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Latest revision as of 06:58, 2 February 2019

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2] Associate Editor(s)-in-Chief: Jogeet Singh Sekhon, M.D. [3]

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^[1].

Reactions of myeloid type:
1. Neutrophilic leukemoid reactions
2. Eosinophilic leukemoid reactions
Reactions of lymphoid type:
1. Lymphomonocytic leukemoid reactions
2. Lymphocytic leukemoid reactions
3. 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^[1].
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.^[2]
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.^[3]

Hematopoietic growth factors in leukocytosis, By Hematopoietic_growth_factors.svg: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007) Rang & Dale's pharmacology, Churchill Livingstone ISBN: 0-443-06911-5.User:Mikael Häggström and A. Radderivative work: Furfur - This file was derived from: Hematopoietic growth factors.svg:, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=31083166

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^[4]^[5].
- 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^[6].
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 ^[7]^[8]^[9]^[10]:
- 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.
Lymphomonocytic leukemoid reactions:
- Infectious mononucleosis.
Lymphocytic leukemoid reaction:
- Acute viral and bacterial infections
Plasmocytic leukemoid reactions:
- 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.
Leukemoid reactions of basophilic type:
- Allergic reactions
- Hemolytic anemia
- Ulcerative colitis
- Hypothyroidism
- Leukemia.

Differentiating Leukemoid reaction from Other Diseases

Leukemoid reaction is differentiated from leukemia by following ways^[11]^[12]:

Differential diagnosis of leukemia vs leukemoid reaction
Differentiating features	Leukemia	Leukemoid reaction
Causes	Carcinogens	Infectious agents, biologically active substances and products of tissue destruction
Pathogenesis	The transformation of normal haematopoietic cells to a tumor	Activation of normal hematopoiesis and exit of immature leukocytes into the bloodstream
Duration	Chronic	Temporary and reversible
Genetic level	Defect	No defect
Splenomegaly	Present	Not present
Peripheral blood	Immature cells, pancytopenia	Mature and immature granulocytes with left shift
Bone marrow	Increase in blasts and immature cells	Myeloid hyperplasia and normal morphology
LAP score	Low	High
Toxic granules (suggestive of infection)	Absent	Present
Dohle inclusion bodies	Absent	Present

Leukemoid reaction should be differentiated from other causes of leucocytosis. The below table discusses different causes of leucocytosis:

