Hemophagocytic Lymphohistiocytosis - Causes, Symptoms, Diagnosis, and Treatment

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon hematological disease that is predominantly seen in infants and young children. It also occurs in adults. Children get it through inheritance and adults acquire HLH through infections and cancers. In hemophagocytic lymphohistiocytosis, the immune system of the body is greatly altered leading to uncontrolled inflammatory reactions. If left untreated, HLH results in life-threatening complications, especially in newborns.

What Is Hemophagocytic Lymphohistiocytosis?

Histiocytosis refers to a cluster of syndromes characterized by a dysregulated rise in levels of histiocytes (a type of white blood cell) in the body. These histiocytes also include other immune cells such as macrophages, dendritic cells, and monocytes. They are found in the blood circulation and also present in tissues such as the bone marrow, lymph nodes, skin, spleen, liver, and lungs. In histiocytosis, these histiocytes move into other tissues and cause damage to the cells.

In hemophagocytic lymphohistiocytosis (HLH), the immune system is overactivated and releases abnormal levels of histiocytes. These histiocytes attack the red blood cells and destroy them. The degraded blood cells get accumulated in organs like the liver and spleen resulting in multiorgan failure. Activated macrophages secrete high levels of cytokines that stimulate other immune cells and enhance inflammation. Increased cytokine production eventually leads to severe tissue damage.

What Causes Hemophagocytic Lymphohistiocytosis?

Hemophagocytic lymphohistiocytosis occurs by inheritance (primary causes) as well as acquired causes (secondary form).

Primary Hemophagocytic Lymphohistiocytosis

• Also called the familial form is transferred through defective genes from one generation to another.

• The genetic defect is due to a gene mutation that is inherited as an autosomal recessive gene.

• If a person acquires a single copy of the defective gene, he or she becomes a carrier and has a 25 % chance of passing it to their offspring.

• A child born to parents who are both carriers of HLH has a 25 % chance of acquiring the disease and a 50 % chance of becoming a carrier of HLH.

• Four different types of gene variations account for genetic predisposition in inheriting hemophagocytic lymphohistiocytosis.

Secondary Hemophagocytic Lymphohistiocytosis

• Here, HLH occurs sporadically when exposed to triggering factors such as viral infections or autoimmune disorders.

• These individuals possess an underlying predisposing component that usually favors the activation of HLH.

• The secondary form occurs more commonly than the familial form.

Factors That Trigger Secondary Hemophagocytic Lymphohistiocytosis

• Viral infections such as the Epstein-Barr virus.

• Other infections are caused by bacterial and fungal agents.

• A weakened and suppressed immune system as in HIV (human immunodeficiency virus) infections, immunodeficiencies, and immunosuppressant therapies.

• Autoimmune and autoinflammatory disorders.

• Rheumatological disease conditions like juvenile idiopathic arthritis.

• Cancers such as non-Hodgkin lymphoma.

• Metabolic disorders that reduce immune activity.

• Drug-induced (chemotherapy, steroid therapy).

• Bone marrow transplantation.

What Are the Signs and Symptoms of Hemophagocytic Lymphohistiocytosis?

The onset, as well as the severity of hemophagocytic lymphohistiocytosis, vary from one person to another. It mostly affects newborns and infants up to 18 months of age.

• Fever with rashes.

• Abnormally enlarged liver (hepatomegaly).

• Abnormal enlargement of the spleen (splenomegaly).

• Fevers prolong and remain persistent. They do not respond to antibiotic therapy.

• Lymph nodes are enlarged (lymphadenopathy).

• Reduced levels of red blood cells (anemia) in blood circulation.

• Decreased levels of platelets (thrombocytopenia) in peripheral blood.

• Tiredness.

• Weakness.

• Lightheadedness and dizziness.

• Irritability.

• Headaches.

• Pale skin coloration.

• Difficulty in breathing (dyspnea)

• cardiovascular symptoms such as cardiac insufficiency.

• In the case of thrombocytopenia, excessive bruising in a minor injury.

• Spontaneous mucosal bleeding from gums.

• Nasal bleeding (epistaxis).

