Articles on Medical Diseases and Conditions

Tag: White Blood Cell

  • Rheumatoid Arthritis (RA)

    Rheumatoid arthritis (RA) is a chronic systemic disease whose most prominent symptom is inflammation of joints. The small joints of the hands and feet, especially the proximal interphalangeal joints, are most frequently affected; involvement of larger joints of the extremities is somewhat less frequent, and occasionally nonextremity joints may be affected. Polyarticular involvement is much more common than monoarticular disease. Articular disease activity may or may not be preceded or accompanied by systemic symptoms such as low-grade fever, myalgias, malaise, and fatigue. Rheumatoid arthritis tends to be a slow, intermittently active, migratory process that is frequently symmetric. Onset is gradual in 75%-80% of affected adults and more severe and abrupt in 20%-25%. Subcutaneous nodules with distinctive microscopic appearance occur in 15%-20% of patients, most frequently distal to (but not far from) the elbows. Inflammatory involvement of nonarticular organs or tissues such as the heart or lungs may sometimes occur. Patients with RA have increased frequency of the antigen HLA-DR4.

    Laboratory findings. In active adult-onset RA, anemia is present in about 40% of men and 60% of women. The anemia usually appears within 2 months after onset of clinical disease, usually does not become more severe, and is usually of mild or moderate degree, with a hemoglobin value less than 10 gm/100 ml (100 g/L) in fewer than 10% of cases. There is said to be some correlation between the degree of anemia and the initial severity of illness. The anemia of RA is usually included with the anemia of chronic disease, which typically is normocytic and normochromic. However, anemia in RA is more likely to be hypochromic (reported in 50%-100% of cases), although microcytosis is found in less than 10% of cases.

    White blood cell (WBC) counts are most often normal or only minimally elevated. About 25% of RA patients are said to have leukocytosis, usually not exceeding 15,000/mm3 (15 Ч 109/L), which is more apt to be present when onset of disease is severe and abrupt. Leukopenia is found in about 3% of cases, usually as part of Felty’s syndrome (RA plus splenomegaly and leukopenia).

    Anemia and leukocytosis are more common in juvenile-onset RA than adult-onset RA.

    In active RA, nonspecific indicators of acute inflammation, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein level, are elevated in most (but not all) patients. The serum uric acid level is normal in most patients. The serum iron level is generally low-normal or decreased, and iron-binding capacity is also low-normal or decreased.

    Rheumatoid factor. RA and related diseases are associated with production of a group of immunoglobulins called rheumatoid factors (RFs) that include IgG, IgM, and IgA varieties. These immunoglobulins (antibodies) have specificity for IgG that has been altered in certain ways. It is still not certain whether the altered IgG is the cause of the inflammatory abnormalities in RA or is a body response against the inflammatory process. From the laboratory standpoint, the most important of the is the one that is an IgM macroglobulin. RF combines with its altered IgG antigen in vivo, accompanied by complement fixation. IgM RF, like other antibodies, is produced by lymphocytes and plasma cells of B-cell origin. In some persons, especially in infants, IgM antibody production against some infectious organism not associated with rheumatoid disease may result in concurrent production of varying amounts of IgM RF. Outside the body, IgM RF can combine with normal gamma globulin without complement fixation (in fact, some patient serum contains excess C1q component of complement, which may cause a nonspecific RF test reaction that can be avoided by heat inactivation of complement before the test).

    Serologic tests. Serologic tests are the usual method of laboratory diagnosis in adult-onset RA. Various types of serologic tests may be set up utilizing reaction of IgM RF with IgG gamma globulin, differing mainly in the type of indicator system used to visually demonstrate results. The original method was known as the “Rose-Waaler test,” or “sheep cell agglutination test.” Anti-sheep red blood cell (RBC) antibodies were reacted with tannic acid-treated sheep RBCs, then the RF in the patient’s serum was allowed to combine with the antibody gamma globulin coating the sheep cells. Clumping of RBCs indicated a positive test result. It was found subsequently that synthetic particles such as latex could be coated with gamma globulin and the coated particles could be clumped by RF, thus giving a flocculation test. Just as happened with the serologic test for syphilis, many combinations of ingredients have been tried, with resulting variations in sensitivity and specificity. These tests are too numerous to discuss individually, but a distinction must be made between tube tests and rapid slide tests. The slide tests in general have a slightly greater sensitivity than tube tests but also produce more false positive results. Therefore, slide tests should be used mainly for screening purposes. As noted previously, some patient serum contains a nonspecific C1q agglutinator that can be eliminated by inactivating patient serum by heating at 56°C for 30 minutes.