Category	Condition	Etiology	Mechanism				Congenital	Acquried	Clinical manifestations											Para−clinical findings								Gold standard	Associated findings
									Demography	History	Symptoms			Signs						Para−clinical findings
											Symptoms			Signs						Lab Findings
			Physiologic	Increased bone marrow production		Demargination of peripheral blood neutrophils					Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint involvement	Other	CBC			PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT
			Physiologic	Autonomous	Reactive	Demargination of peripheral blood neutrophils					Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint involvement	Other	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT
Hematologic	Hereditary neutrophilia^[13]	Unknown Germline mutation in CSF3R	−	+	−	−	+	−	Rare autosomal dominant genetic disorder	Positive family history	Normal	−	−	Nl	−	+	−	−	−	↑	Nl	Nl	Normal granulocytes Histiocytes of Gaucher type	Nl	Nl	Nl	Nl	Molecular testing	High leukocyte alkaline phosphatase Progress to leukemia
	Myeloproliferative neoplasms^[14]	Unknown Mutation	−	+	−	−	+	+	Elderly	Exposure to Chemotherapy Radiation therapy Tobacco smoke	Petechiae Purpura Diffuse erythematous rash	±	+	Nl	−	+	−	−	Shortness of breath Fatigue	↑/↓	↓	↑/↓	Large platelets Ovalomacrocytosis Basophilic stippling Howell-Jolly body Pelger-Huet anomaly Ring sideroblasts	Impaired myeloid maturation Dyserythropoiesis Dysgranulopoiesis Dysmegakaryocytopoiesis Hypercellular bone marrow Fibrosis	↑	Nl	Nl	Bone marrow examination + clinical manifestation	Thrombosis at unusual sites Thrombosis in younger patients Might transformed to acute leukemia
	Polycythemia vera^[15]	Autonomous erythrocyte production JAK2 mutation (> 95%)	−	+	−	−	+	−	Mean age >60 years old	Stroke Visual disturbance	Facial plethora	−	−	↑	−	+	+	−	Painful erythema	Nl to ↑	↑	↑	Elevated normochromic, normocytic RBCs Thrombocytosis ≥ 10% immature myeloid precursors Leukoerythroblastic picture	Increased myeloid:erythroid ratio due to granulocytic proliferation	Nl	Nl	Nl	Bone marrow examination + clinical manifestation	Stroke Venous thrombosis Myelofibrosis Acute leukemia
	Microangiopathic hemolytic anemia (MAHA)^[16]	Microangiopathy Leukemoid reaction	−	+	−	−	+	+	Any	Bleeding disorder Positive family history	Pallor	+	+	↓	−	+	−	−	Shortness of breath Fatigue	↑	↓	↑	Fragmented RBCs Schistocytes	NA	↑	↑	↑	Bone marrow examination + clinical manifestation	Non-immune hemolysis Elevated LDH Elevated alkaline phosphatase Negative direct Coomb's test Thrombosis
	Leukoerythroblastosis^[17]	Space-occupying lesions in the bone marrow Infection	−	+	−	−	−	+	Any	Bleeding disorder	Pallor	−	+	Nl	−	+	−	−	Early satiety Fatigue	↑	↓	↓	Nucleated red cells Reticulocytosis Poikilocytes Circulating immature white cells, generally myelocytes and promyelocytes	Circulating immature white cells, generally myelocytes and promyelocytes Myelofibrosis	↑	Nl	↑	Bone marrow biopsy	Marrow infiltrative disorders Trauma Septicemia Massive hemolysis Megaloblastic anemia Extramedullary hematopoiesis
Immunology/ Rheumatology	Condition	Etiology	Physiologic	Autonomous increased bone marrow production	Reactive increased bone marrow production	Demargination of peripheral blood neutrophils	Congenital	Acquried	Demography	History	Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint involvement	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings
	Leukocyte adhesion deficiency^[18]	Primary immunodeficiency Failure to express CD18	−	+	−	−	+	−	Rare autosomal recessive, LAD II more in Middle East and Brazil	Positive family history	Characteristic facial appearance, short stature, limb malformations, and severe developmental delay in LAD II	+	−	Nl	−	−	−	−	Signs of different infections	↑	↓	↓/↑	Leukocytosis	Leukocytosis	Nl	Nl	Nl	Flow cytometry	Recurrent bacterial infections Delay in umbilical cord sloughing Inability to form abscesses
	Cryopyrin-associated periodic syndromes^[19]	Unknown Mutation	−	+	−	−	+	−	Autosomal dominant autoinflammatory syndrome	Positive family history	Hive-like rash without itching	+	−	Nl	−	−	−	+	Red eyes Vomiting Headache	↑	↓	↓/↑	Leukocytosis	Leukocytosis	↑	Nl	↑	Genetic tests	Blindness Hearing loss
	Rheumatoid arthritis^[20]^[21]	Immune mediated	−	+	−	−	−	+	Any, more in young women, between 30-60 years old	Positive family history Cigarette smoking Obesity	Deformed joints Rheumatoid nodules	+	−	Nl	−	−	−	+	Weight loss Fatigue Dry eyes and mouth	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Clinical manifestation + positive anti-CCP antibodies	Osteoporosis Infections Carpal tunnel syndrome Multi-organ involvement Lymphoma
	Juvenile onset rheumatoid arthritis^[22]	Immune mediated	−	+	−	−	−	+	Children under the age of 16	Positive family history	Blotchy rash on a child's arms and legs	+	−	Nl	−	−	+	+	Fatigue Dry eyes and mouth	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Clinical manifestation + laboratory findings	Uveitis Infections Multi-organ involvement
	Adult Still's disease^[23]	Immune mediated	−	+	−	−	−	+	Rare autoimmune disease	NA	Nonpruritic salmon-colored rash (usually over trunk or extremities while febrile)	+	−	Nl	−	−	+	+	Headache Sore throat Weight loss Muscle pain	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Diagnosis of exclusion	High ferritin Negative ANA Aseptic meningitis Sensorineural hearing loss
	Kawasaki disease^[24]	Immune mediated	−	+	−	−	−	+	Autoimmune disease, more in Asian ethnicity boys	NA	Diffuse maculopapular erythematous rash in the genital area, and red eyes, lips, palms or soles of the feet	+	+	Nl	−	−	+	+	Strawberry tongue Sore throat Diarrhea Bilateral conjunctival inflammation	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Diagnostic criteria	Medium-sized-vessel vasculitis Coronary artery aneurysm
	IBD^[25]	Immune mediated Mutation	−	+	−	−	−	+	Autoimmune disease, more in young	Stress Positive family history	Pyoderma gangrenosum	+	+	Nl	−	+	+	+	Vomiting Diarrhea Rectal bleeding	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Colonoscopy and biopsy	Primary sclerosing cholangitis Non-thyroidal illness syndrome DVT Bronchiolitis obliterans organizing pneumonia
