When Inflammation Goes Rogue: Recognizing and Managing MAS in Pediatric Inpatients

Definition and Pathophysiology

Macrophage Activation Syndrome (MAS) is a serious hyperinflammatory condition caused by uncontrolled activation of immune cells, mainly T lymphocytes and macrophages, which triggers a “cytokine storm.” It is considered part of the secondary Hemophagocytic Lymphohistiocytosis (HLH) spectrum. In MAS, a failure in the immune system’s regulatory mechanisms leads to the release of large amounts of cytokines (such as interferon-γ, interleukin-1β, IL-6, IL-18, and TNF-α), resulting in prolonged fever, systemic inflammation, and multi-organ failure. Histologically, MAS is associated with hemophagocytosis (where macrophages consume blood cells); however, this finding is neither highly sensitive nor specific to MAS, as it may be absent in early stages of MAS and can also occur in other severe inflammatory conditions unrelated to MAS.

Underlying triggers for MAS include severe infections, malignancies, or rheumatic diseases that lead to immune dysregulation. In pediatrics, systemic juvenile idiopathic arthritis (sJIA) is the most common associated condition. Still, MAS can also complicate systemic lupus erythematosus (SLE), Kawasaki disease, juvenile dermatomyositis, and other autoimmune or autoinflammatory diseases. A practical framework is the “threshold model,” which suggests that MAS occurs when three factors—a genetic predisposition, an underlying inflammatory condition, and a precipitating trigger (often an infection)—combine to surpass the threshold for hyperinflammation. Notably, there is genetic overlap between primary (familial) HLH and MAS; for instance, about 40% of children with sJIA who develop MAS have heterozygous mutations in known HLH genes, indicating partial genetic susceptibility. Essentially, MAS is an immunologic catastrophe where impaired cytotoxic function of CD8^+ T cells/NK cells (as observed in familial HLH) results in persistent immune activation and excessive cytokine release, leading to inflammation and tissue damage.

Clinically, MAS appears as a hyperinflammatory shock-like condition. Children typically experience persistent high fevers, often accompanied by hepatosplenomegaly, lymphadenopathy, and rapid progression to multi-organ dysfunction if not treated. The classic “MAS triad” includes persistent fever, cytopenias, and splenomegaly. The inflammation can be so severe that it causes disseminated intravascular coagulation (DIC), liver damage, and central nervous system (CNS) dysfunction, such as encephalopathy or seizures resulting from inflammatory injury. MAS is one of the most urgent pediatric rheumatologic emergencies; if not promptly diagnosed and managed, it has a mortality rate between 8% and 22%. Therefore, early diagnosis and intervention are crucial to stop the hyperinflammatory response and prevent irreversible organ failure.

Relationship to HLH (Hemophagocytic Lymphohistiocytosis)

MAS is best considered a subtype of secondary HLH, with significant overlap in pathophysiology and clinical features. HLH is a broad term for syndromes characterized by severe immune activation, whether primary or secondary. Primary HLH, often called familial HLH, is a genetic disorder that usually appears in infancy, caused by biallelic mutations in genes affecting the perforin-mediated cytolytic pathway, such as PRF1 and UNC13D. These mutations impair the ability of cytotoxic T cells and NK cells to destroy target cells, resulting in excessive macrophage activation and cytokine release. In contrast, secondary HLH, also known as acquired HLH, can occur at any age and often develops as a result of other illnesses, mainly severe infections (like EBV or other viruses), cancers (especially lymphomas), or autoimmune diseases. MAS specifically refers to secondary HLH that occurs within the context of rheumatic diseases, such as systemic juvenile idiopathic arthritis (sJIA) or lupus. Therefore, rheumatologists use the term MAS to describe HLH that arises as a complication of autoimmune or autoinflammatory diseases.

Although the underlying causes may vary, the clinical presentation of MAS closely resembles other types of HLH. Because of immune dysregulation, both conditions are marked by persistent high fevers, cytopenias, organomegaly, coagulopathy, and very high ferritin levels. A useful way to distinguish them is by context. For example, an infant with biallelic PRF1 mutations is diagnosed with familial HLH, while a 10-year-old with systemic juvenile idiopathic arthritis (sJIA) who develops HLH symptoms is classified as having “MAS.” Additionally, primary HLH usually appears acutely in early childhood.

In contrast, MAS is more frequently observed in patients with known inflammatory conditions and may sometimes be associated with a flare or external trigger, such as a new infection. Additionally, in clinical practice, intensivists and hematologists often refer to any acquired case as “HLH,” while rheumatologists prefer the term “MAS” for similar cytokine storms in children with rheumatologic disorders. Nevertheless, in terms of clinical management, MAS and secondary HLH can be treated similarly, with a focus on reducing hyperinflammation and addressing the underlying cause of the disease.

It’s important to recognize that MAS is not the only cause of secondary HLH in children. In hospitalized pediatric patients, HLH can also result from severe infections, often called infection-associated hemophagocytic syndrome (IAHS), or from cancers, known as malignancy-associated HLH. A common example is EBV-driven HLH, which can appear in a previously healthy child during a severe viral infection. MAS is considered the rheumatologic extreme of secondary HLH, sharing the same severe immune problems seen in infection-associated or malignancy-associated HLH but happening during chronic inflammation (such as in Still’s disease or lupus). Because of this overlap, the diagnostic criteria and treatment plans for HLH, originally designed for primary HLH, are often used for MAS cases, with some specific adjustments. It is critical to stay alert and act quickly, whether it’s called “MAS” or “HLH,” because both conditions can rapidly worsen and lead to multi-organ failure.

When to Consider MAS?

