cbc or not cbc? that is the question

SPECIAL CONTRIBUTION CBC, indications; cost effectiveness, laboratory testing, complete blood count; laboratory testing, CBC

CBC or Not CBC? That Is the Question

The complete blood count (CBC) is the laboratory test most frequently ordered by emergency physicians. This is often not cost effective because of the relative inaccuracy of the white blood cell (WBC) and differential cell counts. The WBC and differential counts do not reliably distinguish between bacterial and viral infections because they lack specificity in many patients, nor do they reliably correlate with the severity of disease because they lack sensitivity in some patients. This article briefly summarizes the laboratory, physiologic, and pathophysiologic causes of variations in the WBC and differential counts; reviews some of the literature on pediatric patients with fever and appendicitis and on adult patients with appendicitis and abdominal pain; and presents suggestions for future research into the reliability and cost effectiveness of the CBC. [Young GP: CBC or not CBC? That is the question. Ann Emerg Med March 1986;15:367-371.]

I N T R O D U C T I O N The complete blood count (CBC) is the laboratory test most frequently

ordered in the emergency department. The cost is at least $10 for a CBC alone, and more than $20 if a differential blood count also is ordered. Why do we, as emergency physicians, order CBCs.~ Answered most simply: to "rule out" anemia and to "rule in" infection. To "rule out" anemia, the capillary tube centrifuge hematocrit {spun Hct) is available, inexpensive, and fast. Fin- ger (or heel) stick Hcts are reproducible within 1% to 2% variability. 1 Blood samples from capillary punctures are fairly reliable within the Hct range of 30% to 45%. 1 As an approximation, the spun Hct is relatively reliable and cost effective in the ED.

WBC A N D DIFFERENTIAL C O U N T S To "rule in" bacterial infection, most physicians believe that leukocytosis

(total white blood cell [WBC] count greater than 10,000/mm3) accompanied by an increase in immature band forms is both specific and sensitive. A review of the WBC literature does not support this conclusion. Leukocytosis is most often due to neutrophilia with or without increased bands {left shift). Neutrophilia is most often the result of increased bone marrow production, which is associated with a left shift. The normal band-to-neutrophil (PMN) ratio is less than 10%.1 Any acute stress causes the shift of PMNs and bands out of the bone marrow into the peripheral blood, as well as the redistribu- tion of neutrophils from the marginal pool to the counted peripheral circulat- ing pool. Thus neutrophilia with a left shift can be a nonspecific reaction to acute emotional or physical stress, acute or chronic inflammation, benign or malignant tumors, hemorrhage or hemolysis, splenectomy, myeloprolifela- tive disorders, asthma, seizures, or drugs {most commonly epinephrine, lithium, or steroids). 1

Endogenous demargination of neutrophils occurs with strenuous exercise. WBC counts as high as 35,000/Inm 3 after short sprints and above 20,000/ rams after endurance races have been reported. 2 The range of peripheral WBC counts during the postictal phase in 106 seizure patients ranged from 3,400 to 30,800/Into 3. One-third of these patients had CSF pleocytosis which was attributable to CNS infection or bleed in only four of 35 patients. 3 Major tissue trauma, such as that occurring during major surgery,, causes a 160% to 350% rise in neutrophils that persists into the postoperative phase. Minor

Gary P Young, MD Oakland, California

From the Emergency Department, Highland General Hospital, Oakland, California.

Presented at the Winter Symposium Advances Track of the American College of Emergency Physicians in San Diego, California, April 1985.

Address for reprints: Gary P Young, MD, Emergency Department, Highland General Hospital, 1411 East 31st Street, Oakland, California 94602.

15:3 March 1986 Annals of Emergency Medicine 367/199

CBC Young

tissue trauma, such as tooth extrac- tion, and slight trauma, such as blood donation, cause a 20% to 55% rise in PMNs. 4

In adults, the intramuscular admin- istration of epinephrine more than doubles the total WBC count. 1 Lithi- um has been reported to cause WBC counts up to 24,000/mm a. Most patients on chronic l i thium therapy have WBC counts above 10,000/Inll13. s Steroids both increase bone marrow release of neutrophils and decrease tissue migration of WBCs from the vascular pool. The individual response varies: the total WBC count may exceed 20,000/mm 3 with the first dose, although the mean increase peaked at 6,000/mm 3 above baseline after two weeks of therapy in one study of adults taking steroids. 6 In children on alternate-day prednisone therapy for asthma, the total WBC count was con- sistently elevated in only one-third of patients, but the mean PMN count of all the patients was above 80% during the days on which they took prednisone at doses of 10 mg or more every other day. 7

