View source for Medicine:White blood cell differential

{{Short description|Blood test}}
{{Use Canadian English|date=March 2021}}
{{Infobox diagnostic
| name            = White blood cell differential
| image           = Neutrophil_-_Band_cell-1_(%2Blymphocytes).JPG
| alt             = Neutrophil (left) and lymphocytes (right) seen microscopically on a blood smear
| caption         = [[Biology:Neutrophil|Neutrophil]] (left) and [[Biology:Lymphocyte|lymphocyte]]s (right) seen microscopically on a [[Medicine:Blood smear|blood smear]]
| pronounce       = 
| purpose         = Describing populations of white blood cells in peripheral blood
| test of         =
| based on        =
| synonyms        = Differential leukocyte count,<ref name="GulatiSong2013"/> leukogram,<ref name="ecli_Leuk"/> autodiff,<ref name="Lutinger2002"/> manual diff<ref name="GulatiSong2013"/>
| reference_range =
| calculator      =
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| ICD10           = <!--{{ICD10|Group|Major|minor|LinkGroup|LinkMajor}} or {{ICD10PCS|code|char1/char2/char3/char4}}-->
| ICD9            =
| ICDO            =
| MedlinePlus     = 003657
| eMedicine       = 2085133
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| OPS301          = <!--{{OPS301|code}}-->
| LOINC           = {{LOINC|33255-1}}, {{LOINC|24318-8}}, {{LOINC|69738-3}}
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A '''white blood cell differential''' is a [[Medicine:Medical laboratory|medical laboratory]] test that provides information about the types and amounts of [[Biology:White blood cell|white blood cell]]s in a person's blood. The test, which is usually ordered as part of a [[Medicine:Complete blood count|complete blood count]] (CBC), measures the amounts of the five normal white blood cell types{{snd}}[[Biology:Neutrophil|neutrophil]]s, [[Biology:Lymphocyte|lymphocyte]]s, [[Biology:Monocyte|monocyte]]s, [[Biology:Eosinophil|eosinophil]]s and [[Biology:Basophil|basophil]]s{{snd}}as well as abnormal cell types if they are present. These results are reported as percentages and absolute values, and compared against [[Reference range|reference range]]s to determine whether the values are normal, low, or high. Changes in the amounts of white blood cells can aid in the diagnosis of many health conditions, including [[Medicine:Viral disease|viral]], [[Medicine:Pathogenic bacteria|bacterial]], and [[Medicine:Parasitic disease|parasitic]] infections and blood disorders such as [[Medicine:Leukemia|leukemia]].

White blood cell differentials may be performed by an automated analyzer{{snd}}a machine designed to run laboratory tests – or manually, by examining [[Medicine:Blood smear|blood smear]]s under a microscope. The test was performed manually until white blood cell differential analyzers were introduced in the 1970s, making the '''automated differential''' possible. In the automated differential, a blood sample is loaded onto an analyzer, which samples a small volume of blood and measures various properties of white blood cells to produce a differential count.  The '''manual differential''', in which white blood cells are counted on a [[Staining|stained]] microscope slide, is now performed to investigate abnormal results from the automated differential, or upon request by the healthcare provider. The manual differential can identify cell types that are not counted by automated methods and detect clinically significant changes in the appearance of white   blood cells.

In 1674, [[Biography:Antonie van Leeuwenhoek|Antonie van Leeuwenhoek]] published the first microscopic observations of blood cells. Improvements in microscope technology throughout the 18th and 19th centuries allowed the three cellular components of blood to be identified and counted. In the 1870s, [[Biography:Paul Ehrlich|Paul Ehrlich]] invented a staining technique that could differentiate between each type of white blood cell. Dmitri Leonidovich Romanowsky later modified Ehrlich's stain to produce a wider range of colours, creating the [[Biology:Romanowsky stain|Romanowsky stain]], which is still used to stain blood smears for manual differentials.

Automation of the white blood cell differential began with the invention of the [[Engineering:Coulter counter|Coulter counter]], the first automated [[Medicine:Hematology analyzer|hematology analyzer]], in the early 1950s. This machine used electrical impedance measurements to count cells and determine their sizes, allowing white and red blood cells to be enumerated. In the 1970s, two techniques were developed for performing automated differential counts: digital image processing of microscope slides and [[Biology:Flow cytometry|flow cytometry]] techniques using light scattering and cell staining. These methods remain in use on modern hematology analyzers.

{| class="wikitable plainrowheaders mw-collapsible floatright" style="font-size:85%;"
|+ Example of WBC differential reference ranges<ref name="rodak-rrs">Keohane, E ''et al''. (2015). Front matter.</ref>
|-
! scope="col" | Cell type
! scope="col" | Adult<br/>reference range<br/>(× 10<sup>9</sup>/L)
! scope="col" | Adult<br/>reference range<br/>(percentage)
|-
! scope="row" | Neutrophils
|1.7–7.5
|50–70
|-
! scope="row" | Lymphocytes
|1.0–3.2
|18–42
|-
! scope="row" | Monocytes
|0.1–1.3
|2–11
|-
! scope="row" | Eosinophils
|0.0–0.3
|1–3
|-
! scope="row" | Basophils
|0.0–0.2
|0–2
|}
The white blood cell differential is a common blood test that is often ordered alongside a [[Medicine:Complete blood count|complete blood count]]. The test may be performed as part of a routine medical examination; to investigate certain symptoms, particularly those suggestive of [[Medicine:Infection|infection]] or hematological disorders;<ref name="medline"/><ref name=LTO/> or to monitor existing conditions, such as blood disorders and inflammatory diseases.<ref>Kottke-Marchant, K; Davis, B (2012). p. 33.</ref>

