Diferencia entre revisiones de «Macrophage activation syndrome»
(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...") |
(Strip excess bold) |
||
| Línea 1: | Línea 1: | ||
==Background== | ==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> | *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 | *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 | **"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=== | ===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: | *Other rheumatic diseases: | ||
**[[Adult-onset Still's disease]] (AOSD) | **[[Adult-onset Still's disease]] (AOSD) | ||
| Línea 31: | Línea 31: | ||
===Systemic=== | ===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 | *Profound malaise, rapid clinical deterioration | ||
* | *Paradoxical improvement of arthritis may occur as MAS develops (due to immune exhaustion) | ||
===Organ Involvement=== | ===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) | *'''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=== | ===ED Pearls=== | ||
*In a child with known sJIA, | *In a child with known sJIA, any of the following should prompt evaluation for MAS: | ||
**Fever pattern change from intermittent to continuous | **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 hepatomegaly or transaminitis | ||
**New bleeding or bruising | **New bleeding or bruising | ||
*MAS can be the | *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) | *MAS mimics [[sepsis]] — and the two can coexist (infection is a common MAS trigger) | ||
==Differential Diagnosis== | ==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== | ==Evaluation== | ||
| Línea 74: | Línea 74: | ||
;Hematology: | ;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: | ;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: | ;Coagulation: | ||
* | *Fibrinogen: low or falling (consumed in DIC-like process) — often <150 mg/dL | ||
* | *PT/PTT: prolonged | ||
* | *[[D-dimer]]: elevated | ||
* | *FDP: elevated | ||
;Hepatic: | ;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: | ;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=== | ===Diagnosis=== | ||
| Línea 111: | Línea 111: | ||
====2016 EULAR/ACR/PRINTO Classification Criteria for MAS Complicating sJIA==== | ====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"/> | 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 | **Platelet count ≤181 × 10⁹/L | ||
**AST >48 U/L | **AST >48 U/L | ||
| Línea 120: | Línea 120: | ||
====HLH-2004 Diagnostic Criteria==== | ====HLH-2004 Diagnostic Criteria==== | ||
Diagnosis requires | 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 | #Fever ≥38.5°C | ||
#Splenomegaly | #Splenomegaly | ||
| Línea 130: | Línea 130: | ||
#Elevated sIL-2R (soluble CD25) ≥2400 U/mL | #Elevated sIL-2R (soluble CD25) ≥2400 U/mL | ||
''Note: HLH-2004 criteria may | ''Note: HLH-2004 criteria may underdiagnose MAS in sJIA because baseline inflammatory markers are already elevated in active sJIA'' | ||
====HScore==== | ====HScore==== | ||
| Línea 139: | Línea 139: | ||
====Key Laboratory Trends (Most Useful in the ED)==== | ====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== | ==Management== | ||
| Línea 150: | Línea 150: | ||
===Resuscitation and Stabilization=== | ===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=== | ===Immunosuppressive Therapy=== | ||
| Línea 164: | Línea 164: | ||
;First-line: | ;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 | **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 | **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> | *'''[[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> | ||
| Línea 174: | Línea 174: | ||
;Refractory MAS: | ;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=== | ===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=== | ===Monitoring=== | ||
*Frequent (q6-12h initially) monitoring of: | *Frequent (q6-12h initially) monitoring of: | ||
**Ferritin ( | **Ferritin (most important for tracking response) | ||
**CBC with differential (platelet trend) | **CBC with differential (platelet trend) | ||
**Fibrinogen | **Fibrinogen | ||
| Línea 196: | Línea 196: | ||
===Consultations=== | ===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== | ==Disposition== | ||
* | *ICU admission for nearly all patients with overt MAS: | ||
**Multi-organ dysfunction is common and can progress rapidly | **Multi-organ dysfunction is common and can progress rapidly | ||
**Continuous hemodynamic monitoring required | **Continuous hemodynamic monitoring required | ||
**May need ventilatory support ([[ARDS]]), vasopressors, blood product transfusion | **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 | **Subclinical/early MAS identified on labs with stable clinical exam | ||
**Close monitoring with q6-12h lab trending and ability to rapidly escalate to ICU | **Close monitoring with q6-12h lab trending and ability to rapidly escalate to ICU | ||
Revisión actual - 09:28 22 mar 2026
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[1]
- MAS is a form of secondary hemophagocytic lymphohistiocytosis (HLH) occurring in the context of rheumatic disease[2]
- "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[2]
- Underdiagnosed — frequently confused with sepsis, disease flare of the underlying rheumatic condition, or drug side effects[3]
Triggers and Associations
- Most commonly associated with systemic juvenile idiopathic arthritis (sJIA) — ~10% overt MAS, up to 30-40% subclinical[4]
- 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):
- 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[1]
- 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[5]
- MAS mimics sepsis — and the two can coexist (infection is a common MAS trigger)
Differential Diagnosis
- 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[1]
- 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[6]
- 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)[3]
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:[1]
- 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:[7]
- 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[8]
- 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: 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.[9]
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[9]
- 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[9]
- 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[10]
- 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[2]
See Also
- Systemic JIA
- Hemophagocytic lymphohistiocytosis
- Sepsis (Main)
- DIC
- Kawasaki disease
- Adult-onset Still's disease
- Pericardial effusion and tamponade
External Links
- MDCalc - HScore for Reactive Hemophagocytic Syndrome
- Medscape - Macrophage Activation Syndrome
- PMC - MAS and Secondary HLH in Childhood Inflammatory Disorders (2020)
References
- ↑ 1.0 1.1 1.2 1.3 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.
- ↑ 2.0 2.1 2.2 Carter SJ, Tattersall RS, Ramanan AV. Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatology. 2019;58(1):5-17.
- ↑ 3.0 3.1 Macrophage activation syndrome: A diagnostic challenge (Review). Exp Ther Med. 2021;22(3):904.
- ↑ Schulert GS, Grom AA. Macrophage Activation Syndrome and Cytokine-Directed Therapies. Best Pract Res Clin Rheumatol. 2014;28(2):277-92.
- ↑ Spoorthy Raj DR, Suma Balan. Systemic Juvenile Idiopathic Arthritis: The Challenges and Opportunities. Indian J Rheumatol. 2024.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 9.0 9.1 9.2 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.
- ↑ 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.