MAS often mimics other serious illnesses, requiring clinicians to stay alert for its signs in various situations. Healthcare providers should be especially cautious of MAS/HLH in hospitalized children under these conditions:

Recognized Rheumatic Disease with Sudden Decline: Any child with an existing autoimmune or autoinflammatory disorder (like sJIA, SLE, or Kawasaki disease) who shows unexplained worsening despite appropriate treatment should be evaluated for MAS. For example, a child with sJIA who was improving on medication but then develops high fevers, falling blood counts, and liver issues is more likely to have MAS than just a typical disease flare. Most pediatric MAS cases occur when an underlying rheumatologic condition worsens or flares, often triggered by an infection or changes in therapy. Clinicians use the term “occult MAS” to describe a developing MAS that hasn’t yet met all diagnostic criteria; this emphasizes the risk of MAS progressing unnoticed and being mistaken for a simple ‘bad flare” or infection if we are not vigilant. For instance, nearly 30% of sJIA flares may represent occult MAS, and about 7% of IVIG-resistant Kawasaki disease cases may progress to overt MAS if not recognized. The main point: if a rheumatology patient in the hospital has persistent fever, cytopenias, or organ dysfunction out of proportion to their usual disease activity, consider MAS even if they don’t meet all diagnostic criteria.

Persistent unremitting fever with cytopenias and organ dysfunction (sepsis-like presentation): MAS should be considered in the differential diagnosis for any child with unexplained persistent fever, pancytopenia, elevated inflammatory markers, and signs of organ failure (such as coagulopathy, hepatitis, and neurologic changes), even if there is no prior diagnosis. Clinically, MAS can initially resemble severe sepsis or septic shock due to the presence of fever, shock, and disseminated intravascular coagulation (DIC). However, signs like extraordinarily high ferritin levels, a decreasing erythrocyte sedimentation rate (ESR) due to fibrinogen consumption, and the absence of a focal bacterial source should raise suspicion for a hyperinflammatory syndrome. Importantly, MAS may occur in critically ill children with infections as a complication of sepsis. Studies in pediatric ICU populations indicate that a subset of children with “hyperferritinemic sepsis” (sepsis with ferritin levels exceeding 500 ng/mL) meet the criteria for HLH/MAS; one analysis found that MAS developed in 21% of children with hyperferritinemic sepsis, compared to 4% of those without high ferritin. These children often present with hepatobiliary dysfunction and coagulopathy and may benefit from immunomodulatory therapy alongside antimicrobial treatment. In practice, if a presumed septic patient does not improve with standard treatment and shows features such as ferritin levels greater than 2–3000 ng/mL, cytopenias, and DIC, it is advisable to expand the diagnostic workup to include HLH/MAS and consider initiating therapy for hyperinflammation (e.g., steroids or anakinra) while continuing infection management.

New-onset hyperinflammatory illness (fever of unknown origin or MIS-C differential): Occasionally, MAS/HLH can be the initial presenting sign of an underlying rheumatologic or genetic condition. For example, a teenager with previously undiagnosed lupus might arrive at the emergency department with full MAS symptoms, including fever, coagulopathy, encephalopathy, and high ferritin; only after further workup is SLE diagnosed—with MAS being the first manifestation. Likewise, some children with new-onset sJIA have been observed to develop MAS very early in their disease course, even at presentation. Therefore, MAS should be considered in the differential diagnosis of fever of unknown origin accompanied by cytopenias and elevated inflammatory markers. Another relevant context is MIS-C (Multisystem Inflammatory Syndrome in Children) associated with COVID-19, which shares clinical features with MAS/HLH, such as fever, hyperferritinemia, and organ injury. Although MIS-C is a distinct condition, experts highlight the diagnostic overlap and stress the need for vigilance. Children with MIS-C who exhibit unusually high ferritin levels or persistent fever may show MAS-like hyperinflammation. In any child presenting with hyperinflammatory signs—including fever, elevated CRP and ferritin, or multi-organ involvement—whether diagnosed as MIS-C, severe EBV infection, or “unresolved sepsis,” clinicians should consider MAS, especially if standard treatments are not leading to improvement.

In summary, consider MAS/HLH in any pediatric inpatient with persistent unexplained fever, cytopenias (especially a decreasing platelet count), hypotension or shock, elevated inflammatory markers, liver enzyme increases, coagulopathy or DIC, and an extremely high ferritin level. These red flags often appear before MAS is fully recognized. Since early MAS can be subtle, routine lab trending (CBC, liver function, fibrinogen, ferritin) is recommended in high-risk situations, such as an ICU patient with prolonged fever or a known rheumatic disease flare. It is advisable to involve rheumatology or hematology specialists as soon as MAS is suspected, even if not all criteria are met; treatment may need to begin before diagnosis confirmation in severe cases to prevent deterioration. 

Patient Examples: 

Case 1: MAS in a Child with Systemic JIA. A 9-year-old boy with systemic juvenile idiopathic arthritis was admitted with a two-week history of daily fevers, an evanescent rash, and arthritis. He was started on high-dose naproxen and low-dose corticosteroids for presumed sJIA. On hospital day 5, despite initial improvement, he developed relapsing fevers up to 40°C, lethargy, and new bruising on his skin. Laboratory evaluation now shows a platelet count of 90×10^9/L (down from 300×10^9/L a week prior), AST 150 U/L (elevated from near-normal), ferritin at 12,000 ng/mL (markedly up from 800 ng/mL on admission), and fibrinogen at 1.2 g/L (down from 4 g/L). He also has rising D-dimer levels and experiences hypotension with tachycardia. Blood cultures remain negative, and no infectious source is identified. Given the combination of persistent fever, new cytopenias, coagulopathy, and hyperferritinemia, the care team recognizes this as Macrophage Activation Syndrome complicating sJIA. He is transferred to the PICU for management. Treatment starts immediately with intravenous methylprednisolone pulse therapy and cyclosporine, while broad-spectrum antibiotics are continued until an infection is definitively excluded. His fever curve flattens over the next 48 hours, and his hemodynamics improve. By one week, his ferritin and liver enzymes trend downward, and his blood counts recover. This case illustrates a classic MAS presentation in sJIA – an acute deterioration during a disease flare, with dramatic changes in labs (especially ferritin and platelets) and a rapid response to immunosuppressive therapy once initiated.

