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Primary and Secondary Hemophagocytic Lymphohistiocytosis

Chapter 68 | Harrison's 22e · Part 2 – Cardinal Manifestations & Presentation · Chapter 68

Key Clinical Points

  1. HLH is a highly life-threatening condition of massive, uncontrolled inflammation (hyperinflammation).
  2. It exists in two forms: Primary (genetic/Mendelian) and Secondary (acquired).
  3. Primary HLH (e.g., FHL) is often fatal if not treated promptly, with a median survival of 1–2 months.
  4. Clinical presentation typically includes fever, cytopenias (especially thrombocytopenia), and hepatosplenomegaly.
  5. Bicytopenia (affecting at least two of the three lineages: anemia, neutropenia, and thrombocytopenia) is a diagnostic criterion.
  6. Ferritin serves as a rapid, easily available screening test for HLH, though it is not specific.
  7. sIL-2R (sCD25) serves as a biomarker to monitor the severity of HLH.
  8. CNS involvement occurs in approximately one-third of children with FHL; prompt treatment is essential to prevent permanent neurological sequelae.
  9. Primary HLH predominantly affects children, while Secondary HLH is more common in adults.
  10. Hemophagocytosis is not always present in early stages, necessitating serial bone marrow examinations.

DEFINITION & CLASSIFICATION

• Definition: A highly life-threatening condition of massive, uncontrolled inflammation (hyperinflammation). • Primary HLH (Mendelian Conditions): ◦ Lymphocyte cytotoxic defects: ◦ FHL2 (PRF1) ◦ FHL3 (UNC13D) — often associated with extremely low platelet levels. ◦ FHL4 (STX11) ◦ FHL5 (STXBP2) — may cause severe gastrointestinal symptoms/diarrhea persisting despite HSCT. ◦ XLP1 (SH2D1A) ◦ Griscelli syndrome type 2 (RAB27A) ◦ Chédiak-Higashi syndrome (LYST) ◦ Abnormalities of inflammasome activation: ◦ XLP2 (BIRC4) ◦ NLRC4 ◦ Mendelian disorders affecting inflammation: ◦ Lysinuric protein intolerance (SLC7A7) ◦ Wolman disease (LIPA) • Secondary HLH (Non-Mendelian): ◦ Infection-associated: Virus, Bacteria, Parasite, and Fungal. ◦ Malignancy-related: Malignancy-associated or malignancy-triggered; also includes cases occurring during chemotherapy. ◦ Autoimmune-associated (MAS-HLH): Includes HLH with SoJIA, adult-onset Still’s disease, SLE, vasculitis, and transplant-associated HLH.

EPIDEMIOLOGY

• FHL Incidence: Estimated at 1 in 50,000 live births. • Demographics: ◦ Primary HLH: Mostly affects children; median age of onset is between 3 and 6 months (can be diagnosed in utero or during adolescence/adulthood). ◦ Secondary HLH: Far more common in adults. • Genetics: FHL is autosomal recessive; it is equally common in males and females, but more frequent in regions with high rates of consanguinity.

ETIOLOGY & PATHOPHYISIOLOGY

• Molecular Basis (Figure 1): ◦ Mutations impair the cytotoxic machinery of T lymphocytes at specific steps: granule content, docking, priming, or fusion. ◦ Specific genetic defects lead to failure of T-cells to kill target cells, resulting in uncontrolled immune responses. • Threshold Model (Figure 2): ◦ Pathogenesis is determined by the interplay between genetic factors, background inflammation, and external triggers. ◦ Secondary HLH: Low baseline genetic susceptibility + high inflammatory trigger (e.g., severe infection/malignancy) → exceeds threshold. ◦ Primary HLH: High baseline genetic susceptibility → even a minor or no specific trigger can lead to exceeding the threshold.

