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Ostermayer: Created page with "==Background== *Macrophage activation syndrome (MAS) is a severe, potentially fatal hyperinflammatory syndrome caused by uncontrolled activation and proliferation of T lymphocytes and macrophages, leading to a massive '''cytokine storm''' and widespread hemophagocytosisRavelli A, Minoia F, Davì S, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against R..."

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Created page with "==Background== *Macrophage activation syndrome (MAS) is a severe, potentially fatal hyperinflammatory syndrome caused by uncontrolled activation and proliferation of T lymphocytes and macrophages, leading to a massive '''cytokine storm''' and widespread hemophagocytosis<ref name="Ravelli2016">Ravelli A, Minoia F, Davì S, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against R..."

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==Background==
*Macrophage activation syndrome (MAS) is a severe, potentially fatal hyperinflammatory syndrome caused by uncontrolled activation and proliferation of T lymphocytes and macrophages, leading to a massive '''cytokine storm''' and widespread hemophagocytosis<ref name="Ravelli2016">Ravelli A, Minoia F, Davì S, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2016;75(3):481-9.</ref>
*MAS is a form of '''secondary [[hemophagocytic lymphohistiocytosis]] (HLH)''' occurring in the context of rheumatic disease<ref name="Carter2019">Carter SJ, Tattersall RS, Ramanan AV. Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatology. 2019;58(1):5-17.</ref>
**"MAS" is used when triggered by rheumatic disease; "secondary HLH" is used when triggered by infection or malignancy — the pathophysiology and management are similar
*'''Mortality:''' 20-40% even with treatment; higher if diagnosis is delayed<ref name="Carter2019"/>
*'''Underdiagnosed''' — frequently confused with [[sepsis]], disease flare of the underlying rheumatic condition, or drug side effects<ref name="PMCreview">Macrophage activation syndrome: A diagnostic challenge (Review). Exp Ther Med. 2021;22(3):904.</ref>

===Triggers and Associations===
*'''Most commonly associated with [[Juvenile idiopathic arthritis|systemic juvenile idiopathic arthritis (sJIA)]]''' — ~10% overt MAS, up to 30-40% subclinical<ref name="Schulert2015">Schulert GS, Grom AA. Macrophage Activation Syndrome and Cytokine-Directed Therapies. Best Pract Res Clin Rheumatol. 2014;28(2):277-92.</ref>
*Other rheumatic diseases:
**[[Adult-onset Still's disease]] (AOSD)
**[[Systemic lupus erythematosus]] (SLE)
**[[Kawasaki disease]]
**Juvenile dermatomyositis
**[[Polyarteritis nodosa]]
*Infectious triggers (may precipitate MAS in patients with underlying rheumatic disease or de novo):
**Viral: [[EBV]] (most common), [[CMV]], [[influenza]], [[COVID-19]], HSV, parvovirus B19
**Bacterial: [[sepsis]], [[endocarditis]]
*Malignancy-associated (especially T-cell [[lymphoma]])
*Medication changes (including initiation or alteration of biologic agents)
*Disease flares of underlying rheumatic condition

===Pathophysiology===
*Defective NK cell and cytotoxic T cell function → failure to eliminate antigen-presenting cells → persistent immune activation
*Massive release of pro-inflammatory cytokines (IL-1, IL-6, IL-18, IFN-γ, TNF-α)
*Uncontrolled macrophage activation → phagocytosis of blood cells (hemophagocytosis) in bone marrow, liver, spleen, and lymph nodes
*Results in consumptive cytopenias, coagulopathy, and multi-organ dysfunction

==Clinical Features==
''MAS can develop explosively — a child or adult with known rheumatic disease can deteriorate from stable to critically ill within hours to days''

===Systemic===
*'''Unremitting high [[fever]]''' — in sJIA patients, evolution from quotidian spiking fever to '''continuous fever''' is a red flag<ref name="Ravelli2016"/>
*Profound malaise, rapid clinical deterioration
*'''Paradoxical improvement of arthritis''' may occur as MAS develops (due to immune exhaustion)