Case 2: MAS in a Lupus Flare Triggered by Infection. A 15-year-old girl with systemic lupus erythematosus (pSLE) on moderate immunosuppressive therapy (mycophenolate and low-dose steroids) is admitted with fever, rash, and acute arthritis, raising concerns about a lupus flare versus an infection. She is diagnosed with influenza B infection and begins treatment with antivirals and increased steroids. Over the next few days, however, her symptoms worsen: persistent high fevers, severe headache, and confusion, along with new mucosal bleeding (gum oozing). Laboratory tests indicate worsening pancytopenia (WBC 1.5×10^9/L, hemoglobin 8 g/dL, platelets 50×10^9/L), ALT/AST around 200–300 U/L, triglycerides 300 mg/dL, and ferritin 8,500 ng/mL. Her aPTT is prolonged, and fibrinogen has decreased to 1.0 g/L. Given the combination of a lupus flare and infection, a cytokine storm is suspected. Bone marrow aspiration confirms hemophagocytosis. This clinical picture is diagnostic of MAS secondary to SLE, likely triggered by the viral infection. She is transferred to the ICU for close monitoring, where high-dose glucocorticoids and intravenous immunoglobulin are administered. Due to progressive CNS symptoms (drowsiness, slurred speech) suggesting possible MAS-related encephalopathy, the team adds cyclophosphamide (for lupus flare control) and anakinra (an IL-1 receptor antagonist) to manage the hyperinflammation. The patient stabilizes over the following week: her fevers resolve, and her mental status improves as ferritin and cytokine levels decrease. She is discharged after three weeks on a tapering steroid regimen. This case highlights that MAS can complicate rheumatologic diseases like lupus, particularly with the presence of infection, underscoring the necessity for aggressive immunotherapy alongside standard lupus treatments when MAS develops.

These cases serve as examples, since individual patient management may vary. Key features include the presence of a known disease flare or infection, rapid laboratory changes (cytopenias, high ferritin, low fibrinogen), and the necessity for immediate immunosuppressive treatment treatment.)

Diagnostic Tools and Classification Criteria

Diagnosing MAS requires combining clinical judgment with established criteria and scoring systems. No single test is definitive, but several diagnostic frameworks are available to help identify MAS/HLH in children.

HLH-2004 Diagnostic Criteria: Originally developed by the Histiocyte Society for primary HLH, the HLH-2004 criteria have been widely used for secondary HLH and MAS. A diagnosis requires 5 out of 8 criteria: (1) fever ≥38.5°C; (2) splenomegaly; (3) cytopenias affecting at least 2 of 3 lineages (hemoglobin <90 g/L, platelets <100×10^9/L, neutrophils <1.0×10^9/L); (4) hypertriglyceridemia (TG ≥265 mg/dL) and/or hypofibrinogenemia (fibrinogen ≤1.5 g/L); (5) hemophagocytosis observed on bone marrow, spleen, or lymph node biopsy; (6) low or absent NK cell activity; (7) ferritin ≥500 ng/mL; (8) elevated soluble IL-2 receptor (sCD25) ≥2400 U/mL. These criteria are specific but might lack sensitivity for MAS. For example, MAS patients often present with high platelet counts early in their disease (especially if they are coming from an inflammatory state like active sJIA) and may not yet show hemophagocytosis, which could prevent them from meeting 5 out of 8 criteria initially. Strict application of HLH-2004 criteria can delay diagnosis in MAS until the syndrome has advanced. Nonetheless, these criteria remain central for recognizing HLH/MAS and ensuring other potential diagnoses are considered. In practice, the HLH-2004 criteria are most useful when a child presents with a clear hyperinflammatory picture, prompting consideration of whether it reaches the threshold to initiate full HLH-directed treatment.

2016 MAS Classification Criteria (for sJIA): Since was not created for patients with rheumatic diseases, pediatric rheumatologists developed a specific set of classification criteria for MAS complicating sJIA. In a child with known or suspected sJIA, MAS is considered present if the patient has persistent fever and a Ferritin level >684 ng/mL, along with at least two of the following four criteria:

1. Platelet count ≤ 181 × 10^9/L (thrombocytopenia).

2. AST > 48 U/L (elevated liver enzyme).

3. Triglycerides > 156 mg/dL.

4. Fibrinogen ≤ 360 mg/dL (hypofibrinogenemia).

These cutoff values were derived from pediatric data to differentiate MAS from an active sJIA flare. They intentionally exclude tests such as NK function or sCD25 and focus on readily available labs. The 2016 criteria proved to be highly specific (~95–99%) and moderately sensitive (~73–85%) in validation cohorts. They make diagnosing MAS easier in real-time at the bedside because they rely on standard labs (CBC, ferritin, LFTs, lipids, fibrinogen). It is important to remember that if a patient is on cytokine blockers (IL-1 or IL-6 inhibitors for sJIA), the typical fever or lab patterns might be less clear, meaning MAS could occur without fever or with less apparent lab changes. Therefore, while these criteria serve as a helpful guide, clinicians should still act on strong suspicion of MAS—even if not all thresholds are met—since delays could be fatal. Additionally, it is important to note that the 2016 MAS criteria are officially validated only for sJIA (and, by extension, adult AOSD) and not for MAS in other diseases. Other rheumatic conditions may require different thresholds; for example, preliminary diagnostic criteria for MAS in SLE have been suggested (including features like CNS involvement and higher LDH), as lupus-associated MAS can present subtly. Overall, any child with an autoimmune disease who exhibits features consistent with sJIA MAS (such as high ferritin and cytopenias) should be treated as MAS after ruling out mimics, regardless of the specific disease context.

