Overview
Definition:
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive activation of cytotoxic T lymphocytes and macrophages, leading to hemophagocytosis (phagocytosis of blood cells) in various organs
Genetic forms, also known as primary or familial HLH (FHL), result from inherited defects in immune regulation, typically presenting in infancy or early childhood.
Epidemiology:
Genetic HLH is rare, with an estimated incidence of 1 in 50,000 to 1 in 150,000 live births
The specific incidence varies depending on the genetic subtype
It accounts for a significant proportion of HLH cases in children under 1 year of age.
Clinical Significance:
Genetic HLH is a medical emergency requiring prompt diagnosis and aggressive treatment
Without timely intervention, it is uniformly fatal
Understanding the genetic basis is crucial for accurate diagnosis, genetic counseling, and guiding therapeutic strategies, including allogeneic hematopoietic stem cell transplantation (HSCT).
Genetic Basis And Subtypes
Immune Dysregulation:
Genetic HLH arises from mutations in genes critical for granule exocytosis, lymphocyte proliferation, or cytotoxic function
These defects impair the immune system's ability to clear activated immune cells and pathogens, leading to uncontrolled inflammation.
Autosomal Recessive Fhl:
The most common forms of FHL are autosomal recessive and include mutations in genes such as PRF1 (FHL2), MUNC13-4 (UNC13D, FHL3), STX11 (FHL4), and STXBP2 (FHL5)
These genes are involved in the formation and function of cytotoxic granules in T cells and NK cells.
Xlp Syndromes:
X-linked lymphoproliferative disease (XLP) encompasses several distinct syndromes, with XLP1 (SH2D1A gene) and XLP2 (XIAP/BIRC4 gene) being prominent
These mutations affect T cell and NK cell function, often leading to severe immune dysregulation, particularly following Epstein-Barr virus (EBV) infection.
Other Genetic Syndromes:
Certain other genetic conditions can predispose to HLH-like presentations, including Chediak-Higashi syndrome (LYST gene), Griscelli syndrome type 2 (RAB27A gene), Hermansky-Pudlak syndrome, and Familial Hemophagocytic Lymphohistiocytosis-like Syndrome (HPLHS, various genes)
These are often associated with other specific clinical features.
Clinical Presentation
Symptoms:
Persistent high fever unresponsive to antibiotics
Splenomegaly, often massive and rapidly growing
Hepatomegaly with or without liver dysfunction
Cytopenias (anemia, thrombocytopenia, neutropenia) leading to pallor, bruising, and infections
Neurological symptoms including irritability, seizures, developmental regression, ataxia, and coma
Lymphadenopathy is common but not universal
Rash, often maculopapular or purpuric
Jaundice.
Signs:
Febrile patient
Proportional or disproportionate splenomegaly
Palpable hepatomegaly
Pallor due to anemia
Petechiae or ecchymoses due to thrombocytopenia
Signs of infection (e.g., pneumonia, sepsis)
Neurological signs such as nystagmus, hypotonia, or focal deficits
Edema
Ascites.
Diagnostic Criteria:
The HLH-2004 diagnostic criteria are widely used
Diagnosis requires 5 out of 8 criteria, including molecular confirmation of a genetic defect or evidence of hemophagocytosis
Criteria include: Fever >38.5°C
Splenomegaly >3 cm below costal margin
Cytopenias affecting at least 3 peripheral blood cell lines (Hb <9 g/dL, platelets <100,000/mm3, neutrophils <1,000/mm3)
Hypertriglyceridemia (>2.5 mmol/L or >226 mg/dL) and/or hypofibrinogenemia (<1.5 g/L)
Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver
Low or absent NK cell activity
Soluble CD25 (sIL-2 receptor) >24,000 U/mL
Ferritin >500 mcg/L (often >2000 mcg/L in active HLH).
Diagnostic Approach
History Taking:
Detailed family history for consanguinity or unexplained deaths in siblings or relatives
History of recurrent infections, fevers, or hematological abnormalities
Recent viral infections, particularly EBV, CMV, or parvovirus B19
Onset and progression of symptoms
Prior treatments and response.
Physical Examination:
Thorough examination for fever, splenomegaly, hepatomegaly, lymphadenopathy, pallor, purpura, rash, neurological deficits, and signs of organ dysfunction (e.g., respiratory distress, ascites).