	Sarcoidosis^[26]	Immune mediated Unknown	−	+	−	−	−	+	Autoimmune disease, more in young African American women	Positive family history	Rashes Erythema nodosum Granuloma annulare Lupus pernio	+	+	Nl	−	+	+ Bilateral hilar adenopathy	+	Fatigue Weight loss Blurry vision Shortness of breath Cough	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Diagnosis of exclusion	Interstitial lung disease Systemic inflammatory disease
	Chronic hepatitis^[27]	Infection Autoimmune Ischemic	−	+	−	−	−	+	Elderly	Alcohol use Acute infection	Jaundice Ascites and peripheral edema	+	+	↓	−	+	+	+	Fatigue Weight loss Nausea and vomiting	↑	↓	↑	Leukocytosis	NA	↑	↑	↑	Liver biopsy	Hirsutism Amenorrhea Coagulopathy Hepatic encephalopathy Esophageal varices Hepatorenal syndrome Liver cancer
	Sweet syndrome^[28]	Immune mediated Unknown	−	+	−	−	−	+	Rare	Relapse and remission	Tender, red, well-demarcated papules and plaques on the head, neck, legs, and arms	+	+	Nl	−	−	+	+	Conjunctivitis Iridocyclitis Oral aphthae	↑	↓	↑	Leukocytosis	Papillary and mid-dermal mixed infiltrate of polymorphonuclear leukocytes with nuclear fragmentation and histiocytic cells	↑	Nl	Nl	Diagnostic criteria	Cutaneous marker of systemic disease Acute myelogenous leukemia Immunologic disease Slight increase in alkaline phosphatase
	Acute gout^[29]	Elevated levels of uric acid in the blood Diet Genetic	−	+	−	−	−	+	Older males	Alcohol use Acute infection	Tophi	+	−		−	−	−	+	Fatigue	↑	↓	↑	Leukocytosis	NA	↑	↑	Nl	Clinical manifestation	Arthritis Urate nephropathy
Medication	Condition	Etiology	Physiologic	Autonomous increased bone marrow production	Reactive increased bone marrow production	Demargination of peripheral blood neutrophils	Congenital	Acquried	Demography	History	Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint involvement	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings
	Steroid^[30]	Release of granulocytes from the bone marrow	−	−	+	+	−	+	Any	Steroid use Autoimmune disease Malignancy	Obese	−	+	Nl to ↓	−	−	−	−	Abdominal pain Muscle weakness Growth failure Pubertal delay	↑	Nl to ↓	↑	Megakaryocyticfragments Large numbers of microspherocytes	Proliferation of megakaryocytes	↑	↑	Nl	Clinical manifestation + history of drug consumption	Thromboemboliccomplications Cushing syndrome Diabetes mellitus
	Filgrastim (Myeloid growth factor)^[31]	Release of granulocytes from the bone marrow	−	−	+	+	−	+	Any	Malignancy Neutropenia	Hair loss Local skin reactions at the site of injection	+	−	Nl to ↓	−	−	−	+	Cough Chest pain Vomiting	↑	Nl to ↓	↑	NA	NA	↑	Nl	Nl	Clinical manifestation + history of drug consumption	Alveolar hemorrhage Acute respiratory distress syndrome
	Lithium^[32]	Unknown	−	−	+	+	−	+	Any	Bipolar disorder	Weight gain Acne Hand tremor	−	−	Nl	−	−	−	−	Confusion Constipation or diarrhea Decreased memory Dry mouth Muscle weakness	↑	Nl to ↓	↑	NA	NA	Nl	↑	Nl	Clinical manifestation + history of drug consumption	Extrapyramidal side effects Euthyroid goitre Hypothyroidism Kidney damage
	Catecholamines (epinephrine)^[33]	Stimulation of bone marrow myelopoiesis Egress into the circulation	−	−	+	+	−	+	Any	Anaphylaxis Respiratory diseases	Acutely ill Diaphoretic	−	−	Nl to ↓	−	−	−	−	Dizziness Tremor Anxiety Dyspnea	↑	↑	↑	Megakaryocyticfragments	Proliferation of megakaryocytes	↑	Nl	Nl	Clinical manifestation + history of drug consumption	Thromboemboliccomplications
	ATRA^[34]	Differentiating promyelocytes	−	−	+	+	−	+	Any	Acne Acute promyelocytic leukemia	Skin dryness Hair loss	−	−	Nl	−	−	−	−	Shortness of breath Headache Numbness Depression Itchiness Vomiting Muscle pain	↑	Nl	Nl	NA	NA	↑	Nl	↑	Clinical manifestation + history of drug consumption	Teratogen Thrombosis Benign intracranial hypertension Hypercholesterolemia Liver damage
Other	Condition	Etiology	Physiologic	Autonomous increased bone marrow production	Reactive increased bone marrow production	Demargination of peripheral blood neutrophils	Congenital	Acquried	Demography	History	Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint involvement	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings
	Infections^[35]	Infection	−	+	+	+	−	+	Any	Close contact Immunodeficiency	Acutely ill	+	+	Nl to ↓	−	±	±	±	Fatigue Nausea and vomiting	↑	↓	↑	Howell-Jolly bodies Nucleated RBCs	Proliferation of megakaryocytes	↑	Nl	Nl	Clinical manifestation+ culture	Depends on etiology
	Allergy^[36]	Unknown Activation of chloride transport	−	+	+	+	−	+	Any	Anaphylaxis Respiratory diseases	Acutely ill Diaphoretic	−	−	Nl to ↓	−	−	−	−	Dizziness Tremor Anxiety Dyspnea	↑	↑	↑	Megakaryocyticfragments	Proliferation of megakaryocytes	↑	Nl	Nl	Clinical manifestation	−
	Post splenectomy^[37]	Unknown	−	−	+	+	−	+	Any	Prior surgical removal of the spleen Sickle cell disease	Normal	±	−	Nl	+	−	−	−	−	↑	↓	↑	Howell-Jolly bodies Nucleated RBCs	Proliferation of megakaryocytes	↑	Nl	Nl	Clinical manifestation	Incidental laboratory finding Thrombosis
	Cigarette smoking^[38]	Reduced plasma volume Accelerated erythropoiesis	−	−	+	+	−	+	Any	Cigarette smoking	Cyanosis	−	−	Nl	−	−	−	−	Cough Dyspnea	↑	↑	↑	NA	NA	Nl	Nl	Nl	Clinical manifestation	−
	Stress/exercise^[39]	Reduced plasma volume	+	−	+	−	−	+	Athlete	Exercise	Normal	−	−	Nl	−	−	−	−	−	↑	↑	↑	Howell-Jolly bodies Nucleated RBCs	Proliferation of megakaryocytes	↑	Nl	Nl	Clinical manifestation	−
	Infancy^[40]	Physiologic	+	−	−	−	−	+	Infancy	−	Normal	−	−	Nl	−	−	−	−	−	↑	↑	↑	NA	NA	Nl	Nl	Nl	Clinical manifestation	−
	Pregnancy^[41]	Physiologic	+	−	−	−	−	+	Pregnancy	−	Normal	−	−	Nl	−	−	−	−	−	↑	↓	↑	NA	NA	Nl	Nl	Nl	Clinical manifestation	−
	Platelet clumping^[42]	Spurious	−	−	−	−	−	+	Any	−	Normal	−	−	Nl	−	−	−	−	−	↑	Nl	↑	Cytoplasmic fragments	Nl	Nl	Nl	Nl	Clinical manifestation	−
	Mixed cryoglobulinemia^[43]	Spurious	−	−	−	−	−	+	Any	Malignancy Autoimmune disease Infection	Atypical cutaneous ulcers Palpable purpura	−	−	Nl	−	−	−	+	Headache Confusion Blurry or loss of vision Generalized weakness	↑	Nl to ↓	↑	Cytoplasmic fragments	Nl	Nl	Nl	Nl	Skin biopsy	Vasculitis Neuropathy Raynaud phenomenon
Category	Condition	Etiology	Physiologic	Autonomous increased bone marrow production	Reactive increased bone marrow production	Demargination of peripheral blood neutrophils	Congenital	Acquried	Demography	History	Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint involvement	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings

Epidemiology and Demographics

Age

Patients of all age groups may develop leukemoid reaction^[1]^[44].
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:^[1]
- 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^[45]^[46]

Early clinical features, include:

Complications

Common complications of leukemoid reaction, include:

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^[47]:
- 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

Laboratory findings

Laboratory findings consistent with the diagnosis of leukemoid reaction, include:^[45]:
- 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.^[45]
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.

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.

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 Abramson N, Melton B (2000). "Leukocytosis: basics of clinical assessment". Am Fam Physician. 62 (9): 2053–60. PMID 11087187.
↑ Ward HN, Reinhard EH (1971). "Chronic idiopathic leukocytosis". Ann Intern Med. 75 (2): 193–8. PMID 5558646.
↑ Leukocytosis. Wikipedia. https://en.wikipedia.org/wiki/Leukocytosis Accessed on May 23, 2016
↑ Wanahita A, Goldsmith EA, Musher DM (2002). "Conditions associated with leukocytosis in a tertiary care hospital, with particular attention to the role of infection caused by clostridium difficile". Clin Infect Dis. 34 (12): 1585–92. doi:10.1086/340536. PMID 12032893.
↑ Lawrence YR, Raveh D, Rudensky B, Munter G (2007). "Extreme leukocytosis in the emergency department". QJM. 100 (4): 217–23. doi:10.1093/qjmed/hcm006. PMID 17314214.
↑ McBride JA, Dacie JV, Shapley R (1968). "The effect of splenectomy on the leucocyte count". Br J Haematol. 14 (2): 225–31. PMID 5635603.
↑ Spencer RP, McPhedran P, Finch SC, Morgan WS (1972). "Persistent neutrophilic leukocytosis associated with idiopathic functional asplenia". J Nucl Med. 13 (3): 224–6. PMID 5058244.
↑ Foster NK, Martyn JB, Rangno RE, Hogg JC, Pardy RL (1986). "Leukocytosis of exercise: role of cardiac output and catecholamines". J Appl Physiol (1985). 61 (6): 2218–23. doi:10.1152/jappl.1986.61.6.2218. PMID 3804928.
↑ Brodeur GM, Dahl GV, Williams DL, Tipton RE, Kalwinsky DK (1980). "Transient leukemoid reaction and trisomy 21 mosaicism in a phenotypically normal newborn". Blood. 55 (4): 691–3. PMID 6444534.
↑ Harvey Y, Bleakley S, Blombery P, Bain BJ (2018). "Marked leukemoid reaction in a patient with metastatic breast carcinoma". Am J Hematol. 93 (2): 306–307. doi:10.1002/ajh.24849. PMID 28699170.
↑ Sakka V, Tsiodras S, Giamarellos-Bourboulis EJ, Giamarellou H (2006). "An update on the etiology and diagnostic evaluation of a leukemoid reaction". Eur J Intern Med. 17 (6): 394–8. doi:10.1016/j.ejim.2006.04.004. PMID 16962944.
↑ Updyke KM, Morales-Lappot J, Lee T (2017). "Atypical Presentation of Chronic Myelogenous Leukemia". Cureus. 9 (5): e1280. doi:10.7759/cureus.1280. PMC 5484601. PMID 28656128.
↑ Herring, William Benjamin; Smith, Laurin Gresham; Walker, Richard Isley; Herion, John Carroll (1974). "Hereditary neutrophilia". The American Journal of Medicine. 56 (5): 729–734. doi:10.1016/0002-9343(74)90642-1. ISSN 0002-9343.
↑ Tefferi A (February 2010). "Leukocytosis as a risk factor for thrombosis in myeloproliferative neoplasms-biologically plausible but clinically uncertain". Am. J. Hematol. 85 (2): 93–4. doi:10.1002/ajh.21614. PMID 20052751.
↑ Boiocchi L, Gianelli U, Iurlo A, Fend F, Bonzheim I, Cattaneo D, Knowles DM, Orazi A (November 2015). "Neutrophilic leukocytosis in advanced stage polycythemia vera: hematopathologic features and prognostic implications". Mod. Pathol. 28 (11): 1448–57. doi:10.1038/modpathol.2015.100. PMID 26336886.
↑ Morton JM, George JN (June 2016). "Microangiopathic Hemolytic Anemia and Thrombocytopenia in Patients With Cancer". J Oncol Pract. 12 (6): 523–30. doi:10.1200/JOP.2016.012096. PMID 27288467.
↑ Canbolat Ayhan A, Timur C, Ayhan Y, Kes G (June 2014). "Leukoerythroblastosis Mimicking Leukemia: A case report". Iran J Pediatr. 24 (3): 332–3. PMC 4276592. PMID 25562031.
↑ Levy-Mendelovich S, Rechavi E, Abuzaitoun O, Vernitsky H, Simon AJ, Lev A, Somech R (April 2016). "Highlighting the problematic reliance on CD18 for diagnosing leukocyte adhesion deficiency type 1". Immunol. Res. 64 (2): 476–82. doi:10.1007/s12026-015-8706-5. PMID 26434744.
↑ Labrousse M, Kevorkian-Verguet C, Boursier G, Rowczenio D, Maurier F, Lazaro E, Aggarwal M, Lemelle I, Mura T, Belot A, Touitou I, Sarrabay G (September 2018). "Mosaicism in autoinflammatory diseases: Cryopyrin-associated periodic syndromes (CAPS) and beyond. A systematic review". Crit Rev Clin Lab Sci. 55 (6): 432–442. doi:10.1080/10408363.2018.1488805. PMID 30035647.
↑ Scott DL, Wolfe F, Huizinga TW (September 2010). "Rheumatoid arthritis". Lancet. 376 (9746): 1094–108. doi:10.1016/S0140-6736(10)60826-4. PMID 20870100.
↑ Glant TT, Mikecz K, Rauch TA (February 2014). "Epigenetics in the pathogenesis of rheumatoid arthritis". BMC Med. 12: 35. doi:10.1186/1741-7015-12-35. PMC 3936819. PMID 24568138.
↑ Naz S, Mushtaq A, Rehman S, Bari A, Maqsud A, Khan MZ, Ahmad TM (June 2013). "Juvenile rheumatoid arthritis". J Coll Physicians Surg Pak. 23 (6): 409–12. doi:06.2013/JCPSP.409412 Check |doi= value (help). PMID 23763801.
↑ Kadavath S, Efthimiou P (February 2015). "Adult-onset Still's disease-pathogenesis, clinical manifestations, and new treatment options". Ann. Med. 47 (1): 6–14. doi:10.3109/07853890.2014.971052. PMID 25613167.
↑ Sundel RP (2015). "Kawasaki disease". Rheum. Dis. Clin. North Am. 41 (1): 63–73, viii. doi:10.1016/j.rdc.2014.09.010. PMID 25399940.
