Leukocytosis Clinical Presentation

7/22/2019 Leukocytosis Clinical Presentation

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(BPD).[5]A prospective study of preterm infants showed a significant correlation between the infant's

leukemoid reaction (neutrophil count >40,000/L) and histological evidence of chorioamnionitis. [6] In this

study, the incidence of BPD was significantly higher in infants who had leukemoid reaction compared

with those without leukemoid reaction.Prostaglandin (PGE1): In neonates with ductus-dependent congenital heart disease, administration of

PGE1caused reversible elevation in neutrophil count by an average of 6000/L.[7] This was later

confirmed in a retrospective study with more than 2 weeks of infusion of PGE1.[8] .

Lithium: Lithium carbonate, commonly used for depression and bipolar disorder, is known to cause

modest leukocytosis and neutrophilia (up to twice as many as the baseline count). The increase is due

to increased production of neutrophils. [9]

Heparin: Heparin induces leukocytosis, mainly lymphocytosis, but in some cases, neutrophilia as well.

One in every 230 patients treated with heparin had leukocytosis.[10]

Other: Medications that are known to cause leukocytosis and leukemoid reaction along with

eosinophilia are antiepileptic drugs, including carbamazepine,[11] phenobarbitol, and phenytoin.[12]

Minocycline, which is commonly used for the treatment of acne. [13] have been reported to cause a

severe hypersensitivity reaction called drug rash with eosinophilia and systemic symptoms (DRESS)

syndrome. The neutrophilia and leukocytosis are secondary to hypersensitivity reaction to the drug.

Some patients developed lymphocytosis or leukopenia instead of neutrophilia and leukocytosis with

antiepileptic drugs. The antipsychotic drug clozapine has been known to cause agranulocytosis, but it

also causes dose-related elevation in leukocytes and neutrophil counts.[14]

Familial cold autoinflammatory syndrome (familial cold urticaria) is characterized by development of

multiple purpuric raised erythema a few hours after exposure to cold, fever, chills, arthralgia, and

consistent elevation of neutrophil and WBC counts. It is transmitted in automal dominant fashion. [15]

Malignancy and myeloproliferative disorders

These are rare causes of neutrophilia in children.

Hodgkin lymphomatypically causes mild-to-moderate neutrophilia.

Patients with chronic phase of adult-type chronic myelocytic leukemia and a positive

Philadelphia chromosome present with neutrophilia with immature forms, eosinophilia, basophilia,

and thrombocytosis.

Juvenile myelomonocytic leukemia causes leukocytosis and monocytosis with bizarre-shaped

monocytes rather than neutrophilia alone.Infants with Down syndromefrequently have leukocytosis, neutrophilia, differential shift to the left,

and immature forms (blasts) in the blood (myeloproliferative disorder) during the postnatal period.

In most cases, this change is transient (referred to as transient myeloproliferative disorder);

however, some develop acute leukemia.

Some solid tumors (most commonly described in carcinoma of the lung and in undifferentiated

carcinoma) cause neutrophilia by the tumor cells called paraneoplastic leukemoid reaction. This

is rare in children, but has been well described in adult patients. The presumed mechanism is

production of cytokines, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte

macrophage colony-stimulating factor (GM-CSF), by tumor cells or metastatic cells. However, in

some patients, cytokines measured were not elevated. [16]

Decreased egress from circulation

The neutrophil count is a balance between its production and release into blood circulation and

its destruction and departure from circulation into tissue. Anything that affects any component of

this balance affects the neutrophil count.

Decreased egress from circulation may occur with the administration of corticosteroids,

splenectomy, or congenital leukocyte adhesion molecule deficiency. Persistent leukocytosis and

thrombocytosis are commonly seen in patients postsplenectomy. Leukocyte adhesion molecule

deficiency is a congenital condition. In babies born with this disorder, the umbilical stump may

not fall off in a normal period, and they may have persistent neutrophilia in the absence of clinical

signs of infection,[17] with an increased susceptibility to infection. Flow cytometric demonstration

of the absence of CD11b/CD18 on the patient's leukocytes may assist in establishing the

diagnosis.

Decreased neutrophil margination, including steroid administration, exercise, epinephrine administration,and other stressful situations (eg, trauma, severe pain)

Neutrophilia due to these causes is generally short lived (ie, minutes to hours, not days).

