Hemophagocytic Lymphohistiocytosis (HLH) in Children

Topic Name Introduction Epidemiology Pathophysiology Clinical Presentation Diagnosis Treatment Prognosis

Introduction to Hemophagocytic Lymphohistiocytosis (HLH) in Children

Hemophagocytic Lymphohistiocytosis (HLH) is a rare, life-threatening syndrome of excessive immune activation. It is characterized by fever, hepatosplenomegaly, cytopenias, and hemophagocytosis in bone marrow, liver, or lymph nodes. HLH can occur as a familial (primary) or acquired (secondary) disorder.

Key Points:

• HLH is a severe hyperinflammatory condition caused by uncontrolled proliferation of activated lymphocytes and macrophages.
• It can be primary (genetic) or secondary (triggered by infections, malignancies, or rheumatologic conditions).
• Clinical features include persistent fever, hepatosplenomegaly, cytopenias, and often neurological symptoms.
• Diagnosis is based on specific clinical and laboratory criteria (HLH-2004 diagnostic criteria).
• Prompt recognition and treatment are crucial, as HLH can be rapidly fatal if left untreated.
• Treatment typically involves immunosuppressive and cytotoxic therapies, with hematopoietic stem cell transplantation for primary HLH.

Epidemiology

HLH is a rare disorder, but its exact incidence is difficult to determine due to underdiagnosis and variable presentation:

• Incidence of primary HLH: Estimated at 1 in 50,000 to 1 in 100,000 live births
• Age of onset:
  • Primary HLH: Usually presents in infancy or early childhood (80% in the first year of life)
  • Secondary HLH: Can occur at any age, including in adults
• Gender: No significant gender predilection
• Geographical variation: Higher incidence of familial HLH reported in Turkey, Japan, and Sweden
• Ethnic predisposition: Certain genetic mutations are more common in specific ethnic groups (e.g., PRF1 mutations in Turkish and Japanese populations)

Pathophysiology

The pathophysiology of HLH involves a dysregulated immune response leading to hyperinflammation:

• Primary HLH:
  • Genetic defects affecting lymphocyte cytotoxicity (e.g., PRF1, UNC13D, STX11, STXBP2 mutations)
  • Impaired natural killer (NK) cell and cytotoxic T lymphocyte (CTL) function
• Secondary HLH:
  • Triggered by infections (especially viral), malignancies, or rheumatologic conditions
  • Underlying genetic susceptibility may be present in some cases
• Key pathophysiological features:
  • Defective clearance of antigens leads to persistent T-cell activation
  • Excessive production of inflammatory cytokines (cytokine storm)
  • Uncontrolled activation and proliferation of macrophages
  • Hemophagocytosis: Activated macrophages engulf blood cells and their precursors

Clinical Presentation

The clinical presentation of HLH can be variable and nonspecific, often mimicking other conditions:

• Constitutional symptoms:
  • Persistent high fever (typically >38.5°C for >7 days)
  • Fatigue and malaise
• Hepatosplenomegaly: Present in 95% of cases
• Lymphadenopathy: Common but not universal
• Skin manifestations:
  • Maculopapular rash
  • Erythroderma
  • Petechiae or purpura
• Neurological symptoms (50-75% of cases):
  • Seizures
  • Altered mental status
  • Ataxia
  • Cranial nerve palsies
• Respiratory symptoms:
  • Cough
  • Dyspnea
  • Acute respiratory distress syndrome (ARDS)
• Gastrointestinal symptoms:
  • Diarrhea
  • Vomiting
  • Abdominal pain
• Laboratory findings:
  • Cytopenias (affecting at least two cell lines)
  • Elevated liver enzymes and bilirubin
  • Hypertriglyceridemia
  • Hypofibrinogenemia
  • Hyperferritinemia (>500 ng/mL, often >3000 ng/mL)

Diagnosis

Diagnosis of HLH is based on the HLH-2004 diagnostic criteria. Either molecular diagnosis or clinical criteria can establish the diagnosis:

Molecular Diagnosis:

• Pathogenic mutations in HLH-associated genes (e.g., PRF1, UNC13D, STX11, STXBP2)

Clinical Criteria (5 out of 8 required):

1. Fever ≥38.5°C
2. Splenomegaly
3. Cytopenias affecting at least 2 cell lines:
   • Hemoglobin <9 g/dL
   • Platelets <100,000/μL
   • Neutrophils <1,000/μL
4. Hypertriglyceridemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenemia (fibrinogen <150 mg/dL)
5. Hemophagocytosis in bone marrow, spleen, lymph node, or liver
6. Low or absent NK cell activity
7. Ferritin >500 ng/mL
8. Elevated soluble CD25 (soluble IL-2 receptor) ≥2,400 U/mL

Additional Diagnostic Workup:

• Bone marrow aspiration and biopsy
• Lumbar puncture (if neurological symptoms present)
• Imaging studies: CT or MRI of chest, abdomen, and brain
• Genetic testing for primary HLH-associated mutations
• Screening for underlying triggers (infections, malignancies, rheumatologic conditions)

Treatment

Treatment of HLH is aimed at suppressing the hyperinflammatory state and addressing any underlying triggers. The HLH-2004 protocol is widely used for initial management:

Initial Therapy (8-week induction):

• Etoposide and dexamethasone backbone
• Cyclosporine A (started at week 9 if evidence of active disease)
• Intrathecal methotrexate for patients with CNS involvement

Continuation Therapy:

• Continued until hematopoietic stem cell transplantation (HSCT) is available for primary HLH
• May be weaned in secondary HLH if disease is controlled and trigger addressed

