Leukemoid reaction

# Overview
Leukemoid reaction is a reversible increase in production of white blood cells in response to a stimulus, with white blood cell count of more than 25,000-30,000 per mm3 . Leukocytosis is increase in white blood cell count of more than 10,000 per mm3 and when the count exceeds 25,000 per mm3, with more than 2% immature white blood cells but absence of any blast cells, differentiating it from leukemias. Leukemoid reaction is classified according to the type of hematopoietic lineage of the bone marrow. Leukemoid reactions are mostly triggered by bacterial or viral infections. Leukemoid reaction is differentiated from leukemias by the absence of blast cells on peripheral blood film and high LAP score. Leukemoid reaction can lead to serious complications such as tumor lysis syndrome and DIC. The treatment includes treating the underlying cause and leukapheresis.

# Historical Perspective
- Leukemoid reaction was discovered in 1926 by Krumbharr.

# Classification
Leukemoid reaction can be classified according to the type of hematopoietic lineage of the bone marrow.
- Reactions of myeloid type:
Neutrophilic leukemoid reactions
Eosinophilic leukemoid reactions
- Neutrophilic leukemoid reactions
- Eosinophilic leukemoid reactions
- Reactions of lymphoid type:
Lymphomonocytic leukemoid reactions
Lymphocytic leukemoid reactions
Plasmocytic leukemoid reactions
- Lymphomonocytic leukemoid reactions
- Lymphocytic leukemoid reactions
- Plasmocytic leukemoid reactions
- Leukemoid reaction with blast cells
- Secondary (reactive) thrombocytosis
- Secondary erythrocytosis
- Mixed forms of leukemoid reactions
- Rare forms of leukemoid reaction
- Leukemoid reactions of basophilic type.

# Pathophysiology
- Leukemoid reaction is a reversible increase in production of white blood cells in response to a stimulus, with white blood cell count of more than 25000-30000 per mm3.
- Leukocytosis is increase in white blood cell count of more than 10000 per mm3 and when the count exceeds 25000, with more than 2% immature white blood cells but absence of any blasts, differentiating it from leukemias.
- Leukemoid reaction is classified according to the type of hematopoietic lineage of the bone marrow.
- It is a reactive, functional condition of hematopoietic, lymphatic and immune systems secondary to various diseases accompanied by the development of immature white blood cells in the peripheral blood.
- Leukemoid reaction is diagnosed after the exclusion of a malignant hematological disorder and is a transient condition. white blood cells return to normal when the underlying causes disappear.
- There are no signs of inhibition of normal hematopoiesis.
- Leukemoid reactions are mostly triggered by bacterial or viral infections, emergency stress irritants, and by various bacterial and non-bacterial stimulants causing sensitization.
- The sensitization causes up-regulation of growth or survival factors (eg, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, c-kit ligand), adhesion molecules (eg, CD11b/CD18), and various cytokines (eg, interleukin-1, interleukin-3, interleukin-6, interleukin-8, tumor necrosis factor).
- There is activation of normal hematopoiesis and excessive blood cells output to peripheral blood (reactive hyperplasia of leukopoietic tissue) and output of immature blood cells into peripheral blood.
- The image below demonstrates a graphic figure that illustrates hematopoietic growth factors in leukocytosis.
- Reactions of myeloid type are characterized by a shift to the left, from an increased number of stab cells to singular blast cells with presence of all intermediate forms.
- There is an increase in immature granulocytes of myeloid lineage.
Neutrophilic leukemoid reactions develop in Infections (sepsis, scarlet fever, abscess, diphtheria, lobar pneumonia, tuberculosis, dysentery, etc), exposure to ionizing radiation, Injuries of the skull, intoxication (uremia, CO poisoning), bone marrow metastases of malignant tumors.
Eosinophilic reactions develop in allergic processes or in diseases with allergies, as well as in parasitic diseases. They are characterized by the development of a great number of eosinophils, about 90% of leukocytes.
- Neutrophilic leukemoid reactions develop in Infections (sepsis, scarlet fever, abscess, diphtheria, lobar pneumonia, tuberculosis, dysentery, etc), exposure to ionizing radiation, Injuries of the skull, intoxication (uremia, CO poisoning), bone marrow metastases of malignant tumors.
- Eosinophilic reactions develop in allergic processes or in diseases with allergies, as well as in parasitic diseases. They are characterized by the development of a great number of eosinophils, about 90% of leukocytes.
- Lymphomonocytic leukemoid reactions develop in infectious mononucleosis, there are atypical mononuclear cells, called "lymphomonocytes" which are modulated T- and NK-lymphocytes, which get to the bloodstream by initiation of B lymphocytes. The number of atypical mononuclear cells can be increased in any viral infection.
- Lymphocytic leukemoid reactions develop in acute viral and bacterial infections and are characterized by leukocytosis with absolute lymphocytosis.
- Plasmocytic leukemoid reactions occur in diseases caused by protozoa (toxoplasmosis), viral infections (chickenpox, measles, rubella). Increased level of plasma cells (2%) in splenomegaly, blood and bone marrow.
- Leukemoid reactions with blast cells develop in severe viral infections (cytomegalovirus, etc.). Blast transformation of B-lymphocytes may be observed in the bone marrow, lymph nodes, and peripheral blood.
- Secondary absolute erythrocytosis is caused by increased erythropoiesis, relative hemoconcentration and polycythemia. It is characterized by increased red blood cell count.
- Secondary thrombocytosis is possible in malignant tumors, inflammatory diseases, following bleeding, hemolytic crises, after surgical operations and splenectomy.