HScore (Hemophagocytic Syndrome Score): The HScore is a scoring system developed in 2014 (Fardet et al.) to estimate the likelihood that a patient has HLH/MAS, mainly used in secondary HLH (including adults). It assigns point values to various factors: known immunosuppression, temperature, organomegaly, number of cytopenias, triglyceride level, fibrinogen, serum ferritin, AST level, and the presence of hemophagocytosis on marrow aspirate. For instance, in the HScore, a fever above 39.4°C earns 49 points, splenomegaly earns 38 points, and ferritin levels above 6000 ng/mL earn 50 points, among others. After adding up the points, a score of ≥169 indicates approximately 93% sensitivity and 86% specificity for diagnosing HLH/MAS (in the original study population). The HScore has the benefit of recognizing partial expression of features (e.g., it awards some points for 2-lineage cytopenia and more points for 3-lineage cytopenia instead of an all-or-nothing approach). It also does not require NK cell function or IL-2 receptor levels, making it practical when those specialized tests are unavailable. A pediatric evaluation suggested that the HScore might be more sensitive for MAS in children than the HLH-2004 criteria. During the COVID-19 pandemic, the HScore also gained popularity for detecting hyperinflammation in conditions like MIS-C and COVID-19 cytokine storm. Many clinicians find the HScore useful as a supportive tool; for example, a very high HScore can strengthen the decision to treat aggressively. Nevertheless, like any scoring system, it should complement clinical judgment rather than replace it.

Practical approach: In a hospitalized child suspected of MAS, it is reasonable to use more than one of the above tools simultaneously. One step is to check if the HLH-2004 criteria are met for a formal diagnosis, use the 2016 MAS criteria if sJIA is part of the differential, and even calculate an HScore to estimate the probability. These tools are complementary; for example, one study indicates that combining HLH-2004 and HScore improves diagnostic accuracy in children. Ultimately, no single set of criteria can identify every case. Clinicians are advised to treat impending MAS based on clinical judgment (“triggered hyperinflammation”) even if all criteria are not fully met, and they should not wait for histologic confirmation of hemophagocytosis before starting treatment. Repeated evaluations and laboratory tests over time are crucial; sometimes, a borderline case today will meet criteria tomorrow as more data becomes available or as the disease progresses, but delaying treatment could be dangerous if the child is critically ill.

(See Table 1 below for a comparison of HLH-2004, 2016 MAS, and HScore criteria.)

Parameter	HLH-2004 Criteria (5 of 8)	2016 MAS Criteria (sJIA context)	HScore Contribution (points)
Fever	≥ 38.5°C (persistent)	High fever (must be present)	Temperature 38.4–39.4°C = 33; >39.4°C = 49 points
Splenomegaly	Present (required among 5/8)	Often present (hepatomegaly or splenomegaly common, but not in formal criteria)	Organomegaly: hepatomegaly or splenomegaly = 23; both = 38 points
Cytopenias (≥2 lines)	Hb < 90 g/L, Platelets <100×10^9/L, ANC <1.0×10^9/L	Platelets ≤ 181×10^9/L (one criterion)	Cytopenias: 2 lineages = 24; 3 lineages = 34 points
Ferritin	≥ 500 ng/mL	Ferritin > 684 ng/mL (must have)	2000–6000 ng/mL = 35; >6000 ng/mL = 50 points
Triglycerides	≥ 265 mg/dL (≥3 mmol/L)	> 156 mg/dL (1.78 mmol/L) (one criterion)	1.5–4.0 mmol/L = 44; >4.0 mmol/L = 64 points
Fibrinogen	≤ 1.5 g/L (150 mg/dL)	≤ 360 mg/dL (3.6 g/L) (one criterion)	>2.5 g/L = 0; ≤2.5 g/L = 30 points
AST (Liver enzyme)	(Not in criteria; liver enzymes often elevated)	> 48 U/L (one criterion)	≥ 30 U/L = 19 points
Hemophagocytosis	Required if counting toward 5/8 (if seen on marrow/spleen/LN)	Not required (excluded from MAS criteria)	Present on marrow = 35 points
sCD25 (IL-2Rα)	≥ 2400 U/mL	Not used in criteria	(Not included in HScore)
NK cell activity	Low or absent	Not used in criteria	(Not included in HScore)
Additional factors	–	– (implicitly, context is sJIA)	Immunosuppressed patient = 18 points
Diagnosis threshold	5 of the eight criteria	Ferritin >684 + ≥2 of 4 criteria	HScore ≥ 169 (≈90% probability)

Table 1: Comparison of key diagnostic criteria and tools for HLH/MAS in pediatrics. The HLH-2004 criteria are broad and require invasive or specialized tests (NK function, sCD25) that are not available at all centers. The 2016 MAS criteria focus on children with sJIA, using high ferritin levels and common lab tests for faster diagnosis. The HScore is a point-based calculator that can include partial criteria and various settings. In practice, these tools should be used alongside clinical judgment; meeting full criteria is not necessary to start treatment in a critically ill child suspected of MAS. Abbreviations: Hb = hemoglobin; ANC = absolute neutrophil count; sCD25 = soluble IL-2 receptor α; NK = natural killer cell.