Thus leukocytosis with a left shift is a relatively nonspecific finding in many patients. It is also relatively in- sensitive for bacterial infection due to the fact that leukopenia is most often caused by infection. Leukopenia most commonly results from neutropenia. Although viral infection may be the most common etiology for acute neutropenia, an overwhelming bacterial sepsis may exhaust the bone marrow storage pool of PMNs. Neutropenia is the most reliable predictor of infection in leukemia patients. Twelve percent of acute leukemia patients with total WBC counts < 1,500/mm 3 and 75% to 100% of these patients with < 100 WBC/mm 3 develop bacterial infection. s Li and colleagues did not find the differential to be useful in manag- ing otherwise stable oncology clinic outpatients (other than leukemics) because the absolute PMN count paral- leled the total WBC count. All 126 patients with WBC counts > 5,000/mm 3 had > 1,500 PMNs/mm3.9

The differential is the most time- consuming hematology test. There are three inherent sources of error in the determination of any differential: lo mechanical errors in the techniques for preparation and staining of the peripheral smear; technician errors in the interpretation of white blood cell morphology,, which may cause a vari-

ability of up to 20%; and sampling errors, for only 100 cells represent all white blood cells. For these reasons it has been recommended that each laboratory determine its own range of normal limits for differentials.i, 10

Wesson and coworkers applied ac- cepted normal limits for the differential to 119 of 122 healthy men with normal absolute WBC counts of 5,000 to 10,000/mm3. n Fifty-one percent of the differentials were abnormal when reported as percentages of cell types, but only 10% were outside normal limits when the absolute number of each leukocyte cell type was reported [total WBC count x differential percentage of each individual cell type]. For this reason many laboratories do not routinely perform differentials on CBCs with normal total WBC counts. In adults, the normal range for neutrophils is 1,800 to 8,000/mm3 (lower limit, 1,500/mm 3 in blacks); for lym- phocytes, 1,000 to 5,000; and for bands, 0 to 500 or 750.1 The accuracy of the absolute band cell count is poor when band cells represent fewer than 5% to 10% of all leukocytes. 12 More than 95% of all abnormal absolute differentials involve abnormal numbers of neutrophi l or lymphocy te cell linesdO Although most laboratories re- port percentages rather than absolute counts of differentials, many provide an absolute lymphocyte count performed by machine during the automated CBC determination. This lymphocyte count may be subtracted from the total WBC count to estimate the PMN and band count without the added time and cost of a technician- performed differential.

The WBC and differential counts are different in several normal popu- lations. The lymphocyte is the pre- dominant cell type beginning between the third and tenth day of life and last ing unt i l the age of 3 years. Neutrophils do not become dominant until the age of 5.13 Nonpregnant women and girls have approximately 10% more neutrophils than do boys and men. 14 Normal pregnancy is accompanied by an approximate dou- bling of the absolute neutrophil count in most women and a variable shift to the left in some women. 15 Blacks have more than 10% fewer leukocytes because of more than 20% fewer neutrophils. This difference is maintained during acute infectious illnesses.16A 7 Cigarette smoking causes an abrupt rise in the leukocyte count. Chronic

smokers have a 10% to 20% higher leukocyte count directly related to daily consumption, even when cor- rected for chronic bronchitis. TM Final- ly, there is a diurnal physiologic rise in the leukocyte, neutrophil, and lymphocyte counts of more than 10% from 7 AM to 7 PM. 19 These physiologic alterations in the cell counts of normal patients demonstrate the relative inaccuracy of this laboratory test.

