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Approach to the patient with neutrophilia

Approach to the patient with neutrophilia
Author:
Thomas D Coates, MD
Section Editor:
Peter Newburger, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Sep 2021. | This topic last updated: Jan 04, 2021.

INTRODUCTION — Neutrophilia refers to an increase of peripheral blood neutrophils at least two standard deviations above the mean. For adults, this generally corresponds to >7700 neutrophils/microL (typically seen in patients with >11,000 white blood cells/microL).

This topic will present the clinical evaluation of neutrophilia and its causes. Evaluation of patients with lymphocytosis and eosinophilia are discussed separately. (See "Approach to the adult with lymphocytosis or lymphocytopenia" and "Approach to the patient with unexplained eosinophilia".)

DEFINITIONS — The normal range (ie, two standard deviations above and below the mean) for the white blood cell (WBC) count in adults is 4400 to 11,000 cells/microL in most clinical laboratories. Approximately 60 to 70 percent of leukocytes in the peripheral blood are mature polymorphonuclear neutrophils (PMN) [1]. Thus, the threshold for neutrophilia in most clinical laboratories is approximately 7700/microL (11,000 WBC/microL x 70 percent).

Normal values for WBC in children vary based on age (table 1).

Useful definitions include:

Absolute neutrophil count (ANC) = WBC (cells/microL) x percent (PMNs + bands) ÷ 100 (calculator 1)

Neutrophilia typically corresponds to ANC >7700/microL

Leukocyte refers to any type of WBC, including neutrophils, eosinophils, basophils, monocytes, and lymphocytes. The various types of leukocytes are discussed separately. (See "Evaluation of the peripheral blood smear", section on 'White blood cells'.)

Leukocytosis refers to elevated WBC (leukocyte) count. Neutrophilia is the most common type of leukocytosis, but leukocytosis may also be due to increased monocytes, eosinophils, basophils, and/or lymphocytes. (See "Approach to the adult with lymphocytosis or lymphocytopenia" and "Approach to the patient with unexplained eosinophilia".)

Granulocytosis is often used interchangeably with neutrophilia, but granulocytosis is a broader term that can also reflect increased eosinophils or basophils.

Left shift is an ill-defined term that refers to an increase in the percentage of band forms, generally accompanied by metamyelocytes and myelocytes.

Leukemoid reaction refers to WBC >50,000/microL from causes other than leukemia, with the majority being mature neutrophils, often accompanied by increased numbers of bands, metamyelocytes, and/or myelocytes. (See 'Leukemoid reaction/hyperleukocytosis' below.)

MECHANISMS — Neutrophilia may be due to increased bone marrow production and/or demargination of peripheral blood neutrophils.

The peripheral white blood cell (WBC) count is only a crude reflection of neutrophil production, since the vast majority of neutrophils are present in the bone marrow. Proliferation of neutrophil precursors, the process of myeloid differentiation, and entry of these cells into the circulation are tightly regulated by cytokines and are dependent on orderly control of gene expression by transcription factors. Neutrophils persist in the peripheral blood for only about 10 hours before they enter peripheral tissues in response to infection/inflammation, or undergo apoptosis. (See "Regulation of myelopoiesis".)

Increased production of neutrophils may be autonomous (ie, due to malignant disorders such as myeloproliferative neoplasms) or reactive (ie, in response to infectious or inflammatory processes).

Approximately half of circulating neutrophils are reversibly adherent to the endothelium ("marginated"), so processes that increase neutrophil demargination can rapidly elevate the WBC count.

CAUSES OF NEUTROPHILIA — Causes of neutrophilia (table 2) vary according to the patient population and clinical setting. As examples, the causes of neutrophilia in hospitalized patients differ from those of asymptomatic ambulatory patients, and children are more likely than adults to have inherited disorders.

The urgency and nature of the clinical evaluation of neutrophilia are described below. (See 'Urgency of evaluation' below and 'Clinical evaluation' below.)

Normal variation — There is considerable variability in neutrophil counts in asymptomatic normal populations. Because neutrophilia is defined as at least two standard deviations above the mean, by definition, 2.5 percent of the normal population will be classified as having neutrophilia.

Normal variation is particularly relevant in the asymptomatic patient with persistent mild neutrophilia. Serial evaluation may be required to establish the absence of underlying pathology. Examination of the parents' or siblings' blood counts may be of help in these situations [2,3].

As an example, one report described 34 otherwise healthy subjects with total leukocyte counts of 11,000 to 40,000/microL; other components of the complete blood count were normal other than occasional thrombocytosis, and bone marrow examination was normal [2]. No medical problems became apparent after more than 20 years of follow-up.