Hematopoietic Stem Cell Transplantation (HSCT):

• Definitive treatment for primary HLH
• Considered in severe or persistent secondary HLH

Emerging Therapies:

• Alemtuzumab: Anti-CD52 monoclonal antibody
• Emapalumab: Anti-IFNγ monoclonal antibody (FDA-approved for primary HLH)
• JAK inhibitors (e.g., ruxolitinib)

Supportive Care:

• Treatment of underlying triggers (e.g., antimicrobials for infections)
• Blood product support
• Management of organ dysfunction
• Prophylaxis against opportunistic infections

Prognosis

The prognosis of HLH has improved with advances in treatment, but it remains a severe condition with significant mortality:

• Primary HLH:
  • Without treatment: Nearly 100% mortality
  • With HLH-2004 protocol and HSCT: 5-year overall survival of 60-70%
• Secondary HLH:
  • Variable prognosis depending on the underlying trigger and response to treatment
  • Mortality rates of 20-88% reported in various studies
• Prognostic factors:
  • Age at onset (younger age associated with poorer prognosis in primary HLH)
  • Presence of neurological involvement
  • Time to diagnosis and initiation of treatment
  • Response to initial therapy
• Long-term complications:
  • Neurological sequelae (in patients with CNS involvement)
  • Growth and developmental delays
  • Secondary malignancies (particularly in patients who undergo HSCT)

Early recognition, prompt initiation of treatment, and comprehensive supportive care are crucial for improving outcomes in children with HLH.

Hemophagocytic Lymphohistiocytosis (HLH) in Children

1. What is Hemophagocytic Lymphohistiocytosis (HLH)?
   A severe systemic inflammatory syndrome characterized by excessive immune activation and tissue damage
2. What are the two main types of HLH?
   Primary (familial) HLH and secondary (acquired) HLH
3. What is the typical age of onset for primary HLH in children?
   Usually within the first year of life, but can occur at any age
4. What genetic mutations are commonly associated with primary HLH?
   PRF1, UNC13D, STX11, and STXBP2 genes
5. What are common triggers for secondary HLH in children?
   Infections (especially viral), malignancies, and rheumatologic disorders
6. What virus is most commonly associated with HLH in children?
   Epstein-Barr virus (EBV)
7. What are the key clinical features of HLH?
   Fever, hepatosplenomegaly, cytopenias, and neurological symptoms
8. What is the significance of ferritin levels in HLH diagnosis?
   Extremely elevated ferritin (>10,000 ng/mL) is highly suggestive of HLH
9. What is the characteristic finding in bone marrow aspiration in HLH?
   Hemophagocytosis (macrophages engulfing other blood cells)
10. What are the HLH-2004 diagnostic criteria?
    A set of 8 criteria, of which 5 must be met for diagnosis, including fever, splenomegaly, cytopenias, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low/absent NK cell activity, elevated ferritin, and high soluble CD25
11. What is the role of NK cell function testing in HLH diagnosis?
    Decreased or absent NK cell activity is a diagnostic criterion and can help distinguish primary from secondary HLH
12. What is the significance of soluble CD25 (sIL-2R) levels in HLH?
    Elevated levels indicate T-cell activation and are part of the diagnostic criteria
13. What is the first-line treatment for HLH?
    Immunosuppressive therapy with dexamethasone and etoposide, as per HLH-2004 protocol
14. What is the role of cyclosporine in HLH treatment?
    Used as part of the HLH-2004 protocol to maintain immunosuppression
15. What is the definitive treatment for primary HLH?
    Allogeneic hematopoietic stem cell transplantation (HSCT)
16. How is CNS involvement in HLH treated?
    Intrathecal methotrexate and hydrocortisone, in addition to systemic therapy
17. What is the role of IVIG in HLH treatment?
    Can be used as adjunctive therapy, especially in infection-associated HLH
18. What is the prognosis for children with HLH?
    Generally poor without treatment, but survival rates have improved to 60-70% with current protocols
19. How does HLH differ from Macrophage Activation Syndrome (MAS)?
    MAS is considered a subtype of secondary HLH associated with rheumatologic conditions, particularly systemic juvenile idiopathic arthritis
20. What is the role of anakinra in treating HLH?
    Used in some cases of secondary HLH, particularly MAS, due to its IL-1 inhibition
21. What is the significance of fibrinogen levels in HLH?
    Low fibrinogen (<150 mg/dL) is part of the diagnostic criteria and indicates consumption coagulopathy
22. How does HLH affect the liver?
    Can cause hepatitis, cholestasis, and acute liver failure
23. What is the role of genetic testing in HLH diagnosis?
    Confirms primary HLH and identifies specific mutations, guiding treatment and family counseling
24. How does HLH affect the central nervous system?
    Can cause seizures, ataxia, cranial nerve palsies, and altered mental status
25. What is the significance of sCD163 in HLH?
    Elevated levels indicate macrophage activation and may be used as a biomarker for diagnosis and monitoring
26. How does HLH affect the lungs?
    Can cause acute respiratory distress syndrome (ARDS) and pulmonary hemorrhage
27. What is the role of alemtuzumab in HLH treatment?
    Used as salvage therapy for refractory HLH cases
28. How does HLH affect the kidneys?
    Can cause acute kidney injury and tubular dysfunction
29. What is the significance of perforin staining in HLH diagnosis?
    Absent or decreased perforin staining in NK cells suggests primary HLH due to PRF1 mutations
30. How does HLH affect the cardiovascular system?
    Can cause myocarditis, pericardial effusion, and vascular leak syndrome

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