Updated on: 20.08.2026

Introduction:

• It is an aggressive and potentially fatal hyperinflammatory syndrome that results from inappropriate prolonged activation of lymphocytes and macrophages.
• It is also called as macrophage activation syndrome. Some authorities consider MAS as a separate disease entity which is associated with juvenile rheumatoid arthritis.

Epidemiology:

• 1.2/1million children/ year
• Common in infants from birth to 18 months of age

Etiology:

• Primary/ Familial HLH (Most are autosomal recessive)
  • Mutations in any one of following genes

• Granzyme B
• GATA2 
• LYST (Chediak Higashi syndrome)
• RAB27A (Griscelli syndrome)
• SH2DIA (X linked proliferative disease)
• AP3B1 (HermanskyPudlak disease)
  • Autosomal recessive inheritance
  • Bouts of disease are triggered by infections
  • Invariably fatal disease with median survival of <2months
  • Need initial/continuation therapy, followed by HSCT
• Secondary:
  • Generally, occurs due to
    • Severe infections- Bacteria, mycobacterium, virus (EBV, CMV. HHV-8, HIV, dengue), fungal, and histoplasma, Parasites
    • Immunocompromised host with viral infection
    • Autoimmune disorders- Also called as macrophage activation syndrome
    • Prolonged IV nutrition
    • Leukemia, lymphoma (ALCL, NK lymphomas, DLBCL), Solid tumors
    • Post splenectomy
    • Therapy related: CAR T cells, bi-specific T-cell engager antibodies, and checkpoint
    • inhibitors
  • It may subside spontaneously, but is associated with pronounced mortality
  • Some have impaired NK cell activity
  • Need initial therapy only and treatment of primary disease

Pathogenesis:

• Normally, NK and cytotoxic T cells kill virus infected cell or cancer-transformed cell by inducing apoptosis through perforin–granzyme cell-death pathway
• In HLH,

1.

Defect in the function of NK cells and cytotoxic T cells

↓

Inappropriate activation of T cells and macrophages

↓

Release of proinflammatory cytokines

(Interferon gamma, TNF alpha, IL6, IL10, IL12, soluble IL2 receptor alpha)

+

Hemophagocytosis, tissue infiltration and damage

↓

Multi-organ dysfunction

↓

Death

2.

Lack of perforin

↓

Lack of killing of macrophages and antigen presenting cells by NK cells

↓

Intense and prolonged systemic inflammation

Clinical Features:

• Fever
• Hepatosplenomegaly
• Cytopenia
• Lymphadenopathy
• Skin rash
• Jaundice
• Edema
• CNS manifestations (seen in 1/3^rd of patients)- Seizures, meningismus, decreased consciousness, cranial nerve palsy, psychomotor retardation, ataxia, irritability, hypotonia
• Bleeding due to DIC and hypofibrinogenemia
• Family history of HLH
• H/O consanguinity

Investigations:

• Hemogram- Anemia, neutropenia, thrombocytopenia
• S. Triglyceride levels- Elevated
• Coagulation assay- Decreased fibrinogen due to increased plasminogen secretion from macrophages
• LFT- Deranged with elevated levels of aminotransferases and γ-glutamyl transferase and hyperbilirubinemia, predominantly conjugated
• LDH- Elevated
• Ferritin- Elevated
• CSF- moderately increased lymphocyte count or protein content
• MRI: Diffuse, multifocal white-matter lesions and cerebellar involvement. PRESS changes in some.
• NK cell cytotoxic activity- Decreased
• BM aspiration
  • Hemophagocytosis is seen in 1/3^rd of cases
  • Accumulation of lymphocytes and mature macrophages is noted
  • If not seen, BM can be repeated after few days
  • Finding hemophagocytosis is highly suggestive of HLH, but is neither necessary nor sufficient to make the diagnosis
  • Hypoplasia noted in late cases
• S. Cytokine levels- Elevated soluble IL-2 receptor, CD163
• Electrolytes- Hyponatremia
• MRI- Discrete lesions, leptomeningial involvement, global edema
• Molecular tests for genetic mutations
• Flow cytometry- To detect presence of perforin
• Liver biopsy: Infiltration in the portal tract, resembling chronic, persistent hepatitis
• Flow cytometry: Increased CD38/HLA-DR bright CD8+ T cells

