Management Guide for Hemophagocytic Syndrome (HHS) in Pediatrics

What is Hemophagocytic Syndrome?

Hemophagocytic Lymphohistiocytosis Syndrome (HHS or HLH) is a life-threatening, hyperinflammatory disorder characterized by uncontrolled and dysfunctional activation of the immune system. Immune cells (T lymphocytes and macrophages) are massively activated, infiltrate organs and secrete large amounts of cytokines, leading to a "cytokine storm" state that causes high fever, cytopenias and severe organ damage.

Diagnostic Suspect

Suspect HHS in any child with unexplained prolonged fever and cytopenias. Actively look for the following signs:

✓Persistent fever (>38.5°C)

✓Hepato-splenomegaly

✓Cytopenias (affecting ≥2 of 3 cell lines)

✓Neurological symptoms (irritability, seizures, altered state of consciousness)

✓Skin rash, edema, jaundice

✓Lymphadenopathy

Studies and Diagnostic Criteria

Laboratory Tests to Request

Complete blood count with peripheral blood smear.

Blood biochemistry: Liver profile (transaminases, bilirubins, GGT, LDH), renal profile, triglycerides, fibrinogen.

Inflammatory markers: Ferritin, ESR, CRP.

Coagulation studies: TP, TPT, D-Dimer.

Specific immunological studies: Soluble IL-2 receptor (sCD25), NK cell activity.

Bone marrow study: Aspirate and biopsy to look for hemophagocytosis.

Diagnostic Criteria (HLH-2004) - 5 of 8 must be met

1. Fever: ≥ 38.5°C

2. Splenomegaly

3. Cytopenias (affecting ≥2 lines): Hb < 9 g/dL, Platelets < 100,000/μL, Neutrophils < 1,000/μL.

4. Hypertriglyceridemia and/or Hypofibrinogenemia: Fasting triglycerides > 265 mg/dL, Fibrinogen < 150 mg/dL.

5. Hemophagocytosis: In bone marrow, spleen, lymph nodes or CSF.

6. Low or no NK cell activity

7. Ferritin: >500 ng/mL (often >3,000 or >10,000).

8. Elevated levels of sCD25 (soluble IL-2 receptor)

Note: Molecular diagnosis (mutations in PRF1, UNC13D genes, etc.) confirms familial SHH.

Initial Treatment and Reevaluation

Treatment Protocol (based on HLH-94/2004)

Treatment should be started immediately once suspicion is high, even without meeting all 5 criteria, given the rapid progression of the disease. The goal is to suppress hyperinflammation.

Drug	Dosage and Route	Frequency
Dexamethasone	10 mg/m²/day IV or PO	Weeks 1-2, then taper over 8 weeks
Etoposide (VP-16)	150 mg/m²/dose IV	Twice/week for 2 weeks, then weekly for 6 weeks
Cyclosporin A	3-6 mg/kg/day PO or IV	Maintain levels of 150-250 ng/mL

Reassessment and Monitoring

Evaluate clinical and laboratory response at 2 weeks of starting the treatment. Weekly monitoring of blood count, ferritin, fibrinogen, triglycerides and liver function. Lack of improvement or worsening requires escalation of treatment.

Lack of Improvement and Second Line

If there is no response after 2-4 weeks or there is progression, consider refractory HHS. Options include:

Alemtuzumab (anti-CD52): 1 mg/kg/day for 5 days. Consider prophylaxis for PJP and CMV.
Antithymocyte Globulin (ATG): T cell depletion therapy.
JAK inhibitors (e.g. ruxolitinib): Useful in HHS secondary to rheumatological causes.
Emapalumab (anti-interferon gamma): Approved for primary refractory, recurrent or progressive HHS.
Hematopoietic Stem Cell Transplantation (HSCT): The only curative treatment for familial HHS or severe refractory forms. It must be planned early.

Multidisciplinary Management

Nephrology

When to refer? Urgent in case of Acute Kidney Injury (AKI), fluid overload, severe electrolyte alterations (hyponatremia, hyperkalemia), or difficult-to-control arterial hypertension.

Management by Nephrology:

Strict management of fluids and electrolytes.
Dose adjustment of nephrotoxic drugs (e.g. Ciclosporin).
Consider Renal Replacement Therapy (RRT) if there is severe AKI, anuria, or volume overload refractory to diuretics. Hemodialysis or continuous hemofiltration (CRRT) are the preferred modalities.

Hematology-Oncology

Immediate reference. They lead the management, administer chemotherapy, coordinate the bone marrow study and plan the HSCT.

Immunology/Rheumatology

Essential to look for underlying causes: familial HHS (primary immunodeficiencies) or secondary HHS (Macrophage Activation Syndrome in the context of autoimmune diseases such as Systemic Juvenile Idiopathic Arthritis).

Intensive Care (ICU)

Necessary in patients with hemodynamic instability, respiratory failure, severe coagulopathy or acute neurological deterioration.

Recommendations for Parents

To do

✔Maintain open and constant communication with the medical team.
✔Ensure strict hygiene (hand washing) to prevent infections.
✔Monitor for fever, bleeding (gums, nose, bruising), or behavioral changes and report immediately.
✔Ask about psychological support for you and your child. It is a very stressful process.

WHAT NOT TO DO

✘Administer medications (not even for fever such as paracetamol or ibuprofen) without consulting the doctor.
✘Exposing the child to crowds or sick people due to immunosuppression.
✘Hesitating to seek help or clarify doubts. There are no stupid questions when it comes to your child's health.
✘Ignore your own well-being. Taking care of yourself allows you to better care for your child.

Final Evaluation

Literature

Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131.
Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-4052.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-2477.
Bergsten E, Horne A, Aricó M, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-2738.