Five types of white blood cells are normally found in blood: [[Biology:Neutrophil|neutrophil]]s, [[Biology:Lymphocyte|lymphocyte]]s, [[Biology:Monocyte|monocyte]]s, [[Biology:Eosinophil|eosinophil]]s and [[Biology:Basophil|basophil]]s.<ref name="turgeon-wbc">Turgeon, ML (2016). p. 303.</ref>  Marked shifts in the proportions of these cell types, as measured by the automated or manual differential, can indicate various health conditions.<ref name=BarnesMcfadden2005/> Additionally, cell types which do not normally occur in the blood, such as blast cells, can be identified by the manual differential. These cell types may be found in blood disorders and other pathological states.<ref name="d'OnofrioZini2014">d'Onofrio, G ''et al''. (2014). p. 289.</ref><ref name="Chabot-Richards2015"/> The manual differential can also identify changes in the appearance of white blood cells, such as  reactive lymphocytes,<ref>Bain, B ''et al.'' (2012). pp. 95–7.</ref> or features such as [[Medicine:Toxic granulation|toxic granulation]] and [[Medicine:Toxic vacuolation|vacuolation]] in neutrophils.<ref name="Ciesla, B 2018. p. 153">Ciesla, B (2018). p. 153.</ref> The results of the white blood cell differential are reported as percentages and absolute values. Absolute counts are usually reported in units of cells per microliter (µL) or 10<sup>9</sup> cells per liter (L).<ref name="LTO"/> The result are then compared against [[Reference range|reference range]]s, which are defined by individual laboratories and may vary due to different patient populations and testing methods.<ref name="ICSH2015"/>

CBC and differential testing is usually performed on [[Medicine:Vein|venous]] or [[Biology:Capillary|capillary]] blood. Capillary blood draws are generally used for infants and individuals whose veins are difficult to access.<ref>Bain, B ''et al.'' (2012). pp. 2–4.</ref> To prevent clotting, the sample is drawn into a tube containing the [[Medicine:Anticoagulant|anticoagulant]] compound [[Chemistry:Ethylenediaminetetraacetic acid|ethylenediaminetetraacetic acid]] (EDTA).<ref>Smock, KJ. Chapter 1 in Greer, JP ''et al''. ed. (2018), sec. "Specimen collection".</ref> Tubes containing [[Chemistry:Sodium citrate|sodium citrate]] may be for patients in whom EDTA causes [[Medicine:Pseudothrombocytopenia|platelet clumping]].<ref>Keohane, E ''et al''. (2015). p. 118.</ref> The test is performed on whole blood, meaning blood that has not been [[Medicine:Centrifuge|centrifuge]]d.<ref>Warekois, R; Robinson, R. (2013). p. 116.</ref>

==Types==
===Manual differential===
[[Image:Mononucl%C3%A9ose_infectieuse-7.JPG|thumb|alt=Reactive lymphocytes in infectious mononucleosis|The manual differential technique allows cells to be classified based on subtle changes in appearance, as in these reactive lymphocytes seen in a person with infectious mononucleosis.]]
In a manual differential, a stained [[Medicine:Blood smear|blood smear]] is examined under a microscope and white blood cells are counted and classified based on their appearance. A manual differential is usually performed when the automated differential is flagged for review or when the healthcare provider requests it.<ref name="GulatiSong2013"/><ref name="BarnesMcfadden2005"/> If the manual differential shows findings suggestive of certain serious conditions, such as leukemia, the blood smear is referred to a physician (generally a hematologist or pathologist) for confirmation.<ref name="GulatiSong2013"/>

====Procedure====
[[Image:Stained peripheral blood smear closeup.jpg|thumb|upright=0.7|left|Closeup of the feathered edge of a stained blood smear|alt=Closeup of the feathered edge of a stained blood smear]] A blood smear is prepared by placing a drop of blood on a microscope slide and using a second slide held at an angle to spread the blood and pull it across the slide, forming a "feathered edge" consisting of a single layer of cells at the end of the smear.<ref>Turgeon, ML. (2016). pp. 346–8.</ref> This may be done by hand or using an automated slide maker coupled to a hematology analyzer. The slide is treated with a Romanowsky stain, commonly Wright's stain or Wright-Giemsa, and examined under the microscope. The smear is examined in a systematic pattern, scanning from side to side within the feathered edge and counting cells consecutively. The differential is typically performed at 400x or 500x magnification, but 1000x magnification may be used if abnormal cells are present.<ref>Wang, S; Hasserjian, R. (2018). pp. 10–1.</ref> Cells are identified based on their [[Biology:Morphology|morphologic]] features, such as the size and structure of their nucleus and the colour and texture of their cytoplasm. This allows abnormal cell types and changes in cellular appearance to be identified.<ref name="turgeon-wbc"/> In most cases, the microscopist counts 100 white blood cells, but 200 may be counted for better representation if the white blood cell count is high.<ref>Wang, S; Hasserjian, R. (2018). p. 10.</ref> The manual differential count produces percentages of each cell type, which can be multiplied by the total white blood cell count from the analyzer to derive the absolute values.<ref>Turgeon, ML. (2016). p. 329.</ref>

