, a mildly enlarged liver, and a normal spleen. She also developed two painful papules on the right side of her face.

Given her polyserositis, thrombocytopenia, hematuria, and proteinuria, a battery of laboratory tests were ordered to broaden her examination to include rheumatologic conditions in addition to ruling out infectious processes. As she was ill-appearing, serial laboratory examinations were monitored for the evolution of MAS. Notably her ferritin peaked at 1,384 ng/mL and CRP at >300 mg/L. AST peaked at 111 U/L with ALT at 144 U/L, triglycerides were 151 mg/dL, and platelets remained low but above the presenting 83,000/mcL with no other significant CBC changes. When awaiting autoimmune results, a discoid lesion developed from the papules on the patient's face, along with a malar rash across the bridge of her nose. Intravenous (IV) methylprednisolone therapy was begun with significant improvement of all symptoms. Later, the autoimmune results were notable for positive antinuclear antibody and positive anti-Ro, negative anti-dsDNA and anti-Smith, and normal levels of C3 and C4 complement. Despite her urinalysis findings, a renal biopsy was negative for nephritis. She received the working diagnosis of active systemic lupus erythematosus (SLE) and was discharged with a course of oral prednisone and close observation in the rheumatology clinic, where further testing and management continued for 9 months. She responded well to steroids and hydroxychloroquine with resolution of her symptoms. During a trial when she was not taking hydroxychloroquine 4 months after her initial presentation, her symptoms returned; however, she continues to be an atypical presentation of lupus with inflammatory features requiring ongoing testing.

Discussion

Macrophage Activation Syndrome

MAS is a potentially life-threatening condition that may complicate a number of pediatric rheumatologic diseases. It is classically associated with systemic juvenile idiopathic arthritis (sJIA), although it has been reported in numerous cases of both juvenile- and adult-onset SLE and Kawasaki disease.1,2 It is known to occur in the setting of infection, malignancy, and immunodeficiency as well. Although it was once considered a freestanding diagnostic entity, today MAS is placed on the spectrum of secondary or acquired hemophagocytic lymphohistiocytosis (HLH). Its overall incidence is unknown, but in retrospective studies of patients with an underlying diagnosis of sJIA, it has been estimated to occur in at least 10% of cases and may be present subclinically in more than one-half of patients with sJIA.3,4

MAS pathophysiology is characterized by overactivation and proliferation of macrophages and T lymphocytes leading to overwhelming release of pro-inflammatory cytokines, particularly interleukin (IL)-1 beta, IL-6, interferon-gamma, and tumor necrosis factor (TNF) alpha.3 In patients with familial HLH, this process is known to be the result of defective cytotoxic degranulation of natural killer (NK) and cytotoxic T cells, leading to ineffectual down-regulation of activated macrophages and the inflammatory response. Although the mechanism governing the excessive activation of macrophages in MAS and other forms of secondary HLH has yet to be elucidated, it is reasonable to expect it to be similar to familial versions of the disease. The pathologic hallmark of MAS, as with other forms of HLH, is the presence of histiocytes undergoing hemophagocytosis in the bone marrow aspirate; however, this finding may not be present in the initial stages of the disease.4,5

The clinical presentation of MAS consists primarily of high, nonremitting fever that can be distinguished from the intermittent, spiking fever typical of active sJIA. Additional features include hepatosplenomegaly, generalized lymphadenopathy, central nervous system (CNS) dysfunction, and hemorrhagic manifestations. Heart, kidney, and lung function may be impaired in advanced cases of the disease. Laboratory studies may show cytopenia of multiple cell lineages, abnormal liver function tests, increased lactate dehydrogenase, hypertriglyceridemia, high levels of serum ferritin, elevated D-dimer, and low fibrinogen.5 Erythrocyte sedimentation rate may be paradoxically diminished as well, likely secondary to the hypofibrinogenemia resulting from fibrinogen consumption and liver dysfunction. Specialized testing may reveal elevated levels of soluble IL-2 receptor alpha chain (also known as CD25) or CD163, a marker of macrophage activation, although these tests are not routinely available.6

Diagnostic Considerations

Because of its similarity in presentation to other conditions with overlapping manifestations, such as flares of rheumatologic disease or systemic infection, and the fact that there exists no single pathognomonic clinical finding or laboratory parameter to aid in diagnosis, MAS presents a significant diagnostic challenge to the practicing pediatrician. Meanwhile, its reported mortality of 8%7 and the need for admission to the intensive care unit in up to one-half of cases means it is a diagnosis that should be made expediently and reliably so that appropriate management can be initiated as promptly as possible.1,7

Developing classification and diagnostic criteria for MAS has proven difficult, given the lack of a gold standard for diagnosis beyond expert opinion. Nonetheless, several guidelines have been proposed since MAS was first recognized as a diagnostic entity in 1993. For instance, the similarity in clinical presentation between MAS and HLH led some to recommend using the HLH diagnostic guidelines established by the Histiocyte Society in 2004 (HLH-2004), which based diagnosis on the fulfillment of 5 of 8 of the following criteria: fever, splenomegaly, cytopenia of two or more cell lines, hypertriglyceridemia and/or hyperfibrinogenemia, established hemophagocytosis, low or absent NK cell activity, hyperferritinemia, and high soluble IL-2 levels.8 However, application of these criteria to the diagnosis of MAS was limited by the fact that hemophagocytosis in the bone marrow is not always demonstrable in cases of secondary HLH or may be present only late in the disease course. Furthermore, decreases in white blood cell count, platelets, and fibrinogen may require a different threshold in the hyperinflammatory state associated with sJIA or other rheumatologic causes of secondary HLH.