Are the WBC and differential able to distinguish patients with bacterial and viral infections? Douglas and colleagues observed an acute leukocytosis (total WBC count, 10,000 to 13,000/mm 3) due to moderate neutrophilia followed by a late leukopenia (often < 5,000/mm 3) in response to viral upper respiratory tract infection in 113 adult volunteers. 2o Portnoy and coworkers compared 246 infants and children with viral lower respiratory tract disease with 96 asymptomatic controls whose viral serology had con- verted. 21 The mean WBC count for the symptomatic patients was 14,500/ mm 3 (range, 1,100 to 60,000) with significantly more bands (0 to 45%). Stein found high neutrophil and band counts to be common among 200 outpatient children with fevers above 38.5 C that were later shown to be viral in etiology. 22 Thus leukocytosis with a left shift is common among patients with viral infections.

Steigbigel and colleagues analyzed hematologic findings in 28 adults with positive cultures for bacteria (26) and fungi (two). 23 Only 16 (57%) had W'BC counts > 10,000/mm 3, while 21 (75% I had toxic granulations, eight (29%} had Dohle bodies, and eight (29%} had vacuohzations in the neutrophil cytoplasm. While more common than cytoplasmic vacuoles, nei- ther toxic granules nor Dohle bodies are specific for bacterial infections. Both can be seen in patients with cancer, inflammation, tissue destruction, toxic ingestions, and other disease states. Cytoplasmic vacuoles are rea- sonably specific for bacterial infection; Zieve and coworkers noted that 119 of 122 patients with vacuolization on peripheral smear had bacterial infections. 24 Anticoagulant may cause vacuolization, however, so the peripheral smear should come from a fingerstick puncture. 1

OCCULT BACTEREMIA The pediatric literature is relatively

well developed in the study of the

200/368 Annals of Emergency Medicine 15:3 March 1986

usefulness of total and differential white blood cell counts in febrile children. McGowan and colleagues were the first to publish a large prospective study of blood cultures drawn on febrile children. 2s Only 23% of all febrile children who came to their walk- in clinic were cultured. Total WBC counts between 20,000 and 30,000 were most predictive of baeteremia (13%). WBC counts between 10,000 and 20,000 were no more predictive than were rectal temperatures of 38.9 C or above (7.6%). Thirty-one of 708 cultures (4.4%) were positive for bacterial pathogens, but another 43 (6.1%) grew bacterial contaminants. Impact analysis reveals that only seven of the 31 true culture-positive children had their followup altered by the culture data. Cost analysis reveals that each beneficial intervention required approximately $300 in WBC counts or $600 in differential counts and $3,000 in blood culture charges at a cost of $30 per set (cost analysis per Michael Callaham, MD, Director, Emergency Department, Moffitt-Long Hospital, San Francisco, February 1985).

Teele and coworkers cultured 600 consecutive febrile children in the same walk-in clinic and identified bacterial pathogens in the blood of 19 (3.2%).26 Only two of the 19 had their followup courses altered by these culture data. No patient with a rectal temperature < 38.9 C (102 F) was bacteremic. Bacteremia was significantly more frequent in children with WBC counts > 15,000/ram 3.

Todd retrospectively established criteria for differential WBC counts in distinguishing acute bacterial infections in hospitalized children between the ages of 2 months and 17 yearsY He found absolute neutrophil counts of > 10,000/mm3 or band counts > 500/mm 3 to be 80% specific and 75% sensitive; however, 25% of children with severe bacterial infection did not exceed the combined criteria. McCar- thy and Dolan found Todd's criteria to be present in 36 of 39 febrile outpa- t ient children with proven or presumed bacterial infections, and in 27 of 32 children with viral infections. 28 Morens applied Todd's criteria to 328 consecutive children who were admitted with fever. 29 He found the use of a total WBC count I> 15,000/nlnl 3 to be more specific, but its sensitivity was low (49%). In conclusion, the differential has not proved to be as useful as the total WBC count in evaluating

febrile pediatric patients. Other prospective and retrospective

studies of febrile children have found the WBC and differential to be of no value in distinguishing patients with bacterial infections. Wright and coworkers obtained positive viral isolates from the respiratory tract of 68 of 178 febrile children (38%)under the age of 3 years with rectal temperatures /> 103 E 30 There was a wide overlap of total WBC counts and mini- mal differences in the differential count from these patients with viral isolates compared with eight of 89 patients (9%) with positive bacterial blood cukures. Although there was a correlation between patients with higher total WBC counts and bacterial disease, three of eight children with documented bacteremia had total WBC counts < 15,000/mma.