Infection — Infections are a common cause of neutrophilia in adults and children, in both the inpatient and outpatient settings. Acute infection should be particularly suspected in patients with a total white blood cell (WBC) count >25,000/microL.

Based on personal experience, the WBC count may rise as high as 100,000/microL in patients with infection or inflammation, but the leukocytosis usually decreases within days of starting treatment. As long as the WBC count is decreasing in response to therapy, the neutrophilia is likely to be reactive.

Neutrophilia with a left shift is commonly seen in association with acute bacterial infections. The blood smear may reveal toxic granulations, Döhle bodies, and cytoplasmic vacuoles in neutrophils (picture 1). Support for the diagnosis may come from clinical evaluation, microbiologic studies, and associated clinical findings (eg, disseminated intravascular coagulation); markers of inflammation (eg, C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]) are typically abnormal, but nonspecific. Neutrophilia in the setting of viral infections may be accompanied by "atypical" lymphocytes. (See "Approach to the child with lymphocytosis or lymphocytopenia", section on 'Evaluation of the child with lymphocytosis'.)

Certain bacteria (eg, pneumococcus, staphylococcus, clostridial species) may cause particularly high leukocyte counts. Unexplained leukocytosis in hospitalized patients, even without diarrhea, may be a harbinger of Clostridioides difficile infection, and usually occurs after 5 to 10 days of antibiotic treatment [4,5].

Neutrophilia in children may be associated with certain viral infections (eg, herpes simplex, varicella), various bacterial infections, leptospiral infections, advanced tuberculosis, and mononucleosis (particularly in the child younger than five years).

In one study performed in an emergency department, compared with age-matched controls with moderate leukocytosis (WBC 12,000 to 25,000/microL), patients with WBC count >25,000/microL were more likely to have an infectious disease (74 versus 48 percent) and had a higher mortality rate [6].

Inflammation — Both acute and chronic inflammatory processes can cause neutrophilia. Examples include juvenile onset rheumatoid arthritis, Kawasaki disease (in which a leukemoid reaction can occur), rheumatoid arthritis in adults, and adult-onset Still's disease [7]. Patients with Crohn's disease, ulcerative colitis, granulomatous infections, bronchiectasis, or chronic hepatitis may develop neutrophilia, especially during disease flares.

Sweet syndrome (also called acute febrile neutrophilic dermatosis), is characterized by neutrophilia, fever, and the abrupt appearance of erythematous, painful, cutaneous plaques. Sweet syndrome is discussed in greater detail separately. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

Establishing the diagnosis of inflammation as the cause of neutrophilia entails evaluation of the clinical context and exclusion of other causes. CRP and ESR are typically elevated, but they are nonspecific measures of inflammation; nevertheless, these tests are particularly helpful in detecting occult inflammation or infection. There are no diagnostic findings on the peripheral blood smear. Rather, microbiologic studies that exclude infections, or cytogenetic and/or molecular tests that exclude malignancies (eg, chronic myeloid leukemia) may be required to indict inflammation as the cause of neutrophilia.

One study of 87 patients with noncystic fibrosis bronchiectasis showed that the neutrophil count was the best correlate for active inflammation [8]. In another study of 110 patients at risk for recurrence of Crohn's disease following surgery, preoperative leukocytosis was significantly associated with recurrence [9].

Medications — Many medications may cause neutrophilia. Among the mechanisms by which drugs may cause neutrophilia are:

Stimulation of bone marrow myelopoiesis and/or egress into the circulation (eg, myeloid growth factors and other cytokines, all-trans retinoic acid [ATRA])

Demargination of neutrophils within the vasculature (eg, catecholamines)

Allergic/Inflammatory reaction to a medication (many medications)

Release of granulocytes from the bone marrow (glucocorticoids, plerixafor)

The drugs most commonly associated with neutrophilia (eg, catecholamines, glucocorticoids, myeloid growth factors, plerixafor, lithium, ATRA) are listed in the table (table 2). Any medication can be considered suspect, but other drugs are less commonly associated with neutrophilia. Review of the medication label and/or a literature search may be useful for implicating a medication as the cause of neutrophilia.

Determining the relation between the onset of neutrophilia and administration of medications can provide important clinical clues to the causative agent. Resolution of neutrophilia upon withdrawal of a drug may be the most persuasive evidence of that medication as the cause. There are no diagnostic abnormalities on the peripheral blood smear, but allergic-type drug reactions are often accompanied by modest eosinophilia.