===Organ Involvement===
*'''Hepatic:''' [[hepatomegaly]], transaminitis, [[jaundice]], liver failure
*'''Hematologic:''' petechiae, purpura, mucosal bleeding, easy bruising (from consumptive coagulopathy and thrombocytopenia)
*'''Neurologic:''' [[altered mental status]], lethargy, irritability, [[seizures]], encephalopathy (present in 30-35% of cases)
*'''Spleen:''' [[splenomegaly]] (often rapidly enlarging)
*'''Lymphadenopathy''' (generalized)
*'''Cardiac:''' [[myocarditis]], [[pericardial effusion]]
*'''Pulmonary:''' [[ARDS]], [[pleural effusion]]
*'''Renal:''' [[acute kidney injury]]
*'''[[DIC]]:''' clinical or subclinical disseminated intravascular coagulation

===ED Pearls===
*In a child with known sJIA, '''any''' of the following should prompt evaluation for MAS:
**Fever pattern change from intermittent to continuous
**'''Falling''' platelet count (even if still within "normal" range)
**'''Falling''' ESR (paradoxical — due to fibrinogen consumption)
**'''Rising''' ferritin disproportionate to other acute phase reactants
**New hepatomegaly or transaminitis
**New bleeding or bruising
*MAS can be the '''presenting feature''' of undiagnosed sJIA in 22-53% of cases<ref name="Raj2024">Spoorthy Raj DR, Suma Balan. Systemic Juvenile Idiopathic Arthritis: The Challenges and Opportunities. Indian J Rheumatol. 2024.</ref>
*MAS mimics [[sepsis]] — and the two can coexist (infection is a common MAS trigger)

==Differential Diagnosis==
*'''[[Sepsis (Main)|Sepsis]]/[[septic shock]]''' — most important mimicker; MAS and sepsis can coexist
*'''Primary [[hemophagocytic lymphohistiocytosis]]''' (familial/genetic HLH) — typically presents in infancy
*'''Malignancy-associated HLH''' (T-cell [[lymphoma]], [[leukemia]])
*'''Disease flare''' of underlying rheumatic condition (sJIA, SLE, AOSD) without MAS
*'''[[DIC]]''' from other causes
*'''[[Thrombotic thrombocytopenic purpura]] (TTP)'''
*'''Drug reaction''' (e.g. to biologic agents, NSAIDs)
*'''[[Liver failure]]''' from other causes
*'''[[Toxic shock syndrome]]'''
*'''Severe viral illness''' ([[EBV]], [[CMV]], [[COVID-19]])

==Evaluation==
===Workup===
Order the following in any patient with suspected MAS:

;Hematology:
*'''CBC with differential:''' pancytopenia (or falling counts from previously elevated baseline — especially '''falling platelets''' and '''falling WBC''')
*'''Peripheral blood smear:''' evaluate for hemophagocytosis, blasts ([[leukemia]])
*'''[[Reticulocyte count]]'''

;Inflammatory Markers:
*'''[[Ferritin]]:''' the single most important lab — markedly elevated, often '''>10,000 ng/mL'''; may exceed 100,000 ng/mL in fulminant MAS<ref name="Ravelli2016"/>
*'''ESR:''' may be '''paradoxically low or falling''' (due to fibrinogen consumption) even as CRP rises — this discordance is highly suggestive of MAS
*'''[[CRP]]:''' elevated
*'''Ferritin:ESR ratio >21.5''' is suggestive of MAS in sJIA patients<ref name="Eloseily2019">Eloseily EM, Minoia F, Engel B, et al. Ferritin to Erythrocyte Sedimentation Rate Ratio: Simple Measure to Identify Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis. ACR Open Rheumatol. 2019;1(6):345-349.</ref>

;Coagulation:
*'''Fibrinogen:''' low or falling (consumed in DIC-like process) — often '''<150 mg/dL'''
*'''PT/PTT:''' prolonged
*'''[[D-dimer]]:''' elevated
*'''FDP:''' elevated

;Hepatic:
*'''AST/ALT:''' elevated (AST >48 U/L is part of the 2016 classification criteria)
*'''LDH:''' markedly elevated
*'''Bilirubin:''' may be elevated
*'''Albumin:''' low

;Other:
*'''Triglycerides:''' elevated (>156 mg/dL per HLH-2004 criteria)
*'''[[Lactate]]:''' if concern for tissue hypoperfusion
*'''sIL-2R (soluble CD25):''' markedly elevated if available (may take days to result)
*'''sCD163:''' elevated (marker of macrophage activation; not widely available)
*'''Blood cultures:''' mandatory to evaluate for concurrent infection
*'''Viral studies:''' [[EBV]], [[CMV]], [[influenza]], [[COVID-19]], HSV (infection is a common MAS trigger)
*'''[[CXR]], [[echocardiography]]:''' assess for [[pleural effusion]], [[pericardial effusion]], [[ARDS]]
*'''Bone marrow biopsy:''' may show hemophagocytosis; however, absence of hemophagocytosis does '''not''' rule out MAS (present in only ~60% of cases, and may not be seen early)<ref name="PMCreview"/>

===Diagnosis===
''There is no single gold-standard diagnostic test. MAS is a clinical diagnosis supported by laboratory and sometimes histopathologic findings.''