    The latex fixation tube test for RA, known also as the “Plotz-Singer latex test,” currently is considered the standard diagnostic method. The average sensitivity in well-established clinical cases of adult RA is about 76% (range, 50%-95%). Clinically normal controls have about 1%-2% positive results (range, 0.2%-4%). Latex slide tests offer an average sensitivity of approximately 85% (literature range, 78%-98%), with positive results seen in approximately 5%-8% of normal control persons (range, 0.2%-15%). It may take several weeks or months after onset of clinical symptoms, even as long as 6 months, before RA serologic test results become abnormal.

    False positive results. Certain diseases, especially those associated with increased gamma globulin (“hyperglobulinemia”), produce a significantly high number of positive reactions analogous to the “biologic false positive” reactions of syphilis serology. These include collagen diseases, sarcoidosis, syphilis, viral hepatitis and cirrhosis, bacterial infections (especially subacute bacterial endocarditis[SBE]), and even old age (as many as 10%-25% positive over age 70). The incidence of reactive RA tests is higher with the slide than the tube tests. The percentage of positive reactions in the diseases listed ranges from 5%-40%. Sjцgren’s syndrome (75%-96%) and SBE (50%) are most likely to produce false positive results.

    Differential diagnosis. RA is usually part of the differential diagnosis of joint pain. However, other causes must be considered, especially if symptoms, location of joint involvement, laboratory test results, or other features are atypical. Even a positive test result is not conclusive evidence for RA. Other diseases that frequently enter the differential diagnosis are the so-called seronegative spondyloarthropathies, septic (infectious) arthritis, systemic lupus erythematosus (SLE) and other collagen-vascular diseases, crystal-deposition arthritis, and acute rheumatic fever (ARF). These conditions will be discussed later in this chapter.

  • Basophilia

    Basophilia is most frequently found in chronic myelogenous leukemia. Basophils may be increased in the other “myeloproliferative” diseases and occasionally in certain nonmalignant conditions.

  • Neutrophilic Leukocytosis Due To Infection and Inflammation

    Inflammation is the most frequent condition associated with neutrophilic leukocytosis. Besides an increase in total neutrophil count, there often is some degree of immaturity (“shift to the left”*). Usually a shift to the left involves an increase in the early segmented and the band neutrophil stages. Occasionally even some earlier cells (metamyelocytes or even myelocytes) may appear; this is known as leukemoid reaction. Leukocytosis is most often seen with bacterial infection; viral infections tend to be associated with normal counts or even leukopenia. The granulomatous infections (tuberculosis, sarcoidosis) most often have normal WBC counts, but tuberculosis occasionally demonstrates a leukocytosis. Typhoid fever is a bacterial infection that usually does not have a WBC increase; on the other hand, a neutrophilic leukocytosis may be present in 30% or more of persons with severe enteric cytopathic human orphan (ECHO) virus infection. Overwhelming infection, particularly in debilitated persons or the elderly, may fail to show leukocytosis.

    Deviation from usual white blood cell pattern in infection

    The classic WBC picture of acute bacterial infection is leukocytosis with an increased percentage of neutrophils and band forms. Unfortunately, leukocytosis may be absent in approximately 15%-30% of cases (literature range, 10%-45%), and band forms may remain within reference limits in approximately 30%-40% (range, 21%-61%) of cases. The band count variation can be attributed at least partially to differences in individual technologist interpretation of folded bands versus segmented neutrophils (referred to previously), failure of individual laboratories to establish their own band reference range (rather than using values found in some publication), technical variance such as irregular distribution of cell types on the peripheral smear due to technique in making the smear and the areas chosen for cell counting, and very poor reproducibility (50%-200% variation reported) due to the small numbers involved and the other factors just cited.