The manual differential can be partially automated with digital microscopy software,<ref>Turgeon, ML. (2016). p. 318.</ref> which uses [[Artificial intelligence|artificial intelligence]] to classify white blood cells from photomicrographs of the blood smear.<ref>Bain, B ''et al.'' (2012). pp. 44–5.</ref> However, this technique requires confirmation by manual review.<ref name="KratzLee2019"/><ref name="Da Costa2015"/>

====Limitations====
Because relatively few cells are counted in the manual differential, the variability is higher than in automated techniques, especially when cells are present in low amounts.<ref name="wintrobe-cc">Smock, KJ. Chapter 1 in Greer, JP ''et al''. ed. (2018), sec. "Cell counts".</ref> For example, in a sample containing 5 percent monocytes, the manual differential results could be between 1 and 10 percent due to [[Sampling (statistics)|sampling]] variation.<ref name="Rumke1978"/> Additionally, cell identification is subjective and the accuracy depends on the skills of the person reading the slide.<ref name="wintrobe-cc"/><ref>McClatchey, K (2002). p. 809.</ref> Poor blood smear preparation can cause an uneven distribution of white blood cells, resulting in inaccurate counting,<ref>Bain, B ''et al''. (2012). pp. 30–1.</ref> and improper staining can impede cell identification.<ref name="wintrobe-diff">Smock, KJ. Chapter 1 in Greer, JP ''et al''. ed. (2018). sec. "Leukocyte differentials".</ref> Overall, manual differential counts exhibit [[Coefficient of variation|coefficients of variation]] (CVs) ranging from 5 to 10 percent, while automated differential counts of normal neutrophils and lymphocytes have CVs of about 3 percent.<ref name="wintrobe-diff"/>

In [[Medicine:Leukemia|leukemia]]s and other hematologic malignancies, the lineage and genetic characteristics of white blood cells have important implications for treatment and prognosis, and the microscopic appearance of the cells is often insufficient for accurate classification.<ref>Harmening, D (2009). p. 336.</ref><ref name="ICSH2015"/> In these cases, other techniques such as [[Medicine:Immunophenotyping|immunophenotyping]] by flow cytometry or special staining can be used to definitively identify the cells.<ref>Wang, S; Hasserjian, R. (2018). p. 9.</ref>

===Automated differential===
[[File:Sysmex_WBC_scattergrams.jpg|thumb|right|alt=White blood cell differential scattergram|Example of a white blood cell differential scattergram: differently coloured clusters indicate different cell populations]]

Most [[Medicine:Hematology analyzer|hematology analyzer]]s provide a five-part differential, enumerating neutrophils, lymphocytes, monocytes, eosinophils and basophils. Some instruments can also count immature granulocytes and [[Biology:Nucleated red blood cell|nucleated red blood cell]]s.<ref name="harmening-795">Harmening, D (2009). p. 795.</ref> Hematology analyzers measure various properties of white blood cells, such as impedance, light scattering parameters, and staining reactions. This data is analyzed and plotted on a scattergram, forming distinct clusters which correspond to white blood cell types.<ref name="bain-43">Bain, B ''et al.'' (2012). p. 43.</ref> The analyzer counts many more cells than are counted in a manual differential, resulting in improved precision.<ref name="wintrobe-cc"/> If abnormal features or cell populations that the analyzer cannot identify are present, the instrument can flag the results for manual blood smear review.<ref name="harmening-795"/><ref name="bain-43"/>

====Procedure====
[[Image:Sysmex XT-4000i.jpg|thumb|left|alt=An automated hematology analyzer (Sysmex XT-4000i)|An automated hematology analyzer (Sysmex XT-4000i)]]
Common techniques used by hematology analyzers to identify cells include light scattering, [[Engineering:Coulter counter|Coulter counting]], and cytochemical staining techniques. Some analyzers also use radiofrequency analysis and [[Biology:Monoclonal antibody|monoclonal antibody]] tagging to identify cells.<ref name="wintrobe-cc"/><ref>Harmening, D (2009). pp. 795–803.</ref> Staining techniques used in differential analyzers include staining of [[Biology:Myeloperoxidase|myeloperoxidase]],<ref name="wintrobe-diff"/> an enzyme found in cells of [[Biology:Myelopoiesis|myeloid]] lineage,<ref>Naiem, F ''et al''. (2009). p. 210.</ref> and [[Biology:Nucleic acid|nucleic acid]]s, which are found in higher concentrations in immature cells.<ref name="ArnethMenschikowki2015"/>