Investigations:
Complete blood count (CBC) with differential and peripheral blood smear (looking for hemophagocytosis)
Liver function tests (LFTs) and coagulation profile
Serum ferritin (highly elevated, often >2000 mcg/L)
Triglycerides and fibrinogen
LDH (elevated)
Erythrocyte sedimentation rate (ESR)
Bone marrow aspirate and biopsy (for hemophagocytosis, cellularity, and morphology)
NK cell function assays and flow cytometry for aberrant lymphocyte populations
Soluble CD25 (sIL-2R) levels
Viral serology (EBV, CMV, HIV)
Genetic testing for mutations in known HLH genes (e.g., PRF1, UNC13D, STX11, XIAP, SH2D1A)
Imaging: Ultrasound for organomegaly, CT scans for lymphadenopathy or organ involvement.
Differential Diagnosis:
Sepsis and severe infections (bacterial, viral, fungal, parasitic)
Malignancies (lymphoma, leukemia)
Autoimmune diseases (e.g., Systemic Lupus Erythematosus, Juvenile Idiopathic Arthritis)
Other primary immunodeficiencies
Drug-induced HLH
Viral-associated hemophagocytosis syndrome (VAHS)
Neonatal hemochromatosis.
Management
Initial Management:
Immediate hospitalization and initiation of empiric treatment if HLH is strongly suspected, even before all diagnostic criteria are met
Stabilization of vital signs and organ function
Fluid and electrolyte management
Transfusion support (red blood cells, platelets)
Broad-spectrum antibiotics if infection is suspected.
Medical Management:
The cornerstone of treatment is immunosuppression combined with chemotherapy, as per the HLH-2004 protocol or modified versions
This typically includes: Corticosteroids (e.g., dexamethasone), often initiated with intravenous pulse therapy followed by tapering
Etoposide (VP-16), a cytotoxic agent, is crucial for inducing remission
Cyclosporine A, an immunosuppressant, is used for refractory cases or in combination
Intravenous immunoglobulin (IVIG) for supporting immune function and addressing hypogammaglobulinemia
Treatment duration and intensity are guided by response and disease activity.
Hematopoietic Stem Cell Transplantation:
Allogeneic HSCT is the definitive curative therapy for genetic HLH
It is indicated for patients with confirmed genetic mutations, those who fail to achieve remission with initial immunosuppressive therapy, or those with relapsed disease
HLA-matched sibling donors are preferred, but matched unrelated or haploidentical donors are also options.
Supportive Care:
Aggressive monitoring for infections and prompt treatment of any detected infections
Nutritional support, often requiring nasogastric or parenteral feeding due to poor intake and malabsorption
Management of cytopenias with transfusions
Close monitoring of laboratory parameters (CBC, LFTs, ferritin, triglycerides, fibrinogen, LDH)
Neurological monitoring and management of seizures or other CNS manifestations.
Prognosis And Follow Up
Factors Affecting Prognosis:
The specific genetic mutation, age at diagnosis, severity of organ involvement (especially CNS), response to initial therapy, and successful engraftment after HSCT are critical prognostic factors
Prompt diagnosis and treatment significantly improve outcomes.
Outcomes:
With aggressive management including HSCT, survival rates for genetic HLH have improved significantly, with reported survival rates of 50-80% or higher depending on the subtype and treatment center
Untreated genetic HLH is almost invariably fatal.
Follow Up:
Patients undergoing HSCT require long-term monitoring for graft-versus-host disease (GVHD), infections, graft failure, and potential long-term sequelae of therapy
Regular clinical evaluations, laboratory tests, and immunological assessments are essential
Genetic counseling should be offered to affected families.
Key Points
Exam Focus:
Remember the HLH-2004 diagnostic criteria
Genetic HLH is a hyperinflammatory state due to intrinsic immune defects
Genes like PRF1, UNC13D, STX11, XIAP are key for FHL
HSCT is the curative treatment
Cytopenias, fever, splenomegaly, hyperferritinemia, high triglycerides, low fibrinogen are hallmark findings.
Clinical Pearls:
Always consider HLH in infants and young children with persistent fever and organomegaly, even if infection is suspected
Ask about family history of similar illnesses
Prompt initiation of therapy is life-saving
Genetic testing is critical for definitive diagnosis and family planning.
Common Mistakes:
Delaying diagnosis by attributing symptoms solely to infection or malignancy without considering HLH
Underestimating the severity of the disease and delaying aggressive treatment
Failing to perform bone marrow biopsy for hemophagocytosis assessment and other diagnostic workup
Not considering HSCT as the definitive therapy for genetic forms.