    In addition, band counts vary substantially between different technologists. In one experiment, 15 well-trained ASCP technologists counting the same peripheral smear on two different occasions never obtained the same band count result; the different technologist band counts varied from 3% bands to 27% bands.

    In general, absolute values (total number of neutrophils or bands per cubic millimeter) are more reliable than values expressed as a percent of the total WBC count, since the percentage of one cell type may reflect a change in the number of another cell type rather than a strict increase or decrease of the cell type in question. Total neutrophil count (percentage) is also more reliable because a minimum of subjective interpretation is needed. To illustrate this, I studied hematologic findings from 113 cases of well-documented culture-proven urinary tract infections (UTIs) and 79 patients with bacteremia; as well as 34 cases of acute cholecystitis and 42 cases of acute appendicitis proven by surgical specimens. In all categories of infection, the total neutrophil count was elevated more often than the band count (at least 10% and usually 20% more cases). In UTI and bacteremia, total neutrophil count was elevated more often (about 10% more cases) than the total WBC count; in acute appendicitis and acute cholecystitis, the reverse was true. In summary, the total neutrophil percentage appears to be the most sensitive and useful parameter of infection, while the band count is the least reliable.

    Although an increase in band count is traditionally associated with bacterial infection, it may occur in some patients with viral infection. In one report, 29% of pediatric patients with influenza and no evidence of bacterial infection had elevated band count; also 23% of enterovirus infection; 22% of respiratory syncytial virus infection; and 10% of rotovirus infection.

    Automated cell counter differential counts

    Certain newer automated cell counters can produce a limited differential in percent and absolute numbers. These instruments have much better reproducibility than manual differential cell counts because the machine examines thousands of cells rather than only 100. Each of these instruments has some omissions compared to manual differentials, such as lack of a band count, failure to note WBC and red blood cell (RBC) inclusions, and failure to detect certain abnormally shaped RBCs. As discussed before, lack of a band count is not important, and for the great majority of patients an automated differential is more reliable than a manual differential. A technologist can quickly scan the slide to examine RBC morphology and detect any omission of the automated differential. If abnormal WBCs are found, a manual differential can be performed.

    Special problems in neonates and younger children

    First, age-related reference values are essential. However, reference values for neonates from different sources vary even more than those for adults. Second, as noted previously, total WBC and neutrophil values rise sharply after birth and then fall. Most, although not all, investigators do not consider total WBC or absolute neutrophil values reliable in the first 3 days of life. After that time, absolute neutrophil values are said to be more reliable than total WBC counts. However, although elevated results are consistent with bacterial infection, there may be substantial overlap with WBC values seen in nonbacterial infection, and values within the reference range definitely do not exclude bacterial infection. In fact, it has been reported that neonates with sepsis are more likely to have normal range or low WBC counts than elevated ones. It has been reported that violent crying can temporarily increase WBC and band counts over twice baseline values for as long as 1 hour.

    Neutrophil cytoplasmic inclusions. Certain neutrophil cytoplasmic inclusions are associated with infection (although they are also seen in tissue destruction, burns, and similar toxic states); these include toxic granulation and D?hle bodies. Toxic granulation is accentuation of normal neutrophilic cytoplasm granules, which become enlarged or appear as short, rod-shaped structures of irregular width, either dark blue-black, or the same color as the nucleus. D?hle bodies are moderate-sized, light blue structures most frequently located next to the cytoplasmic border. The presence of vacuoles in the cytoplasm of peripheral blood neutrophils has repeatedly been cited as a clue to septicemia. However, although there is a strong association with bacteremia or septicemia, some neutrophils with a few cytoplasmic vacuoles may occur in patients without definite evidence of bacterial infection.

    Neutrophilic leukocytosis due to tissue destruction. Tissue destruction may be due to burns, abscess, trauma, hemorrhage, infarction, carcinomatosis, active alcoholic cirrhosis, or surgery and is often accompanied by varying degrees of leukocytosis. The leukocytosis varies in severity and frequency according to the cause and amount of tissue destruction.

