Histiocytic Disorders and HLH Overview

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Questions and Answers

What is indicated by elevated levels of CD25 in lymphocytes?

Increased risk of autoimmune disease

Decreased immune response

Activation of lymphocytes (correct)

Presence of a viral infection

Which of the following is NOT a symptom commonly associated with HLH?

Pulmonary dysfunction

Hepatosplenomegaly

Peripheral neuropathy (correct)

Prolonged high fever

How can primary HLH be definitively diagnosed?

Identification of autoimmune markers

Presence of elevated CD25 alone

Blood culture showing an infectious agent

Molecular diagnosis or genetic testing (correct)

What happens to plasmin levels due to histiocyte secretion in HLH?

Increases due to plasminogen activator secretion Signup and view all the answers

Which laboratory finding is typically associated with HLH?

Increased D-dimer Signup and view all the answers

What distinguishes hemophagocytic lymphohistiocytosis (HLH) from clonal myeloid neoplastic disorders?

HLH is characterized by dysfunction of T cells and activated macrophages. Signup and view all the answers

Which of the following best describes the familial forms of hemophagocytic lymphohistiocytosis?

They have a prevalence of 1 in 50,000 live births. Signup and view all the answers

What are common associations with secondary hemophagocytic lymphohistiocytosis?

It can occur due to metabolic diseases and malignancy. Signup and view all the answers

What histopathologic finding characterizes hemophagocytosis?

Macrophages engulfing erythrocytes and hematopoietic cells. Signup and view all the answers

Which of the following components is NOT typically involved in HLH pathophysiology?

Clonal progenitor cells. Signup and view all the answers

What is the characteristic cell shape of a reactive histiocyte?

Irregular with a shaggy contour. Signup and view all the answers

Which genetic mutations have been reported in familial hemophagocytic lymphohistiocytosis?

Mutations in PRF1, UNC13D, and STX11. Signup and view all the answers

What is the main challenge in understanding the pathogenesis of acquired hemophagocytic lymphohistiocytosis?

The mechanisms leading to it are still poorly understood. Signup and view all the answers

What role do mutations in PRF1 and other associated genes play in HLH?

They disrupt the production and secretion of perforin in NK cells. Signup and view all the answers

Which pro-inflammatory cytokines are primarily involved in the pathologic activation of T cells and macrophages during HLH?

IFNγ, TNF-α, and IL-6 Signup and view all the answers

What causes the elevated ferritin levels observed in HLH?

Destruction of red blood cells leading to iron release into the serum. Signup and view all the answers

How does hypertriglyceridemia occur in patients with HLH?

From inhibited lipoprotein lipase activity caused by TNF-α and IFN-γ. Signup and view all the answers

What can result from the hypercytokinemia generated by activated T cells and macrophages in HLH?

Multiorgan dysfunction possibly leading to death. Signup and view all the answers

Which of the following statements about macrophage behavior in HLH is correct?

Macrophages undergo uncontrolled proliferation and release pro-inflammatory cytokines. Signup and view all the answers

What pathway do IL-12 and IL-18 primarily influence in HLH?

Activation of cytotoxic T-lymphocytes. Signup and view all the answers

Which infectious agents are commonly associated with triggering HLH in immunocompromised patients?

Viral, bacterial, fungal, and protozoan infections. Signup and view all the answers

Study Notes

Hemophagocytic Lymphohistiocytosis (HLH)

HLH is a distinct condition from clonal myeloid neoplastic "histiocytic disorders"
Characterized by dysfunction of T cells, activated macrophages, and pathologic inflammation (syndrome of pathologic immune activation)
Hemophagocytosis is a key feature, describing macrophages engulfing erythrocytes or other hematopoietic cells found in bone marrow, lymph nodes, spleen, or liver biopsies.

Histiocytes

Histiocytes are tissue macrophages
Histiocytoses include diseases arising from cells of the mononuclear phagocytic system, including dendritic cell (DC) disorders, macrophage-related disorders, and malignant histiocytic disorders.
Distinction among these diseases is based on clinical characteristics and histopathological staining for unique surface markers. Reactive histiocytes have an irregular, "shaggy" shape.

Classification of Histiocytic Disorders

Table 71-1 presents a historical classification of histiocytic disorders.
Categories of disorders include Dendritic cell-related (Langerhans cell histiocytosis, Juvenile xanthogranuloma/Erdheim-Chester disease) Macrophage-Related (Hemophagocytic syndromes, Primary hemophagocytic lymphohistiocytosis, Secondary hemophagocytic syndromes, Rosai-Dorfman disease) and Malignant Diseases (Monocyte-related leukemias, Extramedullary monocytic tumor, Macrophage-related histiocytic sarcoma, Dendritic cell malignancy).