A small volume of blood (as low as 150 microliters) is aspirated into the analyzer, where [[Biology:Reagent|reagent]]s are applied to [[Biology:Lysis|lyse]] red blood cells and preserve white blood cells. The sample is diluted and passed into a flow cell, which uses [[Biology:Hydrodynamic focusing|hydrodynamic focusing]] to isolate single cells for accurate analysis of their properties. Various cellular parameters, such as size, complexity and staining reactions, are measured and analyzed to identify cell populations. Basophils are often quantified using a reagent that lyses the cytoplasm of other white blood cells but leaves basophils intact.<ref name="wintrobe-diff"/> Samples that have abnormal results<ref name="GulatiSong2013"/> or are suspected to contain abnormal cells are flagged by the analyzer for manual blood smear review.<ref name="bain-43"/>

To ensure that results from the automated analyzer are correct, quality control samples are run at least once per day. These are samples with known results that are most often provided by the instrument manufacturer. Laboratories compare their differential results to the known values to ensure the instrument is operating correctly. A moving average measurement may also be used, in which the average results for patient samples are measured at certain intervals. Assuming that the characteristics of the patient population remain roughly the same over time, the average should remain constant. Large shifts in the average value can indicate instrument problems.<ref>Kottke-Marchant, K; Davis, B (2012). pp. 697–8.</ref><ref name="VisHuisman2016"/>

====Limitations====
When immature or abnormal white blood cells are present, automated differential results may be incorrect, necessitating a manual blood smear review. Overall, 10 to 25 percent of CBC samples are flagged for manual review by the analyzer.<ref name="wintrobe-error">Smock, KJ. Chapter 1 in Greer, JP ''et al'' ed. (2018), sec. "Advantages and sources of error with automated hematology".</ref> Although most abnormal samples are automatically flagged, some may be missed;<ref>Bain, B ''et al.'' (2012). pp. 43–4.</ref> conversely, analyzers may generate false positive flags when no abnormal cells are present.<ref name="wintrobe-error"/> Hematology laboratories compensate for these issues by requiring a smear review when differential or CBC results fall outside certain numerical thresholds, regardless of the presence of analyzer flags.<ref name="GulatiSong2013"/> The [[Sensitivity and specificity|sensitivity and specificity]] of analyzer flagging can be determined by comparing analyzer flags to manual differential results.<ref name="VisHuisman2016"/>

The automated [[Biology:Basophil|basophil]] count is notoriously unreliable,<ref name="Chabot-Richards2015"/><ref name="wintrobe-diff"/> often underestimating counts in [[Medicine:Basophilia|basophilia]] and producing falsely elevated results in the presence of abnormal cells.<ref name="Buttarello2008"/> The manual differential is therefore considered the reference method for these cells.<ref name="Chabot-Richards2015"/><ref>Gibbs, B (2014). p. 88.</ref>

Analyzers may count nucleated red blood cells, giant and clumped platelets,  and red blood cells containing abnormal [[Biology:Hemoglobin|hemoglobin]]s (such as Hemoglobin S in [[Medicine:Sickle cell disease|sickle cell disease]]) as white blood cells, leading to faulty differential results. Automated differential counts on aged specimens may be incorrect due to cellular degeneration.<ref>Keohane, E ''et al''. (2015). p. 226.</ref>

==Cell types and result interpretation==
[[Image:Hem1SegmNeutrophile3.jpg|left|frameless|upright=0.45|alt=Neutrophil]] 
;Neutrophil: [[Biology:Neutrophil|Neutrophil]]s are the most common white blood cells in normal adult blood. When stained with a Romanowsky stain, they exhibit a multi-lobed [[Biology:Cell nucleus|nucleus]] and pink [[Biology:Cytoplasm|cytoplasm]] that contains small purple granules.<ref>Harmening, D (2009). p. 306.</ref><ref>Bain, B ''et al''. (2012). pp. 88–93.</ref>

The neutrophil count is normally higher in newborns and pregnant women than in other groups.<ref name="porwit-252">Porwit, A ''et al''. (2011). p. 252.</ref> Outside of these conditions, increased neutrophil counts (neutrophilia) are associated with bacterial infection, inflammation, and various forms of physiological stress.<ref name="turgeon-306">Turgeon, ML. (2016). p. 306.</ref> Neutrophil counts can become extremely high in response to some infections and inflammatory states, which is termed [[Medicine:Leukemoid reaction|leukemoid reaction]] because the high white blood cell count mimics leukemia.<ref>Porwit, A ''et al''. (2011). p. 253.</ref> Neutrophilia may also occur in myeloproliferative disorders.<ref name="turgeon-306"/><br/>[[Medicine:Neutropenia|Neutropenia]], meaning a low neutrophil count, may occur as a response to drug treatment (especially chemotherapy)<ref name=HoffmanJr.2013>Hoffman, R ''et al.'' (2013). p. 644.</ref> or in certain infections, such as [[Medicine:Tuberculosis|tuberculosis]] and Gram-negative [[Medicine:Sepsis|sepsis]]. Neutropenia also occurs in many hematologic disorders, such as leukemia and [[Medicine:Myelodysplastic syndrome|myelodysplastic syndrome]], and in a variety of autoimmune and congenital diseases.<ref>Porwit, A ''et al''. (2011). pp. 247–52.</ref> A neutrophil count below the reference interval may be normal in individuals of certain ethnicities; this is termed benign ethnic neutropenia.<ref>Porwit, A ''et al.'' (2011). p. 8.</ref><ref name="Atallah-YunesReady2019"/> Very low neutrophil counts are associated with [[Biology:Immunosuppression|immunosuppression]].<ref>Harmening, D (2009). pp. 308–11</ref>