A later set of diagnostic criteria developed specifically for MAS in the setting of sJIA (MAS-2005) emphasized clinical and laboratory features without requiring tissue confirmation of the disease, while also accounting for CNS involvement, hemorrhaging, and hepatomegaly as important clinical features that may aid diagnosis.9 These criteria outperformed the HLH-2004 guidelines in a comparative analysis that assessed their ability to distinguish MAS from the potentially confusable conditions of active sJIA without MAS and systemic infection.10 For distinguishing MAS-2005 from sJIA without MAS, the MAS-2005 criteria had a sensitivity and specificity of 86%, as opposed to a sensitivity of 79% and specificity of 75% for the HLH-2004 criteria.10 For distinguishing MAS from systemic infection, adding the criterion of ferritin level greater than 500 ng/mL to the other MAS-2005 criteria was the best diagnostic performer of all, with a sensitivity of 86% and a specificity of 95%.10

In 2016, the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) sponsored the largest effort yet to create an updated set of criteria based on international expert consensus, evidence from the medical literature, and analysis of patient data (MAS-2016).5 After candidate criteria had been selected by statistical analyses of data from 1,111 patients with sJIA-associated MAS and two potentially confusable conditions, the project culminated in a consensus conference for the selection of final classification criteria.5 These MAS-2016 criteria are listed in Table 1. In addition to the inherent advantage that the MAS-2016 criteria were developed with the participation of 95 pediatric rheumatologists and data from patients in 33 different countries, they improve on the previous diagnostic guidelines in their reliance entirely on widely available laboratory studies. They eschew the criteria for NK cell activity and soluble IL-2 levels included in the HLH-2004 guidelines, which must be tested in a specialized laboratory. Furthermore, bone marrow aspirate demonstrating hemophagocytosis, which has shown poor sensitivity and specificity for diagnosing HLH, is not included as a criterion.11 Clinical findings that typically develop only late in the disease course, such as hepatosplenomegaly, CNS dysfunction, and hemorrhages, are excluded as well. Finally, hyperferritinemia, which is shown to be the single greatest discriminator between MAS and disease states with similar clinical presentation, is set as the sine qua non of diagnosis.5

MAS-2016 Diagnostic Criteria

Table 1:

MAS-2016 Diagnostic Criteria

The bulk of the effort toward establishing reliable criteria for MAS diagnosis has focused on MAS in the setting of sJIA. However, one preliminary guideline does exist for the diagnosis of MAS in patients with underlying SLE, which was developed in 2009 as a retrospective study of 38 patients with underlying SLE diagnosed with MAS based on “typical clinical and laboratory picture of the syndrome.”1 These patients were subdivided into cases of “definite MAS” and “probable MAS” based on the presence or absence, respectively, of macrophage hemophagocytosis on bone marrow aspiration. Similar to other studies5,8,9 in which elevated serum ferritin level was found to be among the most reliable markers of the disease, the laboratory feature with the best sensitivity and specificity was hyperferritinemia, and clinical features were found to have greater specificity than sensitivity—aside from fever, which was highly sensitive but had poor specificity. However, it should be noted that ferritin is an acute-phase reactant and mild to moderate elevations of ferritin can be seen with inflammation from any cause (including infection).

The preliminary diagnostic criteria proposed in the study are included in Table 2.1 Of note, sJIA in the absence of MAS is typically characterized by thrombocytosis. However, thrombocytopenia is frequently noted in SLE at baseline, even in the absence of MAS. Thus, a lower threshold for thrombocytopenia is suggested in the 2009 preliminary criteria for MAS as a complication of juvenile SLE, as compared to sJIA-associated MAS.1 Limitations of the study include the comparatively low number of patients used to develop the criteria and the fact that cases of systemic infection were not included as a control group to ensure ability to distinguish MAS from infection.