Diagnostic Biomarkers and Laboratory Findings

Several laboratory abnormalities are indicative of MAS and can help in diagnosis and monitoring. Key biomarkers include:

Ferritin: Hyperferritinemia is the main laboratory finding in MAS. Ferritin, an acute phase reactant and iron storage protein, often rises to very high levels during the MAS cytokine storm. While a ferritin level over 500 ng/mL is part of the HLH criteria, MAS usually involves levels in the thousands. Most pediatric MAS patients have ferritin levels above 1000 ng/mL, and many exceed 10,000 ng/mL. A ferritin level higher than 10,000 ng/mL is highly sensitive and specific for HLH/MAS and is often considered pathognomonic in the right clinical setting. Extremely high ferritin levels (greater than 100,000 ng/mL) tend to indicate primary HLH or an underlying genetic or immunologic syndrome and should lead to evaluation for inherited predispositions. Monitoring ferritin levels can be useful: a rapid increase often signals the start of MAS, and a decrease with treatment generally indicates a positive response. (Remember, ferritin is not specific – it can be elevated in systemic infections, liver failure, malignancies, etc. – but levels in the tens of thousands are uncommon outside HLH/MAS.)

Complete Blood Count (CBC): Cytopenias are a key feature. MAS typically causes a decrease in at least two of three blood lineages, often mainly affecting platelets and white blood cells. Thrombocytopenia is especially common and frequently the first cytopenia seen. A sudden drop in platelet count in a child with ongoing inflammation should strongly suggest MAS. Leukopenia (neutropenia) and anemia develop as MAS progresses due to cytokine-driven bone marrow suppression and hemophagocytosis. Monitoring trends provides useful information; for example, platelets decreasing from high-normal to low levels in an sJIA patient can indicate MAS even before they reach very low values. In practice, platelet counts of ≤100–150×10^9/L in a sick, febrile child raise serious concerns for MAS, especially if they were previously elevated due to inflammation. Hemoglobin may decline due to anemia of inflammation or hemorrhage related to DIC. Neutropenia (<1.0×10^9/L) often appears later but is included in HLH criteria. Clinicians should also examine the peripheral smear if MAS is suspected, looking for schistocytes (if DIC/TMA is present) or atypical lymphocytes (if a viral trigger is involved).

Inflammatory markers (CRP, ESR) and Acute Phase Reactants: MAS creates a paradoxical inflammatory profile. C-reactive protein (CRP) is usually markedly elevated, reflecting intense inflammation. In contrast, the erythrocyte sedimentation rate (ESR) often drops sharply once MAS develops. This paradox (high CRP but low ESR) occurs because fibrinogen, a significant factor influencing ESR, is consumed in the coagulopathy of MAS. A falling ESR in a patient whose CRP remains high is a classic sign of MAS. Other acute phase reactants include: fibrinogen itself, which is often low (<150–300 mg/dL as it’s utilized in hypercoagulation), and albumin, which is low (a negative acute phase reactant resulting from hemophagocytic consumption). D-dimer and fibrin degradation products are generally elevated due to ongoing DIC. LDH (lactate dehydrogenase) is typically high, indicating tissue damage and hemophagocytosis. Procalcitonin might also be elevated, which can lead to confusion between MAS and bacterial sepsis, making this marker non-discriminatory.

Liver Function Tests: Elevated liver enzymes are common. AST and ALT are typically moderately elevated, with AST often rising first. Very high transaminase levels (e.g., several hundred to thousands) can occur if there is liver necrosis from HLH or ischemic injury due to shock. Bilirubin may increase because of liver dysfunction or hemophagocytic hemolysis. MAS can also cause hepatomegaly and, in rare cases, fulminant liver failure. Because liver involvement is so common, it is included in diagnostic criteria (e.g., AST > 48 U/L in MAS). Lactate levels may rise if hepatic clearance is impaired or in shock. Coagulopathy, indicated by prolonged PT/PTT and low fibrinogen, results partly from hepatic synthetic failure and partly from DIC; it signals severe disease and often coincides with high ferritin.

Triglycerides and Lipid Panel: MAS often involves hypertriglyceridemia caused by cytokine-induced changes in lipid metabolism and hemophagocytic effects on the liver. Triglyceride levels over 265 mg/dL (3 mmol/L) meet the HLH criteria, but MAS is frequently associated with milder elevations (e.g., 150–200 mg/dL) that still indicate an abnormality. Hypertriglyceridemia in MAS correlates with disease severity and liver dysfunction, leading to reduced lipid clearance. Cholesterol levels are often low (due to acute phase effects), and HDL is usually decreased. This serves as an important clue in a febrile child: an unexpectedly high fasting triglyceride level should prompt consideration of HLH/MAS in the differential diagnosis.

Coagulation Markers: DIC is common in MAS, leading to prolonged PT/PTT, elevated D-dimer, low fibrinogen, and sometimes thrombocytopenia that is more severe than bone marrow suppression alone. A fibrinogen level below 1.5 g/L (150 mg/dL) or a rapid drop in fibrinogen is worrisome. Patients may show bleeding signs like mucosal bleeding, petechiae, etc., due to consumptive coagulopathy. About 20% of MAS patients experience serious bleeding or hemorrhagic complications. Thus, monitoring coagulation markers is essential for diagnosis and supportive care (such as replacing fibrinogen or plasma as needed).