Neutrophilia may begin within hours of drug administration (eg, from demargination or accelerated bone marrow release) or days or weeks later (eg, allergic reactions, increased proliferation and/or differentiation).

Asplenia — Moderate neutrophilia is often associated with asplenia, whether it is related to surgical splenectomy [10,11], autoinfarction in sickle cell disease [12], or other causes. Asplenia may cause an exaggerated response to infection or inflammation (ie, leukemoid reaction).

Neutrophilia caused by asplenia may be associated with thrombocytosis and the presence of Howell-Jolly bodies (picture 2) or nucleated red blood cells.

Cigarette smoking — Cigarette smoking is probably the most common cause of mild neutrophilia in adults. The mechanism underlying this phenomenon is unknown, although smoking-related inflammation has been suggested [13].

There are no diagnostic findings in the peripheral blood for cigarette smoking as the cause of neutrophilia, and this diagnosis requires assessment of the clinical context and exclusion of other potential causes.

It has been estimated that the WBC count in smokers is raised by about 25 percent, with an approximate doubling of the absolute neutrophil count in subjects who smoke two packs per day [14,15]. While the total WBC count may stay elevated for up to five years after cessation of smoking [14,16], other observations have indicated normalization within months to one or two years [17-19].

Stress/exercise — A modest elevation in the neutrophil count has been associated with many types of "stress," including exercise, heat stroke, surgery, and seizures.

Neutrophilia can occur within minutes of exercise, stress, or epinephrine injection, and this rapid-onset neutrophilia is presumed to be related to demargination [20-22]. In addition, exercise leads to redistribution of neutrophils from the lungs (due to mechanical and blood flow-related effects) and more delayed leukocytosis (about five hours post-exercise) due to bone marrow release of leukocytes [21,23,24]. (See 'Mechanisms' above.)

There are no diagnostic findings for stress as the cause of neutrophilia, and establishing the diagnosis depends on a plausible temporal association and exclusion of other causes.

Obesity — Isolated leukocytosis, without other explanation, may occasionally be observed in patients with obesity (ie, body mass index [BMI] >30) [25].

Endocrine and other causes — A variety of endocrine disorders (eg, thyroid storm, hypercortisolism) and pregnancy-associated conditions (eg, eclampsia, post-partum state) have been associated with neutrophilia. The underlying pathophysiology is poorly understood, but glucocorticoid-associated neutrophil mobilization from the bone marrow and catecholamine-associated demargination of neutrophils may contribute.  

Myeloproliferative neoplasms — Any of the myeloproliferative neoplasms (MPNs) can be associated with neutrophilia.

Chronic myeloid leukemia — Chronic myeloid leukemia (CML) typically presents with the entire spectrum of maturing granulocytic cells (eg, bands, metamyelocytes, myelocytes, promyelocytes, blasts) in the peripheral blood, along with thrombocytosis, polycythemia, eosinophilia and/or basophilia, and splenomegaly. The diagnosis is confirmed by detection of the Philadelphia chromosome (ie, t(9;22)) and/or the BCR-ABL1 fusion gene. The clinical manifestations and diagnosis of CML are discussed in greater detail separately. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)

Juvenile myelomonocytic leukemia — Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative/myelodysplastic disorder of infancy and childhood that is manifest as neutrophilia and infiltration of the peripheral blood, bone marrow, and viscera by abnormal myelomonocytic cells. JMML is almost always associated with mutations of genes within the RAS/MAPK signaling pathway, and its clinical manifestations and diagnosis are discussed in greater detail separately. (See "Juvenile myelomonocytic leukemia".)

Other myeloproliferative neoplasms — Neutrophilia may accompany any of the MPNs, including polycythemia vera, essential thrombocythemia, chronic myelomonocytic leukemia, and chronic neutrophilic leukemia. Additional details regarding the diagnostic criteria and molecular abnormalities are described separately. (See "Clinical manifestations and diagnosis of polycythemia vera" and "Diagnosis and clinical manifestations of essential thrombocythemia" and "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis" and "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Chronic neutrophilic leukemia'.)

Nonhematologic malignancy — Neutrophilia may be associated with nonhematologic malignancies, due to bone marrow metastases, nonspecific inflammation, and/or paraneoplastic effects [26].

Neutrophilia in the setting of cancer is often associated with anemia of chronic disease/inflammation. Bone marrow metastases may manifest a leukoerythroblastic appearance on the peripheral blood smear. These conditions are discussed in greater detail separately. (See 'Peripheral blood smear' below.)