The WBC and differential is not the s imple so lu t i on to the d i f f icu l t clinical problem of determining which febrile children have bacterial infections. Because of the need for more data rather than because of conclusive literature support, the current standard of community practice seems to be that the febrile child between the ages of 3 months and 2 years without an obvious infectious source should undergo a WBC determination.

NEONATAL SEPSIS Neonatal sepsis in the first weeks of

life is another difficult clinical entity to diagnose by history and physical examination alone. Fever is often ab- sent in the first two weeks of life. Mortality is high despite the availabil- ity of antimicrobial agents. The WBC and differential in neonates is of variable assistance and may be mislead- ing. Capillary WBCs are higher than venous samples {82% of capillary values), which are higher than arterial samples (77% of capillary).31 Violent crying associated with circumcision raises the WBC count by 146% with a left shift. Milder crying associated with heel puncture for capillary blood samples raises the WBC count by 113% without a left shift. A consistent site for blood sampling after a rest pe- riod of 60 minutes is recommended. 32

Crain and Shelov cultured 175 febrile infants up to 8 weeks of age in an outpatient clinic, a3 47% of whom had a focus of infection. Six of the 175 (3.4%) were bacteremic. They found that total WBC counts /> 15,000/ram3 plus the clinical impression of sepsis

Annals of Emergency Medicine

were significant indicators of possible bacterial infection. Nevertheless, the febrile neonate and infant less than 3 months old with a serious infection cannot be identified reliably by history, physical examination, or laboratory screening tests in the outpatient set- ting. It is recommended that these patients undergo a septic workup and be admitted to the hospital.

ACUTE APPENDICITIS AND ABDOMINAL PAIN

Approximately equal numbers of authors find support for and against the reliability of the WBC and differential in the evaluation of patients with acute appendicitis. Most studies of adult patients with appendicitis use the criteria of a total WBC count > 10,000/mm 3 and a neutrophil count > 75%. Of Raftery's 106 patients with appendicitis, 102 (96%) exceeded these values on admission.3a Eleven patients with initially elevated values were observed overnight because of inconsistent clinical examinations. Only the one patient who had an abnormal repeat count had appendicitis. Interestingly, all of the patients with appendicitis who had normal counts had perforations. In Sasso's series of 525 patients, 21% of patients with appendicitis had normal WBC counts and 38% had normal PMN counts, but only 4% had both normal WBC and PMN counts. 3s Lewis and coworkers noted, however, that the patients with nonsurgical (or no) pa- thology at laparotomy for presumed appendicitis had elevated total WBC counts with large standard deviations overlapping the mean WBC count of 15,000 in patients with acute appendicitis.a6 The neutrophil percentage was elevated in patients with appendicitis and pelvic inflammatory disease, but not in patients with mesen- teric adenitis or gastroenteritis. In a prospective, blind study, 37 Miskowiak and Burcharth found that the only WBC and differential result with predictive value (0.89) was a total WBC count < 9,000/ram 3. Although it is too nonspecific to exclude acute appendicitis, many authors believe that a normal WBC and differential, when c o m b i n e d wi th an i n c o n s i s t e n t clinical examination, can support the decision to observe a patient overnight.

The WBC differential is even less reliable in children with appendicitis. Bower used WBC counts > 11,000/

15:3 March 1986 369/201

CBC Young

ram3 and PMN percentages > 50% for children younger than 5 years of age, > 65% between 5 and 10 years, and > 75% in older patients. 3s In his series of 382 chi ldren wi th appendicitis, 13% had normal WBC counts, 8% had no rma l neutrophi l percentages, and 4% had normal values for both tests. Doraiswamy used limits of total WBC counts of 15,000/mm3 under age 10 and 13,000 over age 10, and the PMN percentages noted above. 39 During the first 24 hours of symp- toms, 96% of his children with appendicitis had elevated PMN percentages, but only 18% had elevated total WBC counts, and at the t ime of surgery only 42% of his patients with appendicitis had elevated WBC counts. On the other hand, Lansden found elevated WBC counts in 84% and elevated neu t roph i l s in 88% of 1,000 children with appendicitis. 4o His (un- defined) cr i ter ia were nonspecif ic , however, because 42% of his patients with negative laparotomies also had elevated values. Miskowiak and Bur- charth found no diagnostic value for the WBC and differential in children with appendicitis in their blind, prospective study. 3z Thus the literature is contradictory in regard to WBC values in pediatric patients with appendicitis.