CLINICAL FEATURES

• General Presentation: Fever, sepsis-like condition, cytopenias (especially thrombocytopenia), and hepatosplenomegaly. • Hematologic & Bone Marrow Findings: ◦ Thrombocytopenia: Common; levels may be extremely low in FHL3. ◦ Bicytopenia: At least two of three lineages (anemia, neutropenia, thrombocytopenia) affected → diagnostic criterion. ◦ Bone Marrow: May become hypocellular over time; hemophagocytosis is not always present early. • Liver Involvement & Coagulopathy: ◦ Ferritin & Transaminases: Almost always elevated. ◦ Bilirubin: Predominantly conjugated hyperbilirubinemia (icterus). ◦ Enzymes: Elevated γ-glutamyl transferase; may resemble acute liver failure or chronic persistent hepatitis. ◦ Coagulation: Disseminated intravascular coagulation, severe acute bleeding, and low fibrinogen levels are frequent. • Central Nervous System (CNS) Involvement: ◦ Frequency: ~1/3 of children with FHL have neurologic symptoms at diagnosis; ≈ 50% have abnormal CSF (elevated cell/protein content). ◦ Symptoms: Seizures, decreased consciousness, meningismus, irritability, hypotonia (neonates), cranial nerve palsies, and ataxia. • Other Clinical Findings: ◦ Skin: Petechiae, purpura, transient maculopapular rash. ◦ Lymph Nodes: Enlargement in ~50% of children. ◦ Metabolic: Elevated triglycerides; decreased sodium and albumin levels.

DIFFERENTIAL DIAGNOSIS

• Clinical Overlap: ◦ Secondary HLH may resemble acute liver failure. ◦ Late-onset primary HLH (after age 7) is less typical and presents a diagnostic challenge.

DIAGNOSTIC APPROACH

  1. Initial Clinical Assessment: ◦ Perform blood cultures to rule out infection. ◦ Assess for signs of malignancy.
  2. Decision Pathway: ◦ If blood cultures are negative AND signs of malignancy are absent → lymphocyte cytotoxicity defects should be considered and assessed for promptly.
  3. Laboratory Monitoring & Screening: ◦ Ferritin: Used as a rapid and easily available screening test (not specific). ◦ sIL-2R (sCD25): Used as a biomarker to monitor HLH severity.
  4. Serial Investigations: ◦ Perform serial bone marrow examinations over time to assess for hemophagocytosis and changes in cellularity.

MANAGEMENT & TREATMENT

  1. Early Intervention: ◦ Prompt treatment is essential due to the high risk of rapid death and permanent CNS damage.
  2. Screening & Monitoring: ◦ Use ferritin as a primary screening tool in children with suspected HLH. ◦ Use sIL-2R (sCD25) levels to monitor the severity of the condition.

COMPLICATIONS & PROGNOSIS

• Mortality: ◦ FHL is rapidly fatal without treatment; median survival of 1–2 months. • Neurologic Sequelae (if treatment delayed): ◦ Psychomotor retardation (25%). ◦ Epilepsy (10%). ◦ Attention-deficit/hyperactivity disorder (ADHD) (10%). ◦ Other: Ataxia, hemiplegia, tetraplegia.

KEY PEARLS & HIGH-YIELD POINTS

• Diagnostic Criteria: Bicytopenia (at least 2 of 3 lineages) is a key diagnostic criterion. • Rapid Screening: Ferritin is the most accessible marker for rapid screening, though not specific to HLH. • Severity Marker: sIL-2R (sCD25) levels are often markedly elevated and serve as a biomarker for severity. • CNS Risk: Approximately one-third of FHL patients will have neurologic symptoms; prompt treatment is essential to mitigate these outcomes.

Reference Tables

TABLE 68-1 Simplified Classification of Hemophagocytic Lymphohistiocytosis (HLH) Primary HLH: Mendelian Conditions…

Harrison's 22e, p.464

  • Primary HLH: Mendelian Conditions
  • Lymphocyte cytotoxic defects
  • FHL2 (PRF1)
  • FHL3 (UNC13D)
  • FHL4 (STX11)
  • FHL5 (STXBP2)
  • XLP1 (SH2D1A)
  • Griscelli syndrome type 2 (RAB27A)
  • Chédiak-Higashi syndrome (LYST)
  • Abnormalities of inflammasome activation
  • XLP2 (BIRC4)
  • NLRC4
  • Mendelian disorders affecting inflammation
  • Lysinuric protein intolerance (SLC7A7)
    Wolman disease (LIPA)
  • Secondary HLH (Non-Mendelian)
  • Infection-associated HLH
  • Virus-associated HLH
  • Bacteria-associated HLH
  • Parasite-associated HLH
  • Fungal-associated HLH
  • Malignancy-associated HLH
  • Malignancy-triggered HLH
  • HLH occurring during chemotherapy
  • Autoimmune-associated HLH (MAS-HLH)
  • HLH with SoJIA
  • HLH with adult-onset Still’s disease
  • HLH with SLE
  • HLH with vasculitis
  • Transplant-associated HLH