HLH-2024 Criteria for Diagnosis:

• If a molecular diagnosis is consistent with HLH, it is enough for diagnosis of HLH
• If molecular diagnosis if negative/ not possible- at least 5 out of 7 criteria have to be present for diagnosis of HLH
  • Fever (≥38.5°C)
  • Splenomegaly (≥2 cm below costal margin)
  • Cytopenia affecting >1 cell lineage (Hb<9gm/dL, ANC- <1000/cmm, Platelets <1lac/cmm)
  • Fasting Triglyceride >265mg/dL or Fibrinogen <1.5g/L
  • Hemophagocytosis in BM or lymph node with no evidence of malignancy
  • Ferritin >500microgm/L
  • Soluble CD25 (i.e- soluble IL-2 receptor)- >2400 U/ml
• Diagnostic criteria may not be fulfilled in some patients. But if there is strong clinical suspicion of HLH, therapy should be commenced. Otherwise, overwhelming disease activity may cause irreversible damage.

H-Score for diagnosis of reactive HLH:

(>169 points is the optimal diagnostic threshold for HLH)

Criteria for diagnosis of macrophage activation syndrome (Any 2 Lab criteria and any 2 clinical criteria, with hemophagocytosis demonstrated in BM in doubtful cases):

• Laboratory criteria
  • Platelet count <2.62lac/cmm
  • Increased SGPT- >59 IU/L
  • Decreased TLC- <4000/cmm
  • Decreased fibrinogen- <250mg/dL
• Clinical criteria
  • CNS dysfunction- Irritability, lethargy, disorientation, headache, seizures, coma
  • Haemorrhages- Purpura, mucosal bleed
  • Hepatomegaly- >3cm below subcostal margin

Prognosis:Predictors of death

• Increased ferritin
• Increased bilirubin
• Decreased albumin
• CSF pleocytosis
• Non-subsiding fever

Differential Diagnosis:

• Langerhan cell histiocytosis
• X linked lymphoproliferative syndrome
• Chediak Higashi syndrome
• Griscelli syndrome
• Lysinuric protein intolerance
• SCID
• Digeorge syndrome with HLH
• Omenn syndrome
• Infections causing pancytopenia
• Rheumatological disorders- Kawasaki disease, SLE, RA
• Malignancies- Lymphoma, leukemia

Pretreatment Work-up:

• History
• Examination
• Haemoglobin
• TLC, DLC
• Platelet count
• Peripheral smear
• Reticulocyte count
• BMA and Bx
• FNA of enlarged LN
• Coagulation Profile: PT:           APPT:          Fibrinogen:
• LFT: Bili- T/D       SGPT:       SGOT:Albumin:       Globulin:
• Ferritin: 
• Fasting TG:
• Soluble IL2 receptors, NK- cell activity- If available
• Molecular test for potentially HLH-associated genes
• Creatinine
• Electrolytes: Na:    K:    Ca:Mg:     PO4:
• LDH
• S. Immunoglobulins: IgG:       IgM:       IgA:
• CSF Routine + Cytology
• Investigations for infections (PCR)
  • CMV:                        EBV:                        HSV:                    HHV6:
  • COVID-19:
  • Rubella:                   Varicella:                 Parvo:                Adeno:
  • Leishmania:             Brucella:                 Mycoplasma:          TB:
  • HIV:                          HBsAg:                                 HCV:
• Molecular tests
  • Perforin:                                        hMunc:
• USG- Abdomen
• Chest X Ray
• PET CT with Guided biopsy in cases with suspicion of malignancy associated HLH
• MRI- Brain(If CNS Symptoms)
• HLA Typing (For HSCT eligible pt)
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• Fertility preservation
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment Plan:

• Familial HLH and HLH in less than 18years old- Follow HLH 2004 protocol
• MAS-HLH.
  • IV methylprednisolone- 30 mg per kilogram per dose (maximum, 1000 mg per dose) once daily for 3 to 5 days, followed by oral or intravenous glucocorticoids.
  • Cyclosporine, given at a dose of 2 to 7 mg per kilogram per day (trough value, 100 to 150 μg per liter), can be added. 
  • Anakinra- 2 to 10 mg per kilogram per day also may be added
  • If no response: 
    • one or few moderate weekly doses of etoposide (50-100mg/m2)
    • Emapalumab may be considered
• CART therapy associated HLH: 
  • Anakinra with or without glucocorticoids
  • 2^nd line therapies include: tocilizumab, ruxolitinib, emapalumab, and low-dose etoposide
• All others with moderate disease- Steroids +/- IVIg with treatment of cause initially is sufficient. If no response/ severe disease at diagnosis, HLH 2004 protocol may be given.
• For EBV triggered HLH- Add Rituximab
• In addition to HLH treatment, all treatable infections must be treated.
• Underlying malignancies also must be treated preferably with Etoposide augmented chemotherapies.
• Where indicated, HSCT should be performed as early as possible.
• If it is macrophage activation syndrome/ HLH due to rheumatological disorders: Initial high dose steroids (Methylprednisolone- 2-3mg/kg/day- in 4 divided doses) followed by Cyclosporine A. If no response treat with HLH protocol containing Etoposide. Etanercept and infliximab have also been found to be useful.

Response Criteria:

• No fever
• Reduction in spleen size
• Platelets >1lac/cmm
• Normal fibrinogen
• Decreasing ferritin levels (by 25%)

About Each Modality of Treatment:

• Initial therapy (for 8 weeks)
  • Aims
    • Keep the patient alive
    • Reduce the number and degree of permanent complications during the initial critical period.
    • Achieve resolution of disease
  • Inj. Etoposide
    • 1^st and 2^nd week - 150mg/m2- IV- Twice weekly
    • 3^rd to 8^th week- 150mg/m2- IV- Once a week
    • Age adjusted doses:
      • 100 mg/m2 for adolescents and young adults
      • 75 mg/m2for adults
      • 50 mg/m2for older adults.
  • Dexamethasone (Oral/IV)
    • 1^st and 2^nd week- 10mg/m2/day
    • 3^rd and 4^th week- 5 mg/m2/day
    • 5^th and 6^th week- 2.5 mg/m2/day
    • 7^th week 1.25 mg/m2/day
    • 8^th week- Taper and stop
  • Cap. Cyclosporine A
    • Start with 3mg/kg- BD- Then adjust the dose to maintain trough levels around 200microgm/L
  • Triple IT- 2 doses- 4 weeks apart
• Continuation therapy
  • Aim: Sustain the resolution of disease
  • Inj. Etoposide- 150mg/m2- IV- Every 2^nd week
  • Tab. Dexamethasone- 10mg/m2 for 3 days- Every 2^nd week
  • Cap. Cyclosporine A- With target trough levels around 200 microgm/L
• Stem cell transplantation
  • Indications:
    • Homozygous or compound heterozygous HLH gene mutations
    • Lack of response to initial HLH therapy
    • Central nervous system (CNS) involvement
    • Hematologic malignancy
  • If matched sibling donor is not available, haplo identical transplantation has to be considered
  • Check whether donor carries HLH mutation
  • A complete remission before HSCT is beneficial but not mandatory
  • Conditioning should preferably include- Etoposide, Busulfan, and Cyclophosphamide.
  • If unrelated transplant, use ATG.
  • GVHD prophylaxis: Cyclosporine and Methotrexate 

Supportive Care:

• Broad spectrum antibiotics
• Aggressive transfusion support
• Prophylactic co-trimoxazole
• Oral antimycotic
• Antiviral- Acyclovir
• IVIG- 0.5mg/kg- IV- Once in every 4 weeks (During initial and continuation therapy)

