Overview
Definition:
Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening hyperinflammatory syndrome characterized by excessive activation and proliferation of lymphocytes and macrophages
This leads to systemic inflammation and organ damage, a state often referred to as a "cytokine storm." It can be primary (genetic) or secondary (acquired).
Epidemiology:
HLH is rare, with an incidence of approximately 1 in 8,000 to 1 in 150,000 live births
Primary HLH typically presents in infancy, while secondary HLH can occur at any age, often triggered by infections, malignancies, autoimmune diseases, or immunosuppression
In India, prevalence is similar to global estimates, with an increased recognition of secondary forms in older children and adolescents.
Clinical Significance:
HLH is a critical emergency requiring prompt diagnosis and aggressive management
Untreated, it has a very high mortality rate
Understanding the underlying pathophysiology, particularly the role of ferritin and the cytokine storm, is crucial for timely intervention and improving patient outcomes
Its recognition is vital for DNB and NEET SS candidates preparing for pediatric critical care and hematology scenarios.
Pathophysiology
Cytokine Storm:
The central mechanism in HLH is the dysregulation of immune responses, leading to an uncontrolled release of pro-inflammatory cytokines (e.g., TNF-α, IL-1, IL-6, IL-18)
This cytokine storm activates macrophages and cytotoxic T cells, which then inappropriately phagocytose blood cells (hemophagocytosis) in the bone marrow, spleen, and lymph nodes.
Role Of Ferritin:
Ferritin, the primary intracellular iron-storage protein, is a sensitive marker of macrophage activation and inflammation
In HLH, elevated ferritin levels (hyperferritinemia) are a hallmark, often reaching extremely high levels (>10,000 ng/mL)
It reflects increased iron turnover and macrophage activity, and its elevation often correlates with disease severity and poor prognosis.
Genetic Vs Acquired:
Primary HLH results from inherited genetic mutations affecting cytotoxic lymphocyte function (e.g., perforin, MUNC13-4, STX11)
Secondary HLH arises from acquired conditions that trigger immune dysregulation, where the genetic predisposition might be present but not expressed until a trigger occurs
Differentiating between the two influences treatment strategies.
Clinical Presentation
Symptoms:
Persistent high fever unresponsive to antibiotics
Profound fatigue and lethargy
Irritability
Poor feeding
Enlargement of the spleen and liver causing abdominal distension
Bruising or bleeding tendencies due to thrombocytopenia
Neurological symptoms such as seizures, ataxia, or cranial nerve palsies.
Signs:
Fever (>38.5°C)
Splenomegaly (often massive)
Hepatomegaly
Jaundice
Lymphadenopathy
Pallor
Petechiae or purpura
Signs of organ dysfunction (e.g., respiratory distress, neurological deficits, coagulopathy).
Diagnostic Criteria:
The HLH-2004 diagnostic criteria are widely used, requiring at least 5 of the following 8 criteria: 1
Fever
2
Splenomegaly
3
Cytopenias involving at least two cell lines (hemoglobin < 9 g/dL, platelets < 100,000/µL, neutrophils < 1000/µL)
4
Hypertriglyceridemia (>2.6 mmol/L or 230 mg/dL) or hypofibrinogenemia (<1.5 g/L)
5
Hemophagocytosis in bone marrow, spleen, or lymph nodes
6
Low or absent NK cell activity
7
Hyperferritinemia (>500 µg/L, though much higher levels are typical in active HLH)
8
Elevated soluble IL-2 receptor (sCD25) (>2400 U/mL).
Diagnostic Approach
History Taking:
Detailed history of fever onset and pattern
Recent infections or vaccinations
Family history of similar illnesses or hematological disorders
History of malignancy or autoimmune disease
Medications or recent treatments
Neurological symptoms.
Physical Examination:
Thorough systemic examination to assess fever, degree of organomegaly (spleen, liver), presence of lymphadenopathy, signs of bleeding or bruising, and neurological status
Assess for signs of sepsis or specific triggers.