====2016 EULAR/ACR/PRINTO Classification Criteria for MAS Complicating sJIA====
A febrile patient with known or suspected sJIA is classified as having MAS if:<ref name="Ravelli2016"/>
*'''Ferritin >684 ng/mL''' PLUS any '''2 or more''' of:
**Platelet count ≤181 × 10⁹/L
**AST >48 U/L
**Triglycerides >156 mg/dL
**Fibrinogen ≤360 mg/dL

''Note: These criteria were validated for sJIA. For MAS in other settings, the HLH-2004 criteria or HScore may be more appropriate.''

====HLH-2004 Diagnostic Criteria====
Diagnosis requires '''5 of 8''' criteria:<ref name="HLH2004">Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-31.</ref>
#Fever ≥38.5°C
#Splenomegaly
#Cytopenias in ≥2 lineages (Hgb <9 g/dL; platelets <100 × 10⁹/L; neutrophils <1.0 × 10⁹/L)
#Hypertriglyceridemia (fasting ≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL)
#Hemophagocytosis in bone marrow, spleen, or lymph nodes
#Low or absent NK cell activity
#Ferritin ≥500 ng/mL
#Elevated sIL-2R (soluble CD25) ≥2400 U/mL

''Note: HLH-2004 criteria may '''underdiagnose''' MAS in sJIA because baseline inflammatory markers are already elevated in active sJIA''

====HScore====
*A validated scoring system that calculates the probability of reactive HLH/MAS based on clinical and laboratory variables<ref name="Fardet2014">Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613-20.</ref>
*Variables: temperature, organomegaly, number of cytopenias, ferritin, triglycerides, fibrinogen, AST, hemophagocytosis on aspirate, known immunosuppression
*HScore >169 has 93% sensitivity and 86% specificity for HLH
*Available at: [https://www.mdcalc.com/calc/4053/hscore-reactive-hemophagocytic-syndrome MDCalc - HScore]

====Key Laboratory Trends (Most Useful in the ED)====
*'''Ferritin rising rapidly''' (doubling or tripling over hours to days)
*'''Platelet count falling''' (even if still "normal" — a trend from 400 → 200 × 10⁹/L in a patient with sJIA is ominous)
*'''ESR falling while CRP rises''' (paradoxical ESR drop reflects fibrinogen consumption)
*'''Fibrinogen falling'''
*'''AST/ALT rising'''
*'''LDH rising'''

==Management==
''MAS is a medical emergency. Early aggressive treatment reduces mortality. Initiate treatment based on clinical suspicion — do not wait for bone marrow results.''<ref name="Boom2015">Boom V, Anton J, Lahdenne P, et al. Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2015;13:55.</ref>

===Resuscitation and Stabilization===
*'''ABCs:''' Airway, breathing, circulation — patients may present in or rapidly progress to shock
*'''[[IVF]] resuscitation''' for hypotension
*'''[[Vasopressors]]''' if refractory to fluids (see [[Sepsis (Main)]])
*'''Blood products''' as indicated:
**'''[[Platelets]]''' for active bleeding or platelets <10,000/mm³
**'''[[FFP]]''' or '''[[cryoprecipitate]]''' for severe coagulopathy (DIC) with bleeding
**'''[[pRBCs]]''' for symptomatic anemia
*'''Empiric broad-spectrum [[antibiotics]]''' — MAS and [[sepsis]] can coexist and are clinically indistinguishable; treat for sepsis until infection is excluded
*'''Correct [[DIC]]''' if present (see [[DIC]])

===Immunosuppressive Therapy===
''Definitive treatment targets the underlying hyperinflammatory process. Initiate in consultation with rheumatology and/or hematology.''