When stimulated by infection or inflammation, neutrophils may develop abnormal features in their cytoplasm, such as [[Medicine:Toxic granulation|toxic granulation]], [[Medicine:Toxic vacuolation|toxic vacuolation]] and [[Medicine:Döhle bodies|Döhle bodies]]. These features, which are caused by the release of [[Biology:Cytokine|cytokine]]s,<ref>Hematology and Clinical Microscopy Committee (2019) p. 4.</ref> are collectively known as toxic changes.<ref name="Ciesla, B 2018. p. 153"/>
[[Image:PBLymphozyt.jpg|left|frameless|upright=0.45|alt=Lymphocyte]]
; Lymphocyte: [[Biology:Lymphocyte|Lymphocyte]]s, which are the second most common type of white blood cell in adults, are typically small cells with a round, dark nucleus and a thin strip of pale blue cytoplasm. Some lymphocytes are larger and contain a few blue granules.<ref name="turgeon">Turgeon, ML. (2016). pp. 308–9.</ref>

Increased lymphocyte counts (lymphocytosis) can be caused by viral infections<ref name="turgeon-309">Turgeon, ML (2016). p. 309.</ref> and may also occur after [[Medicine:Splenectomy|splenectomy]]. Children have higher lymphocyte counts than adults.<ref name="porwit-lymph">Porwit, A ''et al''. (2011). p. 258–9.</ref> [[Medicine:Chronic lymphocytic leukemia|Chronic lymphocytic leukemia]] presents with an elevated lymphocyte count and abnormal lymphocyte morphology, in which the lymphocytes have extremely dense, clumped nuclei<ref name="OscierElse2016"/> and some cells appear smudged on the blood smear.<ref name="SP2019"/> <br/> Low lymphocyte counts (lymphopenia) may be seen in infections such as HIV/AIDS, [[Medicine:Influenza|influenza]] and [[Medicine:Viral hepatitis|viral hepatitis]], as well as in protein-energy malnutrition,<ref name="Territo2018"/> acute illnesses and drug reactions.<ref name="porwit-lymph"/>

In response to viral infections (especially [[Medicine:Infectious mononucleosis|infectious mononucleosis]]), lymphocytes may increase greatly in size, developing unusually shaped nuclei and large amounts of dark blue cytoplasm. Such cells are referred to as reactive or atypical lymphocytes<ref>Bain, B ''et al''. (2012). pp. 95–7.</ref> and when present they are either commented on or counted separately from normal lymphocytes in the manual differential.<ref name="ICSH2015"/>
[[Image:Hem1Monocyte.jpg|left|frameless|upright=0.45|alt=Monocyte]]
;Monocyte: [[Biology:Monocyte|Monocyte]]s are large cells with a curved or folded nucleus and finely granulated, grey-blue cytoplasm that often contains [[Biology:Vacuole#animal|vacuoles]]. Monocytes are the third most common white blood cell after neutrophils and lymphocytes.<ref name="turgeon-307">Turgeon, ML. (2016). p. 307.</ref>

Increased monocyte counts (monocytosis) are seen in chronic infection and inflammation. Extremely high monocyte counts, as well as immature forms of monocytes, occur in chronic myelomonocytic leukemia and acute leukemias of monocytic origin.<ref>Bain, B  ''et al''. (2012). p. 95.</ref> Monocyte counts may be decreased (monocytopenia) in individuals who are receiving chemotherapy as well as those with [[Medicine:Aplastic anemia|aplastic anemia]], severe burns, and AIDS.<ref>Porwit, A ''et al.'' (2011). p. 258.</ref> 
[[Image:Hem1Eosinophile.jpg|left|frameless|upright=0.45|alt=Eosinophil]]
;Eosinophil: [[Biology:Eosinophil|Eosinophil]]s have large orange granules in their cytoplasm and bi-lobed nuclei. They are found in low amounts in normal blood.<ref name="turgeon-307"/>

Elevated eosinophil counts (eosinophilia) are associated with allergic reactions, parasitic infections, and asthma.<ref name="bain-94">Bain, B ''et al''. (2012). p. 94.</ref><ref name="porwit-256">Porwit, A ''et al.'' (2011). p. 256.</ref> Eosinophil counts may be decreased in pregnancy and in response to physiological stress, inflammation or treatment with certain drugs, such as [[Biology:Steroid|steroid]]s and epinephrine.<ref name="porwit-256"/>

[[Image:PBBasophil.jpg|left|frameless|upright=0.45|alt=Basophil]] 
;Basophil: [[Biology:Basophil|Basophil]]s exhibit large, dark purple granules that often cover the cell's nucleus. They are the rarest of the five normal cell types.<ref name="bain 94-5"/>

[[Medicine:Basophilia|Basophilia]] and eosinophilia can occur along with other white blood cell abnormalities in chronic myeloid leukemia and other myeloproliferative disorders.<ref name="bain 94-5">Bain, B ''et al.'' (2012). pp. 94–5.</ref> An increased basophil count may also be seen in hypersensitivity reactions and after splenectomy. The basophil count may decrease during ovulation, steroid treatment, and periods of physiological stress.<ref>Porwit, A ''et al.'' (2011). p. 257.</ref>