# Causes
- Neutrophilic leukemoid reactions :
Infections - sepsis, scarlet fever, abscess, diphtheria, lobar pneumonia, tuberculosis, dysentery
Exposure to ionizing radiation.
Injuries of the skull.
Intoxication (uremia, CO-poisoning).
Bone marrow metastases of malignant tumors - Lymphogranulomatosis
Steroid hormones therapy
- Infections - sepsis, scarlet fever, abscess, diphtheria, lobar pneumonia, tuberculosis, dysentery
- Exposure to ionizing radiation.
- Injuries of the skull.
- Intoxication (uremia, CO-poisoning).
- Bone marrow metastases of malignant tumors - Lymphogranulomatosis
- Steroid hormones therapy
- Eosinophilic reactions :
Allergic processes or in diseases with allergies, as well as in parasitic diseases.
- Allergic processes or in diseases with allergies, as well as in parasitic diseases.
- Lymphomonocytic leukemoid reactions:
Infectious mononucleosis.
- Infectious mononucleosis.
- Lymphocytic leukemoid reaction:
Acute viral and bacterial infections
- Acute viral and bacterial infections
- Plasmocytic leukemoid reactions:
Diseases caused by protozoa (toxoplasmosis), and viral infections (chickenpox, measles, rubella).
- Diseases caused by protozoa (toxoplasmosis), and viral infections (chickenpox, measles, rubella).
- Thrombocytosis:
Primary thrombocytosis- chronic myeloproliferative diseases.
Secondary thrombocytosis-
Malignant tumors
Inflammatory diseases
Following bleeding
Hemolytic crises
After surgical operations and splenectomy.
- Primary thrombocytosis- chronic myeloproliferative diseases.
- Secondary thrombocytosis-
Malignant tumors
Inflammatory diseases
Following bleeding
Hemolytic crises
After surgical operations and splenectomy.
- Malignant tumors
- Inflammatory diseases
- Following bleeding
- Hemolytic crises
- After surgical operations and splenectomy.
- Leukemoid reactions of basophilic type:
Allergic reactions
Hemolytic anemia
Ulcerative colitis
Hypothyroidism
Leukemia.
- Allergic reactions
- Hemolytic anemia
- Ulcerative colitis
- Hypothyroidism
- Leukemia.

# Differentiating Leukemoid reaction from Other Diseases
Leukemoid reaction is differentiated from leukemia by following ways:
Leukemoid reaction should be differentiated from other causes of leucocytosis. The below table discusses different causes of leucocytosis:

# Epidemiology and Demographics

## Age
- Patients of all age groups may develop leukemoid reaction.
- Normal white blood cell count changes with age.
- Leukemoid reaction in neonates is more common, compared to children and adults.