Soluble IL-2 Receptor (sCD25) and IL-18: sCD25 (also known as soluble IL-2 receptor α or sIL-2R) is a marker of T-cell activation that is typically significantly elevated in HLH/MAS, often reaching levels far above the 2400 U/mL cutoff used in HLH criteria. It is included in HLH-2004 criteria, but it is usually a send-out lab with a longer turnaround time, making it less practical in acute settings at some centers. When available, an extremely high sCD25 level can support the diagnosis. IL-18 is another cytokine that is extraordinarily elevated in MAS, especially in MAS associated with sJIA. Levels in the tens of thousands pg/mL are reported in active MAS, which is much higher than in other hyperinflammatory conditions, making IL-18 a promising biomarker. Some specialized centers may measure IL-18 to help distinguish MAS from septic shock or active lupus, for example. However, IL-18 testing is not yet routine everywhere. IL-6 and IL-10 are also elevated in most MAS cases; a high IL-10:IL-6 ratio has been noted as a potential way to differentiate between HLH and typical sepsis, since IL-10 (an anti-inflammatory cytokine) is significantly elevated in HLH. These interleukins are not part of standard criteria, but they can help confirm the nature of the cytokine storm if measured. CXCL9 (a chemokine induced by interferon-γ) and sCD163 (a macrophage activation marker) are two additional specialized biomarkers associated with MAS activity. They are mainly used in research or in specialized labs to monitor interferon-γ activity (CXCL9) or macrophage activation (sCD163). In summary, while ferritin and standard labs form the foundation for MAS diagnosis, cytokine and immune markers (such as sCD25, IL-18, IL-1, IL-6, IL-10, interferon-γ levels, etc.) are increasingly recognized for their role in understanding the disease process and may become more clinically available soon.

Bone Marrow Aspiration: Although not a serum “biomarker,” mentioning bone marrow studies is warranted. A bone marrow aspirate or biopsy showing hemophagocytosis (macrophages engulfing RBCs, WBCs, or platelets) can support the diagnosis of HLH/MAS. However, hemophagocytosis is often absent early in MAS; one series found it in only 60% of sJIA/MAS cases at diagnosis. Conversely, it can occur in severe sepsis or other conditions (macrophages can activate in any inflammatory ICU patient). Thus, a negative marrow does not rule out MAS, and a positive marrow must be interpreted in context. Bone marrow examination is helpful in excluding other causes (such as leukemia or malignancy) and investigating for infection (like leishmania or Histoplasma, which can cause HLH). If MAS is strongly suspected, one should not wait for a bone marrow result to start therapy. If the diagnosis is unclear, a marrow study is often part of the workup while concurrently initiating treatment.

In practice, a combination of these markers—for example, a ferritin level greater than 5000 ng/mL, elevated D-dimer with fibrinogen consumption, AST elevation, platelets dropping below 100,000, and high LDH—paints a compelling picture of MAS in a febrile child. The pattern and constellation of abnormalities, rather than any single laboratory result, confirm the diagnosis. Serial lab tests are often more informative than a one-time “snapshot,” as trends (worsening cytopenias, rising ferritin, falling fibrinogen) may indicate MAS over 1 to 3 days. Recognizing this pattern early allows for prompt therapy, which can dramatically reverse many of these abnormalities days.

First-Line Treatment of MAS in Hospitalized Children

MAS is a medical emergency, and treatment has two main goals: (1) reduce the hyperinflammation that causes organ damage and (2) address or eliminate the triggering factor (infection, disease flare-up, etc.). Since no randomized trials exist for pediatric MAS (a rare and heterogeneous condition), current recommendations rely on expert consensus and successful case series. Management usually occurs in an intensive care or specialized setting. The first-line therapy for MAS in children includes:

High-Dose Corticosteroids: Corticosteroids are essential for MAS treatment because of their strong anti-inflammatory and immunosuppressive effects. Intravenous pulse methylprednisolone is commonly used; a typical regimen is 30 mg/kg/day IV (up to 1 gram) for 3 to 5 days. As the child’s condition improves, this pulse is often followed by a tapering dose of IV or oral steroids (e.g., high-dose daily prednisone). Steroids help suppress T-cell activation and stabilize endothelial and macrophage activation. They are known for their rapid effect. In many cases, steroids alone can induce remission of MAS if started early. Dexamethasone is an alternative (the HLH-94 protocol uses dexamethasone starting at 10 mg/m²/day and tapering), and some ICU protocols may use high-dose dexamethasone for better CNS penetration if neurological symptoms are present. The differences between the two are minor; what’s important is that a prompt, sufficiently high dose of steroids is administered. Regular reassessment is necessary; if there is no improvement within 24-48 hours of steroid treatment, additional therapies should be started immediately.

Cyclosporine A (CSA): Cyclosporine, a calcineurin inhibitor that targets T-cell function, is often used as an adjunct first-line agent in MAS. It is especially popular among pediatric rheumatologists for MAS linked to sJIA. CSA, usually dosed at around 2–7 mg/kg/day in divided doses to maintain therapeutic trough levels, can be started alongside steroids if MAS is severe or added if steroid response is inadequate. CSA works by inhibiting T-lymphocyte activation and may help decrease the cytokine cascade, especially by suppressing IL-2 and interferon-γ production. In a study from India, 39% of MAS patients received steroids combined with CSA as initial therapy, with good results. A practical approach might include IV methylprednisolone pulse therapy followed by CSA at 2-5 mg/kg/day starting on day 1. However, CSA carries risks such as nephrotoxicity and hypertension, requiring close monitoring. Many U.S. centers are opting to replace cyclosporine with anakinra, an IL-1 blocker, as the first-line treatment for sJIA-MAS because of anakinra’s better safety profile. The choice often depends on the provider’s experience and the clinical situation.