[[Image:Nonsegmented Neutrophile.jpg|left|frameless|upright=0.45|alt=Band neutrophil]] 
;Band neutrophil: Band neutrophils are young forms of neutrophils which lack segmentation of the [[Biology:Cell nucleus|nucleus]]. These cells, which are identified by manual counting, are found in low numbers in normal adult blood.<ref name="bain-93">Bain, B ''et al''. (2012). p. 93.</ref>

A [[Medicine:Left shift|left shift]], meaning an increase in band neutrophils or immature granulocytes, can indicate infection, [[Medicine:Inflammation|inflammation]] or bone marrow disorders, although it can also be a normal finding in [[Medicine:Pregnancy|pregnancy]].<ref name="bain-93"/><ref name="ciesla 153-4">Ciesla, B. (2018). pp. 153–4.</ref> Some laboratories do not separate bands from mature neutrophils in the differential count because the classification is highly subjective and unreliable.<ref name="ICSH2015"/>

[[Image:Hem1Myelocyte.jpg|left|frameless|upright=0.45|alt=Immature granulocyte (myelocyte)]] 
;Immature granulocyte: Immature granulocytes are immature forms of neutrophils and other granulocytes (eosinophils and basophils). This classification consists of [[Biology:Metamyelocyte|metamyelocyte]]s, myelocytes and [[Biology:Promyelocyte|promyelocyte]]s, which may be enumerated separately in the manual differential or reported together as immature granulocytes (IG) by automated methods.<ref>Bain, B ''et al.'' (2012). p. 44.</ref> Immature granulocytes are normally found in the [[Biology:Bone marrow|bone marrow]], but not in peripheral blood.<ref name="Curry2015"/>

When present in significant quantities in the blood, immature granulocytes can indicate infection and inflammation,<ref name="Chabot-Richards2015"/>  as well as myeloproliferative disease, [[Medicine:Leukemia|leukemia]] and other conditions affecting the marrow.<ref name="Curry2015"/> IGs may also be increased in steroid use and pregnancy.<ref name="Chabot-Richards2015"/> Chronic myeloid leukemia often presents with a high number of immature granulocytes in the peripheral blood.<ref name="Emadi2018"/> Abnormal promyelocytes with multiple [[Medicine:Auer rod|Auer rod]]s, called [[Biology:Faggot cell|faggot cell]]s, occur in acute promyelocytic leukemia.<ref name="Adams2015"/>

[[File:Myeloblast with Auer Rod smear 2009-11-23 cropped.jpg|left|frameless|upright=0.45|alt=Blast cell]]
;Blast cell: Blast cells are very immature cells that are normally found in the bone marrow, where they develop into mature cells (hematopoiesis) before being released into the blood. They can be identified by their large overall size, deep blue [[Biology:Cytoplasm|cytoplasm]], and large nucleus with fine [[Biology:Chromatin|chromatin]] and prominent nucleoli.<ref name="d'OnofrioZini2014"/>

When seen on the blood smear, blast cells are an abnormal finding and may be indicative of acute leukemia or other serious blood disorders. Rarely, they may be seen in severe cases of left shift. The presence of Auer rods inside blast cells indicates that they are of [[Medicine:Acute myeloid leukemia|myeloid]] origin, which has important implications for leukemia treatment.<ref name="d'OnofrioZini2014"/><ref>Glassy, E. (1998). pp. 6–7.</ref> Other morphologic features can provide information about the lineage of blast cells: for example, [[Biology:Myeloblast|myeloblast]]s tend to be large with distinct nucleoli, while [[Biology:Lymphoblast|lymphoblast]]s can be smaller with a denser chromatin pattern. However, these features are not diagnostic, and flow cytometry or special staining is generally used to confirm the lineage.<ref>Hematology and Clinical Microscopy Committee (2019). pp. 13–22.</ref>

[[File:Flower_cell_in_mantle_cell_lymphoma_cropped.jpg|left|frameless|upright=0.45|alt=Lymphoma cell]]
;Other cells: Various other abnormal cells may be present in the blood in certain conditions. For example, lymphoma cells may be found on the manual differential in some cases of [[Medicine:Lymphoma|lymphoma]],<ref>Glassy, E. (1998). p. 228.</ref> and in [[Medicine:Mast cell leukemia|mast cell leukemia]], [[Biology:Mast cell|mast cell]]s, which are normally confined to tissue, circulate in the blood.<ref>Glassy, E. (1998). p. 328.</ref> There is a very rare phenomenon called [[Medicine:Carcinocythemia|carcinocythemia]] in which tumour cells are seen on the peripheral blood smear.<ref>Pereira, I ''et al.'' (2011). p. 185.</ref>
{{Clear}}