## Gender
- Leukemoid reaction affects men and women equally.

## Race
- There is no racial predilection for the development of leukemoid reaction.

# Risk Factors
- Common risk factors in the development of leukocytosis, include:
Physiologic processes (eg, stress, exercise, pregnancy)
Drugs (e.g.corticosteroids)
Trauma
- Physiologic processes (eg, stress, exercise, pregnancy)
- Drugs (e.g.corticosteroids)
- Trauma

# Screening
No screening is done for leukemoid reaction.

# Natural History, Complications, and Prognosis

## History
The majority of patients with leukemoid reaction have the following complaints
- Early clinical features, include:
Fever
Hyperhidrosis
Fatigue
- Fever
- Hyperhidrosis
- Fatigue

## Complications
- Common complications of leukemoid reaction, include:
Tumor lysis syndrome
Disseminated intravascular coagulopathy
Acute respiratory failure
Pulmonary hemorrhage
CNS infarction
Splenic infarction
Myocardial ischemia
Renal failure
- Tumor lysis syndrome
- Disseminated intravascular coagulopathy
- Acute respiratory failure
- Pulmonary hemorrhage
- CNS infarction
- Splenic infarction
- Myocardial ischemia
- Renal failure

## Prognosis
- Prognosis generally depends on the underlying etiologies.
- If the white blood cell count reaches more than 50,000 per mm3, life threatening complications can occur.

# Diagnosis

## Symptoms
- Leukemoid reaction is usually symptomatic.
- Symptoms of leukemoid reaction are often unspecific, such as:
Weight loss
Fevers of unknown origin
Hyperhidrosis
Chronic pain
Fatigue
Dyspnea
Malaise
- Weight loss
- Fevers of unknown origin
- Hyperhidrosis
- Chronic pain
- Fatigue
- Dyspnea
- Malaise
- Obtain history of the following:
Clinical features
Duration (e.g. days, weeks, months)
Remainder of complete blood count
- Clinical features
- Duration (e.g. days, weeks, months)
- Remainder of complete blood count

## Laboratory findings
- Laboratory findings consistent with the diagnosis of leukemoid reaction, include::
White blood cell count above the normal range, greater than 25,000 per mm3.
Bone marrow aspiration revealing hyperplasia of normal hematopoietic cells in proliferative reactions.
Presence of blast and immature forms of leukocyte, platelet and erythrocytes in the proliferative reactions.
Peripheral blood smear showing myelocytes, metamyelocytes, promyelocytes, and few myeloblasts.
Leukocyte alkaline phosphatase score more than 100.
- White blood cell count above the normal range, greater than 25,000 per mm3.
- Bone marrow aspiration revealing hyperplasia of normal hematopoietic cells in proliferative reactions.
- Presence of blast and immature forms of leukocyte, platelet and erythrocytes in the proliferative reactions.
- Peripheral blood smear showing myelocytes, metamyelocytes, promyelocytes, and few myeloblasts.
- Leukocyte alkaline phosphatase score more than 100.

## Electrocardiogram
No specific ECG changes in leukemoid reaction.

## X-Ray
No specific x ray changes in leukemoid reaction.

## Echocardiography and Ultrasound
No echocardiography and ultrasound findings.

## CT
No CT scan findings in leukemoid reaction.

## MRI
No specific MRI findings in leukemoid reaction.

# Treatment

## Medical Therapy
- The treatment of leukemoid reaction depends on the underlying cause.
- Measures to reduce white blood cell count include:
Leukapheresis or exchange blood transfusion.
Hydration
Urine alkalinization
Administration of allopurinol or rasburicase to reduce serum uric acid and minimize tumor lysis syndrome.
- Leukapheresis or exchange blood transfusion.
- Hydration
- Urine alkalinization
- Administration of allopurinol or rasburicase to reduce serum uric acid and minimize tumor lysis syndrome.

## Surgery
The treatment depends on the underlying cause. In general, there is no role for surgery.

## Primary prevention
Prevention and treatment of infections.

## Secondary prevention
Treatment of underlying cause and reduction of white blood cell count.