Investigations:
Complete blood count (CBC) with differential and peripheral smear (to assess cytopenias and look for hemophagocytes)
Liver function tests (LFTs) and coagulation profile
Ferritin levels (critical for diagnosis and monitoring)
Triglycerides and fibrinogen
Blood cultures and viral serologies to identify triggers
Bone marrow aspirate and biopsy (for morphology, cytogenetics, flow cytometry, and to confirm hemophagocytosis)
NK cell function assays and sCD25 levels
Genetic testing for primary HLH mutations
Imaging (ultrasound abdomen for organomegaly, chest X-ray/CT for pulmonary involvement).
Differential Diagnosis:
Sepsis with multi-organ dysfunction
Kawasaki disease
Macrophage activation syndrome (MAS) in systemic lupus erythematosus
Viral infections (e.g., EBV, CMV)
Malignancies (leukemia, lymphoma)
Aplastic anemia
Storage diseases.
Management
Initial Management:
Prompt initiation of immunosuppressive therapy
Treatment of underlying trigger if identified (e.g., antibiotics for bacterial infection)
Supportive care including blood product transfusions (packed red blood cells, platelets), fluid management, and nutritional support.
Medical Management:
The cornerstone is the HLH-94 or HLH-2004 protocols
This typically involves: 1
Corticosteroids (e.g., dexamethasone or methylprednisolone)
2
Calcineurin inhibitors (e.g., cyclosporine A)
3
Chemotherapy (e.g., etoposide)
4
Intravenous immunoglobulin (IVIG) in specific cases
5
Treatment of identified triggers
Doses are weight-based and adjusted based on response and toxicity.
Hematopoietic Stem Cell Transplantation:
Allogeneic hematopoietic stem cell transplantation (HSCT) is the definitive curative therapy for primary HLH and for refractory or relapsed secondary HLH
It replaces the defective immune system or eliminates the underlying disease.
Supportive Care:
Aggressive monitoring of vital signs, fluid balance, and laboratory parameters (CBC, LFTs, ferritin, triglycerides)
Management of fever
Nutritional support, often requiring parenteral nutrition
Prophylaxis against opportunistic infections (e.g., with trimethoprim-sulfamethoxazole, ganciclovir) and Pneumocystis jirovecii pneumonia (PCP).
Prognosis
Factors Affecting Prognosis:
Timeliness of diagnosis and initiation of treatment
Underlying cause (primary HLH generally has a poorer prognosis without HSCT)
Presence and severity of organ damage
Response to initial therapy
Availability of HSCT
Genetic mutations in primary HLH.
Outcomes:
With timely and appropriate treatment, including HSCT when indicated, survival rates for primary HLH have improved significantly
Secondary HLH outcomes depend on the treatability of the underlying condition
Without treatment, mortality is nearly 100%.
Follow Up:
Long-term follow-up is essential for patients who have undergone HSCT, monitoring for graft-versus-host disease (GVHD), infections, and potential long-term complications
Patients with resolved secondary HLH require monitoring for recurrence of the underlying condition.
Key Points
Exam Focus:
Recognize HLH as a medical emergency
Hyperferritinemia is a key diagnostic clue, often >10,000 ng/mL
Cytokine storm is the central pathophysiology
HLH-2004 criteria are essential
Etoposide is a critical chemotherapeutic agent
HSCT is curative for primary HLH.
Clinical Pearls:
Always consider HLH in a child with prolonged fever, organomegaly, and cytopenias
Don't wait for all 8 criteria
if suspicion is high, initiate treatment empirically
Ferritin is not just an inflammatory marker but a reflection of macrophage activation
Differentiating triggers is vital for effective secondary HLH management.
Common Mistakes:
Delaying treatment due to uncertainty or awaiting all diagnostic criteria
Misattributing symptoms to common infections without considering HLH
Inadequate supportive care
Failure to consider HSCT in primary or refractory HLH
Not monitoring ferritin levels closely during treatment as an indicator of response.