Transient but significant elevation in white cell numbers and neutrophil counts have been

described after a brief period of exercise, afebrile seizure including status epilepticus, and mild

head trauma with Glasgow Coma Scale of 15. [18, 19, 20] See the Glasgow Coma Scalecalculator.
http://reference.medscape.com/calculator/glasgow-coma-scalehttp://emedicine.medscape.com/article/943216-overviewhttp://www.medscape.com/resource/hodgkins-lymphoma


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A significant elevation in the leukocyte count (and lymphopenia) during the first week after

isolated spinal cord injury was observed in patients with neurological impairment compared with

controls who had isolated spinal cord injury without neurological impairment. [21] This elevation

was not due to steroid administration. Authors speculated that alpha adrenergic stimuli,

endogenous corticosteroid increase, or both may be the cause. Contrary to the simultaneous

lymphopenia in this study, lymphocytosis was observed after a brief exercise.[18]

Increased release of neutrophils from marrow: This occurs in infection, stress, and hypoxia; it also

occurs due to endotoxin stimulation and steroid administration.

A mutation in the CSF3Rgene: A familial neutrophilia (neutrophil count 22,900/L) has been described

due to a mutation in the transmembrane domain of G-CSF receptor (T617N). [22]

Therapeutic repetitive injections of pegylated G-CSF or G-CSFcaused hyperleukocytosis[23]

Lymphocytosis conventionally refers to a lymphocyte count greater than 4 X 109/L (4000/L); however, a

lymphocyte count that exceeds this is physiologically present in infants and young children. The upper

normal limit of lymphocyte count in this age group has not been well defined in a healthy population.

Marked lymphocytosis is observed in individuals infected with pertussis(total leukocyte count of 40-50 X

109/L, or X 40-50 X 103/L). An exceedingly high lymphocyte count such as 100 X 109/L indicates poor

prognosis.

Viral infection generally causes lymphocytosis (relative or absolute) with or without neutropenia. Typical

examples include infectious mononucleosisor cytomegalovirus infection, respiratory syncytial virus

infections, and infectious hepatitis. On the other hand, some viral infection results in remarkable

leukemoid reaction with a shift to left. An example is the Hantavirus pulmonary syndrome. [24] The

highest WBC count during the 1993 outbreak was reported to be 65,000/L with shift to left. The author

has seen neutrophilia and leukocytosis in the early phase of Epstein-Barr virus infection in children.

Chronic lymphocytic leukemia that is routinely characterized by mature lymphocytosis is extremely rare

in children and is usually not considered in the differential diagnosis of lymphocytosis.

An increase in absolute eosinophil count greater than 0.5 X 109/L (500/L) is generally considered eosinophilia.

The following are common causes of eosinophilia.

Allergy and drug hypersensitivity: This includes asthma, hay fever, angioneurotic edema, urticaria,

atopic dermatitisand eczema, anticonvulsant hypersensitivity reaction, allergy to drugs, eosinophilic

esophagitis and enteritis, and other allergic conditions (see above under the heading of neutrophilia forfamilial cold autoimflammatory syndrome).

Parasitic infections: The most commonly observed parasitic infection causing marked eosinophilia in the

United States is caused by visceral larva migransdue to Toxocara canis.Toxocara catialso causes

visceral larva migrans, but this is rare. Other parasitic infections that cause tissue invasion also cause

marked eosinophilia.

Other infections: Scarlet fever (recovery phase), viral infections (recovery phase), and chlamydial

infectioncause an absolute increase in eosinophils but generally do not cause leukocytosis.

Dermatologic disorders: Dermatitis herpetiformis, pemphigus, and erythema multiforme cause

eosinophilia.

Hypereosinophilic syndrome

Other conditions: Most other conditions that cause eosinophilia rarely lead to leukocytosis and,

therefore, are not listed. However, other rare disorders that should be considered include eosinophiliaassociated with malignant disease. Pulmonary infiltration with eosinophilia (PIE) and a combination of

eosinophilia, leukocytosis, and hepatosplenomegaly may be noteworthy. PIE is characterized by

bilateral pulmonary infiltrates and eosinophilia. The symptoms are similar to those of chronic

pneumonia. The etiologies are multiple and include various infections (bacterial, viral, fungal, and

parasitic) and neoplastic conditions (eg, Hodgkin lymphoma). The combination of leukocytosis,

eosinophilia, and hepatosplenomegaly could be true eosinophilic leukemia (with blasts observed in the

peripheral blood) or marked eosinophilia with a chronic indolent course.

Hyperleukocytosis: This disorder refers to a WBC count 100 X 109/L (100 X 103/L). It is observed

almost exclusively in leukemia and myeloproliferative disorders. Hyperleukocytosis may cause life-

threatening complications (eg, cerebral infarct, cerebral hemorrhage, pulmonary insufficiency). The

frequency of complications is higher in acute myelocytic leukemia than in acute lymphoblastic leukemia

because myeloblasts are larger and more adhesive than lymphoblasts.