↑ Zhang YZ, Li YY (January 2014). "Inflammatory bowel disease: pathogenesis". World J. Gastroenterol. 20 (1): 91–9. doi:10.3748/wjg.v20.i1.91. PMC 3886036. PMID 24415861.
↑ Modaresi Esfeh J, Culver D, Plesec T, John B (March 2015). "Clinical presentation and protocol for management of hepatic sarcoidosis". Expert Rev Gastroenterol Hepatol. 9 (3): 349–58. doi:10.1586/17474124.2015.958468. PMID 25473783.
↑ Gish RG, Given BD, Lai CL, Locarnini SA, Lau JY, Lewis DL, Schluep T (September 2015). "Chronic hepatitis B: Virology, natural history, current management and a glimpse at future opportunities". Antiviral Res. 121: 47–58. doi:10.1016/j.antiviral.2015.06.008. PMID 26092643.
↑ Das A, Burmeister R, Chhaya R, Eisenga B, Kumar A (September 2018). "Sweet Syndrome in a Patient With Systemic Lupus Erythematosus". J Clin Rheumatol. doi:10.1097/RHU.0000000000000904. PMID 30247226.
↑ Dalbeth N, Zhong CS, Grainger R, Khanna D, Khanna PP, Singh JA, McQueen FM, Taylor WJ (March 2014). "Outcome measures in acute gout: a systematic literature review". J. Rheumatol. 41 (3): 558–68. doi:10.3899/jrheum.131244. PMC 4217650. PMID 24334652.
↑ Shoenfeld Y, Gurewich Y, Gallant LA, Pinkhas J (November 1981). "Prednisone-induced leukocytosis. Influence of dosage, method and duration of administration on the degree of leukocytosis". Am. J. Med. 71 (5): 773–8. PMID 7304648.
↑ Crawford J, Armitage J, Balducci L, Becker PS, Blayney DW, Cataland SR, Heaney ML, Hudock S, Kloth DD, Kuter DJ, Lyman GH, McMahon B, Rugo HS, Saad AA, Schwartzberg LS, Shayani S, Steensma DP, Talbott M, Vadhan-Raj S, Westervelt P, Westmoreland M, Dwyer M, Ho M (October 2013). "Myeloid growth factors". J Natl Compr Canc Netw. 11 (10): 1266–90. PMID 24142827.
↑ Aiff H, Attman PO, Aurell M, Bendz H, Ramsauer B, Schön S, Svedlund J (May 2015). "Effects of 10 to 30 years of lithium treatment on kidney function". J. Psychopharmacol. (Oxford). 29 (5): 608–14. doi:10.1177/0269881115573808. PMID 25735990.
↑ Bedoui S, Lechner S, Gebhardt T, Nave H, Beck-Sickinger AG, Straub RH, Pabst R, von Hörsten S (November 2002). "NPY modulates epinephrine-induced leukocytosis via Y-1 and Y-5 receptor activation in vivo: sympathetic co-transmission during leukocyte mobilization". J. Neuroimmunol. 132 (1–2): 25–33. PMID 12417430.
↑ Bi KH, Jiang GS (December 2006). "Relationship between cytokines and leukocytosis in patients with APL induced by all-trans retinoic acid or arsenic trioxide". Cell. Mol. Immunol. 3 (6): 421–7. PMID 17257495.
↑ Horasan ES, Dağ A, Ersoz G, Kaya A (October 2013). "Surgical site infections and mortality in elderly patients". Med Mal Infect. 43 (10): 417–22. doi:10.1016/j.medmal.2013.07.009. PMID 24012414.
↑ Davis M, van der Hilst J (2018). "Mimickers of Urticaria: Urticarial Vasculitis and Autoinflammatory Diseases". J Allergy Clin Immunol Pract. 6 (4): 1162–1170. doi:10.1016/j.jaip.2018.05.006. PMID 29871797. Vancouver style error: initials (help)
↑ Bilello JF, Sharp VL, Dirks RC, Kaups KL, Davis JW (2018). "After the embo: predicting non-hemorrhagic indications for splenectomy after angioembolization in patients with blunt trauma". Trauma Surg Acute Care Open. 3 (1): e000159. doi:10.1136/tsaco-2017-000159. PMC 5887792. PMID 29766137.
↑ Lymperaki E, Makedou K, Iliadis S, Vagdatli E (2015). "Effects of acute cigarette smoking on total blood count and markers of oxidative stress in active and passive smokers". Hippokratia. 19 (4): 293–7. PMC 5033137. PMID 27688691.
↑ Simpson RJ, Kunz H, Agha N, Graff R (2015). "Exercise and the Regulation of Immune Functions". Prog Mol Biol Transl Sci. 135: 355–80. doi:10.1016/bs.pmbts.2015.08.001. PMID 26477922.
↑ Nouatin O, Gbédandé K, Ibitokou S, Vianou B, Houngbegnon P, Ezinmegnon S, Borgella S, Akplogan C, Cottrell G, Varani S, Massougbodji A, Moutairou K, Troye-Blomberg M, Deloron P, Luty AJ, Fievet N (2015). "Infants' Peripheral Blood Lymphocyte Composition Reflects Both Maternal and Post-Natal Infection with Plasmodium falciparum". PLoS ONE. 10 (11): e0139606. doi:10.1371/journal.pone.0139606. PMC 4651557. PMID 26580401.
↑ Perseghin P (December 2015). "Erythrocyte exchange and leukapheresis in pregnancy". Transfus. Apher. Sci. 53 (3): 279–82. doi:10.1016/j.transci.2015.11.007. PMID 26621538.
↑ Castrillo A, Álvarez I, Tolksdorf F (April 2015). "In vitro evaluation of platelet concentrates suspended in additive solution and treated for pathogen reduction: effects of clumping formation". Blood Transfus. 13 (2): 281–6. doi:10.2450/2014.0162-14. PMC 4385077. PMID 25369589.
↑ Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D (September 2015). "Cryoglobulinemia Vasculitis". Am. J. Med. 128 (9): 950–5. doi:10.1016/j.amjmed.2015.02.017. PMID 25837517.
↑ Hoofien A, Yarden-Bilavski H, Ashkenazi S, Chodick G, Livni G (2018). "Leukemoid reaction in the pediatric population: etiologies, outcome, and implications". Eur J Pediatr. 177 (7): 1029–1036. doi:10.1007/s00431-018-3155-5. PMID 29696475.
↑ ^45.0 ^45.1 ^45.2 Ellison TA, Mandal K (2018). "Leukemoid reaction: Case report". J Thorac Cardiovasc Surg. 155 (4): e117–e118. doi:10.1016/j.jtcvs.2017.08.125. PMID 29366572.
↑ Wang Z, Cai Q, Li G, Jiang N, Niu Y (2017). "Giant Pheochromocytoma With Leukemoid Reaction: A Case Report". Urology. 99: e17–e19. doi:10.1016/j.urology.2016.08.021. PMID 27720771.
↑ Agrawal D, Kurwale N, Sharma BS (2016). "Leukocytosis after routine cranial surgery: A potential marker for brain damage in intracranial surgery". Asian J Neurosurg. 11 (2): 109–13. doi:10.4103/1793-5482.145066. PMC 4802930. PMID 27057215.