Monitoring After Treatment/ Follow-up:

• Once a month for 3-4 months, then once in 3 months for 2 years
• Monitor- Fever, hepatosplenomegaly, neurological abnormalities
• Hemogram, ferritin, transaminases

Other treatment options:

• Anakinra (IL1 receptor antagonist)
• Emapalumab (monoclonal antibody against IFN-gamma)
• Ruxolitinib

Recent advances:

Ruxolitinib-based regimen in children with primary hemophagocyticlymphohistiocytosis

The study aimed to evaluate the effectiveness and safety of a ruxolitinib (RUX)-based regimen as a bridge to hematopoietic stem cell transplantation (HSCT) in children with primary hemophagocyticlymphohistiocytosis (pHLH). Patients received RUX until HSCT or unacceptable toxic side-effects, with methylprednisolone and etoposide added sequentially if the disease was suboptimally controlled. The primary endpoint was 1-year overall survival. Results showed that 90.5% of patients achieved a complete response within the first 8 weeks, and 81.0% were alive at the last follow-up, with a 1-year overall survival of 90.5%. Most patients tolerated the RUX-based regimen well, with hematologic adverse events being the most frequently observed. 

https://doi.org/10.3324/haematol.2023.283478

Etoposide improves survival in primary hemophagocyticlymphohistiocytosis

In a study of 88 patients with primary hemophagocyticlymphohistiocytosis (pHLH) from 2016 to 2021, first-line etoposide-based therapy was administered to 86% of symptomatic patients, leading to improved survival rates compared to previous studies. Hematopoietic stem cell transplantation (HSCT) was performed in 75 patients, with a 3-year probability of survival of 82% for the entire cohort and 77% for those receiving first-line etoposide. Survival rates pre- and post-HSCT improved compared to previous studies, attributed to reduced-toxicity conditioning and shorter time from diagnosis to HSCT. Notably, early HSCT for asymptomatic patients resulted in 100% survival, highlighting the potential benefit of newborn screening for pHLH.

https://doi.org/10.1182/blood.2023022281

The effectiveness of the doxorubicin-etoposide-methylprednisolone regimen for adult HLH secondary to rheumatic disease

This retrospective study evaluated the efficacy of the doxorubicin-etoposide-methylprednisolone (DEP) regimen in 58 adult patients with hemophagocyticlymphohistiocytosis (HLH) secondary to rheumatic disease. The overall response rate was 82.8%, with 13.8% achieving complete response and 69% partial response. Serum markers such as ferritin, sCD25, ALT, AST, and DBIL significantly decreased over time. The mortality rate was 20.7%, and poor prognosis factors included advanced age, low hemoglobin and platelet counts, and CNS involvement. The DEP regimen showed high efficacy with acceptable side effects in this patient population.

https://doi.org/10.1007/s00277-024-05796-8

Emapalumab therapy for hemophagocyticlymphohistiocytosis before reduced-intensity transplantation improves chimerism

This retrospective study highlights the benefits of emapalumab, an anti–IFN-γ antibody, in improving post-HSCT outcomes for pediatric hemophagocyticlymphohistiocytosis (HLH) patients undergoing reduced-intensity conditioning (RIC) HSCT. Among 50 patients, emapalumab use within 21 days before conditioning was associated with significantly lower rates of mixed chimerism (48% vs. 77%) and severe mixed chimerism (5% vs. 38%). Furthermore, intervention-free survival (IFS) was significantly improved with emapalumab (73% vs. 43%), particularly in infants aged <12 months, a high-risk group (75% vs. 20%). While overall survival was higher in the emapalumab group (82% vs. 71%), the difference was not statistically significant. These findings suggest that emapalumab effectively reduces graft failure risk and enhances IFS, making it a valuable adjunct in managing HLH before RIC-HSCT.

https://doi.org/10.1182/blood.2024025977

Figures:

Figure 11.2.1- Hemophagocytosis in bone marrow