Interleukin-1 Blockade (Anakinra): Anakinra, an IL-1 receptor antagonist, has become a key therapy for MAS, especially in the context of sJIA or Still’s disease, where IL-1 plays a vital role as a cytokine. Although it has traditionally been considered a second-line treatment or adjunct for refractory cases, many experts now recommend using anakinra early in MAS management. It can be started alongside steroids (or even instead of cyclosporine) to better control inflammation. Anakinra is given daily, with typical doses ranging from 2 to 10 mg/kg SC or IV, with higher doses or more frequent administration in critical cases. Reports and case series have shown remarkable responses to anakinra in refractory MAS. Targeting IL-1 can quickly reverse fever and hyperferritinemia in sJIA-associated MAS. Many pediatric centers now include anakinra in their first-line treatment for MAS, such as IV methylprednisolone plus anakinra, with or without CSA. Anakinra is relatively safe, with the main concern being infection risk, which is acceptable given that MAS patients are often already infected or at risk. If anakinra is unavailable or contraindicated, an IL-6 blocker like tocilizumab may be considered, although IL-6 blockade is generally seen as less effective than IL-1 blockade in severe MAS cases.

Intravenous Immunoglobulin (IVIG): IVIG is sometimes used in MAS, especially when an infectious trigger is suspected or in infection-associated HLH. IVIG can modulate the immune system, provide passive immunity, and help neutralize pathogens. In children, MAS and infection often coexist, making IVIG a reasonable adjunct while waiting for specific viral studies or when considering an autoimmune process like Kawasaki disease in the differential. Doses range from 1–2 g/kg (similar to those used in Kawasaki disease or immune thrombocytopenia). In one series, about 19% of MAS patients initially received IVIG plus steroids. Although IVIG alone is usually insufficient for MAS, it may be combined with steroids in mild cases, mainly if there is diagnostic uncertainty (for example, if it’s unclear whether it’s MAS or severe EBV infection, IVIG might help with both). Due to its low side-effect profile, IVIG is often added empirically during the acute phase.

Treat the Underlying Trigger: Alongside immunosuppressive therapy, address any identifiable trigger or concurrent condition. This includes using broad-spectrum antibiotics if bacterial sepsis is a concern (many MAS presentations resemble sepsis and the two can coexist), antiviral therapy if a virus like EBV, CMV, or influenza is involved, and treatment for the rheumatologic disease flare (e.g., high-dose corticosteroids are beneficial for lupus or Still’s disease flares, and cyclophosphamide may be necessary for a catastrophic lupus flare, etc.). If a specific drug is suspected to have triggered MAS (for example, some MAS cases in sJIA have been linked to NSAIDs or methotrexate), that medication should be discontinued. Essentially, optimize treatment for the underlying disease (which often involves increasing immunosuppression during a flare) and support the patient through any infections or organ failure. Close coordination among intensivists, rheumatologists, hematologists, and infectious disease specialists is crucial. The EULAR/ACR 2022 guidelines emphasize the importance of early multidisciplinary input and simultaneous management of triggers (e.g., starting antimicrobials while also treating HLH).

Supportive Care: Children with MAS are usually very ill and often need ICU-level support. This includes aggressive hemodynamic support (fluids and vasopressors if in shock), respiratory support (possibly mechanical ventilation if ARDS develops), and close monitoring. Blood products are often necessary, such as transfusions for severe anemia, platelets for bleeding risk, and plasma or cryoprecipitate for coagulopathy. Correcting coagulopathy with fibrinogen concentrates or cryoprecipitate can be life-saving in bleeding cases. Managing complications like increased intracranial pressure (if CNS involvement occurs), renal replacement therapy for acute kidney injury, or even ECMO (extracorporeal membrane oxygenation) for refractory shock may be needed in severe cases. Each organ system must be supported while immunotherapy takes effect. The good news is that once hyperinflammation is controlled, organ function often recovers.

If the above measures (steroids ± CSA, ± anakinra, ± IVIG) are taken quickly, many children will improve within days. Fever reduction, increasing platelet counts, and lowering ferritin levels show the treatment is working. Close daily monitoring of lab results is crucial to evaluate the response. Therapy can then be gradually tapered over weeks to months, usually transitioning to oral steroids.

Refractory MAS: Some patients will not improve with first-line treatment or may even worsen, showing persistent critical condition or increasing organ failures. In such cases, second-line therapies are intensified. Traditionally, the HLH-94 protocol (etoposide + dexamethasone ± cyclosporine) is used for refractory or severe HLH and can also be applied to MAS. Etoposide, a cytotoxic chemotherapy agent, effectively removes activated T cells and macrophages. It is especially indicated if EBV-driven HLH is suspected, as it improves survival by eliminating infected T cells. Many hematologists recommend adding etoposide early in fulminant cases, even if it’s MAS, particularly when there is central nervous system involvement or life-threatening organ failure. However, due to potential bone marrow suppression and long-term toxicity, rheumatologists often reserve it for truly refractory MAS. Other second-line options include anti-thymocyte globulin (ATG) to broadly eliminate T cells, higher-dose anakinra, or switching to another cytokine inhibitor like the IL-6 inhibitor tocilizumab or the IFN-γ blocker emapalumab if available, along with plasmapheresis in certain situations to remove cytokines. Rituximab (anti-CD20) is used if EBV drives HLH to target B cells harboring the virus. Emerging therapies for refractory cases include JAK inhibitors such as ruxolitinib to reduce widespread cytokine signaling and IL-18 binding agents. If a patient is diagnosed with primary HLH or a known genetic syndrome, hematopoietic stem cell transplant offers a definitive cure, though this is a long-term strategy and not part of acute management.