Finally, in a s tudy of 1,000 consecutive emergency depar tment patients wi th abdominal pain, 93% of those wi th appendicitis had elevated WBC counts, as did 77% of patients with cholecystit is and 52% of those with intestinal obstruction.41 Forty- seven percent of the patients with gastroenteritis and one-third without a final diagnosis also had elevated WBC counts. The authors concluded that the WBC and differential was no t helpful as a screening test for patients with possible intraabdominal surgical or infectious lesions.

S U M M A R Y The most popular test ordered out

of the emergency depar tment lacks the necessa ry specif ic i ty and sensitivity to benefit most emergency patients and, at the same time, to be cost effective. The WBC and differential is at best supportive of clinical decision making; at worst, it may mislead our care of patients. Unfortunate- ly it is often not possible to predict which pat ients will benefit f rom a CBC determination. Should a CBC be drawn on every (potentially) sick patient? Most CBCs ordered by reflex

will not alter therapy. And the cost of these "ref lex" CBCs is staggering! Medicolegal real i t ies aside, a CBC should not be ordered unless there is a reasonable chance that the result will change the clinical course.

The absolute count of each leukocyte cell type is easily calculated from the total WBC count and the differential percentages which are more common ly reported by laboratories. Be- cause absolute differential counts are more accurate than differential percentages, the emergency phys ic i an can rapidly enhance the data gained from any WBC and differential at no added cost. Future research on the proper use of the WBC and differential mus t lead to improved pat ient care and cost conta inment . The pat ient subgroups or disease entities chosen for study are in need of accurate (sensitive and/or specific), simple, and less expensive diagnostic tests. The follow- ing are examples of patients and/or diseases that might be investigated for the reliability and cost effectiveness of the WBC and differential:

1) Febrile adults at r isk for bacteremia (eg, the elderly, alcohol and drug abusers, diabetics and patients on steroids);

2) Febrile adults w i thou t obvious source;

3) Frequent ED patients at risk for significant morbidity (eg, asthmatics, epileptics);

4) Infec t ious diseases w i t h diag- nost ic and/or disposi t ion d i lemmas (eg, pe lv ic i n f l a m m a t o r y disease, anorectal abscesses);

5) Blunt t rauma to the abdomen wi thout hemoper i toneum (eg, bowel rupture with negative peritoneal la- vage); and

6) In t raabdominal surgical lesions causing abdominal pain other than appendicitis.

The author thanks Robert H Dailey, MD, Michael Callaham, MD, and Charles G Brown, MD, for their assistance.

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3. Prokesch RC, Rimland D, Petrini JL, et al: Cerebrospinal fluid pleocytosis after seizure. South Med J 1983;76:322-327.

Annals of Emergency Medicine

4. Kirov SM, Shepherd JJ, Donald KD: In- traoperative and postoperative changes in peripheral white blood cell counts. NZ J Surg 1979;49:738-742.

5. Pi EH, Stramek JJ, Simpson GM: Effect of lithium on leukocytes. ] Clin Psychia- try 1983;44:139-140.

6. Shoenfeld Y, Gurewich Y, Gallant LA, et al: Prednisone induced leukocytosis. Am J Med 1981~71:773-778.

7. Chai H, Gilbert A: The effect of alternate day prednisone on the white blood count in children with chronic asthma. J Allergy Clin Immunol 1973;51:65-70.

8. Bodey GP, Buckley M, Sathe YS, et al: Quantitative relationships between cir- culating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966;64:328-340.

9. Li FP, Danahy J, Gelman R: Utility of differential leukocyte counts in cancer management. JAMA 1984;252:1312-1314.

10. Rumke CL, Bezemer PD, Kuik DJ: Normal values and least significant differences for differential leukocyte counts. J Chron Dis 1975;28:661-668.

11. Wesson SK, Mercado T, Austin M, et ah Percentage and absolute differential counts on 119 healthy US Navy mid- shipmen {letter). Lancet 1980~1:552.