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[pmid5558646-2] Ward HN, Reinhard EH (1971). "Chronic idiopathic leukocytosis". Ann Intern Med. 75 (2): 193–8. PMID 5558646.

[wiki-3] Leukocytosis. Wikipedia. https://en.wikipedia.org/wiki/Leukocytosis Accessed on May 23, 2016

[pmid12032893-4] Wanahita A, Goldsmith EA, Musher DM (2002). "Conditions associated with leukocytosis in a tertiary care hospital, with particular attention to the role of infection caused by clostridium difficile". Clin Infect Dis. 34 (12): 1585–92. doi:10.1086/340536. PMID 12032893.

[pmid17314214-5] Lawrence YR, Raveh D, Rudensky B, Munter G (2007). "Extreme leukocytosis in the emergency department". QJM. 100 (4): 217–23. doi:10.1093/qjmed/hcm006. PMID 17314214.

[pmid5635603-6] McBride JA, Dacie JV, Shapley R (1968). "The effect of splenectomy on the leucocyte count". Br J Haematol. 14 (2): 225–31. PMID 5635603.

[pmid5058244-7] Spencer RP, McPhedran P, Finch SC, Morgan WS (1972). "Persistent neutrophilic leukocytosis associated with idiopathic functional asplenia". J Nucl Med. 13 (3): 224–6. PMID 5058244.

[pmid3804928-8] Foster NK, Martyn JB, Rangno RE, Hogg JC, Pardy RL (1986). "Leukocytosis of exercise: role of cardiac output and catecholamines". J Appl Physiol (1985). 61 (6): 2218–23. doi:10.1152/jappl.1986.61.6.2218. PMID 3804928.

[pmid6444534-9] Brodeur GM, Dahl GV, Williams DL, Tipton RE, Kalwinsky DK (1980). "Transient leukemoid reaction and trisomy 21 mosaicism in a phenotypically normal newborn". Blood. 55 (4): 691–3. PMID 6444534.

[pmid28699170-10] Harvey Y, Bleakley S, Blombery P, Bain BJ (2018). "Marked leukemoid reaction in a patient with metastatic breast carcinoma". Am J Hematol. 93 (2): 306–307. doi:10.1002/ajh.24849. PMID 28699170.

[pmid16962944-11] Sakka V, Tsiodras S, Giamarellos-Bourboulis EJ, Giamarellou H (2006). "An update on the etiology and diagnostic evaluation of a leukemoid reaction". Eur J Intern Med. 17 (6): 394–8. doi:10.1016/j.ejim.2006.04.004. PMID 16962944.

[pmid28656128-12] Updyke KM, Morales-Lappot J, Lee T (2017). "Atypical Presentation of Chronic Myelogenous Leukemia". Cureus. 9 (5): e1280. doi:10.7759/cureus.1280. PMC 5484601. PMID 28656128.

