Leukoerythroblastosis can be defined as the presence of both immature WBCs (metamyelocytes or earlier cells) and nucleated RBCs in the peripheral blood smear. Although the relative frequency of etiologies is different in different reports, approximately 25%-30% of patients with leukoerythroblastosis have metastatic tumor in the bone marrow, about 20% have leukemia, about 10% have myeloid metaplasia or polycythemia vera, and about 8% have hemolytic anemia. Severe infection, megaloblastic anemia, and severe acute hemorrhage account for about 5% each. There is a miscellaneous nonneoplastic group with relatively few cases of any single etiology comprising 5%-15% of the total.
Category: White Blood Cells
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Neutropenia (Granulocytopenia)
Neutropenia is usually defined as a WBC count less than 4,000/mm3. Some conditions associated with neutropenia include (1) conditions associated with pancytopenia, such as megaloblastic anemia, aplastic anemia, acute or aleukemic leukemia, hypersplenism of varying etiology (e.g., cirrhosis, systemic lupus, Gaucher’s disease), and paroxysmal nocturnal hemoglobinuria, (2) drug-induced neutropenia (agranulocytosis), (3) certain infections, such as typhoid, some viral infections (e.g., Epstein-Barr, in the first week of illness, and the hepatitis viruses), overwhelming bacterial infection (septicemia, miliary tuberculosis), and (4) cyclic and chronic idiopathic neutropenia. In one study, neutropenia was present in 3% of inpatient children and 7% of outpatient children. In another study, the median duration of isolated neutropenia in children was 7-14 days, with total duration of 30 days in 70% of patients. In two studies, the risk of developing an infection in a febrile neutropenic child who otherwise appears well was about 3%-5%.
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Lymphocytosis
Lymphocytosis is most commonly associated with a normal or a decreased total WBC count. The most common etiology is viral infection. The lymphocytosis seen in the majority of viral infections is actually a relative type due to a decrease in granulocytes while total (absolute) lymphocyte numbers remain constant. The same phenomenon is found in Addison’s disease and in drug-induced agranulocytosis. A real (absolute) lymphocytosis with leukocytosis occurs in pertussis, infectious lymphocytosis, lymphocytic leukemia, and in some infants with adenovirus infection. Infectious mononucleosis, adult cytomegalovirus infection, and sometimes hepatitis virus infection are associated with absolute lymphocytosis and atypical lymphocytes; there may be leukopenia in the early stages, which is followed by leukocytosis. Toxoplasmosis sometimes produces absolute lymphocytosis. One report indicates that severe trauma may be associated with absolute lymphocytosis that changes to lymphopenia accompanied by increased granulocytes within 24 hours.
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Leukemoid Reaction
Leukemoid reaction is usually defined as a nonleukemic WBC count more than 50,000/mm3 (50 х 109/L) or a differential count with more than 5% metamyelocytes or earlier cells. It is basically a more severe or pronounced form of ordinary nonneoplastic granulocyte reaction. Some conditions associated with leukemoid reaction are severe bacterial infections, severe toxic states (burns, tissue necrosis, etc.), extensive bone marrow replacement by tumor, severe hemolytic anemia, severe acute blood loss, and juvenile rheumatoid arthritis.
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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.
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Eosinophilia
Parasites. Eosinophilia is most often associated with roundworms and infestation by various flukes. In the United States, roundworms predominate, such as Ascaris, Strongyloides, and Trichinella (Trichina). The condition known as visceral larva migrans, caused by the nematode Toxocara canis (common in dogs) is sometimes seen in humans. In Trichinella infection an almost diagnostic triad is bilateral upper eyelid edema, severe muscle pain, and eosinophilia. (Eosinophilia, however, may be absent in overwhelming infection.)
Acute allergic attacks. Asthma, hay fever, and other allergic reactions may be associated with eosinophilia.
Certain extensive chronic skin diseases. Eosinophilia is often found in pemphigus; it also may appear in psoriasis and several other cutaneous disorders.
Certain bacterial infections. Eosinophilia may occur in scarlet fever and brucellosis.
Miscellaneous conditions. Eosinophilia is reported in 20% of polyarteritis nodosa cases and 25% of sarcoidosis patients. It also has been reported in up to 20% of patients with Hodgkin’s disease, but the degree of eosinophilia is usually not impressive. Eosinophilia is associated with certain types of pneumonitis such as Lцffler’s syndrome and the syndrome of “pulmonary infiltration with eosinophilia.” Eosinophilia may occur with various types of cancer, but the overall incidence is less than 1%. A substantial number of patients undergoing peritoneal dialysis for chronic renal failure are reported to have intermittent eosinophilia (about 60% of cases in one report), most often following insertion of the dialysis catheter. A number of other diseases have been reported to produce eosinophilia, but either the diseases are rare or there is a low incidence of eosinophilia.
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Monocytosis
Monocytosis may occur in the absence of leukocytosis. Monocytosis is most frequently found in subacute bacterial endocarditis (about 15%-20% of patients), disseminated TB (15%-20% of patients), during the recovery phase of various acute infections, in many types of hematologic disorders (including nonmonocytic leukemias, myeloma, and hemolytic anemias), in malignant lymphomas and carcinomas, in rheumatoid-collagen diseases, and in typhoid fever. Malaria and leishmaniasis (kala-azar) are frequent causes of monocytosis outside the United States. Monocytic leukemia and myelodysplastic syndromes (Chapter 7) also enter the differential diagnosis.
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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.
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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.
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Pelger-Hu?t Anomaly
Of various hereditary abnormalities of WBC morphology, the most important is the Pelger-Huлt nuclear anomaly. This is manifested by WBC nuclear hyposegmentation. In the neutrophil series, many of the segmented cells appear to have bilobed nuclei shaped like a dumbbell or a pair of eyeglasses. There is also an increase in bandlike forms and forms with round or oval nuclei resembling myelocytes. Eosinophils normally may have a bilobed nuclear form. Although occasional normal neutrophils may have this nuclear shape, it is not a common finding, and more than two or three neutrophils with a bilobed nucleus per 100 WBCs would be unusual. The Pelger-Huлt anomaly may be congenital, inherited as a mendelian dominant trait; the congenital form is not common and is asymptomatic. An increased number of neutrophils with similar appearance may represent an acquired change (known as pseudo-Pelger-Hu?t); this is most often seen in myeloproliferative disorders, myeloid leukemia, and agranulocytosis, in some patients with metastatic tumor to bone marrow, or under conditions of drug toxicity. Neutrophils of the Pelger-Hu?t anomaly must be differentiated from true neutrophil immaturity such as that seen with infection or chronic myelogenous leukemia.