12. England JM: Prospects for automated leukocyte counting in the routine laboratory. Clin Lab Haematol 1979;1:263-273.

13. Weitzman M: Diagnostic utility of white blood cell and differential cell counts. Am J Dis Child 1975;129:183-189.

14. Bain BJP: Normal hematological values: Sex difference in neutrophil count. Br Med ] 1975;1:306-309.

15. Pitkin RM, Witte DL: Platelet and leukocyte counts in pregnancy. JAMA 1979;242:2696-2698.

16. Sadowitz PD, Oski FA: Differences in polymorphonuclear cell counts between healthy white and black infants: Re- sponse to meningitis. Pediatrics 1983;72: 405-407. 17. Hyman P, Westring DW: Leukocytosis in acute appendicitis, lAMA 1974;229: 1630-1631.

18. Helman N, Rubenstein LS: The ef- fects of age, sex and smoking on erythrocytes and leukocytes. Am J Clin Pathol 1974;63:35-44.

19. Winkel P, Statland BE, Saunders AM, et al: Within day physiologic variation of leukocyte types in healthy subjects. Am l Clin Pathol 1981;75:694-700.

20. Douglas GD, Alford RH, Cate TR, et al: The leukocyte response during viral respiratory illness in man. Ann Intern Med 1966;64:521-530. 21. Portnoy B, Hanes B, Salvatore MA, et

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al: The peripheral white blood cell count in respovirus infection. J Pediatr 1966; 68:181-188.

22. Stein RC: The white blood cell count in fevers of unknown origin. Am J Dis Child 1972;124:60-63.

23. Steigbigel RT, Johnson PK, Remington JS: The nitroblue tetrazolium reduction test versus conventional hematology in the diagnosis of bacterial infection. N Engl J Med 1974;290:235-238.

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25. McGowan JE, Bratton L, Klein JO, et al: Bacteremia in febrile children seen in a "walk-in" pediatric clinic. N Engl J Med 1973;288:1309-1313.

26. Teele DW, Pelton SI, Grant MJA, et al: Bacteremia in febrile children under two years of age. J Pediatr 1975;87:227-230.

27. Todd JK: Childhood infections: Diag- nostic value of peripheral white blood cell and differential cell counts. Am ] Dis Child 1974; 127:810-816.

28. McCarthy PL, Dolan TF: Hyperpyrex-

ia in children: Eight year emergency room experience. Am J Dis Child 1976;130: 849-851.

29. Morens DM: WBC count and differential: Value in predicting bacterial diseases in children. Am J Dis Child 1979; 133:25-27.

30. Wright PF, Thompson J, McKee KT, et al: Patterns of illness in the highly febrile young child. Pediatrics 1981;67:694-700.

31. Thomas WJ, Collins TiM: Comparison of venipuncture blood counts with micro- capillary measurements in screening for anemia in one-year-old infants. J Pediatr 1982; t01:32-35.

32. Christensen RD, Rothstein G: Pitfalls in the interpretation of leukocyte counts of newborn infants. Am ] Clin Pathol 1979;72:608-611.

33. Crain EF, Shelov SP: Febrile infants: Predictors of bacteremia. J Pediatr 1982; 101:686-689.

34. Raftery AT: The value of the leukocyte count in the diagnosis of acute appendicitis. Br ] Surg 1976;63:143-144.

35. Sasso RD, Hanna EA, Moore DL: Leu-

kocytic and neutrophilic counts in acute appendicitis. Am J Surg 1970;120:563-566.

36. Lewis FP, Holcroft JW, Boey J, et al: Appendicitis: A critical review of diagnosis and treatment in 1000 cases. Arch Surg 1975; 110:677-684.

37. Miskowiak J, Burcharth F: The white cell count in acute appendicitis: A prospective blind study. Dan Med Bull 1981;29:210-211.

38. Bower RJ, Bell MJ, Ternberg JL: Diag- nostic value of the white blood cell count and neutrophil percentage in the evaluation of abdominal pain in children. Surg Gynecol Obstet 1981;152:424-426.

39. Doraiswamy NV: Leukocyte counts in the diagnosis and prognosis of acute appendicitis in children. Br J Surg 1979; 66:782-784.

40. Lansden FT: Acute appendicitis in children. Am J Surg 1963;106:938-942.

41. Brewer RJ, Golden GT, Hitch DC, et al: Abdominal pain: An analysis of 1000 consecutive cases in a university hospital emergency room. Am J Surg 1976;131: 219-223.

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cbc or not cbc? that is the question

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