[HerringSmith1974-13] Herring, William Benjamin; Smith, Laurin Gresham; Walker, Richard Isley; Herion, John Carroll (1974). "Hereditary neutrophilia". The American Journal of Medicine. 56 (5): 729–734. doi:10.1016/0002-9343(74)90642-1. ISSN 0002-9343.

[pmid20052751-14] Tefferi A (February 2010). "Leukocytosis as a risk factor for thrombosis in myeloproliferative neoplasms-biologically plausible but clinically uncertain". Am. J. Hematol. 85 (2): 93–4. doi:10.1002/ajh.21614. PMID 20052751.

[pmid26336886-15] Boiocchi L, Gianelli U, Iurlo A, Fend F, Bonzheim I, Cattaneo D, Knowles DM, Orazi A (November 2015). "Neutrophilic leukocytosis in advanced stage polycythemia vera: hematopathologic features and prognostic implications". Mod. Pathol. 28 (11): 1448–57. doi:10.1038/modpathol.2015.100. PMID 26336886.

[pmid27288467-16] Morton JM, George JN (June 2016). "Microangiopathic Hemolytic Anemia and Thrombocytopenia in Patients With Cancer". J Oncol Pract. 12 (6): 523–30. doi:10.1200/JOP.2016.012096. PMID 27288467.

[pmid25562031-17] Canbolat Ayhan A, Timur C, Ayhan Y, Kes G (June 2014). "Leukoerythroblastosis Mimicking Leukemia: A case report". Iran J Pediatr. 24 (3): 332–3. PMC 4276592. PMID 25562031.

[pmid26434744-18] Levy-Mendelovich S, Rechavi E, Abuzaitoun O, Vernitsky H, Simon AJ, Lev A, Somech R (April 2016). "Highlighting the problematic reliance on CD18 for diagnosing leukocyte adhesion deficiency type 1". Immunol. Res. 64 (2): 476–82. doi:10.1007/s12026-015-8706-5. PMID 26434744.

[pmid30035647-19] Labrousse M, Kevorkian-Verguet C, Boursier G, Rowczenio D, Maurier F, Lazaro E, Aggarwal M, Lemelle I, Mura T, Belot A, Touitou I, Sarrabay G (September 2018). "Mosaicism in autoinflammatory diseases: Cryopyrin-associated periodic syndromes (CAPS) and beyond. A systematic review". Crit Rev Clin Lab Sci. 55 (6): 432–442. doi:10.1080/10408363.2018.1488805. PMID 30035647.

[pmid20870100-20] Scott DL, Wolfe F, Huizinga TW (September 2010). "Rheumatoid arthritis". Lancet. 376 (9746): 1094–108. doi:10.1016/S0140-6736(10)60826-4. PMID 20870100.

[pmid24568138-21] Glant TT, Mikecz K, Rauch TA (February 2014). "Epigenetics in the pathogenesis of rheumatoid arthritis". BMC Med. 12: 35. doi:10.1186/1741-7015-12-35. PMC 3936819. PMID 24568138.

[pmid23763801-22] Naz S, Mushtaq A, Rehman S, Bari A, Maqsud A, Khan MZ, Ahmad TM (June 2013). "Juvenile rheumatoid arthritis". J Coll Physicians Surg Pak. 23 (6): 409–12. doi:06.2013/JCPSP.409412 Check |doi= value (help). PMID 23763801.

[pmid25613167-23] Kadavath S, Efthimiou P (February 2015). "Adult-onset Still's disease-pathogenesis, clinical manifestations, and new treatment options". Ann. Med. 47 (1): 6–14. doi:10.3109/07853890.2014.971052. PMID 25613167.

[pmid25399940-24] Sundel RP (2015). "Kawasaki disease". Rheum. Dis. Clin. North Am. 41 (1): 63–73, viii. doi:10.1016/j.rdc.2014.09.010. PMID 25399940.

[pmid24415861-25] Zhang YZ, Li YY (January 2014). "Inflammatory bowel disease: pathogenesis". World J. Gastroenterol. 20 (1): 91–9. doi:10.3748/wjg.v20.i1.91. PMC 3886036. PMID 24415861.

[pmid25473783-26] Modaresi Esfeh J, Culver D, Plesec T, John B (March 2015). "Clinical presentation and protocol for management of hepatic sarcoidosis". Expert Rev Gastroenterol Hepatol. 9 (3): 349–58. doi:10.1586/17474124.2015.958468. PMID 25473783.

[pmid26092643-27] Gish RG, Given BD, Lai CL, Locarnini SA, Lau JY, Lewis DL, Schluep T (September 2015). "Chronic hepatitis B: Virology, natural history, current management and a glimpse at future opportunities". Antiviral Res. 121: 47–58. doi:10.1016/j.antiviral.2015.06.008. PMID 26092643.

[pmid30247226-28] Das A, Burmeister R, Chhaya R, Eisenga B, Kumar A (September 2018). "Sweet Syndrome in a Patient With Systemic Lupus Erythematosus". J Clin Rheumatol. doi:10.1097/RHU.0000000000000904. PMID 30247226.

[pmid24334652-29] Dalbeth N, Zhong CS, Grainger R, Khanna D, Khanna PP, Singh JA, McQueen FM, Taylor WJ (March 2014). "Outcome measures in acute gout: a systematic literature review". J. Rheumatol. 41 (3): 558–68. doi:10.3899/jrheum.131244. PMC 4217650. PMID 24334652.

[pmid7304648-30] Shoenfeld Y, Gurewich Y, Gallant LA, Pinkhas J (November 1981). "Prednisone-induced leukocytosis. Influence of dosage, method and duration of administration on the degree of leukocytosis". Am. J. Med. 71 (5): 773–8. PMID 7304648.