==History==
Before automated cell counters were introduced, cell counts were performed manually; white and red blood cells, and platelets were counted using microscopes.<ref>Keohane, E ''et al''. (2015). pp. 1–4.</ref> The first person to publish microscopic observations of blood cells was [[Biography:Antonie van Leeuwenhoek|Antonie van Leeuwenhoek]],<ref>Kottke-Marchant, K; Davis, B. (2012). p. 1.</ref> who reported on the appearance of red cells in a 1674 letter to the ''Proceedings of the Royal Society of London'';<ref>Wintrobe, MM. (1985). p. 10.</ref> Jan Swammerdam had described red blood cells some years earlier, but had not published his findings at the time. Throughout the 18th and 19th centuries, improvements in microscope technology such as [[Physics:Achromatic lens|achromatic lens]]es allowed white blood cells and [[Biology:Platelet|platelet]]s to be counted in unstained samples. In the 1870s, [[Biography:Paul Ehrlich|Paul Ehrlich]] developed a staining technique that could differentiate between the five white blood cell types. Ehrlich's stain used a combination of an acidic and basic dye to stain white and red blood cells simultaneously.<ref name="kottke-hist">Kottke-Marchant, K; Davis, B. (2012). pp. 3–4.</ref> Dmitri Leonidovich Romanowsky improved on this technique in the 1890s by using a mixture of [[Chemistry:Eosin|eosin]] and aged [[Chemistry:Methylene blue|methylene blue]], which produced a wide range of hues that was not present when either of the stains was used alone. This was termed the Romanowsky effect and became the basis for [[Biology:Romanowsky stain|Romanowsky stain]]ing, the technique that is still used to stain blood smears for manual differentials.<ref name="Bezrukov2017"/>

By the early years of the 20th century, the white blood cell differential had become a common practice in the United States, but difficulties in interpreting the results cast doubt on the test's utility.<ref>Koepke, JA (1977). p. 2.</ref> In 1906,<ref name="Gibson1906">{{cite journal|last1=Gibson|first1=CL|title=The value of the differential leukocyte count in acute surgical diseases|journal=Annals of Surgery|volume=43|issue=4|year=1906|pages=485–499|issn=0003-4932|doi=10.1097/00000658-190604000-00001|pmid=17861781|pmc=1426203}}</ref> Charles Langdon Gibson introduced the Gibson chart, which compared the total white blood cell count against the neutrophil count to distinguish between "pyogenic" and "non-pyogenic" conditions and to predict the severity of infections.  Around the same time, Josef Arneth proposed a system of classifying neutrophils by their number of nuclear lobes – termed the "lobe index" or [[Medicine:Arneth count|Arneth count]] – and established a set of reference ranges for neutrophil lobularity. Arneth's analysis of neutrophil segmentation was later found to have limited clinical significance, but the association of [[Biology:Hypersegmented neutrophil|hypersegmented neutrophil]]s with [[Biology:Vitamin B12|vitamin B12]] and [[Medicine:Folate deficiency|folate deficiency]] remains accepted.<ref>Koepke, JA (1977). pp. 2–3.</ref><ref>Kottke-Marchant, K; Davis, B (2012). pp. 593–4.</ref><ref>{{cite book|last=Arneth|first=J|date=1904|title=Die neutrophilen weissen Blutkörperchen bei Infektionskrankheiten|language=de|publisher=Fischer}}</ref> {{ill|Viktor Schilling|de}} in 1912 proposed a different classification of neutrophils, separating them into "''myelozyten'', ''jugendliche'', ''stabkernige'' and ''segmentkernige''" – that is, myelocytes, "juveniles" (metamyelocytes), band neutrophils (sometimes called "stabs"), and mature, fully segmented neutrophils – and remarked on the clinical significance of the neutrophilic left shift in conjunction with the white blood cell count and the presence of toxic changes. Schilling's monograph, ''Das Blutbild und seine klinische Verwertung'' (''The Blood Picture and its Clinical Significance''), was translated into English in 1926, and his neutrophil classification system quickly found acceptance in American laboratories.<ref>Koepke, JA (1977). pp. 3–4.</ref><ref>{{cite book|last=Schilling|first=V|date=1912|title=Das Blutbild und seine klinische Verwertung, mit Einschluss der Tropenkrankheiten; kurzgefasste technische, theoretische und praktische Anleitung zur mikroskopischen Blutuntersuchung|language=de|publisher=Fischer|url=https://catalog.hathitrust.org/Record/011713708}}</ref>

The first automated hematology analyzer, the [[Engineering:Coulter counter|Coulter counter]], was invented in the early 1950s by Wallace H. Coulter.<ref>Harmening, D (2009). p. 794.</ref><ref name="Graham2003"/> The analyzer worked on the Coulter principle, which states that when cells are suspended in a fluid carrying an [[Physics:Electric current|electric current]] and passed through an aperture, they cause decreases in current proportional to their volume because of their poor [[Physics:Electrical conductivity|electrical conductivity]]. The number and magnitude of these decreases can be used to count blood cells and calculate their sizes. The Coulter counter was initially designed for counting [[Biology:Red blood cell|red blood cell]]s, but it proved effective for counting white blood cells as well.<ref name="Graham2003"/>

[[Image:Model_A_COULTER_COUNTER_from_Advertisement.jpg|thumb|left|alt=The Model A Coulter counter, the first commercial hematology analyzer|The Model A Coulter counter, the first commercial hematology analyzer]]