• Neurological symptoms such as seizures.

• Altered mental status.

• Paralysis.

• Uncoordinated voluntary movements (ataxia).

• Posterior encephalopathy syndrome (rapid onset of headaches, seizures, and visual disturbances).

• Neurological problems are frequently seen in familial hemophagocytic lymphohistiocytosis.

• Lung dysfunction.

• Severe reduction in blood pressure (hypotension).

• Inflammation of the liver (hepatitis).

• kidney failure.

• Jaundice (yellow discoloration of skin and eyes).

• Edema (abnormal fluid accumulation).

• Abdominal swelling (ascites).

• Reddening and inflammation of the skin (erythroderma)

• Tiny blood spots (purpura) under the skin.

• Purplish spots on the skin (petechiae).

• multiorgan involvement.

• Failure to thrive (seen in neonates).

How Is Hemophagocytic Lymphohistiocytosis Diagnosed?

Hemophagocytic lymphohistiocytosis is diagnosed based on the presentation of clinical symptoms, a detailed past medical and family history, along with clinical examination and laboratory investigations.

Diagnostic Criteria

Specific guidelines are established for the clinical diagnosis of hemophagocytic lymphohistiocytosis. Five out of eight clinical symptoms are to be present to confirm its diagnosis. These symptoms are as follows -

• Fever.

• Abnormal enlargement of the spleen (splenomegaly).

• Reduced levels of red blood cells (anemia), white blood cells (leucopenia), or platelets (thrombocytopenia).

• Extremely high levels of triglycerides in the circulating blood (hypertriglyceridemia).

• Decreased levels of fibrin (hypofibrinogenemia) that help in clotting.

• destruction of red blood cells (hemophagocytosis) by macrophages in the bone marrow.

• Diminished or absence of natural killer cell activity.

• Abnormally high levels of ferritin (the storage form of iron) in the blood plasma (ferritinemia).

• Elevated levels of interleukin-2 receptor (sCD25) which is released due to stimulation of the immune system.

Laboratory Investigations

• Complete blood count (CBC) which included estimation of red blood cells, white blood cells, and platelets.

• Blood tests to detect ferritin levels in plasma.

• Lipid profile to detect elevated levels of triglycerides

• Coagulation tests such as bleeding time (BT), and prothrombin time (PTT).

• Liver function tests.

• Bone marrow biopsy is done to assess the indicators of hemophagocytosis such as the accumulation of macrophages and infectious agents.

• Molecular genetic tests help in the detection of mutations that cause familial HLH.

• CT (computed tomography) scan reveals an enlarged spleen and liver.

What Are the Standard Therapies for Hemophagocytic Lymphohistiocytosis?

Treatment for hemophagocytic lymphohistiocytosis depends on the underlying cause, age of onset, and severity of the disease. Secondary hemophagocytic lymphohistiocytosis responds better to treatment than the familial form. The treatment intervention for hemophagocytic lymphohistiocytosis includes -

• Chemotherapy.

• Radiation therapy to clear hyperinflammatory stem cells.

• Immunotherapy including immunomodulating agents.

• Steroid administration is given to minimize infections.

• Antibiotic drugs in case of bacterial infections.

• Antiviral drugs to control viral replication.

• Emapalumab is used in pediatric and adult HLH patients who show signs of recurrence.

• Blood transfusion in case of reduced levels of circulating red blood cells and platelets.

• Allogeneic stem cell transplantation in case of persistent secondary HLH and severe familial form of HLH.

• Although hemophagocytic lymphohistiocytosis is not preventable, early diagnosis and treatment intervention yield a better prognosis, particularly in children.

• Genetic counseling is beneficial in individuals with hereditary hemophagocytic lymphohistiocytosis.

Conclusion

Hemophagocytic lymphohistiocytosis is a hyper-inflammatory condition that causes devastating consequences such as multi-organ failure and fatal complications. Although commonly seen in children, it could affect individuals belonging to any age group. Early detection and prompt therapeutic intervention are essential. Treatment with immunosuppressive agents, cytotoxic chemotherapy, and supportive care ensures a better prognosis.