    Neutrophilic leukocytosis due to metabolic toxic states. The most frequent metabolic toxic states are uremia, diabetic acidosis, acute gout attacks, and convulsions. A similar effect under nontoxic circumstances is seen after severe exercise and during the last trimester of pregnancy. During labor there is often a neutrophil leukocytosis that increases with duration of labor; in one report the majority of patients had total WBC counts less than 18,000/mm3 (18 Ч 109/L), but some rose as high as 24,000/mm3. In 100 consecutive obstetrical patients admitted to our hospital for childbirth, 38% had a count between 10,500 and 18,000/mm3. The highest WBC count was 23,000/mm3. Twenty percent had elevated band counts, and 26% had elevated total neutrophil counts.

    Neutrophilic leukocytosis due to certain drugs and chemicals. Adrenal cortical steroids even in relatively low doses often produce a considerable increase in mature segmented neutrophils, with total WBC counts rising within 48 hours to levels that are often double baseline values. Peak counts remain for 2-3 weeks and then slowly decline somewhat, although not to baseline. Therapy with lithium carbonate for psychiatric depression produces an average WBC elevation of about 30%. Epinephrine therapy for asthma frequently produces a significant leukocytosis. Poisoning by various chemicals, especially lead, is another cause of leukocytosis. On the other hand, certain drugs may cause leukopenia from idiosyncratic bone marrow depression.

    Neutrophilic leukocytosis due to other etiologies. Cigarette smokers, especially heavy smokers, are reported to have total WBC counts that average 1,000/mm3 (1.0 Ч 109/L) or even more above those for nonsmokers. Other causes of neutrophilic leukocytosis are acute hemorrhage or severe hemolytic anemia (acute or chronic), myelogenous leukemia, and the myeloproliferative syndromes, including some cases of polycythemia vera.

  • Neonatal Leukocytosis

    At birth, there is a leukocytosis of 18,000-22,000/ mm3 (18-22 Ч 109/L) for the first 1-3 days. This drops sharply at 3-4 days to levels between 8,000 and 16,000/mm3. At roughly 6 months, approximately adult levels are reached, although the upper limit of normal is more flexible. Although the postnatal period is associated with neutrophilia, lymphocytes slightly predominate thereafter until about age 4-5 years, when adult values for total WBC count and differential become established (see Table 37-1). Capillary (heelstick) blood WBC reference values are about 20% higher than venous WBC values on the first day of life and about 10% higher on the second day.

  • White Blood Cell Maturation Sequence

    Normal WBC maturation sequence begins with the blast form, derived from hematopoietic stem cells that, in turn, are thought to be derived from tissue reticulum cells (Fig. 6-1). In the myelocytic (granulocytic or neutrophilic) series, the blast is characterized by a large nucleus with delicate very uniform-appearing light-staining chromatin and with one or more nucleoli. Typically, a blast has relatively scanty basophilic cytoplasm without granules,* but the French-American-British (FAB) group (Chapter 7) describes a category of blasts with cytoplasm that may contain a few “azurophilic” granules. Next in sequence is the progranulocyte (promyelocyte), which is similar to the blast but has a variable number of cytoplasmic granules. The promyelocyte gives rise to the myelocyte. Myelocyte nuclear chromatin is more condensed, there is no nucleolus, and the nucleus itself is round or oval, sometimes with a slight flattening along one side. The cytoplasm is mildly basophilic and is granular to varying degrees, although sometimes granules are absent. Often there is a small, localized, pale or clear area next to the flattened portion (if present) of the nucleus, called the myeloid spot. Next, the nucleus begins to indent; when it does, the cell is called a metamyelocyte (juvenile). As the metamyelocyte continues to mature, the nucleus becomes more and more indented. The nuclear chromatin becomes more and more condensed, clumped, and darkly stained, and the cytoplasm becomes progressively less basophilic. The entire cell size becomes somewhat smaller, with the nucleus taking up increasingly less space. Finally, the band (stab) neutrophil stage is reached. There is some disagreement as to what constitutes a band as opposed to a metamyelocyte or band as opposed to an early mature polymorphonuclear leukocyte. Basically, a band is distinguished from a late metamyelocyte when the nucleus has indented more than one half its diameter and has formed a curved rod structure that is roughly the same thickness throughout. As the band matures, nuclear indentation continues and may also occur in other areas of the nucleus. When at least one area of nuclear constriction becomes a thin wire, the cell has reached the final stage of maturity, called the polymorphonuclear (poly) or segmented neutrophil. The nucleus has segmented into two or more lobes, at least one of which is connected only by a threadlike filament to the next. The nuclear chromatin is dense and clumped. The cytoplasm is a very slightly eosinophilic color, or at least there is no basophilia. There usually are small irregular granules, which often are indistinct.