;First-line:
*'''High-dose IV [[methylprednisolone]]:''' 30 mg/kg/dose IV (max 1g), typically daily for 3 consecutive days, then taper<ref name="Boom2015"/>
**May be given as pulse therapy for fulminant MAS
*'''[[Cyclosporine A]]:''' 2-7 mg/kg/day divided BID (oral or IV); monitor levels and renal function<ref name="Boom2015"/>
**Used in combination with IV steroids, especially in sJIA-associated MAS
*'''[[Anakinra]]''' (IL-1 receptor antagonist): increasingly used as '''first-line''' combination therapy with IV steroids, especially in the United States<ref name="Schulert2024">Schulert GS, Grom AA. Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Childhood Inflammatory Disorders: Diagnosis and Management. Paediatr Drugs. 2020;22(1):29-44.</ref>
**Typical dose: 2-10 mg/kg/day SC or IV (doses higher than standard RA dosing may be needed)
**Advantages: rapid onset, short half-life (allows quick titration), effective even in MAS refractory to steroids
**May be started in the ED or inpatient setting by rheumatology

;Refractory MAS:
*'''Etoposide:''' cytotoxic chemotherapy agent used in HLH-2004 protocol; reserved for refractory cases given risk of myelosuppression
*'''IVIG:''' 2 g/kg over 2-5 days; may be helpful particularly in infection-triggered MAS
*'''Emapalumab''' (anti-IFN-γ): FDA-approved for primary HLH; used off-label in refractory MAS
*'''Ruxolitinib''' (JAK inhibitor): emerging evidence for refractory HLH/MAS
*'''Tocilizumab''' (anti-IL-6): may be used when anakinra is unavailable, though evidence is more limited
*'''Rituximab:''' for EBV-triggered HLH/MAS

===Treat the Underlying Trigger===
*'''Infection:''' aggressive antimicrobial therapy; specific antiviral therapy if EBV, CMV, HSV identified
*'''Malignancy:''' urgent hematology/oncology consultation for chemotherapy
*'''Rheumatic disease flare:''' optimize control of underlying sJIA, SLE, or AOSD

===Monitoring===
*Frequent (q6-12h initially) monitoring of:
**Ferritin ('''most important''' for tracking response)
**CBC with differential (platelet trend)
**Fibrinogen
**AST/ALT, LDH
**Coagulation studies
*Improving trends = response to therapy; worsening trends = consider escalation or alternative diagnosis

===Consultations===
*'''Pediatric rheumatology''' (or adult rheumatology for AOSD/SLE): all patients
*'''Hematology/oncology:''' to rule out malignancy-associated HLH and for consideration of etoposide or bone marrow biopsy
*'''Critical care/ICU:''' most patients with overt MAS require ICU-level monitoring
*'''Infectious disease:''' if infection trigger suspected

==Disposition==
*'''ICU admission''' for nearly all patients with overt MAS:
**Multi-organ dysfunction is common and can progress rapidly
**Continuous hemodynamic monitoring required
**May need ventilatory support ([[ARDS]]), vasopressors, blood product transfusion
*'''Ward admission''' may be appropriate for:
**Subclinical/early MAS identified on labs with stable clinical exam
**Close monitoring with q6-12h lab trending and ability to rapidly escalate to ICU
*'''Do not discharge''' patients with suspected MAS
*Mortality remains 20-40% even with treatment; delay in diagnosis and treatment is the primary driver of mortality<ref name="Carter2019"/>

==See Also==
*[[Juvenile idiopathic arthritis|Systemic JIA]]
*[[Hemophagocytic lymphohistiocytosis]]
*[[Sepsis (Main)]]
*[[DIC]]
*[[Kawasaki disease]]
*[[Adult-onset Still's disease]]
*[[Pericardial effusion and tamponade]]

==External Links==
*[https://www.mdcalc.com/calc/4053/hscore-reactive-hemophagocytic-syndrome MDCalc - HScore for Reactive Hemophagocytic Syndrome]
*[https://emedicine.medscape.com/article/1380671-overview Medscape - Macrophage Activation Syndrome]
*[https://pmc.ncbi.nlm.nih.gov/articles/PMC7334831/ PMC - MAS and Secondary HLH in Childhood Inflammatory Disorders (2020)]

==References==
{{reflist|2}}

[[Category:Rheumatology]]
[[Category:Heme/Onc]]
[[Category:Pediatrics]]
[[Category:Critical Care]]

Macrophage activation syndrome - Revision history

Danbot: Strip excess bold