Preliminary Diagnostic Guidelines for MAS as a Complication of Juvenile SLE

Table 2:

Preliminary Diagnostic Guidelines for MAS as a Complication of Juvenile SLE

Options for Treatment

Unfortunately, to the best of our knowledge, no controlled studies on therapies for MAS have been published, and evidence for effective management of the disease is anecdotal. Common practice is to consider high-dose IV corticosteroids as first-line therapy, with cyclosporine as an appropriate second-line medication in refractory cases.3 The emergence of biologic agents as therapeutic options for a variety of disease states provides further potential avenues for MAS treatment. Indeed, there are several reports of effective treatment with the TNF-inhibitor etanercept, the IL-1 inhibitor anakinra, the IL-6 receptor monoclonal antibody tocilizumab, and cytotoxic T-lymphocyte-associated protein 4 immunoglobulin.3 However, some investigators12–14 also recount instances of MAS that were likely triggered by these drugs. Further clinical experience and dedicated research trials with these agents may elucidate their role in the management of MAS.

An additional consideration in treating cases of probable MAS in the acute setting is the potentially confounding diagnosis of systemic infection, which may proceed rapidly and with devastating consequences in the event of delayed diagnosis or misdiagnosis. Thus, the authors of this article propose that concurrent treatment with empiric antibiotics be a reasonable course of action until an infectious process can be definitively ruled out.

Conclusion

The establishment of these MAS-2016 criteria, which have been approved by both the EULAR and ACR after validation against an independent data set, should make it easier for pediatricians practicing in the community with limited immediate access to a consulting pediatric rheumatologist to diagnose and treat MAS. Its parameters are consistently reliable and easily measured without specialized testing facilities. Furthermore, they do away with the need to perform bone marrow aspiration, as pathologic evidence of hemophagocytosis is often not sufficiently sensitive, specific, or practical to be useful in a community setting.11

These guidelines are not without limitations, which are necessary to keep in mind when suspicion for MAS is high. For one, it is important to note the relatively low sensitivity of 79% and high specificity of 99% of the MAS-2016 criteria.5 The classification criteria were created primarily for use in research studies and clinical trials and may miss some instances of MAS seen in the community setting—especially those with incomplete clinical expression.

Furthermore, although the project did examine the role of changes in laboratory values over time for their potential usefulness in the detection of MAS, there was not sufficient data in the control group to include them in consideration as candidate criteria.15 Therefore, the final diagnostic criteria include only “snapshot” values from the single point in time of the patients' initial presentation, and do not account for the concept of MAS as a “moving target.” In the acute setting, a proportional drop in white blood cell count and platelet counts or an increase in ferritin level should alert the pediatrician that MAS may be evolving, especially in patients who exhibit high white blood cell counts and platelet levels as a baseline function of their underlying sJIA.16

Finally, and perhaps most relevant to the above illustrative case, these criteria were developed specifically for the classification of MAS in the setting of sJIA. The applicability to MAS in other disease states, such as SLE or Kawasaki disease or in patients whose underlying disease state is unknown, has not been tested.

The patient in the illustrative case was ultimately diagnosed and managed as SLE, and she made rapid clinical improvement with systemic steroids. Throughout her hospital stay, MAS was held by the primary pediatric team as a “must not miss” diagnosis and was monitored for actively. As you can see in the discussion above, by some standards, she met MAS criteria. The fact that MAS can occur as the initial, presenting manifestation of rheumatic disease (and thus occur in a patient similar to the patient in the illustrative case, who did not have a previously established diagnosis of an autoimmune condition), and that MAS can so closely mimic classic presentations of other—potentially related—conditions such as flare of active SLE or sJIA, or even systemic infection, make MAS an exceptionally challenging diagnosis to make in the inpatient setting.17 But with a mortality rate as high as 8%, it is an important diagnosis to make or exclude with confidence and in a timely fashion.7

References

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MAS-2016 Diagnostic Criteria

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Platelets <181,000 per mL

</list-item><list-item>

AST >48 IU/dL

</list-item><list-item>

Triglycerides >156 mg/dL

</list-item><list-item>

Fibrinogen <360 mg/L

</list-item>

Preliminary Diagnostic Guidelines for MAS as a Complication of Juvenile SLE

Clinical criteria   Fever >38   Hepatomegaly   Splenomegaly   Hemorrhagic manifestations (purpura, easy bruising, or mucosal bleeding)   CNS dysfunction (irritability, disorientation, lethargy, headache, seizures, or coma) Laboratory criteria   Cytopenia affecting ≥2 cell lineages (white blood cell count ≤4 × 109/L, hemoglobin ≤90 g/L, or platelet count ≤150 × 109/L)   Increased aspartate aminotransferase (>40 units/L)   Increased lactate dehydrogenase (>567 U/L)   Hypofibrinogenemia (fibrinogen ≤1.5 g/L)   Hypertriglyceridemia (triglycerides >178 mg/dL)   Hyperferritinemia (ferritin >500 mcg/L)
Authors

J. Palmer Greene, MD, is a Medical Student. Bridget M. Wild, MD, is a Pediatric Hospitalist, NorthShore University HealthSystem; and a Clinical Assistant Professor. Both authors are affiliation with the Pritzker School of Medicine, The University of Chicago.

Address correspondence to Bridget M. Wild, MD, NorthShore University HealthSystem, 2650 Ridge Avenue, Office B648, Evanston, IL 60201; email: bwild@northshore.org.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20190918-01

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