Genetic/inherited disorders — The likelihood of an inherited cause of neutrophilia is greatest in neonates and children, but some hereditary forms of neutrophilia may not be detected until adulthood.

Suspicion for inherited neutrophilia should be higher when other family members manifest hematologic or somatic abnormalities, especially in the setting of abnormalities on the peripheral blood smear. Confirming the diagnosis of a genetic disorder as the cause of neutrophilia requires bone marrow examination, cytogenetic and/or molecular studies, and may benefit from referral to an investigator/center with expertise in this type of disorder.

Leukocyte adhesion deficiency — Leukocyte adhesion deficiency (LAD) is a rare disorder caused by inherited defects of leukocyte adhesion molecules. Neonates with LAD typically present with persistent, 5- to 20-fold elevation of leukocytes, delayed separation of the umbilical cord, and recurrent infections.

Defining LAD as the cause of leukocytosis depends on proper clinical context and molecular testing to distinguish between infants with LAD I (defects of CD18), LAD II (lack of sialyl Lewis X, the ligand for L-selectin), and LAD III. Additional details are presented separately. (See "Leukocyte-adhesion deficiency".)

Chronic neutrophilic leukemia — Chronic neutrophilic leukemia (CNL), which has also been called hereditary chronic neutrophilia, is a rare disorder associated with an activating germline mutation in CSF3R, the gene that encodes the granulocyte colony-stimulating factor (G-CSF) receptor [27,28]. The mutation leads to chronic neutrophilia by constitutively activating the G-CSF receptor, thereby promoting granulocyte proliferation and differentiation. The marrow is hypercellular with increased mature granulocytes, no dysplasia and <5 percent blasts [29]. One-third of patients have significant splenomegaly, which may be painful. The prevalence of CNL is not well defined. The neutrophil count can be very high, but is typically in the range of 20,000 to 35,000/microL, with otherwise normal blood counts. This suggests that otherwise asymptomatic patients with persistent, moderately elevated neutrophil counts should be evaluated for the mutations of CSFR3. Progression to a myelodysplastic syndrome was observed in approximately 20 percent of cases [27,28].

Down syndrome — Infants with Down syndrome (trisomy of chromosome 21) may have a transient abnormal myelopoiesis (also called transient myeloproliferative disorder [TMD] of Down syndrome) that resembles congenital acute leukemia or chronic myeloid leukemia [30]. Affected children can also have exaggerated leukemoid responses to stress [31]. The mechanism by which this occurs is unclear. TMD may resolve spontaneously, but evolves into overt acute myeloid leukemia in a subset of patients. (See "Transient myeloproliferative disorder of Down syndrome".)

The diagnosis is established by identification of blasts on the peripheral blood smear; cytogenetic, immunophenotypic, and molecular testing (ie, detection of GATA1 mutation); and exclusion of acute myeloid leukemia. (See "Transient myeloproliferative disorder of Down syndrome", section on 'Diagnosis'.)

Transient leukemoid reactions simulating acute leukemia have also been seen in phenotypically normal children who expressed trisomy 21 mosaicism in myeloid cells but not in skin fibroblasts. The chromosomal abnormalities disappeared after the leukemoid reaction resolved [32,33].

Cryopyrin-associated periodic syndromes — Cryopyrin-associated periodic syndromes, including familial cold autoinflammatory syndrome (also called familial cold-induced urticaria) and the Muckle-Wells syndrome, are rare inherited conditions with protean clinical manifestations that may include neutrophilia and inflammation of skin, joints, central nervous system, and eyes.

There are no defining features on the peripheral blood smear, but these disorders may be diagnosed by detection of mutations in NLRP3 (the gene encoding cryopyrin). These disorders are discussed in greater detail separately. (See "Cryopyrin-associated periodic syndromes and related disorders".)

URGENCY OF EVALUATION — The urgency of evaluation of neutrophilia is guided by the patient's clinical condition, the presence of worrisome findings on other blood tests (eg, leukemic blasts, disseminated intravascular coagulation), and the degree and rate of rise of neutrophilia (if known).

As examples:

Neutrophilia accompanied by clinical instability (eg, hypotension, high fever, hypothermia, abdominal rebound tenderness) usually requires immediate hospitalization and urgent evaluation.

Asymptomatic, modest neutrophilia may be monitored and evaluated as an outpatient if the patient is clinically stable.