After basic cell counting had been automated, the white blood cell differential remained a challenge. Research into automating the differential count began in the 1970s and took two main approaches: digital image processing and flow cytometry. Using technology developed in the 1950s and 60s to automate the reading of Pap smears, several models of image processing analyzers were produced.<ref>Groner, W (1995). pp. 12–4.</ref> These instruments would scan a stained blood smear to find cell nuclei, then take a higher resolution snapshot of the cell to analyze it through [[Engineering:Densitometry|densitometry]].<ref name="Lewis1981">{{cite journal|last1=Lewis|first1=SM|title=Automated differential leucocyte counting: Present status and future trends|journal=Blut|volume=43|issue=1|year=1981|pages=1–6|issn=0006-5242|doi=10.1007/BF00319925|pmid=7260399|s2cid=31055044}}</ref> They were expensive, slow, and did little to reduce workload in the laboratory because they still required blood smears to be prepared and stained, so flow cytometry-based systems became more popular,<ref>Da Costa, L (2015). p. 5.</ref><ref>Groner, W (1995). pp. 12–5.</ref> and by 1990, no digital image analyzers were commercially available in the United States or western Europe.<ref name="Bentley1990">{{cite journal|last1=Bentley|first1=SA|title= Automated differential white cell counts: a critical appraisal|journal=Baillière's Clinical Haematology|volume=3|issue=4|year=1990|pages=851–69|issn=0950-3536|doi=10.1016/S0950-3536(05)80138-6 |pmid=2271793}}</ref> These techniques enjoyed a resurgence in the 2000s with the introduction of more advanced image analysis platforms using [[Artificial neural network|artificial neural network]]s.<ref name="KratzLee2019"/><ref name="DaCosta2019">{{cite journal|last1=Da Costa|first1=L|title=Digital image analysis of blood cells|journal=Clinics in Laboratory Medicine|volume=35|issue=1|year=2015|pages=105–22|issn=0272-2712|doi=10.1016/j.cll.2014.10.005|pmid=25676375}}</ref><ref>McCann, SR (2016). p. 193.</ref>

Early flow cytometry devices shot beams of light at cells in specific wavelengths and measured the resulting absorbance, fluorescence or light scatter, collecting information about the cells' features and allowing cellular contents such as [[Biology:DNA|DNA]] to be quantified.<ref>Melamed, M (2001). pp. 5–6.</ref> One such instrument—the Rapid Cell Spectrophotometer, developed by Louis Kamentsky in 1965 to automate cervical cytology—could generate blood cell scattergrams using cytochemical staining techniques. Leonard Ornstein, who had helped to develop the staining system on the Rapid Cell Spectrophotometer, and his colleagues later created the  first commercial flow cytometric white blood cell differential analyzer, the Hemalog&nbsp;D.<ref>Shapiro, HM (2003). pp. 84–5.</ref><ref name="melamed-8">Melamed, M. (2001). p. 8.</ref> Introduced in 1974,<ref name="PicotGuerin2012"/><ref name="MansbergSaunders1974"/> this analyzer used light scattering, absorbance and cell staining to identify the five normal white blood cell types in addition to "large unidentified cells", a classification that usually consisted of atypical lymphocytes or blast cells. The Hemalog&nbsp;D could count 10,000 cells in one run, a marked improvement over the manual differential.<ref name="melamed-8"/><ref name="Pierre2002"/> 
By 1977 it was estimated that "at least 200" automated differential analyzers were in use throughout the world.<ref>Koepke, JA (1977). p. 96.</ref> In 1981, Technicon combined the Hemalog&nbsp;D with the Hemalog-8 analyzer to produce the Technicon&nbsp;H6000, the first combined complete blood count and differential analyzer. This analyzer was unpopular with hematology laboratories because it was labour-intensive to operate, but in the late 1980s to early 1990s similar systems were widely produced by other manufacturers such as Sysmex, [[Organization:Abbott Laboratories|Abbott]], [[Company:Roche Diagnostics|Roche]] and [[Company:Beckman Coulter|Beckman Coulter]].<ref>Kottke-Marchant, K; Davis, B (2012). pp. 8–9.</ref>

==See also==
*[[Biology:Flow cytometry|Flow cytometry]]
*[[Biology:Cell counting|Cell counting]]

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*{{cite book|last=Turgeon|first=ML|title=Linné & Ringsrud's Clinical Laboratory Science: Concepts, Procedures, and Clinical Applications|url=https://books.google.com/books?id=QyvRoQEACAAJ|year=2016|publisher=Elsevier Mosby|isbn=978-0-323-22545-8|edition=7}}
*{{cite book|author1=Sa A. Wang|author2=Robert P. Hasserjian|title=Diagnosis of Blood and Bone Marrow Disorders|url=https://books.google.com/books?id=xbVeDwAAQBAJ&pg=PA15|date=4 June 2018|publisher=Springer|isbn=978-3-319-20279-2}}
*{{cite book|last=Wintrobe|first=MM|title=Hematology, the Blossoming of a Science: A Story of Inspiration and Effort|url=https://books.google.com/books?id=eExrAAAAMAAJ|year=1985|publisher=Lea & Febiger|isbn=978-0-8121-0961-0}}
{{Refend}}
{{Myeloid blood tests}}

[[Category:Blood tests]]

{{Sourceattribution|White blood cell differential}}