For pediatricians in hospital settings managing MAS, immediate actions are essential: identify the syndrome, quickly start high-dose steroids (and sometimes cyclosporine or anakinra), consult specialists, and provide comprehensive supportive care. Following these guidelines can often control hyperinflammation before irreversible damage occurs. Early intervention greatly reduces MAS mortality rates. The treatment plan should be reviewed regularly (at least every 24–48 hours) and intensified if the patient shows no improvement. Time is critical—children with fulminant MAS can develop shock and multi-organ failure within days, so front-line treatments are given empirically at the bedside rather than waiting for exhaustive confirmation. This proactive and aggressive approach, guided by the latest criteria and biomarkers mentioned earlier, offers the best chance for a favorable outcome in children with MAS.

References and further reading: 

1. Ravelli A, Minoia F, Davì S, et al. (2016). 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A EULAR/ACR/PRINTO Collaborative Initiative. Arthritis & Rheumatology, 68(3): 566–576. DOI: 10.1002/art.39332

2. Shakoory B, Geerlinks A, Wilejto M, et al. (2023). The 2022 EULAR/ACR Points to Consider at the Early Stages of Diagnosis and Management of Suspected HLH/MAS. Arthritis & Rheumatology, 75(10): 1714–1732. DOI: 10.1002/art.42636

3. Baldo F, Erkens RGA, Mizuta M, et al. (2025). Current Treatment in Macrophage Activation Syndrome Worldwide: A Systematic Literature Review to Inform the METAPHOR Project. Rheumatology (Oxford), 64(1): 32–44. DOI: 10.1093/rheumatology/keae391

4. Lee J, Bae KS, Rhim JW, et al. (2024). Macrophage Activation Syndrome in Children: Update on Diagnosis and Treatment. Children (Basel), 11(7): 755. DOI: 10.3390/children11070755

5. Sztajnbok F, Fonseca AR, Campos LR, et al. (2024). Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome: Two Rare Sides of the Same Devastating Coin. Advances in Rheumatology, 64: 28. DOI: 10.1186/s42358-024-00370-2

6. Gámez-González LB, Murata C, García-Silva J, et al. (2024). Macrophage Activation Syndrome in MIS-C. Pediatrics, 154(6): e2024066780. DOI: 10.1542/peds.2024-066780

7. Abdirakhmanova A, Sazonov V, Mukusheva Z, et al. (2021). Macrophage Activation Syndrome in Pediatric Systemic Lupus Erythematosus: A Systematic Review of Diagnostic Aspects. Frontiers in Medicine, 8: 681875. DOI: 10.3389/fmed.2021.681875

8. Canna SW & Marsh RA (2020). Pediatric Hemophagocytic Lymphohistiocytosis (including Macrophage Activation Syndrome). Blood, 135(16): 1332–1343. DOI: 10.1182/blood.2019000936

9. Hines MR, von Bahr Greenwood T, Beutel G, et al. (2022). Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults. Critical Care Medicine, 50(5): 860–872. DOI: 10.1097/CCM.0000000000005361

10. Minoia F, Bovis F, Davì S, et al. (2019). Development and Initial Validation of the MS Score for Diagnosis of MAS in Systemic JIA. Annals of the Rheumatic Diseases, 78(10): 1357–1362. DOI: 10.1136/annrheumdis-2019-215211

11. Reiff DD & Cron RQ (2021). Performance of Cytokine Storm Syndrome Scoring Systems in Pediatric COVID-19 and MIS-C. ACR Open Rheumatology, 3(12): 820–826. DOI: 10.1002/acr2.11331

12. Weiss ES, Girard‐Guyonvarc’h C, Holzinger D, et al. (2018). Interleukin-18 Diagnostically Distinguishes and Pathogenically Promotes Human and Murine Macrophage Activation Syndrome. Blood, 131(13): 1442–1455. DOI: 10.1182/blood-2017-12-820852

13. Mehta P, Cron RQ, Hartwell J, Manson JJ, Tattersall RS (2020). Silencing the Cytokine Storm: The Use of Intravenous Anakinra in HLH/MAS. The Lancet Rheumatology, 2(6): e358–e367. DOI: 10.1016/S2665-9913(20)30096-5

14. Schulert GS & Grom AA (2015). Pathogenesis of Macrophage Activation Syndrome and Potential for Cytokine-Directed Therapies. Annual Review of Medicine, 66: 145–159. DOI: 10.1146/annurev-med-061813-012806

15. Behrens EM & Koretzky GA (2017). Review: Cytokine Storm Syndrome – Looking Toward the Precision Medicine Era. Arthritis & Rheumatology, 69(6): 1135–1143. DOI: 10.1002/art.40071

16. Benevenuta C, Mussinatto I, El-Demerdash A, et al. (2023). Secondary Hemophagocytic Lymphohistiocytosis in Children (Review). Experimental and Therapeutic Medicine, 26(3): 423. DOI: 10.3892/etm.2023.12122

17. Dong Y, Wang T, Wu H (2024). Heterogeneity of Macrophage Activation Syndrome and Treatment Progression. Frontiers in Immunology, 15: 1389710. DOI: 10.3389/fimmu.2024.1389710

18. El-Miedany Y, El-Deriny G, Mortada M, et al. (2022). Egyptian Consensus on Diagnosis and Treat-to-Target Management of Macrophage Activation Syndrome in Children. Egyptian Rheumatology and Rehabilitation, 49: 36. DOI: 10.1186/s43166-022-00135-z

19. Henderson LA & Cron RQ (2020). Macrophage Activation Syndrome and Secondary HLH in Childhood Inflammatory Disorders: Diagnosis and Management. Paediatric Drugs, 22(1): 29–44. DOI: 10.1007/s40272-019-00367-120. Crayne CB & Cron RQ (2020). Pediatric Macrophage Activation Syndrome: Recognizing the Tip of the Iceberg. European Journal of Rheumatology, 7(Suppl 1): S13–S20. DOI: 10.5152/eurjrheum.2019.19150