White blood cell count >100,000/microL may warrant urgent hematologic consultation, including consideration of emergency leukapheresis to prevent vaso-occlusive complications of hyperviscosity. Leukemic blast cells, because of their nondeformability, cause hyperviscosity at lower cell counts (approximately 75,000/microL). (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

CLINICAL EVALUATION — Neutrophilia may be encountered in the course of evaluating other clinical findings or as an incidental abnormality on a complete blood count (CBC). Initial evaluation includes history and physical examination, review of the peripheral blood smear, and other laboratory studies. The abnormal CBC should be repeated in order to exclude laboratory error and other reasons for spurious reports of neutrophilia. The repeated specimen should be evaluated by the clinical laboratory promptly. (See 'Spurious neutrophilia (artifacts)' below.)

History and physical examination — The history should seek evidence of underlying causes of reactive or malignant disorders that can account for neutrophilia. (See 'Causes of neutrophilia' above.)

When available, a history of previous CBCs (normal and abnormal) can provide crucial information about the duration and trajectory of neutrophilia.

Important aspects of the history include evidence of:

Active or prior infection or inflammation (see 'Infection' above and 'Inflammation' above)

Hematologic malignancies (eg, myeloproliferative neoplasms, acute leukemias) or other hematologic disorders (eg, sickle cell disease) (see 'Myeloproliferative neoplasms' above)

Surgical or functional asplenia (see 'Asplenia' above)

Cigarette smoking (see 'Cigarette smoking' above)

Vigorous exercise (see 'Stress/exercise' above)

Extreme physical or emotional distress (see 'Stress/exercise' above)

Conditions that may be associated with neutrophilia (eg, pregnancy, eclampsia, post-partum, thyroid storm, hypercortisolism)

Family history of neutrophilia (see 'Genetic/inherited disorders' above)

The physical examination should seek evidence of infection, inflammation, or malignancy, such as fever, lymphadenopathy, hepatosplenomegaly, joint redness, abdominal pain, and pulmonary abnormalities.

Medications — Numerous medications may cause neutrophilia. The relationship between the onset of neutrophilia and administration of various medications should be defined.

The most commonly associated drugs are listed in the table (eg, catecholamines, glucocorticoids, myeloid growth factors, lithium, all-trans retinoic acid) (table 2). Other drugs are occasionally reported to be associated with neutrophilia. (See 'Medications' above.)

Complete blood count (CBC) — The CBC and differential count provide essential information about the number and nature of neutrophils (and immature precursors), other leukocytes, red blood cells (RBCs), and platelets.

Neutrophilia may be the sole abnormality on the CBC or it may be accompanied by abnormalities in other lineages. (See 'Neutrophilia combined with other hematologic abnormalities' below.)

Automated particle counters provide a differential count (the percentage of various types of leukocytes, including immature granulocytic forms). In the setting of neutrophilia, the differential count should be confirmed and validated by a review of the peripheral blood smear (below). (See "Automated hematology instrumentation".)

Peripheral blood smear — Review of the peripheral blood smear is important to evaluate the neutrophils, identify abnormalities in other lineages, and exclude spurious leukocytosis. Examination of the peripheral blood smear and findings relevant to the evaluation of neutrophilia are discussed in greater detail separately. (See "Evaluation of the peripheral blood smear".)

Neutrophil abnormalities — Examples include:

Left shift of granulocytes (ie, abundant band forms, metamyelocytes, myelocytes) may be due to severe infection/sepsis or chronic myeloid leukemia (CML), while the presence of significant number of myeloid blasts suggests acute myeloid leukemia (AML) (picture 3); occasionally, blasts can be seen with extreme inflammation/bone marrow stimulation.

Döhle bodies and toxic granulations suggest an infectious or inflammatory process (picture 1).

Dysplastic leukocytes may be due to chronic myelomonocytic leukemia (CMML) (picture 4).

Spurious neutrophilia (artifacts) — Examples of artifacts that may yield falsely elevated (spurious) neutrophilia include:

Platelet clumping — Clumping of platelets can cause spurious neutrophilia in an automated particle counter. Examination of the peripheral smear will reveal platelet clumping. A repeat blood sample adequately anticoagulated with citrate or heparin (rather than EDTA) should resolve this problem.

Platelet clumping can occur under the following circumstances:

Insufficient anticoagulation – Inadequate anticoagulation may cause platelet aggregation by some automated cell counters. However, the white blood cell (WBC) count is rarely increased by more than 10 percent and there is usually an associated spurious thrombocytopenia [34].

