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.