    Maturation sequence of granulocytic (myelocytic) series

    Fig. 6-1 Maturation sequence of granulocytic (myelocytic) series. A, Blast; B, promyelocyte; C, myelocyte (top, early stage; bottom, late stage); D, metamyelocyte (top, early stage; bottom, late stage) E, band granulocyte (top, early stage; bottom, late stage) F, segmented granulocyte (top, early stage; bottom, hypersegmented late stage).

    Terminology of blood cells

    Table 6-1 Terminology of blood cells

    In some cases there may be a problem differentiating bands from segmented neutrophils when a bandlike nucleus is folded over itself in such a way as to hide the possibility of a thin wirelike constricted area (Fig. 6-2). The majority of investigators classify this cell as a segmented form. However, many laboratorians consider these cells bands; unless the reference range takes into account the way these cells will be interpreted, the number of bands reported can differ considerably between persons or between laboratories and could lead to incorrect diagnosis. When there is multiple nuclear segmentation and the lobes connected only by a thin wire number more than five, the cell is termed hypersegmented. Some investigators believe that hypersegmentation is present if more than 5% of the neutrophils have five lobes. Naturally, there are transition forms between any of the maturation stages just described (Fig. 6-1).

    Folded segment versus folded band

    Fig. 6-2 Folded segment versus folded band. A, One end folded (“mushroom” effect). B, Nuclear fold closer to center. a, True band; b, segment with hidden constriction.

    Monocytes are often confused with metamyelocytes or bands. The monocyte tends to be a larger cell. Its nuclear chromatin is a little less dense than chromatin of the myeloid cell and tends to have a strandlike configuration of varying thickness rather than forming discontinuous masses or clumps. The nucleus typically has several pseudopods, which sometimes are obscured by being superimposed on the remainder of the nucleus and must be looked for carefully. Sometimes, however, a monocyte nuclear shape that resembles a metamyelocyte is found. The monocyte cytoplasm is light blue or light gray, is rather abundant, and frequently has a cytoplasm border that appears frayed or has small irregular tags or protrusions. The granules of a monocyte, when present, usually are tiny or pinpoint in size, a little smaller than those of a neutrophil. In some cases, the best differentiation is to find undisputed bands or monocytes and compare their nucleus and cytoplasm with that of the cell in question.

    The reference range for peripheral blood WBCs is 4,500-10,500/mm3 (4.5-10.5 Ч 109/L). Most persons have WBC counts of 5,000-10,000/mm3, but there is significant overlap between normal and abnormal in the wider range, especially between 10,000 and 11,000/mm3. The mean WBC count in African Americans may be at least 500/mm3 (0.5 Ч 109/L) less than those in Europeans, with some investigators reporting differences as much as 3,500/mm3. This difference would be important, since it would produce a greater than expected incidence of apparent leukopenia and less than expected leukocyte response to infection and inflammation. However, not all reports agree that there is a consistent difference between the two racial groups. Normal WBC differential values are listed here:

    The value for each cell type traditionally is known as the cell “count” (i.e., band count), although the findings are expressed as a percentage of 100 WBCs rather than the actual cell number counted.

    Some investigators report a diurnal variation for neutrophils and eosinophils. Neutrophil peak levels were reported about 4 P.M. and lowest values reported about 7 A.M., with an average change of about 30%. Eosinophil levels roughly paralleled serum cortisol levels, with highest values about 7 A.M. and lowest values about 4 P.M. The average change was about 40%. The remainder of this chapter describes anomalies of WBC morphology or count and associated disease states.