[pmid24142827-31] Crawford J, Armitage J, Balducci L, Becker PS, Blayney DW, Cataland SR, Heaney ML, Hudock S, Kloth DD, Kuter DJ, Lyman GH, McMahon B, Rugo HS, Saad AA, Schwartzberg LS, Shayani S, Steensma DP, Talbott M, Vadhan-Raj S, Westervelt P, Westmoreland M, Dwyer M, Ho M (October 2013). "Myeloid growth factors". J Natl Compr Canc Netw. 11 (10): 1266–90. PMID 24142827.

[pmid25735990-32] Aiff H, Attman PO, Aurell M, Bendz H, Ramsauer B, Schön S, Svedlund J (May 2015). "Effects of 10 to 30 years of lithium treatment on kidney function". J. Psychopharmacol. (Oxford). 29 (5): 608–14. doi:10.1177/0269881115573808. PMID 25735990.

[pmid12417430-33] Bedoui S, Lechner S, Gebhardt T, Nave H, Beck-Sickinger AG, Straub RH, Pabst R, von Hörsten S (November 2002). "NPY modulates epinephrine-induced leukocytosis via Y-1 and Y-5 receptor activation in vivo: sympathetic co-transmission during leukocyte mobilization". J. Neuroimmunol. 132 (1–2): 25–33. PMID 12417430.

[pmid17257495-34] Bi KH, Jiang GS (December 2006). "Relationship between cytokines and leukocytosis in patients with APL induced by all-trans retinoic acid or arsenic trioxide". Cell. Mol. Immunol. 3 (6): 421–7. PMID 17257495.

[pmid24012414-35] Horasan ES, Dağ A, Ersoz G, Kaya A (October 2013). "Surgical site infections and mortality in elderly patients". Med Mal Infect. 43 (10): 417–22. doi:10.1016/j.medmal.2013.07.009. PMID 24012414.

[pmid29871797-36] Davis M, van der Hilst J (2018). "Mimickers of Urticaria: Urticarial Vasculitis and Autoinflammatory Diseases". J Allergy Clin Immunol Pract. 6 (4): 1162–1170. doi:10.1016/j.jaip.2018.05.006. PMID 29871797. Vancouver style error: initials (help)

[pmid29766137-37] Bilello JF, Sharp VL, Dirks RC, Kaups KL, Davis JW (2018). "After the embo: predicting non-hemorrhagic indications for splenectomy after angioembolization in patients with blunt trauma". Trauma Surg Acute Care Open. 3 (1): e000159. doi:10.1136/tsaco-2017-000159. PMC 5887792. PMID 29766137.

[pmid27688691-38] Lymperaki E, Makedou K, Iliadis S, Vagdatli E (2015). "Effects of acute cigarette smoking on total blood count and markers of oxidative stress in active and passive smokers". Hippokratia. 19 (4): 293–7. PMC 5033137. PMID 27688691.

[pmid26477922-39] Simpson RJ, Kunz H, Agha N, Graff R (2015). "Exercise and the Regulation of Immune Functions". Prog Mol Biol Transl Sci. 135: 355–80. doi:10.1016/bs.pmbts.2015.08.001. PMID 26477922.

[pmid26580401-40] Nouatin O, Gbédandé K, Ibitokou S, Vianou B, Houngbegnon P, Ezinmegnon S, Borgella S, Akplogan C, Cottrell G, Varani S, Massougbodji A, Moutairou K, Troye-Blomberg M, Deloron P, Luty AJ, Fievet N (2015). "Infants' Peripheral Blood Lymphocyte Composition Reflects Both Maternal and Post-Natal Infection with Plasmodium falciparum". PLoS ONE. 10 (11): e0139606. doi:10.1371/journal.pone.0139606. PMC 4651557. PMID 26580401.

[pmid26621538-41] Perseghin P (December 2015). "Erythrocyte exchange and leukapheresis in pregnancy". Transfus. Apher. Sci. 53 (3): 279–82. doi:10.1016/j.transci.2015.11.007. PMID 26621538.

[pmid25369589-42] Castrillo A, Álvarez I, Tolksdorf F (April 2015). "In vitro evaluation of platelet concentrates suspended in additive solution and treated for pathogen reduction: effects of clumping formation". Blood Transfus. 13 (2): 281–6. doi:10.2450/2014.0162-14. PMC 4385077. PMID 25369589.

[pmid25837517-43] Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D (September 2015). "Cryoglobulinemia Vasculitis". Am. J. Med. 128 (9): 950–5. doi:10.1016/j.amjmed.2015.02.017. PMID 25837517.

[pmid29696475-44] Hoofien A, Yarden-Bilavski H, Ashkenazi S, Chodick G, Livni G (2018). "Leukemoid reaction in the pediatric population: etiologies, outcome, and implications". Eur J Pediatr. 177 (7): 1029–1036. doi:10.1007/s00431-018-3155-5. PMID 29696475.

[pmid29366572-45] 45.0 ^45.1 ^45.2 Ellison TA, Mandal K (2018). "Leukemoid reaction: Case report". J Thorac Cardiovasc Surg. 155 (4): e117–e118. doi:10.1016/j.jtcvs.2017.08.125. PMID 29366572.

[pmid27720771-46] Wang Z, Cai Q, Li G, Jiang N, Niu Y (2017). "Giant Pheochromocytoma With Leukemoid Reaction: A Case Report". Urology. 99: e17–e19. doi:10.1016/j.urology.2016.08.021. PMID 27720771.

[pmid27057215-47] Agrawal D, Kurwale N, Sharma BS (2016). "Leukocytosis after routine cranial surgery: A potential marker for brain damage in intracranial surgery". Asian J Neurosurg. 11 (2): 109–13. doi:10.4103/1793-5482.145066. PMC 4802930. PMID 27057215.

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