Pseudothrombocytopenia – Normal subjects with EDTA-dependent agglutinins may exhibit platelet clumping that can be erroneously reported as leukocytosis (pseudoleukocytosis) (picture 5) [35]. (See "Diagnostic approach to the adult with unexplained thrombocytopenia", section on 'Pseudothrombocytopenia'.)

Cryoglobulinemia — When cold-insoluble plasma proteins are present, a temperature-dependent increase in leukocyte and platelet counts occurs at temperatures of 30°C or less. This can result in WBC counts as high as 50,000/microL and a doubling of the platelet count, both of which are attributed to various sizes of precipitated cryoglobulin particles [36]. This effect is increased if the sample is allowed to cool to lower temperatures and disappears if the sample is kept at body temperature. A repeat blood sample maintained at body temperature should resolve this problem. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Detection of cryoglobulins'.)

Neutrophilia combined with other hematologic abnormalities — Neutrophilia may be an isolated abnormality (the sole abnormality on CBC and/or blood smear) or it may be associated with abnormalities of other leukocytes, RBCs, and/or platelets.

Examples of conditions in which neutrophilia is associated with other abnormalities include:

Other leukocyte abnormalities — Certain causes of neutrophilia are more common in patients with elevated levels of monocytes, eosinophils, or basophils. (See "Approach to the patient with unexplained eosinophilia".)

Monocytes Monocytosis may accompany neutrophilia in various conditions, including:

Infections: brucellosis, varicella-zoster, bacterial endocarditis, tuberculosis, malaria, typhoid fever, syphilis, trypanosomiasis, and others

Malignancies: CMML, CML, AML, Hodgkin lymphoma

Inflammatory conditions: sarcoidosis, inflammatory bowel disease, other autoimmune conditions

Medications: corticosteroids, myeloid growth factors

Other conditions: pregnancy, asplenia

Eosinophils or basophils – Eosinophilia and or basophilia accompanying neutrophilia may be due to:

Allergic conditions

Infections (eg, helminths, toxocariasis, trichinellosis, protozoal infections, other parasites)

Malignancies (eg, CML, other MPNs, Hodgkin lymphoma, acute eosinophilic leukemia, systemic mastocytosis, others)

Inflammatory conditions: sarcoidosis, inflammatory bowel disease

Red blood cells (RBCs) — Disorders of RBCs are often associated with neutrophilia. Review of RBC indices, the peripheral blood smear, and other laboratory tests may provide important information about underlying causes. (See "Evaluation of the peripheral blood smear" and "Diagnostic approach to anemia in adults" and "Approach to the child with anemia".)

Examples of RBC abnormalities that may be associated with neutrophilia include:

Microangiopathic hemolytic anemia (MAHA) – MAHA (ie, fragmented RBCs on peripheral blood smear) is suspicious for thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), and related disorders, which require urgent evaluation. These are discussed in greater detail separately. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Disseminated intravascular coagulation (DIC) in adults: Evaluation and management".)

Leukoerythroblastosis – Leukoerythroblastosis (picture 6) is characterized by teardrop-shaped red cells (picture 7), nucleated red cells, and immature WBC forms. Detection of leukoerythroblastosis suggests a myelophthisic process (eg, primary myelofibrosis, other MPNs, cancer metastatic to the bone marrow, and occasionally, vasculitis or fungal or tuberculous infection) (table 2).

Anemia – Anemia has numerous causes and is frequently associated with neutrophilia. Anemia is discussed in greater detail separately. (See "Diagnostic approach to anemia in adults" and "Approach to the child with anemia".)

Polycythemia – Polycythemia (elevated hemoglobin and/or hematocrit) suggests an underlying MPN (eg, polycythemia vera, CML, others), especially if accompanied by eosinophilia and/or basophilia. Relative polycythemia due to loss of plasma volume may be seen in sepsis or other infectious conditions. (See "Diagnostic approach to the patient with polycythemia" and "Clinical manifestations and diagnosis of polycythemia vera".)

Platelets — Examples of platelet abnormalities that may be associated with neutrophilia include:

Thrombocytosis – Thrombocytosis accompanying neutrophilia may be due to various infectious, inflammatory, or malignant conditions (eg, MPNs), or following periods of marrow recovery. (See "Approach to the patient with thrombocytosis" and "Diagnosis and clinical manifestations of essential thrombocythemia".)

Thrombocytopenia – Thrombocytopenia associated with neutrophilia may be seen in sepsis from acute bacterial infection, with or without DIC. Associated findings on the peripheral smear are a pronounced left shift and toxic granulations, Döhle bodies, and cytoplasmic vacuoles (picture 1).