Monocytosis is defined as a monocyte count that exceeds the upper limit of the reference range of 0.95 X

199/L (950/L). Monocytosis is commonly caused by the following conditions:
http://emedicine.medscape.com/article/886861-overviewhttp://emedicine.medscape.com/article/214823-overviewhttp://emedicine.medscape.com/article/1000527-overviewhttp://emedicine.medscape.com/article/911574-overviewhttp://emedicine.medscape.com/article/137362-overviewhttp://www.medscape.com/resource/asthmahttp://emedicine.medscape.com/article/971488-overviewhttp://emedicine.medscape.com/article/963090-overviewhttp://emedicine.medscape.com/article/963894-overviewhttp://emedicine.medscape.com/article/967268-overview


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Bacterial infections: These include tuberculosis, subacute bacterial endocarditis, and brucellosis.

Other infections: Syphilis, viral infections (eg, infectious mononucleosis), and many protozoal and

rickettsial infections (erg, kala azar, malaria, Rocky Mountain spotted fever).

Malignancies: Malignancies include chronic myelomonocytic leukemia, monocytic leukemia, Hodgkin

disease, and myeloproliferative disorders; in adults, they include metastatic carcinoma, lung cancer,

and other malignant neoplasms (paraneoplastic leukemoid reaction).

Recovery phase of neutropenia or an acute infection.

Autoimmune disease and vasculitis: These include systemic lupus erythematosus, rheumatoid arthritis,

ulcerative colitis, and inflammatory bowel disease.

Miscellaneous causes: Sarcoidosisand lipid storage diseaseare included.

A basophil count that exceeds 0.10-0.15 X 109/L (100-150/L) that leads to leukocytosis is rare. Chronic

myelogenous leukemia (adult type) typically exhibits basophilia and leukocytosis as described above (see

Malignancy and myeloproliferative disorder).

Contributor Information and DisclosuresAuthor

Susumu Inoue, MD Professor of Pediatrics and Human Development, Michigan State University College of

Human Medicine; Clinical Professor of Pediatrics, Wayne State University School of Medicine; Director of

Pediatric Hematology/Oncology, Associate Director of Pediatric Education, Department of Pediatrics, Hurley

Medical Center

Susumu Inoue, MD is a member of the following medical societies:American Academy of Pediatrics,American

Society of Clinical Oncology,American Society of Hematology,American Society of Pediatric

Hematology/Oncology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Gary R Jones, MD Associate Medical Director, Clinical Development, Berlex Laboratories

Gary R Jones, MD is a member of the following medical societies:American Academy of Pediatrics,American

Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research


Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of

Pharmacy; Editor-in-Chief, Medscape Drug Reference


Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship,

Department of Pediatrics, Uniformed Services University of the Health Sciences

Gary D Crouch, MD is a member of the following medical societies:American Academy of PediatricsandAmerican Society of Hematology


Helen SI Chan, MBBS, FRCP(C), FAAP Associate Senior Scientist, Research Institute; Professor, Division of

Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto Faculty of

Medicine, Canada

Helen SI Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of

Pediatrics,American Association for Cancer Research,American Society of Hematology, and Royal College of

Physicians and Surgeons of Canada


Chief Editor

Robert J Arceci, MD, PhD King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and

the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns
http://rcpsc.medical.org/index.php?pass=1http://www.hematology.org/http://www.aacr.org/http://www.aap.org/http://www.hematology.org/http://www.aap.org/http://www.aps-spr.org/Regional_Societies/WSPR/default.htmhttp://www.aspho.org/i4a/pages/index.cfm?pageid=1http://www.aap.org/http://www.aps-spr.org/http://www.aspho.org/i4a/pages/index.cfm?pageid=1http://www.hematology.org/http://www.asco.org/http://www.aap.org/http://emedicine.medscape.com/article/945966-overviewhttp://emedicine.medscape.com/article/1003964-overviewhttp://emedicine.medscape.com/article/930146-overviewhttp://emedicine.medscape.com/article/1008066-overviewhttp://emedicine.medscape.com/article/971714-overviewhttp://emedicine.medscape.com/article/998942-overviewhttp://emedicine.medscape.com/article/969023-overviewhttp://emedicine.medscape.com/article/962194-overviewhttp://emedicine.medscape.com/article/896540-overviewhttp://emedicine.medscape.com/article/969401-overview


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Hopkins University School of Medicine

Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer

Research,American Association for the Advancement of Science,American Pediatric Society ,American

Society of Hematology, andAmerican Society of Pediatric Hematology/Oncology


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Leukocytosis Clinical Presentation