Types of HLH

Primary (Familial) HLH:
- Affects neonates and infants (incidence of 1 in 50,000 live births)
- An autosomal recessive disease, without a clearly defined genetic defect.
- Gene defects in genes associated with perforin (PRF1), Munc13-4 (UNC13D), and syntaxin 11 (STX11) have been reported.
- Males and females equally affected.
Secondary (Acquired) HLH:
- Commonly known as macrophage activation syndrome (MAS)
- Associated with various conditions including Chediak-Higashi syndrome, Griscelli syndrome, X-linked lymphoproliferative syndrome, infections, autoinflammatory/autoimmune diseases, malignancies, immunosuppression, hematopoietic stem cell transplantation, organ transplantation, HIV infection, and metabolic diseases.

Pathophysiology

HLH is a hyperinflammatory, uncontrolled immune response triggered by various stimuli.
Pathogenesis of familial HLH is better understood than acquired HLH.
Both familial and acquired forms can be precipitated by viral infections (particularly Epstein-Barr virus and other herpes viruses), bacterial, fungal, and protozoan infections, frequently in immunocompromised hosts.

Genetics of HLH

Most genetic syndromes causing HLH have impaired cytotoxic NK and T-cell function, caused by mutations in genes encoding perforin, MUNC13-4, STXBP2, syntaxin 11, and RAB27A
These gene defects prevent the normal sequence of perforin production, packaging, and secretion from NK and cytotoxic T cells upon activation.
This prevents pore formation in target cell membranes, and subsequent granzyme injection leading to apoptosis (cell death).

Immunologic Defects

HLH results from pathologic activation of T cells and macrophages, leading to the production of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-6, IL-10, IL-12, and soluble IL-2 receptor α (soluble CD25)).
This hypercytokinemia (excess cytokines) leads to multiorgan dysfunction that can rapidly lead to death.

Clinical Features

HLH is hard to diagnose because symptoms overlap with other conditions in critically ill patients.
Key symptoms include prolonged high fever, hepatosplenomegaly, neurological symptoms (seizures, decreased consciousness, meningitis), rash, pulmonary dysfunction and lymphadenopathy.
Possible CNS symptoms that mimic encephalitis are also seen.

Diagnostic Guidelines

HLH diagnosis is established via either molecular testing or by meeting clinical and laboratory criteria.
Genetic testing can be used for patients and siblings with suspected HLH.
The patient must fulfill at least 5 of the 8 criteria listed. Examples of the 8 criteria include fever, splenomegaly, and certain cytopenia levels.

Bone Marrow

Bone marrow examination helps evaluate for hemophagocytosis to identify underlying conditions and rule out benign or neoplastic mimics.
Hemophagocytosis is characteristic but not always pathognomonic for HLH, with 20% of patients potentially not showing it in biopsies.
Hypercellular bone marrow and increased histiocytes may be seen.
Cellular damage in HLH is induced by inflammatory cytokines (TNF-α and IFN-γ), suppressing hematopoiesis, inducing apoptosis, and further activating histiocytes.

Treatment

Treatment for HLH depends on the underlying cause and severity of presentation, focusing on suppressing inflammation and treating the underlying disease whenever possible.
International protocol developed by the Histiocyte Society uses a combination of chemotherapy and immunotherapy (such as etoposide, corticosteroids, cyclosporine A, intrathecal methotrexate) with potential follow-up bone marrow transplant for patients with familial HLH or other gene defects, relapsed/refractory disease, or CNS involvement.

Differential Diagnosis

HLH may imitate other conditions, such as fever of unknown origin, infections, sepsis, multiorgan dysfunction, hepatitis, anemia, thrombocytopenia, and autoimmune disorders (Kawasaki, lupus, etc.)
HLH should be suspected and investigated if no clear cause is identified in patients and if the patient's condition is deteriorating.

Prognosis and Potential Treatment Outcomes

Initial response to therapy with etoposide and dexamethasone can sometimes be good, but some patients experience progressive disease, especially with serum ferritin elevation, increasing coagulopathy, or intensified respiratory support needs.
The overall three-year survival rate using the HLH-94 and HLH-2004 protocols is ~55%-67%.
EBV-associated HLH in children can be fatal.
Adult patients with HLH generally have poorer outcomes compared to children, with the exception of potentially better response to transient infections. Malignancy related HLH is more common in adults.
Potential hematopoietic cell transplantation (HCT) may be an option for certain patients, with sibling donors requiring testing for inherited HLH genes and immune dysfunction. Adult patients are evaluated with a focused approach.

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Description

This quiz explores Hemophagocytic Lymphohistiocytosis (HLH) and the classification of histiocytic disorders. Learn about the characteristics, dysfunctions, and key features related to T cells and macrophages. Test your knowledge on tissue macrophages and the clinical distinction of histiocytoses.