Thrombocytopenia accompanied by MAHA may represent DIC, TTP, or hemolytic uremic syndrome. (See "Overview of hemolytic uremic syndrome in children".)

Other laboratory tests — Examples of testing that may help to distinguish malignant disorders from reactive causes of neutrophilia in the initial evaluation of neutrophilia include:

Renal and liver function tests should be performed in all patients as they may identify associated medical conditions or complications.

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated in inflammation and infection, and may be helpful in evaluating the cause of neutrophilia in an asymptomatic patient.

Coagulation testing may support the diagnosis of neutrophilia associated with sepsis (eg, elevated D-dimer in DIC).

Tests for Clostridioides difficile may be considered in a hospitalized patient with unexplained leukocytosis after antibiotic treatment, since this disorder has a protean clinical presentation. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis".)

Specialized testing — Findings from the initial evaluation (history, physical examination, CBC, peripheral blood smear) should permit the clinician to generate a differential diagnosis for neutrophilia. In many cases, serial observation alone may be sufficient when no cause has been identified from the initial clinical evaluation. As an example, an asymptomatic patient with modest, stable neutrophilia might simply be followed as an outpatient with serial CBCs.

In some cases, additional testing may be required to confirm the underlying cause of neutrophilia. However, these tests should not be routinely or universally applied; rather, they should be utilized to confirm or exclude particular diagnoses.

Examples of specialized testing that may be useful based on findings from the initial evaluation include:

Bone marrow aspirate and biopsy – Bone marrow examination is not required for the evaluation of most cases of neutrophilia. Nevertheless, it may yield critical information based on marrow morphology, flow cytometry, microbiologic testing (eg, stains and/or cultures for fungi and mycobacteria, if warranted), and cytogenetic and molecular analysis. Bone marrow biopsy is essential for confirming the diagnosis in AML and in some other hematologic malignancies.

Flow cytometry – Immunophenotyping of the peripheral blood may demonstrate clonal disorders, such as CML, polycythemia vera, essential thrombocythemia, and other hematologic malignancies.

Molecular/genetic testing – In some patients, molecular testing may be required to confirm or exclude a diagnosis. Examples include testing of peripheral blood or bone marrow for BCR/ABL1 to confirm the diagnosis of CML, or for karyotype and GATA1 to assess transient abnormal myelopoiesis of Down syndrome.

LEUKEMOID REACTION/HYPERLEUKOCYTOSIS — Leukemoid reaction refers to a white blood cell (WBC) count >50,000/microL from causes other than leukemia. The majority of cells are mature neutrophils, often accompanied by a prominent left shift.

Examples of conditions that may be associated with leukemoid reactions include:

Infections: Clostridioides difficile, tuberculosis, pertussis, visceral larva migrans (associated with prominent eosinophilia)

Medications: myeloid cytokines, all-trans retinoic acid (see "Differentiation syndrome associated with treatment of acute leukemia")

Asplenia/hyposplenia (surgical or functional)

Nonhematologic malignancies [26]

WBC >100,000/microL may warrant urgent hematologic consultation, including consideration of emergency leukapheresis to prevent the vaso-occlusive complications of hyperviscosity. Leukemic blast cells, because of their nondeformability, cause hyperviscosity at lower cell counts (approximately 75,000/microL). (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

SUMMARY

Neutrophilia refers to an increase of peripheral blood neutrophils at least two standard deviations above the mean. For adults, in most clinical laboratories, this corresponds to >7700 neutrophils/microL (typically seen in patients with >11,000 white blood cells [WBC]/microL). (See 'Definitions' above.)

Normal values for WBC in children vary based on age (table 1).

Neutrophilia may be caused by increased production (autonomous or reactive) and/or increased demargination of neutrophils. (See 'Mechanisms' above.)

Causes of neutrophilia include the following (table 2) (see 'Causes of neutrophilia' above):

Normal variation

Infection

Inflammation (acute or chronic)

Medications (eg, glucocorticoids, catecholamines)

Cigarette smoking, exercise, and various types of physical or emotional stress

Asplenia/hyposplenia

Myeloproliferative neoplasms

Laboratory artifact (eg, platelet clumping, cryoglobulinemia)

Urgency of evaluation of neutrophilia is guided by the patient's clinical condition, the presence of worrisome findings on peripheral blood smear (eg, leukemic blasts, disseminated intravascular coagulation), and the degree and rate of rise of neutrophilia. (See 'Urgency of evaluation' above.)

Clinical evaluation of a patient with leukocytosis should include a history and physical examination, complete blood count with differential count, and examination of the peripheral blood smear. (See 'Clinical evaluation' above.)

Review of the peripheral blood smear is important to define the nature of the increased neutrophils, identify abnormalities in other lineages, and exclude spurious leukocytosis. (See 'Peripheral blood smear' above.)

For some patients, other laboratory studies may be useful. Examples include nonspecific markers of inflammation (eg, C-reactive protein, erythrocyte sedimentation rate), serum chemistries to evaluate associated conditions or complications, and coagulation studies to assess possible disseminated intravascular coagulation. (See 'Other laboratory tests' above.)

Specialized testing, including bone marrow examination, flow cytometry, cytogenetics, and molecular studies may be critical for establishing certain diagnoses (eg, chronic myeloid leukemia, acute myeloid leukemia), but should not be universally or routinely performed. Rather, the selection of specific specialized tests should be guided by clinical findings and the differential diagnosis. (See 'Specialized testing' above.)

Leukocytosis to values in excess of 50,000 cells/microL, when due to causes other than leukemia, is termed a leukemoid reaction or hyperleukocytosis. Leukemoid reaction may be associated with infections, medications, asplenia, and other conditions. (See 'Leukemoid reaction/hyperleukocytosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.

REFERENCES

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Topic 8381 Version 39.0

References

1 : Hematological and iron-related analytes--reference data for persons aged 1 year and over: United States, 1988-94.

2 : Chronic idiopathic leukocytosis.

3 : Leukocyte count differences in healthy white and black children 1 to 5 years of age.

4 : Conditions associated with leukocytosis in a tertiary care hospital, with particular attention to the role of infection caused by clostridium difficile.

5 : Diagnosis and treatment of Clostridium difficile in adults: a systematic review.

6 : Extreme leukocytosis in the emergency department.

7 : Adult Still's disease: manifestations, disease course, and outcome in 62 patients.

8 : Systemic markers of inflammation in stable bronchiectasis.

9 : Prognostic factors for postoperative recurrence of Crohn's disease. Gruppo Italiano per lo Studio del Colon e del Retto (GISC)

10 : The effect of splenectomy on the leucocyte count.

11 : Persistent neutrophilic leukocytosis associated with idiopathic functional asplenia.

12 : Functional asplenia in sickle-cell anemia.

13 : Independent association of various smoking characteristics with markers of systemic inflammation in men. Results from a representative sample of the general population (MONICA Augsburg Survey 1994/95).

14 : Smoking, alcohol consumption, and leukocyte counts.

15 : Cigarette smoking and peripheral blood leukocyte differentials.

16 : Smoking-induced leukocytosis can persist after cessation of smoking.

17 : Quitting smoking may restore hematological characteristics within five years.

18 : Effects of biochemically confirmed smoking cessation on white blood cell count.

19 : Leukocytosis and Tobacco Use: An Observational Study of Asymptomatic Leukocytosis.

20 : Diminished polymorphonuclear leukocyte adherence. Function dependent on release of cyclic AMP by endothelial cells after stimulation of beta-receptors by epinephrine.

21 : Exercise-induced changes in the blood concentration of leukocyte populations in teenage athletes.

22 : Pitfalls in the interpretation of leukocyte counts of newborn infants.

23 : Leukocytosis of exercise: role of cardiac output and catecholamines.

24 : Leucocytosis induced by exercise.

25 : Leukocytosis in obese individuals: possible link in patients with unexplained persistent neutrophilia.

26 : Etiology and outcome of extreme leukocytosis in 758 nonhematologic cancer patients: a retrospective, single-institution study.

27 : Inherited transmission of the CSF3R T618I mutational hotspot in familial chronic neutrophilic leukemia.

28 : Chronic neutrophilic leukemia: 2018 update on diagnosis, molecular genetics and management.

29 : The 2016 revision of the World Health Organization classification of lymphoid neoplasms.

30 : Congenital leukaemia and the neonatal myeloproliferative disorders associated with Down's syndrome.

31 : Hypoglycemia and leukemoid reaction with hypernephroma.

32 : Transient blastemia in phenotypically normal newborns.

33 : Transient leukemoid reaction and trisomy 21 mosaicism in a phenotypically normal newborn.

34 : Spurious leukocytosis and thrombocytopenia. A dual phenomenon caused by clumping of platelets in vitro.

35 : Pseudoleukocytosis due to EDTA-induced platelet clumping.

36 : Pseudoleucocytosis and pseudothrombocytosis due to cryoglobulinaemia.